umu.sePublications
Change search
Refine search result
123 1 - 50 of 142
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the 'Create feeds' function.
  • 1. Achouiti, A.
    et al.
    Vogl, T.
    Urban, Constantin
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hommes, T. J.
    van Zoelen, M. A.
    Florquin, S.
    Roth, J.
    van 't Veer, C.
    de Vos, A. F.
    van der Poll, T.
    Myeloid related protein (mrp) 8/14 contributes to an antibacterial host response against klebsiella (k.) pneumoniae2012In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no S1, 56-56 p.Article in journal (Other academic)
  • 2. Acosta, Stefan
    et al.
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Current status on plasma biomarkers for acute mesenteric ischemia2012In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 33, no 4, 355-361 p.Article in journal (Refereed)
    Abstract [en]

    Clinical diagnosis of acute mesenteric ischemia is difficult. The aim of this review is to provide current status on the search for an accurate plasma biomarker for acute mesenteric ischemia. A search using the medical subject heading terms marker and mesenteric ischemia or intestinal ischemia or superior mesenteric artery occlusion or mesenteric venous thrombosis in the Medline and Embase databases from 1980 to 2011. Studies without a control group or a control group consisted of healthy individuals (human studies), or studies on intestinal reperfusion were excluded. Twenty animal and twelve human studies were identified. In human studies, the studied series of patients had a control group that had a need of laparotomy (n = 2), suspected acute mesenteric ischemia (n = 7), acute abdomen (n = 2) or systemic inflammatory response syndrome (n = 1). D: -dimer has been found to be the most consistent highly sensitive early marker, but specificity was low. The follow-up study on α-glutathione S-transferase yielded inferior sensitivity and accuracy than the preliminary study, clearly questioning the value of this marker. Intestinal fatty acid binding globulin (I-FABP) and D: -lactate are both interesting markers, but the results were conflicting. Different cut-off levels have been used in the studies on I-FABP. The encouraging preliminary result of cobalt-albumin and urinary FABP as an accurate marker needs to be addressed in other study populations. The early clinical and laboratory diagnosis of intestinal ischemia remains a challenge. None of the proposed plasma-derived tests for acute mesenteric ischemia has as yet entered routine clinical practice. The proposed biomarkers need to be evaluated in a prospective clinical research project in patients with acute abdomen.

  • 3. Andersen, Mette K.
    et al.
    Autio, Kirsi
    Barbany, Gisela
    Borgstroem, Georg
    Cavelier, Lucia
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johannsson, Johann H.
    Johansson, Bertil
    Kjeldsen, Eigil
    Nordgren, Ann
    Palmqvist, Lars
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13): clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols2011In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, no 2, 235-243 p.Article in journal (Refereed)
    Abstract [en]

    The translocation t(1;19)(q23;p13)/der(19) t(1;19) is a risk stratifying aberration in childhood B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the Nordic countries. We have identified 47 children/adolescents with t(1;19)/der(19) t(1;19)-positive BCP ALL treated on two successive Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols between 1992 and 2007 and have reviewed the clinical and cytogenetic characteristics of these cases, comprising 1.8% of all cases. The translocation was balanced in 15 cases (32%) and unbalanced in 29 cases (62%). The most common additional chromosome abnormalities were del(9p), i(9q), del(6q), and del(13q). The median age was 7 years, the median white blood cell (WBC) count was 16 x 10(9)/l, and the female/male ratio was 1.2. The predicted event-free survival (EFS) at 5 and 10 years was 0.79, whereas the predicted overall survival (OS) at 5 and 10 years was 0.85 and 0.82, respectively. Nine patients had a bone marrow relapse after a median of 23 months; no patient had a central nervous system relapse. Additional cytogenetic abnormalities, age, gender, WBC count or whether the t(1;19) was balanced or unbalanced did not influence EFS or OS. Compared to cases with t(12,21) and high hyperdiploidy, EFS was similar, but overall survival was worse in patients with t(1;19)/der(19) t(1;19) (P = 0.004).

  • 4. Arnlov, Johan
    et al.
    Ruge, Toralph
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ingelsson, Erik
    Larsson, Anders
    Sundström, Johan
    Lind, Lars
    Serum Endostatin and Risk of Mortality in the Elderly Findings From 2 Community-Based Cohorts2013In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 33, no 11, 2689-2695 p.Article in journal (Refereed)
    Abstract [en]

    Objective Experimental data imply that endostatin, a proteolytically cleaved fragment of collagen XVIII, could be involved in the development of cardiovascular disease and cancer. Prospective data concerning the relation between circulating endostatin and mortality are lacking. Accordingly, we aimed to study associations between circulating endostatin and mortality risk. Approach and Results Serum endostatin was analyzed in 2 community-based cohorts: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 50%, n=931; mean age, 70 years; median follow-up, 7.9 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=748; mean age, 77 years; median follow-up, 9.7 years). During follow-up, 90 participants died in PIVUS (1.28/100 person-years at risk), and 417 participants died in ULSAM (6.7/100 person-years at risk). In multivariable Cox regression models adjusted for age and established cardiovascular risk factors, 1 SD higher ln(serum endostatin level) was associated with a hazard ratio of mortality of 1.39 and 95% confidence interval, 1.26 to 1.53, on average in both cohorts. In the ULSAM cohort, serum endostatin was also associated with cardiovascular mortality (177 deaths; hazard ratio per SD of ln[endostatin] 1.45, 95% confidence interval [1.25-1.71]) and cancer mortality (115 deaths; hazard ratio per SD of ln[endostatin] 1.35, 95% confidence interval [1.10-1.66]). Conclusions High serum endostatin was associated with increased mortality risk in 2 independent community-based cohorts of the elderly. Our observational data support the importance of extracellular matrix remodeling in the underlying pathophysiology of cardiovascular disease and cancer.

  • 5. Berge-Seidl, Victoria
    et al.
    Pihlstrøm, Lasse
    Maple-Grødem, Jodi
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Larsen, Jan Petter
    Tysnes, Ole-Bjørn
    Toft, Mathias
    The GBA variant E326K is associated with Parkinson's disease and explains a genome-wide association signal2017In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 658, 48-52 p.Article in journal (Refereed)
    Abstract [en]

    Objective: Coding variants in the GBA gene have been identified as the numerically most important genetic risk factors for Parkinson's disease (PD). In addition, genome-wide association studies (GWAS) have identified associations with PD in the SYT11-GBA region on chromosome 1q22, but the relationship to GBA coding variants have remained unclear. The aim of this study was to sequence the complete GBA gene in a clinical cohort and to investigate whether coding variants within the GBA gene may be driving reported association signals. Methods: We analyzed high-throughput sequencing data of all coding exons of GBA in 366 patients with PD. The identified low-frequency coding variants were genotyped in three Scandinavian case-controls series (786 patients and 713 controls). Previously reported risk variants from two independent association signals within the SYT11-GBA locus on chromosome 1 were also genotyped in the same samples. We performed association analyses and evaluated linkage disequilibrium (LD) between the variants. Results: We identified six rare mutations (1.6%) and two low-frequency coding variants in GBA. E326K (rs2230288) was significantly more frequent in PD patients compared to controls (OR 1.65, p = 0.03). There was no clear association of T369M (rs75548401) with disease (OR 1.43, p = 0.24). Genotyping the two GWAS hits rs35749011 and rs114138760 in the same sample set, we replicated the association between rs35749011 and disease status (OR 1.67, p = 0.03), while rs114138760 was found to have similar allele frequencies in patients and controls. Analyses revealed that E326K and rs35749011 are in very high LD (r(2) 0.95). Conclusions: Our results confirm that the GBA variant E326K is a susceptibility allele for PD. The results suggest that E326K may fully account for the primary association signal observed at chromosome 1q22 in previous GWAS of PD.

  • 6. Birgegård, Gunnar
    et al.
    Björkholm, Magnus
    Kutti, Jack
    Larfars, Gerd
    Löfvenberg, Eva
    Markevärn, Berit
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Merup, Mats
    Palmblad, Jan
    Mauritzson, Nils
    Westin, Jan
    Samuelsson, Jan
    Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders.2004In: Haematologica, ISSN 1592-8721, Vol. 89, no 5, 520-7 p.Article in journal (Refereed)
  • 7.
    Björck, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Warfarin treatment quality in stroke prevention2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Ischemic stroke is a serious condition often associated to presence of atrial fibrillation (AF). Use of anticoagulants for AF patients greatly reduces the risk of stroke. Warfarin is the most commonly used anticoagulant in Sweden. The aim of this thesis was to study the impact of warfarin treatment quality in Swedish stroke prevention.

    Methods

    Study I, II and IV were relatively large multicentre, retrospective, cohort studies based on Swedish registries, especially AuriculA, a quality register for AF and anticoagulation. Background data as well as bleeding and thromboembolic complications were retrieved from the National Patient Register. The Cause of Death Register was used in study II and IV. The Swedish Prescribed Drug Register was used in study IV, for data on concomitant acetylsalicylic acid (ASA) use. Study period was January 1, 2006, to December 31, 2011. Study III enrolled all warfarin treated AF patients in Sundsvall, registered in AuriculA on January 1, 2010. This smaller cohort was followed until discontinuation or study-stop December 31, 2013. All used data were collected from each patient’s medical record.

    Results

    The annual risk of major bleedings and thromboembolic events for warfarin treated patients, including all different indications for warfarin, was relatively low (2.24% and 2.66%), with incidence of intracranial bleeding of 0.37% per treatment year. The overall mean time in therapeutic range (TTR) was 76.5%. Patients started on warfarin due to AF had a mean TTR of 68.6%, with an annual risk of major bleeding and thromboembolic events of 2.23% and 2.95%, and with 0.44% annual risk of intracranial bleeding. No significant differences in overall complications were found when comparing treatment monitored in anticoagulation clinics (ACC) with treatment monitored in primary health care centers (PHCC). There were significantly increased risk of both overall major bleedings and thromboembolic events for those warfarin treated AF patients receiving additional ASA treatment, having individual TTR (iTTR) below 70%, or having high international normalized ratio (INR) variability. AF patients with low INR variability had generally lower complication rates, compared with patients with high INR variability. There were however no alteration on cumulative incidence of complications due to INR variability, for AF patients with iTTR ≥70%. The overall proportion of persistence to warfarin treatment for stroke patients with AF was found to be 0.69 after 2 years treatment and 0.47 after 5 years. Stroke patients with diagnosed dementia at baseline were more than two-times likely of discontinuing warfarin than others. Excessive alcohol use, chronic obstructive pulmonary disease, cancer and chronic heart failure were baseline diagnoses each associated with over 20% increased risk of treatment discontinuation. Lower persistence to treatment was linked to increasing start-age and CHA2DS2-VASc scores. As documented reasons for warfarin treatment discontinuation in AF patients, we found regained sinus rhythm as the most common addressed cause (31.2%), followed by problematic monitoring and bleedings. We estimated that only half (49.5%) of the treatment discontinuations were clinically well motivated.

    Conclusions

    Quality of Swedish warfarin treatment in initiated stroke prevention is high, with generally low rates of complications and high TTRs, no matter treatment in ACC or PHCC, including high long time persistence to warfarin in secondary stroke prevention. For better outcome in future warfarin stroke prophylactic treatment clinicians should aim for iTTRs above 70%, avoid additional ASA therapy, support fragile patients like those with excessive alcohol use and dementia, and base decisions on treatment discontinuations on solid medical arguments.

  • 8.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ek, Agnes
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Warfarin persistence among atrial fibrillation patients – why is treatment ended?2016In: Cardiovascular Therapeutics, ISSN 1755-5914, Vol. 34, no 6, 468-474 p.Article in journal (Refereed)
    Abstract [en]

    Background and Aim

    Warfarin treatment discontinuation is significant among patients with atrial fibrillation (AF). Studies mainly focused on whether the proportion of warfarin persistence and discontinuationare clinically appropriate are absent. This study evaluates warfarin persistence with focus on predictors for, and reasons to, warfarin discontinuation in AF patients.

    Methods

    From the national quality register AuriculA, all AF patients in Sundsvall, Sweden, on warfarin treatment on January first, 2010 were included. These 478 patients were followed until discontinuation or study-stop December 31, 2013. By going through each patient’s medical record risk factors for thromboembolism, bleeding and causes of discontinuation were obtained.

    Results

    Proportion of warfarin persistence was 0.91 (95% confidence interval (CI) 0.89 to 0.93) after one year and 0.73 (95% CI 0.69 to 0.77) after four years. Previous intracranial bleeding, excessive alcohol use, anemia and pulmonary or peripheral emboli were each associated with over two times higher risk of discontinuation (hazard ratio (HR) 5.66, CI 2.23-14.36, HR 2.54, CI 1.48-4.37, HR 2.40, CI 1.38-4.17, and HR 2.13, CI 1.02-4.46). Among patients discontinuing, 50.5% were due to questionable causes, such as sinus rhythm (33.9%), patients demand (10.1%) and falls (8.2%). The majority (43.1%) of treatment discontinuers were changed to aspirin, while 40.4% of them were left without medical stroke prophylaxis.

    Conclusions

    Although persistence to warfarin among AF patients proves higher than previously reported, there is room for improvement since half of the discontinuers have questionable reasons for treatment stop and the majority of them receive no other efficient stroke prophylaxis.

  • 9.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renlund, Henrik
    Svensson, Peter J
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Warfarin persistence among stroke patients with atrial fibrillation2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 4, 744-748 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Warfarin treatment discontinuation is significant among patients with atrial fibrillation (AF). For AF patients with stroke a warfarin persistence rate of 0.45 after 2years has previously been reported. No consistent predictors for discontinuation have been established.

    AIMS: Evaluation of warfarin persistence and variables associated with discontinuation, in a large Swedish cohort with unselected stroke/TIA patients with AF treated with warfarin.

    MATERIALS AND METHODS: 4 583 patients with stroke/TIA and AF in the Swedish National Patient Register (NPR), from 1. Jan 2006 to 31. Dec 2011, were matched with the Swedish national quality register AuriculA. They were followed until treatment cessation, death or end of study. Baseline characteristics and CHA2DS2VASc score were retrieved from NPR. Treatment-time was retrieved from AuriculA.

    RESULTS: Overall proportion of warfarin persistence was 0.78 (95% confidence interval (CI) 0.76 to 0.80) after one year, 0.69 (95% CI 0.67 to 0.71) after 2years and 0.47 (95% CI 0.43 to 0.51) after 5years. Variables clearly associated with higher discontinuation were dementia (hazard ratio (HR) 2.22, CI 1.51-3.27) and alcohol abuse (HR 1.66, CI 1.19-2.33). Chronic obstructive pulmonary disease (COPD), cancer and chronic heart failure (CHF) were each associated with over 20% increased risk of treatment discontinuation. Higher CHA2DS2VASc score and start-age lead to lower persistence (p<0.001).

    CONCLUSIONS: Persistence to warfarin in unselected stroke/TIA patients with AF is in Sweden greater than previously reported. Lower persistence is found among patients with high treatment start-age, incidence of dementia, alcohol abuse, cancer, CHF, COPD and/or high CHA2DS2VASc score.

  • 10.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sandén, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renlund, Henrik
    Svensson, Peter J
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 2, 216-220 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Warfarin treatment in Sweden holds a high standard with time in therapeutic range (TTR) over 75%. Internationally, specialized anticoagulation clinics (ACC) have shown higher TTR compared to primary health care centres (PHCC).

    OBJECTIVES: To compare warfarin treatment quality in Sweden for ACC versus PHCC, thereby clarifying whether centralization is for the better.

    PATIENTS/METHODS: In total 77.058 patients corresponding to 217.058 treatment years with warfarin in the Swedish national quality register AuriculA from 1. Jan 2006 to 31. Dec 2011. Information regarding TTR was calculated from AuriculA, while patient characteristics and complications were retrieved from the Swedish National Patient Register.

    RESULTS: Of the 100.554 treatment periods examined, 78.7% were monitored at ACC. Mean TTR for INR 2-3 for all patients irrespective of intended target range was 76.5% with an annual risk of bleeding or thrombotic events of 2.24% and 2.66%, respectively. TTR was significantly higher in PHCC compared to ACC (79.6% vs. 75.7%, p<0.001), with no significant difference in overall risk of complications. Treatment periods for atrial fibrillation, except intended direct current conversion, showed similar results between ACC and PHCC without significant difference in annual risk of bleeding (2.50% vs. 2.51%) or thrombosis (3.09% vs. 3.16%). After propensity score matching there was still no significant difference in complication risk found.

    CONCLUSIONS: Warfarin treatment quality is consistently high in both ACC and PHCC when monitored through AuriculA in Sweden, both measured as TTR and as risk of complications. In this setting, centralized warfarin monitoring is not likely to improve the results.

  • 11.
    Borssen, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Cullman, Inger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sundstrom, Christer
    Porwit, Anna
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup2011In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, no 12, 1144-1151 p.Article in journal (Refereed)
    Abstract [en]

    Telomere maintenance, important for long-term cell survival and malignant transformation, is directed by a multitude of factors, including epigenetic mechanisms, and has been implicated in outcomes for patients with leukemia. In the present study, the objective was to investigate the biological and clinical significance of telomere length and promoter methylation of the human telomerase reverse transcriptase gene in childhood acute lymphoblastic leukemia. A cohort of 169 childhood acute lymphoblastic leukemias was investigated for telomere length, human telomerase reverse transcriptase gene promoter methylation status, genomic aberrations, immunophenotype, and clinical outcomes. Methylation of the core promoter of the human telomerase reverse transcriptase (hTERT) gene was demonstrated in 24% of diagnostic samples, with a significant difference between B-cell precursor (n = 130) and T-cell acute lymphoblastic leukemia (ALL) (n = 17) cases (18% and 72%, respectively; p < 0.001). No remission sample demonstrated hTERT promoter methylation (n = 40). Within the B-cell precursor group, t(12;21)(p13;q22) [ETV6/RUNX1] cases (n = 19) showed a much higher frequency of hTERT methylation than high-hyperdiploid (51 61 chromosomes) ALL (n = 44) (63% and 7%, respectively; p < 0.001). hTERT messenger RNA levels were negatively associated with methylation status and, in the t(12;21) group, methylated cases had shorter telomeres (p = 0.017). In low-risk B-cell precursor patients (n = 101), long telomeres indicated a worse prognosis. The collected data from the present study indicate that the telomere biology in childhood ALL has clinical implications and reflects molecular differences between diverse ALL subgroups. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

  • 12.
    Borssén, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schmiegelow, Kjeld
    Åsberg, Ann E.
    Kanerva, Jukka
    Madsen, Hans O.
    Marquart, Hanne
    Heyman, Mats
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Department of Paediatrics, University Hospital of Trondheim, Norway.
    DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, 1185-1192 p.Article in journal (Refereed)
    Abstract [en]

    Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.

  • 13.
    Brundin, Peik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Zhao, Chunyan
    Dahlman-Wright, Karin
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Gene Expression of Estrogen Receptors in Pbmc From Patients With Puumala-Virus Infection2012In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no 4, 355-359 p.Article in journal (Refereed)
    Abstract [en]

    The influence of estrogen signaling on infectious diseases is not fully known. Males seem to be more susceptible to infections than females. This has also been noted for the Scandinavian form of hemorrhagic fever with renal syndrome caused by Puumala hantavirus (PUUV). To investigate the differences in estrogen receptors in relation to sex and clinical severity, 20 patients (10 males, 10 females) with confirmed PUUV infection were studied. Real-time polymerase chain reaction was performed for analyzing mRNA expression of estrogen receptor-alpha (ERV), ER beta, and ER beta 2 (ER beta cx) in peripheral blood mononuclear cells from patients and healthy age-and sex-matched blood donors. Blood chemistry and peripheral blood mononuclear cells sampling were performed during the acute and convalescent phases. None or very small amounts of ER beta were detected, and ER alpha and ER beta 2 mRNA were elevated in the patient group. The samples from the males were correlated with ER beta 2; the female samples, with ER alpha. Furthermore, the female and male samples are partly separated using multivariate statistic analysis (principal component analysis), supporting findings that clinical symptoms differ depending on sex.

  • 14. Buitenkamp, Trudy D.
    et al.
    Izraeli, Shai
    Zimmermann, Martin
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Heerema, Nyla A.
    van den Heuvel-Eibrink, Marry M.
    Pieters, Rob
    Korbijn, Carin M.
    Silverman, Lewis B.
    Schmiegelow, Kjeld
    Liang, Der-Cheng
    Horibe, Keizo
    Arico, Maurizio
    Biondi, Andrea
    Basso, Giuseppe
    Rabin, Karin R.
    Schrappe, Martin
    Cario, Gunnar
    Mann, Georg
    Morak, Maria
    Panzer-Grumayer, Renate
    Mondelaers, Veerle
    Lammens, Tim
    Cave, Helene
    Stark, Batia
    Ganmore, Ithamar
    Moorman, Anthony V.
    Vora, Ajay
    Hunger, Stephen P.
    Pui, Ching-Hon
    Mullighan, Charles G.
    Manabe, Atsushi
    Escherich, Gabriele
    Kowalczyk, Jerzy R.
    Whitlock, James A.
    Zwaan, C. Michel
    Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 123, no 1, 70-77 p.Article in journal (Refereed)
    Abstract [en]

    Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Munster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% +/- 2% vs 15% +/- 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% +/- 1% vs 2.0% +/- < 1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% +/- 2% vs 81% +/- 2%, P < .0001) and overall survival (74% +/- 2% vs 89% +/- 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 x 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.

  • 15. Buitenkamp, Trudy
    et al.
    Izraeli, Shai
    Zimmermann, Martin
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Heerema, Nyla A.
    van den Heuvel, Marry M.
    Pieters, Rob
    de Haas, Valerie
    Silverman, Lewis B.
    Schmiegelow, Kjeld
    Liang, Der-Cherng
    Horibe, Keizo
    Arico, Maurizio
    Cazzaniga, Giovanni
    Basso, Giuseppe
    Rabin, Karen R.
    Schrappe, Martin
    Cario, Gunnar
    Mann, Georg
    Mondelaers, Veerle
    Lammens, Tim
    Cave, Helene
    Stark, Batia
    Moorman, Anthony V.
    Vora, Ajay J.
    Hunger, Stephen
    Pui, Ching-Hon
    Mullighan, Charles G.
    Manabe, Atsushi
    Escherich, Gabriele
    Kowalczyk, Jerzy
    Whitlock, James A.
    Zwaan, Christian M.
    Acute Lymphoblastic Leukemia in children with Down Syndrome: A report from the Ponte Di Legno Study Group2011In: 53rd ASH Annual Meeting and Exposition, December 10-13, 2011: Program: Oral and Poster AbstractsSession: 612. Acute Lymphoblastic Leukemia - Biology and Pathophysiology: Poster III Monday, December 12, 2011, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center), American Society of Hematology , 2011, Vol. 118, no 21Conference paper (Refereed)
  • 16. Cesaro, Simone
    et al.
    Marsh, Judith
    Tridello, Gloria
    Rovò, Alicia
    Maury, Sebastien
    Montante, Barbara
    Masszi, Tamás
    Van Lint, Maria Teresa
    Afanasyev, Boris
    Iriondo Atienza, Arturo
    Bierings, Marc
    Carbone, Cecilia
    Doubek, Michael
    Lanino, Edoardo
    Sarhan, Mahmoud
    Risitano, Antonio
    Steinerova, Katerina
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Pegoraro, Anna
    Passweg, Jakob
    Retrospective survey on the prevalence and outcome of prior autoimmune diseases in patients with aplastic anemia reported to the registry of the European group for blood and marrow transplantation.2010In: Acta Haematologica, ISSN 0001-5792, E-ISSN 1421-9662, Vol. 124, no 1, 19-22 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Aplastic anemia (AA) is rarely described after a diagnosis of autoimmune disease (aID). AIMS: To assess the prevalence of prior aID in patients with AA recorded in the registry of the European Group for Blood and Marrow Transplantation (EBMT) and to evaluate treatment and outcome. METHODS: 1,251 AA patients from 18 EBMT centers were assessed. RESULTS: Fifty patients (4%) were eligible: 22 males and 28 females with a median age of 46 years at the diagnosis of aID and of 51 years at the diagnosis of AA. Information on the treatment of AA was available in 49 patients: 38 received only immunosuppressive therapy (IST), 8 patients underwent hematopoietic stem cell transplantation (HSCT) - 6 as first-line therapy and 2 after failure of IST - whilst 3 patients had a spontaneous recovery. After a median follow-up of 3.19 years, 32 patients were alive, including 7 of the 8 patients who underwent HSCT. Only 6 of 32 patients who were alive at the last follow-up were receiving IST for AA. CONCLUSIONS: Most cases of AA following aID benefitted from IST or HSCT if a matched donor was available. Further prospective investigation is needed to assess the effects of IST on the outcome of underlying aID.

  • 17.
    Christiansson, Lisa
    et al.
    Uppsala, Sweden.
    Söderlund, Stina
    Uppsala, Sweden.
    Mangsbo, Sara
    Uppsala, Sweden.
    Hjorth-Hansen, Henrik
    Trondheim, Norway.
    Höglund, Martin
    Uppsala, Sweden.
    Markevärn, Berit
    Department of Hematology, Norrland University Hospital, Umeå, Sweden.
    Richter, Johan
    Lund, Sweden.
    Stenke, Leif
    Stockholm, Sweden.
    Mustjoki, Satu
    Helsinki, Finland.
    Loskog, Angelica
    Uppsala, Sweden.
    Olsson-Strömberg, Ulla
    Uppsala, Sweden.
    The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses2015In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 5, 1181-1191 p.Article in journal (Refereed)
    Abstract [en]

    Immune escape mechanisms promote tumor progression and are hurdles of cancer immunotherapy. Removing immunosuppressive cells before treatment can enhance efficacy. Tyrosine kinase inhibitors (TKI) may be of interest to combine with immunotherapy, as it has been shown that the inhibitor sunitinib reduces myeloid suppressor cells in patients with renal cell carcinoma and dasatinib promotes expansion of natural killer-like lymphocytes in chronic myeloid leukemia (CML). In this study, the capacity of dasatinib and imatinib to reduce myeloid suppressor cells and to induce immunomodulation in vivo was investigated ex vivo. Samples from CML patients treated with imatinib (n = 18) or dasatinib (n = 14) within a Nordic clinical trial (clinicalTrials.gov identifier: NCT00852566) were investigated for the presence of CD11b(+)CD14(-)CD33(+) myeloid cells and inhibitorymolecules (arginase I, myeloperoxidase, IL10) as well as the presence of natural killer cells, T cells (naive/memory), and stimulatory cytokines (IL12, IFN gamma, MIG, IP10). Both imatinib and dasatinib decreased the presence of CD11b(+)CD14(-)CD33(+) myeloid cells as well as the inhibitory molecules and the remaining myeloid suppressor cells had an increased CD40 expression. Monocytes also increased CD40 after therapy. Moreover, increased levels of CD40, IL12, natural killer cells, and experienced T cells were noted after TKI initiation. The presence of experienced T cells was correlated to a higher IFNg and MIG plasma concentration. Taken together, the results demonstrate that both imatinib and dasatinib tilted the immunosuppressive CML tumor milieu towards promoting immune stimulation. Hence, imatinib and dasatinib may be of interest to combine with cancer immunotherapy. (C) 2015 AACR.

  • 18. d'Amore, Francesco
    et al.
    Relander, Thomas
    Lauritzsen, Grete F.
    Jantunen, Esa
    Hagberg, Hans
    Anderson, Harald
    Holte, Harald Jr.
    Osterborg, Anders
    Merup, Mats
    Brown, Peter de Nully
    Kuittinen, Outi
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ostenstad, Bjorn
    Fagerli, Unn-Merete
    Gadeberg, Ole
    Sundstrom, Christer
    Delabie, Jan
    Rafkiaer, Elisabeth
    Vornanen, Martine
    Toldbod, Helle
    High-dose chemotherapy and autologuos stem cell transplantation in previously untreated peripheral T-Cell Lymphoma: Final analysis of a large prospective multicenter study (NLG-T-01)2011In: 53rd ASH Annual Meeting and Exposition: Session: 731. Clinical Allogeneic and Autologous Transplantation - Results: Myeloma, Lymphomas and Multiple Sclerosis ; Monday, December 12, 2011: 7:00 AM Douglas Pavilion C (Manchester Grand Hyatt San Diego), washington, USA: American Society of Hematology , 2011, Vol. 118, no 21, 155-156 p.Conference paper (Refereed)
  • 19. den Hollander, J
    et al.
    Rimpi, Sara
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Doherty, JR
    Rudelius, M
    Buck, A
    Hoellein, A
    Kremer, M
    Graf, N
    Scheerer, M
    Hall, MA
    Goga, A
    von Bubnoff, N
    Duyster, J
    Peschel, C
    Cleveland, JL
    Nilsson, Jonas A
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Keller, U
    Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 116, no 9, 1498-1505 p.Article in journal (Refereed)
    Abstract [en]

    Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant-Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function. (Blood. 2010;116(9):1498-1505)

  • 20. Engert, Andreas
    et al.
    Balduini, Carlo
    Brand, Anneke
    Coiffier, Bertrand
    Cordonnier, Catherine
    Doehner, Hartmut
    de Wit, Thom Duyvene
    Eichinger, Sabine
    Fibbe, Willem
    Green, Tony
    de Haas, Fleur
    Iolascon, Achille
    Jaffredo, Thierry
    Rodeghiero, Francesco
    Salles, Gilles
    Schuringa, Jan Jacob
    Andre, Marc
    Andre-Schmutz, Isabelle
    Bacigalupo, Andrea
    Bochud, Pierre-Yves
    den Boer, Monique
    Bonini, Chiara
    Camaschella, Clara
    Cant, Andrew
    Cappellini, Maria Domenica
    Cazzola, Mario
    Lo Celso, Cristina
    Dimopoulos, Meletios
    Douay, Luc
    Dzierzak, Elaine
    Einsele, Hermann
    Ferreri, Andres
    De Franceschi, Lucia
    Gaulard, Philippe
    Gottgens, Berthold
    Greinacher, Andreas
    Gresele, Paolo
    Gribben, John
    de Haan, Gerald
    Hansen, John-Bjarne
    Hochhaus, Andreas
    Kadir, Rezan
    Kaveri, Srini
    Kouskoff, Valerie
    Kuehne, Thomas
    Kyrle, Paul
    Ljungman, Per
    Maschmeyer, Georg
    Mendez-Ferrer, Simon
    Milsom, Michael
    Mummery, Christine
    Ossenkoppele, Gert
    Pecci, Alessandro
    Peyvandi, Flora
    Philipsen, Sjaak
    Reitsma, Pieter
    Maria Ribera, Jose
    Risitano, Antonio
    Rivella, Stefano
    Ruf, Wolfram
    Schroeder, Timm
    Scully, Marie
    Socie, Gerard
    Staal, Frank
    Stanworth, Simon
    Stauder, Reinhard
    Stilgenbauer, Stephan
    Tamary, Hannah
    Theilgaard-Monch, Kim
    Thein, Swee Lay
    Tilly, Herve
    Trneny, Marek
    Vainchenker, William
    Vannucchi, Alessandro Maria
    Viscoli, Claudio
    Vrielink, Hans
    Zaaijer, Hans
    Zanella, Alberto
    Zolla, Lello
    Zwaginga, Jaap Jan
    Martinez, Patricia Aguilar
    van den Akker, Emile
    Allard, Shubha
    Anagnou, Nicholas
    Andolfo, Immacolata
    Andrau, Jean-Christophe
    Angelucci, Emanuele
    Anstee, David
    Aurer, Igor
    Avet-Loiseau, Herve
    Aydinok, Yesim
    Bakchoul, Tamam
    Balduini, Alessandra
    Barcellini, Wilma
    Baruch, Dominique
    Baruchel, Andre
    Bayry, Jagadeesh
    Bento, Celeste
    van den Berg, Anke
    Bernardi, Rosa
    Bianchi, Paola
    Bigas, Anna
    Biondi, Andrea
    Bohonek, Milos
    Bonnet, Dominique
    Borchmann, Peter
    Borregaard, Niels
    Braekkan, Sigrid
    van den Brink, Marcel
    Brodin, Ellen
    Bullinger, Lars
    Buske, Christian
    Butzeck, Barbara
    Cammenga, Jorg
    Campo, Elias
    Carbone, Antonino
    Cervantes, Francisco
    Cesaro, Simone
    Charbord, Pierre
    Claas, Frans
    Cohen, Hannah
    Conard, Jacqueline
    Coppo, Paul
    Vives Corrons, Joan-Lluis
    da Costa, Lydie
    Davi, Frederic
    Delwel, Ruud
    Dianzani, Irma
    Domanovic, Dragoslav
    Donnelly, Peter
    Drnovsek, Tadeja Dovc
    Dreyling, Martin
    Du, Ming-Qing
    Dufour, Carlo
    Durand, Charles
    Efremov, Dimitar
    Eleftheriou, Androulla
    Elion, Jacques
    Emonts, Marieke
    Engelhardt, Monika
    Ezine, Sophie
    Falkenburg, Fred
    Favier, Remi
    Federico, Massimo
    Fenaux, Pierre
    Fitzgibbon, Jude
    Flygare, Johan
    Foa, Robin
    Forrester, Lesley
    Galacteros, Frederic
    Garagiola, Isabella
    Gardiner, Chris
    Garraud, Olivier
    van Geet, Christel
    Geiger, Hartmut
    Geissler, Jan
    Germing, Ulrich
    Ghevaert, Cedric
    Girelli, Domenico
    Godeau, Bertrand
    Goekbuget, Nicola
    Goldschmidt, Hartmut
    Goodeve, Anne
    Graf, Thomas
    Graziadei, Giovanna
    Griesshammer, Martin
    Gruel, Yves
    Guilhot, Francois
    von Gunten, Stephan
    Gyssens, Inge
    Halter, Jorg
    Harrison, Claire
    Harteveld, Cornelis
    Hellstrom-Lindberg, Eva
    Hermine, Olivier
    Higgs, Douglas
    Hillmen, Peter
    Hirsch, Hans
    Hoskin, Peter
    Huls, Gerwin
    Inati, Adlette
    Johnson, Peter
    Kattamis, Antonis
    Kiefel, Volker
    Kleanthous, Marina
    Klump, Hannes
    Krause, Daniela
    Hovinga, Johanna Kremer
    Lacaud, Georges
    Lacroix-Desmazes, Sebastien
    Landman-Parker, Judith
    LeGouill, Steven
    Lenz, Georg
    von Lilienfeld-Toal, Marie
    von Lindern, Marieke
    Lopez-Guillermo, Armando
    Lopriore, Enrico
    Lozano, Miguel
    MacIntyre, Elizabeth
    Makris, Michael
    Mannhalter, Christine
    Martens, Joost
    Mathas, Stephan
    Matzdorff, Axel
    Medvinsky, Alexander
    Menendez, Pablo
    Migliaccio, Anna Rita
    Miharada, Kenichi
    Mikulska, Malgorzata
    Minard, Veronique
    Montalban, Carlos
    de Montalembert, Mariane
    Montserrat, Emili
    Morange, Pierre-Emmanuel
    Mountford, Joanne
    Muckenthaler, Martina
    Mueller-Tidow, Carsten
    Mumford, Andrew
    Nadel, Bertrand
    Navarro, Jose-Tomas
    el Nemer, Wassim
    Noizat-Pirenne, France
    O'Mahony, Brian
    Oldenburg, Johannes
    Olsson, Martin
    Oostendorp, Robert
    Palumbo, Antonio
    Passamonti, Francesco
    Patient, Roger
    de Latour, Regis Peffault
    Pflumio, Francoise
    Pierelli, Luca
    Piga, Antonio
    Pollard, Debra
    Raaijmakers, Marc
    Radford, John
    Rambach, Ralf
    Rao, A. Koneti
    Raslova, Hana
    Rebulla, Paolo
    Rees, David
    Ribrag, Vincent
    Rijneveld, Anita
    Rinalducci, Sara
    Robak, Tadeusz
    Roberts, Irene
    Rodrigues, Charlene
    Rosendaal, Frits
    Rosenwald, Andreas
    Rule, Simon
    Russo, Roberta
    Saglio, Guiseppe
    Sanchez, Mayka
    Scharf, Ruediger E.
    Schlenke, Peter
    Semple, John
    Sierra, Jorge
    So-Osman, Cynthia
    Manuel Soria, Jose
    Stamatopoulos, Kostas
    Stegmayr, Bernd
    Umeå University.
    Stunnenberg, Henk
    Swinkels, Dorine
    Taborda Barata, Joao Pedro
    Taghon, Tom
    Taher, Ali
    Terpos, Evangelos
    Thachil, Jecko
    Tissot, Jean Daniel
    Touw, Ivo
    Toye, Ash
    Trappe, Ralf
    Traverse-Glehen, Alexandra
    Unal, Sule
    Vaulont, Sophie
    Viprakasit, Vip
    Vitolo, Umberto
    van Wijk, Richard
    Wojtowicz, Agnieszka
    Zeerleder, Sacha
    Zieger, Barbara
    The European Hematology Association Roadmap for European Hematology Research: a consensus document2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, 115-208 p.Article in journal (Refereed)
    Abstract [en]

    The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

  • 21. Fogelstrand, Linda
    et al.
    Staffas, Anna
    Wasslavik, Carina
    Sjogren, Helene
    Soderhall, Stefan
    Frost, Britt-Marie
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Behrendtz, Mikael
    Heldrup, Jesper
    Karrman, Kristina
    Johansson, Bertil
    Heyman, Mats
    Abrahamsson, Jonas
    Palmqvist, Lars
    Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols2014In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, no 3, 424-430 p.Article in journal (Refereed)
    Abstract [en]

    Background In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.

    Procedure We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.

    Results Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen.

    Conclusions Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.

  • 22.
    Forsberg, Ulf
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jonsson, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Christofer
    Umeå University, Faculty of Science and Technology, Umeå Institute of Technology.
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A high blood level in the air trap reduces microemboli during hemodialysis2012In: Artificial Organs, ISSN 0160-564X, E-ISSN 1525-1594, Vol. 36, no 6, 525-529 p.Article in journal (Refereed)
    Abstract [en]

    Previous studies have demonstrated the presence of air microemboli in the dialysis circuit and in the venous circulation of the patients during hemodialysis. In vitro studies indicate that a high blood level in the venous air trap reduces the extent of microbubble formation. The purpose of this study was to examine whether air microbubbles can be detected in the patient's access and if so, whether the degree of microbubble formation can be altered by changing the blood level in the venous air trap. This was a randomized, double-blinded, interventional study of 20 chronic hemodialysis patients. The patients were assigned to hemodialysis with either an elevated or a low blood level in the air trap. The investigator and the patient were blinded to the settings. The numbers of microbubbles were measured at the site of the arteriovenous (AV) access for 2 min with the aid of an ultrasonic Doppler device. The blood level in the air trap was then altered to the opposite setting and a new measurement was carried out after an equilibration period of 30 min. Median (range) for the number of microbubbles measured with the high air trap level and the low air trap level in AV access was 2.5 (0-80) compared with 17.5 (0-77), respectively (P = 0.044). The degree of microbubble formation in hemodialysis patients with AV access was reduced significantly if the blood level in the air trap was kept high. The exposure of potentially harmful air microbubbles was thereby significantly reduced. This measure can be performed with no additional healthcare cost.

  • 23.
    Fransson, Filip
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Kyrk, Tobias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Skagerlind, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rinsing the extra corporeal circuit with a heparin and albumin solution reduces the need for systemic anticoagulant in hemodialysis2013In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 36, no 10, 725-729 p.Article in journal (Refereed)
    Abstract [en]

    Background: Systemic anticoagulation during hemodialysis (HD) increases the risk for bleeding complications pre- or post-operatively. Based on the concept of blood-membrane interaction, we developed a heparin-albumin solution to rinse the dialysis circuit before start. The aim of this study was to investigate if this method was a valuable tool for our patients at risk for bleeding complications.

    Material and methods: This retrospective, comparative, quality assessment study included 248 HD in 68 patients; Group 1: 178 treatments were performed at patients for risk of bleeding using heparin-albumin-priming and Group 2: 70 acute HD were performed on patients without increased risk of bleeding using a bolus of heparin at start and a continuous infusion of heparin. In Group 1 additional heparin was given upon suspicion of progressive clotting. One L saline contained albumin (1 g/I) and heparin (5000 U/I) used for priming. Excess priming solution was removed by filling the circuit with blood at start of treatment.

    Results: In Group 1, a mean total dose of 2000 U of heparin was given during the HD (18% performed HD without any heparin) and Group 2 used a mean total dose of 5500 U (p<0.001). There was no increased incidence of clotting in Group 1 versus Group 2 compared to standard HD. No bleeding complications were reported during any of the HA-priming treatments.

    Conclusions: Heparin-albumin priming resulted in a reduced total dose of heparin. There was no increased clotting and no incidence of bleeding was reported in either group.

  • 24. Frost, Britt-Marie
    et al.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Gustafsson, Göran
    Nygren, Peter
    Hellebostad, Marit
    Jonsson, Olafur G
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Larsson, Rolf
    Lönnerholm, Gudmar
    Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia2004In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 104, no 8, 2452-2457 p.Article in journal (Refereed)
    Abstract [en]

    The t(12;21) (p13;q22) translocation resulting in ETV6/RUNX1 (previously named TEL/AML1) gene fusion is present in about 25% of children with precursor B-lineage acute lymphoblastic leukemia (B-ALL). We successfully tested 275 precursor BALL samples from children aged 1 to 17 years to determine the relation between t(12;21) and in vitro cellular drug resistance, measured by the fluorometric microculture cytotoxicity assay (FMCA). Samples from 83 patients (30%) were positive for t(12;21). The ETV6/RUNX1(+) samples were significantly more sensitive than ETV6/RUNX1(-) samples to doxorubicin, etoposide, amsacrine, and dexamethasone, whereas the opposite was true for cytarabine. After matching for unevenly distributed patient characteristics, that is, excluding patients with high hyperdiploidy (> 51 chromosomes), t(g;22), t(1;19), or 11q23 rearrangement, the ETV6/RUNX1(+) samples remained significantly more sensitive to doxorubicin (P = .001) and etoposide (P = .001). For the other drugs tested (amsacrine, cytarabine, dexamethasone, prednisolone, vincristine, 6-thioguanine, and 4-hydroper-oxy-cyclophosphamide), no significant difference in cellular drug sensitivity was found. In conclusion, we found that the presence of the t(12;21) translocation in childhood precursor B-ALL is associated with a high tumor cell sensitivity to doxorubicin and etoposide. High throughput techniques should now be used to elucidate the cellular mechanisms by which ETV6/RUNX1 gene fusion is linked to increased sensitivity to these drugs.

  • 25. Georgiadis, Panagiotis
    et al.
    Liampa, Irene
    Hebels, Dennie G
    Krauskopf, Julian
    Chatziioannou, Aristotelis
    Valavanis, Ioannis
    de Kok, Theo M C M
    Kleinjans, Jos C S
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Spaeth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palli, Domenico
    Vermeulen, R C H
    Vlaanderen, J
    Chadeau-Hyam, Marc
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, 728Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance.

    RESULTS: We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p.

    CONCLUSIONS: Our findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential.

  • 26. Ghez, D.
    et al.
    Fortpied, C.
    Mounier, N.
    Carde, P.
    Perrot, A.
    Khaled, H.
    Amorim, S.
    Ramadan, S.
    Le Bras, F.
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Herbaux, C.
    Marolleau, J. P.
    Nicolas-Virelizier, E.
    Casasnovas, O.
    Stamatoullas-Bastard, A.
    Ferme, C.
    STEM CELL COLLECTION AFTER FAILURE OF UPFRONT ABVD OR BEACOPP IN PATIENTS WITH HIGH RISK ADVANCED STAGE III-IV HODGKIN'S LYMPHOMA2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no S5, 50-50 p., P091Article in journal (Refereed)
  • 27. Graaff, Reindert
    et al.
    Arsov, Stefan
    Ramsauer, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Koetsier, Marten
    Sundvall, Nils
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Engels, Gerwin E.
    Sikole, Aleksandar
    Lundberg, Lennart
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rakhorst, Gerhard
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Skin and Plasma Autofluorescence During Hemodialysis: A Pilot Study2014In: Artificial Organs, ISSN 0160-564X, E-ISSN 1525-1594, Vol. 38, no 6, 515-518 p.Article in journal (Refereed)
    Abstract [en]

    Skin autofluorescence (AF) is related to the accumulation of advanced glycation end products (AGEs) and is one of the strongest prognostic markers of mortality in hemodialysis (HD) patients. The aim of this pilot study was to investigate whether changes in skin AF appear after a single HD session and if they might be related to changes in plasma AF. Skin and plasma AF were measured before and after HD in 35 patients on maintenance HD therapy (nine women and 26 men, median age 68 years, range 33-83). Median dialysis time was 4h (range 3-5.5). Skin AF was measured noninvasively with an AGE Reader, and plasma AF was measured before and after HD at 460nm after excitation at 370nm. The HD patients had on average a 65% higher skin AF value than age-matched healthy persons (P<0.001). Plasma AF was reduced by 14% (P<0.001), whereas skin AF was not changed after a single HD treatment. No significant influence of the reduced plasma AF on skin AF levels was found. This suggests that the measurement of skin AF can be performed during the whole dialysis period and is not directly influenced by the changes in plasma AF during HD.

  • 28. Greve, Anders M.
    et al.
    Boman, Kurt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gohlke-Baerwolf, Christa
    Kesaniemi, Y. Antero
    Nienaber, Christoph
    Ray, Simon
    Egstrup, Kenneth
    Rossebo, Anne B.
    Devereux, Richard B.
    Kober, Lars
    Willenheimer, Ronnie
    Wachtell, Kristian
    Clinical implications of electrocardiographic left ventricular strain and hypertrophy in asymptomatic patients with aortic stenosis the simvastatin and ezetimibe in aortic stenosis study2012In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 125, no 2, 346-353 p.Article in journal (Refereed)
    Abstract [en]

    Background-The prognostic impact of ECG left ventricular strain and left ventricular hypertrophy (LVH) in asymptomatic aortic stenosis is not well described.

    Methods and Results-Data were obtained in asymptomatic patients randomized to simvastatin/ezetimibe combination versus placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Primary end point was the first of myocardial infarction, nonhemorrhagic stroke, heart failure, aortic valve replacement, or cardiovascular death. The predictive value of ECG left ventricular strain (defined as T-wave inversion in leads V(4) through V(6)) and LVH, assessed by Sokolow-Lyon voltage criteria (R(V5-6) +/- S(V1) >= 35 mV) and Cornell voltage-duration criteria {[RaVL + S(V3) + (6 mV in women)] x QRS duration >= 2440 mV.ms}, was evaluated by adjustment for other prognostic covariates. A total of 1533 patients were followed for 4.3 +/- 0.8 years (6592 patient-years of follow-up), and 627 cardiovascular events occurred. ECG strain was present in 340 patients (23.6%), with LVH by Sokolow-Lyon voltage in 260 (17.1%) and by Cornell voltage-duration product in 220 (14.6%). In multivariable analyses, ECG left ventricular strain was associated with 3.1-fold higher risk of in-study myocardial infarction (95% confidence interval, 1.4-6.8; P = 0.004). Similarly, ECG LVH by both criteria predicted, compared with no ECG LVH, 5.8-fold higher risk of heart failure (95% confidence interval, 2.0 -16.8), 2.0-fold higher risk of aortic valve replacement (95% confidence interval, 1.3-3.1; both P = 0.001), and 2.5-fold higher risk of a combined end point of myocardial infarction, heart failure, or cardiovascular death (95% confidence interval, 1.3-4.9; P = 0.008).

    Conclusions-ECG left ventricular strain and LVH were independently predictive of poor prognosis in patients with asymptomatic aortic stenosis.

  • 29.
    Grzymala-Lubanski, Bartosz
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renlund, Henrik
    Svensson, Peter J.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Computer aided warfarin dosing in the Swedish national quality registry AuriculA: algorithmic suggestions are performing better than manually changed doses2013In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 131, no 2, 130-134 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Warfarin treatment with a high time in therapeutic range (TTR) is correlated to fewer complications. The TTR in Sweden is generally high but varies partly depending on local expertise and traditions. A dosing algorithm could minimize variations and increase treatment quality. Here we evaluate the performance of a computerized dosing algorithm.

    MATERIALS AND METHODS: 53.779 warfarin treated patients from 125 centers using the Swedish national quality registry AuriculA. If certain criteria are met, the algorithm gives one of seven possible dose suggestions, which can be unchanged, decreased or increased weekly dose by 5, 10 or 15%. The outcome evaluated by the resulting INR value was compared between dose suggestions arising from the algorithm that were accepted and those that were manually changed. There were no randomization, and outcomes were retrospectively analyzed.

    RESULTS: Both the algorithm-based and the manually changed doses had worse outcome if only two instead of three previous INR values were available. The algorithm suggestions were superior to manual dosing regarding percent samples within the target range 2-3 (hit-rate) or deviation from INR 2.5 (mean error). Of the seven possible outcomes from the algorithm, six were significantly superior and one equal to the manually changed doses when three previous INR:s were present.

    CONCLUSIONS: The algorithm-based dosing suggestions show better outcome in most cases. This can make dosing of warfarin easier and more efficient. There are however cases where manual dosing fares better. Here the algorithm will be improved to further enhance its dosing performance in the future.

  • 30. Grövdal, Michael
    et al.
    Karimi, Mohsen
    Khan, Rasheed
    Aggerholm, Anni
    Antunovic, Petar
    Astermark, Jan
    Bernell, Per
    Engström, Lena-Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kjeldsen, Lars
    Linder, Olle
    Nilsson, Lars
    Olsson, Anna
    Holm, Mette S
    Tangen, Jon M
    Wallvik, Jonas
    Oberg, Gunnar
    Hokland, Peter
    Jacobsen, Sten E
    Porwit, Anna
    Hellström-Lindberg, Eva
    Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy2010In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 150, no 3, 293-302 p.Article in journal (Refereed)
    Abstract [en]

    This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.

  • 31.
    Gunnarsson, Niklas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Chronic myeloid leukemia and cancer2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Chronic myeloid leukemia (CML) is a relatively rare hematological malignancy with a constant incidence of approximately 90 new cases each year in Sweden (0.9 cases/100 000 inhabitants). The etiology is largely unknown but high doses of ionizing radiation are a known but rare risk factor. The treatment options were for a long time limited to chemotherapies i.e. hydroxyurea and busulfan, interferon’s and allogeneic hematopoietic stem cell transplantation and the median survival were only about four years.

    Since the beginning of the 21st century a new way of treating CML has been introduced, the tyrosine kinase inhibitors (TKI), leading to a rapid decrease in leukemic cells and symptoms. Due to the TKIs, the overall 5-year survival is nowadays approximately 85 % and CML patients have time to develop other diseases, including other malignancies.

    The aims of this thesis was to investigate the present and future prevalence of CML and the prevalence of other malignancies prior and subsequent to the diagnosis of CML, malignancies among first-degree relatives of persons with CML. In addition, the incidence of autoimmune and chronic inflammatory diseases among patients with CML was also investigated.

     

    Methods

    From the Swedish CML register, data over nearly all Swedish CML patients from 2002 and forward were obtained for paper II-IV.

    For paper I, the Swedish cancer register was used to identify all Swedish CML patients since 1970 and the Swedish cause of death register was used to identify an eventual date of death for these patients. With a constant incidence and the relative survival rates for CML patients between 2006 and 2012 as a model, the present and future prevalence was calculated.

    For paper II-IV, data from the Swedish cancer register was used to identify other malignancies than CML. For paper II, information about autoimmune and chronic inflammatory diseases was retrieved from the Swedish national patient register.

    For paper II and IV, five controls matched for year of birth, gender and county of residence were randomly selected from the Swedish register of the total population. To calculate odds ratio (OR), conditional logistic regression was used.

    To calculate the risk of a second malignancy for paper III, Standardized incidence ratio (SIR) was used.

    In paper IV, first-degree relatives (parents, siblings and offsprings) for both cases and controls were retrieved from the Swedish multi-Generation Register, where persons born later than 1932 and registered in Sweden at some time since 1961 are registered.

     

    Results

    Prevalence and survival

    As shown in paper I, the 5-year overall survival for CML patients increased remarkably from 0.18 to 0.82 between 1970 and 2012. The prevalence increased from 3.9 to 11.9 per 100 000 inhabitants in Sweden between 1985 and 2012. By assuming no further improvements in relative survival as compared to the survival rates between 2006 and 2012, the prevalence by 2060 is expected to increase to 22.0 per 100 000 inhabitants. This corresponds to 2 587 CML patients as compared to 1 137 CML patients in 2012.

     

    Malignancies, autoimmune and chronic inflammatory diseases prior to CML

    In study II, more than 45 000 person-years of follow-up were evaluated in 984 CML patients diagnosed between 2002 and 2012. With an OR of 1.47 (95 % CI 1.20–1.82) and 1.55 (95 % CI 1.21–1.98), respectively, the prevalence of prior malignancies and autoimmune diseases were significantly increased as compared to matched controls. On the other hand, no association between CML and chronic inflammatory diseases was shown.

     

    Second malignancies

    In 868 CML patients, diagnosed between 2002 and 2011, 52 malignancies were observed in the Swedish cancer register, as shown in paper III. When compared to expected rates in the background population, a significantly increased risk of second malignancies with a SIR of 1.52 (95 % CI 1.13–1.99) was shown. When looking at specific cancer types, gastrointestinal as well as nose and throat cancer were significantly increased.

     

    Familial aggregation of malignancies

    984 CML patients were identified in paper IV. However, 184 had a birth date prior to 1932, subsequently only 800 patients were analyzed. Among them, 4 287 first-degree relatives were identified, compared to 20 930 first-degree relatives of the matched controls. 611 malignancies were retrieved; no significant increase of malignancies in first-degree relatives of CML patients was shown (OR 1.06; 95 % CI: 0.96–1.16).

     

    Conclusion

    Since CML patients nowadays have a high survival rate, the calculations in this thesis shows that the prevalence of CML will almost double by 2060. CML patients have an increased risk of developing malignancies prior and subsequent to the diagnosis of CML, suggesting a hereditary or acquired predisposition to develop cancer. Since there is no familial aggregation of malignancies in CML patients, a hereditary predisposition to develop cancer is unlikely to be part of the pathogenesis of CML, leaving an acquired predisposition more likely.

  • 32.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Höglund, M.
    Stenke, L.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Sandin, F.
    Björkholm, M.
    Dreimane, A.
    Lambe, M.
    Markevärn, Berit
    Olsson-Strömberg, U.
    Wadenvik, H.
    Richter, J.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Increased prevalence of prior malignancies and autoimmune diseases in patients diagnosed with chronic myeloid leukemia2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 7, 1562-1567 p.Article in journal (Refereed)
    Abstract [en]

    We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.

  • 33.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Höglund, Martin
    Stenke, Leif
    Wållberg Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sandin, Fredrik
    Björkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevärn, Berit
    Olsson-Strömberg, Ulla
    Wadenvik, Hans
    Richter, Johan
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Increased Prevalence of Prior Malignancies and Autoimmune Diseases in Patients Diagnosed with Chronic Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 34.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sandin, Fredrik
    Höglund, Martin
    Stenke, Leif
    Björkholm, Magnus
    Lambe, Mats
    Olsson-Strömberg, Ulla
    Richter, Johan
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Population-based assessment of chronic myeloid leukemia in Sweden: striking increase in survival and prevalence2016In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 97, no 4, 387-392 p.Article in journal (Refereed)
    Abstract [en]

    The clinical outcome for patients with chronic myeloid leukemia (CML) has improved dramatically following the introduction of tyrosine kinase inhibitors. An improved survival, combined with a constant incidence, is expected to increase the prevalence of CML. However, data on the prevalence of CML remain scarce. We examined the overall and relative (age and gender matched) survival and assessed the past, present, and projected future prevalence of CML in Sweden. Data on all patients diagnosed with CML between 1970 and 2012 were retrieved from the Swedish Cancer Register and the Swedish Cause of Death Register. The 5-year overall survival increased from 0.18 to 0.82, during the observed time period. Between 2006 and 2012, the 5-year relative survival was close to normal for 40-year-old, but considerably lower for 80-year-old CML patients. The observed prevalence tripled from 1985 to 2012, from 3.9 to 11.9 per 100 000 inhabitants. Assuming no further improvements in relative survival, the prevalence is projected to further increase by 2060 to 22.0 per 100 000 inhabitants (2587 persons in Sweden). The projected dramatic increase in CML prevalence has major medical and health economic implications and needs to be considered in planning how to organize future care of CML patients.

  • 35.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stenke, Leif
    Höglund, Martin
    Sandin, Fredrik
    Björkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevärn, Berit
    Department of Haematology, University Hospital, Umeå.
    Olsson-Strömberg, Ulla
    Richter, Johan
    Wadenvik, Hans
    Wallvik, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era2015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, no 5, 683-688 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 36. Hadimeri, Ursula
    et al.
    Warme, Anna
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    A single treatment, using Far Infrared light improves blood flow conditions in arteriovenous fistula2017In: Clinical hemorheology and microcirculation, ISSN 1386-0291, E-ISSN 1875-8622, Vol. 66, no 3, 211-217 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A native arteriovenous fistula (AVF) is recommended for angio access in patients on chronic hemodialysis (HD). Fistula patency has been improved by exposure to Far Infrared light (FIR).

    OBJECTIVE: To investigate whether a single FIR treatment could alter blood velocity, AVF diameter or inflammatory markers. METHODS: Thirty patients with a native AVF in the forearm were included. Each patient was his/her own control. Ultrasound (US) examinations were performed before and after a single FIR treatment.

    RESULTS: A single FIR treatment resulted in a significant increase in blood velocity over the AV fistula from a mean of 2.1 +/- 1.0 m/s to 2.3 +/- 1.0 m/s (p = 0.02). The diameter of the arterialized vein became wider; 0,72 cm +/- 0.02 to 0,80 cm +/- 0.02, (p = 0.006). The increase in fistula blood velocity correlated positively with base line serum-urate p = 0.004) and the increase in venous diameter with the base line plasma orosomucoid concentration (p = 0.005).

    CONCLUSIONS: This study shows that a single FIR treatment significantly increased AVF blood velocity and vein diameter. Thus, one FIR treatment can help maturation of AVF in the early postoperative course.

  • 37. Hagglund, H.
    et al.
    Askmark, H.
    Stromberg, U.
    Axelsson, H.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Isaksson, C.
    Wahlin, A.
    Andersen, O.
    Johansson, J.
    Press, R.
    Autologous haematopoietic stem cell transplantation: a viable treatment option for chronic inflammatory demyelinating polyneuropathy2013In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 48, S336-S336 p.Article in journal (Other academic)
  • 38. Hallböök, H
    et al.
    Hägglund, H
    Stockelberg, D
    Nilsson, P-G
    Karlsson, K
    Björkholm, M
    Linderholm, M
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Linder, O
    Smedmyr, B
    Autologous and allogeneic stem cell transplantation in adult ALL: the Swedish Adult ALL Group experience2005In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 35, no 12, 1141-1148 p.Article in journal (Refereed)
    Abstract [en]

    Adult patients with acute lymphoblastic leukaemia (ALL) have been treated according to national protocols in Sweden since 1986. Stem cell transplantation (SCT) has been recommended in first remission for patients with risk factors for relapse, and for standard risk patients only after relapse. In this retrospective study, the results of autologous and allogeneic SCT in these populations were evaluated. In total, 187 patients with a median age of 34 years (17-66 years) underwent SCT. The 5-year disease-free survival (DFS), for all patients, was 26% (Confidence intervals (CI) 20-32%). The 5-year DFS was higher for patients transplanted in first remission 32% (CI 24-40%) compared to 14% (CI 5-23%; P<0.0001) in patients transplanted beyond first remission. No significant differences in DFS (P=0.06) were determined between autologous, related donor and unrelated donor SCT in the whole cohort. A lower relapse rate was counterbalanced by higher treatment-related mortality in patients undergoing allogeneic SCT. In Philadelphia-positive ALL, allogeneic SCT was superior to autologous SCT, with a 5-year DFS of 30% (CI 12-47%) vs 0% (P=0.04). Limited chronic graft-versus-host-disease (GVHD) was associated with an improved DFS of 53% (CI 38-69%) compared to no chronic GVHD of 22% (CI 10-36%; P=0.0008), indicating a clinically important graft-versus-leukaemia effect.

  • 39. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur Gisli
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 20042012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 5, 978-984 p.Article in journal (Refereed)
    Abstract [en]

    There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m(2) and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of venoocclusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541). (Blood. 2012;120(5):978-984)

  • 40.
    Hernestål-Boman, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Individual PAI-1 increase over nine years relates differently in men and women to changes in anthropometric, glycaemic, inflammatory and lipid markers.Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Levels of plasminogen activator inhibitor-1 (PAI-1) is known to correlate to factors related to the metabolic syndrome. We have previously shown that PAI-1 antigen increased by 75% in men and 95% in women over nine years.

    Objective: The aim of this study was to explore relationships between intra-individual changes in PAI-1 and changes in anthropometric measurements, blood pressure, glycaemic, lipid and inflammatory markers, separately for men and women.

    Method: In northern Sweden, 125 men and 116 women were examined first in 1990 and re-examined in 1999 during the morning hours. Changes over time (Δ) were calculated as the value at 1999 minus the value at 1990.

    Results: In men, ΔPAI-1 was significantly correlated to ΔBMI (r =0.33), ΔCRP (r =0.25), Δtriglycerides (r =0.39), Δfasting plasma glucose (r =0.41) and Δ2-hour plasma glucose (r =0.29). In women, ΔPAI-1 was significantly correlated to ΔBMI (r =0.36), Δwaist circumference (r =0.38), Δhip circumference (r =0.27), ΔCRP (r =0.27) and Δtotal cholesterol (r =0.19). The multivariate linear regression analysis showed that ΔPAI-1 was significantly related to Δfasting plasma glucose and ΔCRP in men (R2 for the complete model was 0.31). In women, ΔPAI-1 was significantly related to Δwaist circumference (R2 for the complete model was 0.17).

    Conclusion: We expected that changes in anthropometric, glycaemic, inflammatory and lipid markers would explain a large part of the observed PAI-1 increase. However, the multivariate analysis explained only 20% of the variation in ΔPAI-1 in women and 30% in men. Interestingly, the patterns of components correlating with the changes in PAI-1 differed between sexes.

  • 41.
    Hernestål-Boman, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Individual changes in fibrinolytic factors, von Willebrand factor, and C-reactive protein over a nine-year period.Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Intra-individual changes in haemostatic factor concentrations over time are unknown, in the general population.

    Objective: To describe intra-individual longitudinal changes in tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), tPA/PAI-1 complex, von Willebrand factor (VWF), and C-reactive protein (CRP) over nine years, in different age groups, stratified for sex.

    Methods: The MONICA survey in 1990 examined randomly selected men and women in four age groups (25–64 years) who were re-examined in 1999. A total of 309 individuals donated venous blood samples in Stabilyte tubes for both surveys during the morning hours, after an overnight fast. We analysed tPA activity and antigens of tPA, PAI-1, tPA/PAI-1 complex, VWF, and CRP.

    Results: Over nine years, in both men and women, we found significant intra-individual increases in the antigen levels of tPA, PAI-1, tPA/PAI-1 complex, VWF, and CRP (P < 0.001). PAI-1 antigen levels increased by 75% for men and 95% for women. Compared to men, women had a significantly higher CRP increase (0.92 vs. 0.22 mg/L; P = 0.044). The P for trend for mean Δ1999–1990 across age groups showed a significant linear trend for VWF (P = 0.001 for men; P < 0.001 for women), but not for the other studied variables.

    Conclusions: There were intra-individual longitudinal increases in the antigen levels of tPA, PAI-1, tPA/PAI-1 complex, VWF, and CRP over nine years in both men and women, with PAI-1 showing the highest relative increase. VWF increased significantly across age groups; however, fibrinolytic variables did not.

  • 42. Hosnijeh, Fatemeh Saberi
    et al.
    Lan, Qing
    Rothman, Nathaniel
    Liu, Chin San
    Cheng, Wen-Ling
    Nieters, Alexandra
    Guldberg, Per
    Tjonneland, Anne
    Campa, Daniele
    Martino, Alessandro
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Krogh, Vittorio
    Tumino, Rosario
    Panico, Salvatore
    Masala, Giovanna
    Weiderpass, Elisabete
    Castano, Jose Maria Huerta
    Ardanaz, Eva
    Sala, Nuria
    Dorronsoro, Miren
    Quiros, J. Ramon
    Sanchez, Maria-Jose
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ann Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Malm, Johan
    Borgquist, Signe
    Peeters, Petra H.
    Bueno-de-Mesquita, H. Bas
    Wareham, Nick
    Khaw, Kay-Tee
    Travis, Ruth C.
    Brennan, Paul
    Siddiq, Afshan
    Riboli, Elio
    Vineis, Paolo
    Vermeulen, Roel
    Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 4, 530-535 p.Article in journal (Refereed)
    Abstract [en]

    It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n=102) with increasing mtDNA copy number (odds ratio=1.34, 1.44, and 1.80 for quartiles 2-4, respectively; Ptrend=.001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.

  • 43. Ilander, M
    et al.
    Olsson-Strömberg, U
    Schlums, H
    Guilhot, J
    Brück, O
    Lähteenmäki, H
    Kasanen, T
    Koskenvesa, P
    Söderlund, S
    Höglund, M
    Markevärn, B
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lotfi, K
    Dreimane, A
    Lübking, A
    Holm, E
    Björeman, M
    Lehmann, S
    Stenke, L
    Ohm, L
    Gedde-Dahl, T
    Majeed, W
    Ehrencrona, H
    Koskela, S
    Saussele, S
    Mahon, F-X
    Porkka, K
    Hjorth-Hansen, H
    Bryceson, Y T
    Richter, J
    Mustjoki, S
    Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 5, 1108-1116 p.Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56(bright) NK cells had decreased relapse free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.

  • 44. Ilander, Mette Matilda
    et al.
    Olsson-Strömberg, Ulla
    Lahteenmaki, Hanna
    Tiina, Kasanen
    Koskenvesa, Perttu
    Söderlund, Stina
    Höglund, Martin
    Markevärn, Berit
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lotfi, Kourosh
    Malm, Claes
    Lubking, Anna
    Ekblom, Marja
    Holm, Elena
    Bjoreman, Mats
    Lehmann, Soren
    Stenke, Leif
    Ohm, Lotta
    Majeed, Waleed
    Pfirrmann, Markus
    Muller, Martin C.
    Guilhot, Joelle
    Ehrencrona, Hans
    Hjorth-Hansen, Henrik
    Saussele, Susanne
    Mahon, Francois-Xavier
    Porkka, Kimmo
    Richter, Johan
    Mustjoki, Satu
    Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and Impaired Function of NK-Cells2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 45. Ilander, Mette
    et al.
    Schlums, Heinrich
    Olsson-Stromberg, Ulla
    Lahteenmäki, Hanna
    Kasanen, Tiina
    Koskenvesa, Perttu
    Söderlund, Stina
    Höglund, Martin
    Markevärn, Berit
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lotfi, Kourosh
    Malm, Claes
    Lubking, Anna
    Ekblom, Marja
    Holm, Elena
    Björeman, Mats
    Lehmann, Soren
    Stenke, Leif
    Ohm, Lotta
    Majeed, Waleed
    Muller, Martin C
    Ehrencrona, Hans
    Hjorth-Hansen, Henrik
    Saussele, Susanne
    Mahon, Francois-Xavier
    Porkka, Kimmo
    Guilhot, Joelle
    Bryceson, Yenan
    Richter, Johan
    Mustjoki, Satu
    Mature, Adaptive-like CD56(DIM) NK Cells in Chronic Myeloid Leukemia Patients in Treatment Free Remission2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 46. Inaba, Hiroto
    et al.
    Zhou, Yinmei
    Abla, Oussama
    Adachi, Souichi
    Auvrignon, Anne
    Beverloo, H. Berna
    de Bont, Eveline
    Chang, Tai-Tsung
    Creutzig, Ursula
    Dworzak, Michael
    Elitzur, Sarah
    Fynn, Alcira
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Nordic Society for Pediatric Hematology and Oncology, Stockholm, Sweden.
    Hasle, Henrik
    Liang, Der-Cherng
    Lee, Vincent
    Locatelli, Franco
    Masetti, Riccardo
    De Moerloose, Barbara
    Reinhardt, Dirk
    Rodriguez, Laura
    Van Roy, Nadine
    Shen, Shuhong
    Taga, Takashi
    Tomizawa, Daisuke
    Yeoh, Allen E. J.
    Zimmermann, Martin
    Raimondi, Susana C.
    Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 13, 1575-1584 p.Article in journal (Refereed)
    Abstract [en]

    Comprehensive clinical studies of patients with acute megakaryoblastic leukemia (AMKL) are lacking. We performed an international retrospective study on 490 patients (age <= 18 years) with non-Down syndrome de novo AMKL diagnosed from 1989 to 2009. Patients with AMKL (median age 1.53 years) comprised 7.8% of pediatric AML. Five-year event-free (EFS) and overall survival (OS) were 43.7% +/- 2.7% and 49.0% +/- 2.7%, respectively. Patients diagnosed in 2000 to 2009 were treated with higher cytarabine doses and had better EFS (P = .037) and OS (P = .003) than those diagnosed in 1989 to 1999. Transplantation in first remission did not improve survival. Cytogenetic data were available for 372 (75.9%) patients: hypodiploid (n = 18, 4.8%), normal karyotype (n = 49, 13.2%), pseudodiploid (n = 119, 32.0%), 47 to 50 chromosomes (n = 142, 38.2%), and >50 chromosomes (n=44, 11.8%). Chromosome gain occurred in 195 of 372 (52.4%) patients: +21 (n = 106, 28.5%), +19 (n = 93, 25.0%), +8 (n = 77, 20.7%). Losses occurred in 65 patients (17.5%): -7 (n = 13, 3.5%). Common structural chromosomal aberrations were t(1; 22)(p13; q13) (n = 51, 13.7%) and 11q23 rearrangements (n = 38, 10.2%); t(9; 11)(p22; q23) occurred in 21 patients. On the basis of frequency and prognosis, AMKL can be classified to 3 risk groups: good risk-7p abnormalities; poor risk-normal karyotypes, -7, 9p abnormalities including t(9;11)(p22;q23)/MLL-MLLT3, -13/13q-, and -15; and intermediate risk-others including t(1;22)(p13;q13)/OTT-MAL (RBM15-MKL1) and 11q23/MLL except t(9;11). Risk-based innovative therapy is needed to improve patient outcomes.

  • 47. Iolascon, Achille
    et al.
    Heimpel, Hermann
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tamary, Hannah
    Congenital dyserythropoietic anemias: molecular insights and diagnostic approach2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 13, 2162-2166 p.Article in journal (Refereed)
    Abstract [en]

    The congenital dyserythropoietic anemias (CDAs) are hereditary disorders characterized by distinct morphologic abnormalities of marrow erythroblasts. The unveiling of the genes mutated in the major CDA subgroups (I-CDAN1 and II-SEC23B) has now been completed with the recent identification of the CDA III gene (KIF23). KIF23 encodes mitotic kinesin-like protein 1, which plays a critical role in cytokinesis, whereas the cellular role of the proteins encoded by CDAN1 and SEC23B is still unknown. CDA variants with mutations in erythroid transcription factor genes (KLF1 and GATA-1) have been recently identified. Molecular diagnosis of CDA is now possible in most patients.

  • 48. Jonsdottir, Gudbjörg
    et al.
    Lund, Sigrún H.
    Björkholm, Magnus
    Turesson, Ingemar
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Mailankody, Sham
    Blimark, Cecilie
    Hultcrantz, Malin
    Porwit, Anna
    Landgren, Ola
    Kristinsson, Sigurdur Y.
    Survival in multiple myeloma patients who develop second malignancies: a population-based cohort study2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 4, e145-e148 p.Article in journal (Refereed)
  • 49. Karlsson, Lene
    et al.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hasle, Henrik
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Nyström, Ulrika Noren
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Palle, Josefine
    Tierens, Anne
    Zeller, Bernward
    Abrahamsson, Jonas
    Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia2017In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, no 4, 592-602 p.Article in journal (Refereed)
    Abstract [en]

    Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS5y) was 39 +/- 4% for the whole group and 43 +/- 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) +/- anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse >= 1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 +/- 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML.

  • 50. Kimby, Eva
    et al.
    Östenstad, Björn
    Brown, Peter de Nully
    Holte, Harald, Jr.
    Hagberg, Hans
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Linden, Ola
    Nordström, Marie
    Sundström, Christer
    Rituximab (R) in Combination with Interferon-a2a (IFN) Versus Single R in Patients with Follicular or Other CD20+Low-Grade (indolent) Lymphoma. Final Results From a Randomized Phase III Study From the Nordic Lymphoma Group2012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 21Article in journal (Other academic)
123 1 - 50 of 142
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf