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  • 201.
    Dolinska, Monika
    et al.
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Klang, Johannis
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Xiao, Pingnan
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Durgaryan, Andranik
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Sandhow, Lakshmi
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Johansson, Anne-Sofie
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Kondo, Makoto
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Deneberg, Stefan
    Karolinska Univ Hosp, Ctr Hematol, Stockholm, Sweden..
    Ungerstedt, Johanna
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Le Blanc, Katarina
    Karolinska Inst, Lab Med Clin Immunol, Stockholm, Sweden..
    Stenke, Leif
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Ekblom, Marja
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Lehmann, Soren
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Qian, Hong
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Phenotypic and Functional Alterations of Bone Marrow Mesenchymal Stem and Progenitor Cells in Chronic Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 202.
    Dolinska, Monika
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Piccini, Alexandre
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Wong, Wan Man
    Lund Univ, Dept Lab Med, Lund, Sweden..
    Gelali, Eleni
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Johansson, Anne-Sofie
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Klang, Johannis
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Xiao, Pingnan
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Yektaei-Karin, Elham
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Strömberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Clin Chem & Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland..
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ekblom, Marja
    Lund Univ, Dept Lab Med, Lund, Sweden..
    Qian, Hong
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34 (+)CD38(-) stem and progenitor cells in chronic myeloid leukemia2017In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 490, no 2, p. 378-384Article in journal (Refereed)
    Abstract [en]

    Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein in chronic myeloid leukemia (CML) are remarkably effective inducing deep molecular remission in most patients. However, they are less effective to eradicate the leukemic stem cells (LSC), resulting in disease persistence. Therefore, there is great need to develop novel therapeutic strategies to specifically target the LSC. In an experimental mouse CML model system, the leukotriene pathway, and specifically, the expression ALOX5, encoding 5-lipoxygenase (5-LO), has been reported as a critical regulator of the LSC. Based on these results, the 5-LO inhibitor zileuton has been introduced in clinical trials as a therapeutic option to target the LSC although its effect on primary human CML LSC has not been studied. We have here by using multiplex single cell PCR analyzed the expression of the mediators of the leukotriene pathway in bone marrow (BM) BCR-ABL(+)CD34(+)CD38(-) cells at diagnosis, and found low or undetectable expression of ALOX5. In line with this, zileuton did not exert significant overall growth inhibition in the long-term culture-initiating cell (LTC-IC) and colony (CFU-C) assays of BM CD34(+)CD38(-) cells from 7 CML patients. The majority of the single leukemic BCR-ABL(+)CD34(+)CD38(-) cells expressed cysteinyl leukotriene receptors CYSLTI and CYSLT2. However, montelukast, an inhibitor of CYSLTI, also failed to significantly suppress CFU-C and LTC-IC growth. These findings indicate that targeting ALOX5 or CYSLTI signaling with leukotriene antagonists, introduced into the clinical practice primarily as prophylaxis and treatment for asthma, may not be a promising pharmacological strategy to eradicate persisting LSC in CML patients. (C) 2017 The Author(s). Published by Elsevier Inc.

  • 203. Douketis, J.
    et al.
    Healey, J. S.
    Brueckmann, M.
    Fraessdorf, M.
    Spyropoulos, A.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Oldgren, J.
    Reilly, P.
    Ezekowitz, M.
    Connolly, S.
    Yusuf, S.
    Bleeding and thromboembolic outcomes in warfarin-and dabigatran-treated patients in the RE-LY trial who required an urgent surgery or procedure2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 393-394, article id PO362-MONArticle in journal (Other academic)
  • 204.
    Drott, Kristina
    et al.
    Skane Univ Hosp, Dept Oncol, Lasarettsg 23 A, SE-22185 Lund, Sweden.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Papworth, Karin
    Norrland Univ Hosp, Dept Oncol, Umea, Sweden.
    Relander, Thomas
    Skane Univ Hosp, Dept Oncol, Lasarettsg 23 A, SE-22185 Lund, Sweden.
    Jerkeman, Mats
    Skane Univ Hosp, Dept Oncol, Lasarettsg 23 A, SE-22185 Lund, Sweden.
    Valproate in combination with rituximab and CHOP as first-line therapy in diffuse large B-cell lymphoma (VALFRID)2018In: BLOOD ADVANCES, ISSN 2473-9529, Vol. 2, no 12, p. 1386-1392Article in journal (Refereed)
    Abstract [en]

    The aims of the present study were to establish the maximally tolerated dose (MTD) of the histone deacetylase inhibitor valproate together with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with diffuse large B-cell lymphoma (DLBCL). A phase 1 dose escalation study of valproate together with R-CHOP followed by a dose expansion study using the established MTD of valproate was performed. MTD of valproate together with R-CHOP was established at 60 mg/kg per day, as higher doses resulted in auditory adverse events (AEs). In the study population, 2-year progression-free survival was 84.7% (95% confidence interval [CI], 73.2%-98%). The 2-year overall survival (OS) was 96.8% (n = 31; 95% CI, 90.8%-100%). These data were compared with 2 risk-factor matched populations of R-CHOP-treated patients from the Swedish Lymphoma Registry (cohort A, n = 330 and B, n = 165). As compared with the matched cohorts, we observed a statistically significant (P = .034 and 0.028, respectively) beneficial effect of the addition of valproate to R-CHOP on the OS in the studied population. In conclusion, addition of valproate to R-CHOP is a feasible strategy in first-line treatment of DLBCL. The proposed phase 2 dose is 60 mg/kg per day together with prednisone. Auditory AEs were unexpected and warrant close monitoring. Our findings suggest that drugs that target histone deacetylation may add benefit and are tolerable when combined with standard R-CHOP in DLBCL.

  • 205.
    Drott, Kristina
    et al.
    Lund Univ, Dept Oncol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Relander, Thomas
    Lund Univ, Dept Oncol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Graffman, Cecilia
    Lund Univ, Dept Oncol, Lund, Sweden.;Skane Univ Hosp, Lund, Sweden..
    Drott, Johan
    Respiratorius AB, Lund, Sweden..
    Jerkeman, Mats
    Lund Univ, Dept Oncol, Skane Univ Hosp, Lund, Sweden..
    Valproate in Combination with Rituximab and CHOP As First Line Therapy in Diffuse Large B-Cell Lymphoma (VALFRID): Preliminary Results from a Phase I Trial with a Dose Expansion Cohort2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 206. Eckerle, S.
    et al.
    Brune, V.
    Döring, C.
    Tiacci, E.
    Bohle, V.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kodet, R.
    Paulli, M.
    Falini, B.
    Klapper, W.
    Chaubert, A. B.
    Willenbrock, K.
    Metzler, D.
    Bräuninger, A.
    Küppers, Ralf
    Hansmann, M-L.
    Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma2009In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 23, no 11, p. 2129-2138Article in journal (Refereed)
    Abstract [en]

    Anaplastic large cell lymphoma (ALCL) is a main type of T-cell lymphomas and comprises three distinct entities: systemic anaplastic lymphoma kinase (ALK) positive, systemic ALK(-) and cutaneous ALK(-) ALCL (cALCL). Little is known about their pathogenesis and their cellular origin, and morphological and immunophenotypical overlap exists between ALK(-) ALCL and classical Hodgkin lymphoma (cHL). We conducted gene expression profiling of microdissected lymphoma cells of five ALK(+) and four ALK(-) systemic ALCL, seven cALCL and sixteen cHL, and of eight subsets of normal T and NK cells. The analysis supports a derivation of ALCL from activated T cells, but the lymphoma cells acquired a gene expression pattern hampering an assignment to a CD4(+), CD8(+) or CD30(+) T-cell origin. Indeed, ALCL display a down-modulation of many T-cell characteristic molecules. All ALCL types show significant expression of NFkappaB target genes and upregulation of genes involved in oncogenesis (e.g. EZH2). Surprisingly, few genes are differentially expressed between systemic and cALCL despite their different clinical behaviour, and between ALK(-) ALCL and cHL despite their different cellular origin. ALK(+) ALCL are characterized by expression of genes regulated by pathways constitutively activated by ALK. This study provides multiple novel insights into the molecular biology and pathogenesis of ALCL.

  • 207.
    Edgren, G.
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, SE-17177 Stockholm, Sweden;Soder Sjukhuset, Dept Cardiol, Stockholm, Sweden.
    Hjalgrim, H.
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark;Copenhagen Univ Hosp, Dept Hematol, Copenhagen, Denmark.
    Rostgaard, K.
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark.
    Dahl, V.
    Publ Hlth Agcy Sweden, Dept Monitoring & Evaluat, Stockholm, Sweden.
    Titlestad, K.
    Odense Univ Hosp, Dept Clin Immunol, Odense, Denmark.
    Erikstrup, C.
    Aarhus Univ Hosp, Dept Clin Immunol, Aarhus, Denmark.
    Wikman, A.
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden;Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Norda, Rut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Majeed, A.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, SE-17177 Stockholm, Sweden;Alfred Hlth, Dept Gastroenterol, Melbourne, Vic, Australia;Monash Univ, Cent Clin Sch, Melbourne, Vic, Australia.
    Searching for unknown transfusion-transmitted hepatitis viruses: a binational cohort study of 1.5 million transfused patients2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 284, no 1, p. 92-103Article in journal (Refereed)
    Abstract [en]

    Background. Both hepatitis B and C viruses were transmitted through blood transfusion before implementation of donor screening. The existence of additional, yet unknown transfusion transmittable agents causing liver disease could have important public health implications.

    Methods. Analyses were based on the Scandinavian Donations and Transfusions (SCANDAT2) database. Cox regression models were used to estimate the hazard ratio (HR) of developing chronic liver disease in recipients of blood from donors who later developed any chronic liver disease compared to recipients who received blood transfusion from healthy donors. We also studied whether the risk of liver disease was increased in patients who received units from high-risk' donors, defined as donors who had a higher than expected occurrence of liver disease amongst their previous recipients. All analyses were stratified before and after 1992 to account for the effect of screening for hepatitis C virus.

    Results. A total of 1 482 922 transfused patients were included in the analyses. Analyses showed evidence of transfusion transmission of liver diseases before, but not after the implementation of hepatitis C virus screening in 1992, with HRs for any liver disease of 1.38 [95% confidence interval (CI), 1.30-1.46] and 0.99 (95% CI, 0.91-1.07), before and after 1992, respectively. Similarly, blood components from 'high-risk' donors conferred increased risks before, but not after 1992.

    Conclusions. Our data provide no evidence for transfusion transmission of agents causing liver disease after the implementation of screening for hepatitis B and C, and suggest that if such transmission does occur, it is rare.

  • 208.
    Edgren, Gustaf
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Rostgaard, Klaus
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Vasan, Senthil K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Wikman, Agneta
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Norda, Rut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Pedersen, Ole Birger
    Naestved Hosp, Dept Clin Immunol, Naestved, Denmark..
    Erikstrup, Christian
    Aarhus Univ Hosp, Dept Clin Immunol, DK-8000 Aarhus, Denmark..
    Nielsen, Kaspar Rene
    Aalborg Univ Hosp, Dept Clin Immunol, Aalborg, Denmark..
    Titlestad, Kjell
    Odense Univ Hosp, Dept Clin Immunol, DK-5000 Odense, Denmark..
    Ullum, Henrik
    Univ Copenhagen Hosp, Rigshosp, Dept Clin Immunol, Blood Bank, DK-2100 Copenhagen, Denmark..
    Melbye, Mads
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark.;Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark.;Stanford Sch Med, Dept Med, Stanford, CA USA..
    Nyren, Olof
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Hjalgrim, Henrik
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    The new Scandinavian Donations and Transfusions database (SCANDAT2): a blood safety resource with added versatility2015In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 55, no 7, p. 1600-1606Article in journal (Refereed)
    Abstract [en]

    BackgroundRisks of transfusion-transmitted disease are currently at a record low in the developed world. Still, available methods for blood surveillance might not be sufficient to detect transmission of diseases with unknown etiologies or with very long incubation periods. Study Design and MethodsWe have previously created the anonymized Scandinavian Donations and Transfusions (SCANDAT) database, containing data on blood donors, blood transfusions, and transfused patients, with complete follow-up of donors and patients for a range of health outcomes. Here we describe the re-creation of SCANDAT with updated, identifiable data. We collected computerized data on blood donations and transfusions from blood banks covering all of Sweden and Denmark. After data cleaning, two structurally identical databases were created and the entire database was linked with nationwide health outcomes registers to attain complete follow-up for up to 47 years regarding hospital care, cancer, and death. ResultsAfter removal of erroneous records, the database contained 25,523,334 donation records, 21,318,794 transfusion records, and 3,692,653 unique persons with valid identification, presently followed over 40 million person-years, with possibility for future extension. Data quality is generally high with 96% of all transfusions being traceable to their respective donation(s) and a very high (>97%) concordance with official statistics on annual number of blood donations and transfusions. ConclusionsIt is possible to create a binational, nationwide database with almost 50 years of follow-up of blood donors and transfused patients for a range of health outcomes. We aim to use this database for further studies of donor health, transfusion-associated risks, and transfusion-transmitted disease.

  • 209.
    Ednersson, Susanne Bram
    et al.
    Sahlgrens Univ Hosp, Dept Pathol, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Stenson, Martin
    Kungalvs Hosp, Sect Haematol, Dept Med, Kungalv, Sweden;Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Stern, Mimmie
    South Alvsborg Hosp, Dept Med, Sect Haematol, Boras, Sweden;Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Fagman, Henrik
    Sahlgrens Univ Hosp, Dept Pathol, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Nilsson-Ehle, Herman
    Sahlgrens Univ Hosp, Sect Haematol & Coagulat, Gothenburg, Sweden;Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Hasselblom, Sverker
    Dept Res Dev & Educ, Halmstad, Region Halland, Sweden.
    Andersson, Per-Ola
    South Alvsborg Hosp, Dept Med, Sect Haematol, Boras, Sweden;Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Expression of ribosomal and actin network proteins and immunochemotherapy resistance in diffuse large B cell lymphoma patients2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, no 6, p. 770-781Article in journal (Refereed)
    Abstract [en]

    Diffuse large B cell lymphoma (DLBCL) patients with early relapse or refractory disease have a very poor outcome. Immunochemotherapy resistance will probably, also in the era of targeted drugs, remain the major cause of treatment failure. We used proteomic mass spectrometry to analyse the global protein expression of micro-dissected formalin-fixed paraffin-embedded tumour tissues from 97 DLBCL patients: 44 with primary refractory disease or relapse within 1year from diagnosis (REF/REL), and 53 who were progression-free more than 5years after diagnosis (CURED). We identified 2127 proteins: 442 were found in all patients and 102 were differentially expressed. Sixty-five proteins were overexpressed in REF/REL patients, of which 46 were ribosomal proteins (RPs) compared with 2 of the 37 overexpressed proteins in CURED patients (P=7<bold></bold>6x10(-10)). Twenty of 37 overexpressed proteins in CURED patients were associated with actin regulation, compared with 1 of 65 in REF/REL patients (P=1<bold></bold>4x10(-9)). Immunohistochemical staining showed higher expression of RPS5 and RPL17 in REF/REL patients while MARCKS-like protein, belonging to the actin network, was more highly expressed in CURED patients. Even though functional studies aimed at individual proteins and protein interactions to evaluate potential clinical effect are needed, our findings suggest new mechanisms behind immunochemotherapy resistance in DLBCL.

  • 210.
    Edvardsson, Maria
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Finspång.
    Sund-Levander, Märtha
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Milberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in East Östergötland, Department of Advanced Home Care in Norrköping.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Grodzinsky, Ewa
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Elevated levels of CRP and IL-8 are related to reduce survival time: 1-year follow-up measurements of different analytes in frail elderly nursing home residents2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 5, p. 288-292Article in journal (Refereed)
    Abstract [en]

    There are only few studies with specific focus on predictors of survival in nursing home residents (NHRs). The aim was to study whether 1-year changes in complete blood count (including hemoglobin, red blood cells, erythrocyte volume fraction, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cells count and platelet count), C-reactive protein and interleukin-1 beta (IL-1 beta), IL-1Ra, IL-6, IL-8 and IL-10, are associated with 8-year survival in elderly NHRs, aged amp;gt;= 80 years. Complete blood count, C-reactive protein and interleukins were measured at baseline, after 6 and 12 months from 167 NHRs aged 80-101 years, mean age 88 +/- 4.5 years, 75% of whom were women. Dates of death were collected from the National Death Register 8 years after baseline. Levels of hemoglobin, red blood cells and mean corpuscular hemoglobin concentration were lower after 1-year, but higher for mean corpuscular volume and IL-1 beta, compared to baseline or 6 month follow-up. In the Cox regression model with a time-dependent covariate, raised levels of C-reactive protein and IL-8 were associated with reduced survival time. Elevated levels of C-reactive protein and IL-8 during 1-year follow-up were related to reduce lengths of survival in elderly NHRs.

  • 211.
    Edén, Desireé
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Mokhtari, Dariush
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Tissue factor/factor VIIA signaling promotes cytokine-induced beta cell death and impairs glucose stimulated insulin secretion from human pancreatic islets2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 465-465, article id PO563-MONArticle in journal (Other academic)
  • 212. Eissler, N.
    et al.
    Mao, Y.
    Brodin, D.
    Reuterswärd, Philippa
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Svahn Andersson, Helene
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Johnsen, J. I.
    Kiessling, R.
    Kogner, P.
    Combination Therapy of Anti-PD-1 Antibody and CSF-1R Inhibitor Reverses Induction of Suppressive Myeloid Cells and Controls Spontaneous Neuroblastoma Progression2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, p. S28-S28Article in journal (Refereed)
  • 213.
    Ekberg, Sara
    et al.
    Karolinska Inst, Div Clin Epidemiol, Dept Medicin Solna, Stockholm, Sweden.
    Jerkeman, Mats
    Lund Univ, Inst Clin Sci, Dept Pathol & Oncol, Lund, Sweden.
    Andersson, Per-Ola
    Gothenburg Univ, Boras & Sahlgrenska Acad, South Alvsborg Hosp, Dept Hematol, Gothenburg, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wahlin, Bjoern E.
    Karolinska Inst, Div Hematol, Deparment Med Huddinge, Stockholm, Sweden.
    Hasselblom, Sverker
    Deparment Res Dev & Educ, Halmstad, Sweden.
    Andersson, Therese M.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Eloranta, Sandra
    Karolinska Inst, Div Clin Epidemiol, Dept Medicin Solna, Stockholm, Sweden.
    Smedby, Karin E.
    Karolinska Univ Hosp, Ctr Hematol, Solna, Sweden;Karolinska Inst, Div Clin Epidemiol, Dept Medicin Solna, Stockholm, Sweden.
    Long-term survival and loss in expectancy of life in a population-based cohort of 7114 patients with diffuse large B-cell lymphoma2018In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 93, no 8, p. 1020-1028Article in journal (Refereed)
    Abstract [en]

    Survival has improved among patients with diffuse large B-cell lymphoma (DLBCL) with the addition of anti-CD20 antibody therapy. We aimed to quantify trends and remaining loss in expectation of life (LEL) due to DLBCL at a national population-based level. Patients diagnosed with DLBCL 2000-2013 (N=7114) were identified through the Swedish Lymphoma Registry and classified according to the age-adjusted International Prognostic Index (aaIPI). The novel measure LEL is the difference between remaining life years among patients and the general population and was predicted using flexible parametric models from diagnosis and among 2-year survivors, by age and sex. Median age at DLBCL-diagnosis was 70 (18-105) years and 54.8% presented with stage III-IV disease. On average, LEL due to DLBCL decreased from 8.0 (95% CI: 7.7-8.3) to 4.6 (95% CI: 4.5-4.6) years over the study period. By risk group, LEL was most reduced among patients with aaIPI >= 2 aged 50-60 years. However, these patients were still estimated to lose >8 years in 2013 (eg, LELmales50years 8.6 years (95% CI: 5.0-12.3)). Among 2-year survivors, LEL was reduced from 6.1 years (95% CI: 5.6-6.5) (aaIPI >= 2) and 3.8 years (95% CI: 3.6-4.1) (aaIPI<2) to 1.1 (95% CI: 1.1-1.2) and 1.0 year (95% CI: 0.8-1.1), respectively. The reduction was observed across all ages. Results for females were similar. By using LEL we illustrate the improvement of DLBCL survival over time. Despite adequate immunochemotherapy, substantial LEL among patients with IPI >= 2 points to remaining unmet medical needs. We speculate that observed reduced losses among 2-year survivors indicate a reduction of late relapses.

  • 214.
    Eketorp Sylvan, Sandra
    et al.
    Karolinska Inst, Sweden.
    Asklid, Anna
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Johansson, Hemming
    Karolinska Inst, Sweden.
    Klintman, Jenny
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    Bjellvi, Jenny
    Sahlgrens Univ Hosp, Sweden.
    Tolvgard, Staffan
    Ostersunds Hosp, Sweden.
    Kimby, Eva
    Karolinska Inst, Sweden.
    Norin, Stefan
    Karolinska Inst, Sweden.
    Andersson, Per-Ola
    South Alvsborg Hosp, Sweden.
    Karlsson, Claes
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Karlsson, Karin
    Skane Univ Hosp, Sweden.
    Lauri, Birgitta
    Sunderby Hosp, Sweden.
    Mattsson, Mattias
    Uppsala Univ Hosp, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Strandberg, Maria
    Sundsvall Hosp, Sweden.
    Osterborg, Anders
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hansson, Lotta
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    FFirst-line therapy in chronic lymphocytic leukemia: a Swedish nation-wide real-world study on 1053 consecutive patients treated between 2007 and 20132019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 4, p. 797-805Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate long-term outcome following first-line therapy in consecutive chronic lymphocytic leukemia (CLL) patients in a well-defined geographic area: Sweden. All patients diagnosed with CLL (2007-2013) (n=3672) were identified from national registries, screening of patient files identified all (100%) treated first line (n=1053) and for those, an in-depth analysis was performed. End points were overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Median age was 71 years; 53% had Rai stage III-IV and 97% had performance status grade 0-2. Fluorescence in situ hybridization (FISH) was performed in 57% of patients: 15% had del(17p). Chlorambucil + prednisone was used in 39% (5% also received rituximab). Fludarabine+cyclophosphamide+rituximab or fludarabine+cyclophosphamide was used in 43% and bendamustine + rituximab in 6%. Overall response rate was 64%; chlorambucil 43%, fludarabine+cyclophosphamide+rituximab 84%, fludarabine+cyclophosphamide 75% and bendamustine + rituximab 75%. Median PFS and OS was 24 and 58 months, respectively, both were significantly associated (multivariate analysis) with type of treatment, del(17p), performance status, gender, age and geographical region (OS only). Chlorambucil-treated patients had a median PFS and OS of only 9 and 33 months, respectively. Chlorambucil usage declined gradually throughout the study period, but one-third of patients still received chlorambucil + rituximab in 2013. Infections amp;gt;= grade III were significantly associated with treatment; chlorambucil 19% versus fludarabine+cyclophosphamide+rituximab 30%. Richter transformation occurred in 5.5% of the patients, equally distributed across therapies. This is the largest retrospective, real-world cohort of consecutive first-line treated CLL patients with a complete follow up. In elderly patients, an unmet need for more effective, well-tolerated therapies was identified.

  • 215.
    Eklöf, Motzi
    Linnaeus University, Faculty of Health and Life Sciences, Department of Health and Caring Sciences.
    En blodig historia: Recension av boken: Blodflöden: Blodgivning och blodtransfusion i det svenska samhället Bokens författare: Boel BernerLund: Arkiv förlag, 2012 (Open Access)2013In: Socialmedicinsk Tidskrift, ISSN 0037-833X, Vol. 90, no 3, p. 468-470Article, book review (Other academic)
  • 216.
    Ekstrand, C.
    et al.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Linder, M.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, H.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Bahmanyar, S.
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Solna, Sweden..
    Increased susceptibility to infections before the diagnosis of immune thrombocytopenia2016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 4, p. 807-814Article in journal (Refereed)
    Abstract [en]

    Background Infections after diagnosis of primary chronic immune thrombocytopenia (cITP) have mostly been connected to the immunomodulation treatment. Infections may trigger autoimmune diseases and may be a complication of an already impaired immune system. Objectives To investigate the association of cITP with infection before diagnosis. We also estimated the incidence of cITP based on the new definition by the International ITP Working Group. Methods We identified 1087 adults with primary cITP between 2006 and 2012 using the Swedish Patient Register. Data on infections not already associated with secondary ITP were also retrieved from the register. The standardized incidence ratios (SIRs), using the rates from the general population, and 95% confidence intervals (CIs) were estimated as a measure of relative risk. We used data from the Prescribed Drug Register to estimate SIR for anti-infective treatment. Results The incidence of cITP was 2.30 per 100 000 person-years (95% CI, 2.15-2.45). cITP was associated with an increased risk of serious infections requiring inpatient or outpatient care within 5 years before cITP diagnosis (SIR = 8.74; 95% CI, 7.47-10.18). Higher magnitude SIRs were observed for candidiasis, viral infection at an unspecified site and acute upper respiratory infections. For anti-infective drugs the SIR was 1.37 (1.25-1.50) and the highest SIRs were observed for amoxicillin, macrolides, nitrofurantoin and antivirals. Conclusion Patients with cITP have increased risks of infection and anti-infective treatments before their cITP diagnosis, with a more marked risk for candidiasis and viral infections. The findings indicate that infection is not only related to the immunomodulation treatment but also to the disease itself.

  • 217.
    Ekstrand, Charlotta
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Linder, Marie
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Increased Anti-infective Treatments Preceding a Diagnosis of Primary Immune Thrombocytopenia2015In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 24, p. 411-412Article in journal (Other academic)
  • 218.
    Ekstrand, Charlotta
    et al.
    Karolinska Inst, Med, Stockholm, Sweden..
    Linder, Marie
    Karolinska Inst, Med, Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Med, Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Med, Stockholm, Sweden..
    Susceptibility to Infection before Diagnosis of Primary Chronic Immune Thrombocytopenia2015In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 24, p. 519-519Article in journal (Other academic)
  • 219.
    El Missiry, M.
    et al.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Hjorth-Hansen, H.
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Canc Res & Mol Med, Trondheim, Norway..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, L.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Porkka, K.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Kreutzmann, A.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Mustjoki, S.
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland..
    Assessment Of Therapy Response In Chronic Myeloid Leukemia Via 1 Month Bcr-Abl1 Transcript Decline2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 63-63Article in journal (Other academic)
  • 220.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit, Helsinki, Finland..
    Adnan, Shady
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Rajala, Hanna
    Univ Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, HRUH, Helsinki, Finland..
    Al-Samadi, Ahmed
    Univ Helsinki, Inst Clin Med, Helsinki, Finland..
    Ekblom, Marja
    Skane Univ Hosp, Lund, Sweden..
    Markevan, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Astrand-Grundstrom, Ingbritt
    Skane Univ Hosp, Lund, Sweden..
    Wold, Maren
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Juhl, Birgitte Ravn
    Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark..
    Bjerrum, Ole Weis
    Univ Copenhagen Hosp, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Haulin, Inger
    Akademiska sjukhuset, Uppsala..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland..
    Bone Marrow Lymphocytic Status during Tyrosine Kinase Inhibitor Therapy and Its Relation to Therapy Response in Chronic Phase Chronic Myeloid Leukemia Patients2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 221.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit, Helsinki, Finland..
    Adnan, Shady
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Rajala, Hanna
    Univ Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, HRUH, Helsinki, Finland..
    Al-Samadi, Ahmed
    Univ Helsinki, Inst Clin Med, Helsinki, Finland..
    Ekblom, Marja
    Skane Univ Hosp, Lund, Sweden..
    Markevan, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Astrand-Grundstrom, Ingbritt
    Skane Univ Hosp, Lund, Sweden..
    Wold, Maren
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Juhl, Birgitte Ravn
    Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark..
    Bjerrum, Ole Weis
    Univ Copenhagen Hosp, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Haulin, Inger
    Univ Uppsala Hosp, Dept Pathol, S-75185 Uppsala, Sweden..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland..
    Bone Marrow Lymphocytic Status during Tyrosine Kinase Inhibitor Therapy and Its Relation to Therapy Response in Chronic Phase Chronic Myeloid Leukemia Patients2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 222.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Canc Res & Mol Med, Trondheim, Norway..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Kreutzman, Anna
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland..
    Early BCR-ABL1 Transcript Decline after 1 Month of Tyrosine Kinase Inhibitor Therapy as an Indicator for Treatment Response in Chronic Myeloid Leukemia2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0171041Article in journal (Refereed)
    Abstract [en]

    In chronic myeloid leukemia (CML), early treatment prediction is important to identify patients with inferior overall outcomes. We examined the feasibility of using reductions in BCR-ABL1 transcript levels after 1 month of tyrosine kinase inhibitor (TKI) treatment to predict therapy response. Fifty-two first-line TKI-treated CML patients were included (imatinib n = 26, dasatinib n = 21, nilotinib n = 5), and BCR-ABL1 transcript levels were measured at diagnosis (dg) and 1, 3, 6, 12, 18, 24, and 36 months. The fold change of the BCR-ABL1 transcripts at 1 month compared to initial BCR-ABL1 transcript levels was used to indicate early therapy response. In our cohort, 21% of patients had no decrease in BCR-ABL1 transcript levels after 1 month and were classified as poor responders. Surprisingly, these patients had lower BCR-ABL1 transcript levels at dg compared to responders (31% vs. 48%, p = 0.0083). Poor responders also significantly more often had enlarged spleen (55% vs. 15%; p< 0.01) and a higher percentage of Ph+ CD34+CD38- cells in the bone marrow (91% vs. 75%, p< 0.05). The major molecular response rates were inferior in the poor responders (at 12m 18% vs. 64%, p< 0.01; 18m 27% vs. 75%, p< 0.01; 24m 55% vs. 87%, p< 0.01). In conclusion, early treatment response analysis defines a biologically distinct patient subgroup with inferior long-term outcomes.

  • 223.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Live and Let Die: Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The hematopoietic stem cell (HSC) is characterized by its ability to self-renew and produce all mature blood cells throughout the life of an organism. This is tightly regulated to maintain a balance between survival, proliferation, and differentiation. The HSCs are located in specialized niches in the bone marrow thought to be low in oxygen, which is suggested to be involved in the regulation of HSC maintenance, proliferation, and migration. However, the importance of hypoxia in the stem cell niche and the molecular mechanisms involved remain fairly undefined. Another important regulator of human HSCs maintenance is the tyrosine kinase receptor FLT3, which triggers survival of HSCs and progenitor cells. Mutations in FLT3 cause constitutively active signaling. This leads to uncontrolled survival and proliferation, which can result in development of acute myeloid leukemia (AML). One of the purposes with this thesis is to investigate how survival, proliferation and self-renewal in normal HSCs are affected by hypoxia. To study this, we used both in vitro and in vivo models with isolated Lineage-Sca-1+Kit+ (LSK) and CD34-Flt3-LSK cells from mouse bone marrow. We found that hypoxia maintained an immature phenotype. In addition, hypoxia decreased proliferation and induced cell cycle arrest, which is the signature of HSCs with long term multipotential capacity. A dormant state of HSCs is suggested to be critical for protecting and preventing depletion of the stem cell pool. Furthermore, we observed that hypoxia rescues HSCs from oxidative stress-induced cell death, implicating that hypoxia is important in the bone marrow niche to limit reactive oxidative species (ROS) production and give life-long protection of HSCs. Another focus in this thesis is to investigate downstream pathways involved in tyrosine kinase inhibitor-induced cell death of primary AML cells and cell lines expressing mutated FLT3. Our results demonstrate an important role of the PI3K/AKT pathway to mediate survival signals from FLT3. We found FoxO3a and its target gene Bim to be key players of apoptosis in cells carrying oncogenic FLT3 after treatment with tyrosine kinase inhibitors. In conclusion, this thesis highlights hypoxic-mediated regulation of normal HSCs maintenance and critical effectors of apoptosis in leukemic cells expressing mutated FLT3.

  • 224.
    El-Jawahri, Areej
    et al.
    Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Chen, Yi-Bin
    Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Brazauskas, Ruta
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA.;Med Coll Wisconsin, Milwaukee, WI 53226 USA..
    He, Naya
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Lee, Stephanie J.
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA..
    Knight, Jennifer M.
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Majhail, Navneet
    Cleveland Clin, Cleveland, OH 44106 USA..
    Buchbinder, David
    Childrens Hosp Orange Cty, Orange, CA USA..
    Schears, Raquel M.
    Brandeis Univ, Waltham, MA USA..
    Wirk, Baldeep M.
    Seattle Canc Care Alliance, Seattle, WA USA..
    Wood, William A.
    Univ N Carolina, Chapel Hill, NC USA..
    Ahmed, Ibrahim
    Childrens Mercy Hosp & Clin, Kansas City, MO USA..
    Aljurf, Mahmoud
    King Faisal Specialist Hosp & Res Ctr, Riyadh, Saudi Arabia..
    Szer, Jeff
    Royal Melbourne Hosp, Parkville, Vic, Australia..
    Beattie, Sara M.
    Univ Ottawa, Ottawa, ON, Canada..
    Battiwalla, Minoo
    NHLBI, Bldg 10, Bethesda, MD 20892 USA..
    Dandoy, Christopher
    Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA..
    Diaz, Miguel-Angel
    Hosp Infantil Univ Nino Jesus, Madrid, Spain..
    D'Souza, Anita
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Freytes, Cesar O.
    Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA..
    Gajewski, James
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Gergis, Usama
    New York Presbyterian Hosp, New York, NY USA..
    Hashmi, Shahrukh K.
    Brandeis Univ, Waltham, MA USA..
    Jakubowski, Ann
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Kamble, Rammurti T.
    Baylor Coll Med, Houston, TX 77030 USA..
    Kindwall-Keller, Tamila
    Univ Virginia Hlth Syst, Charlottesville, VA USA..
    Lazarus, Hilard M.
    Seidman Canc Ctr, Cleveland, OH USA..
    Malone, Adriana K.
    Tisch Canc Inst, New York, NY USA..
    Marks, David I.
    Univ Hosp Bristol NHS Trust, Bristol, Avon, England..
    Meehan, Kenneth
    Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA..
    Savani, Bipin N.
    Vanderbilt Univ, Med Ctr, Nashville, TN USA..
    Olsson, Richard F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Stockholm, Sweden..
    Rizzieri, David
    Duke Univ, Durham, NC USA..
    Steinberg, Amir
    Mt Sinai Hosp, New York, NY 10029 USA..
    Speckhart, Dawn
    Northside Hosp, Atlanta, GA USA..
    Szwajcer, David
    Univ Manitoba, Winnipeg, MB, Canada..
    Schoemans, Helene
    Univ Hosp Leuven, Leuven, Belgium..
    Seo, Sachiko
    East Hosp, Kashiwa, Chiba, Japan..
    Ustun, Celalettin
    Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA..
    Atsuta, Yoshiko
    Japanese Data Ctr Hematopoiet Cell Transplantat, Nagoya, Aichi, Japan.;Nagoya Univ, Grad Sch Med, Nagoya, Aichi, Japan..
    Dalal, Jignesh
    Childrens Mercy Hosp & Clin, Kansas City, MO USA..
    Sales-Bonfim, Carmem
    Univ Fed Parana, Hosp Clin, Curitiba, Parana, Brazil..
    Khera, Nandita
    Mayo Clin, Phoenix, AZ USA..
    Hahn, Theresa
    Roswell Pk Canc Inst, Buffalo, NY 14263 USA..
    Saber, Wael
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Impact of pre-transplant depression on outcomes of allogeneic and autologous hematopoietic stem cell transplantation2017In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 123, no 10, p. 1828-1838Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post-transplantation.

    METHODS: We analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n=3786) or allogeneic (n=7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre-HCT depression requiring treatment versus those without pre-HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post-HCT using Poisson models. We also compared the incidence of grade 2-4 acute and chronic graft-versus-host disease (GVHD) in allogeneic HCT.

    RESULTS: The study included 1116 (15%) patients with pre-transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre-transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04-1.23; P=0.004) and a higher incidence of grade 2-4 acute GVHD (HR, 1.25; 95% CI, 1.14-1.37; P<0.0001), but similar incidence of chronic GVHD. Pre-transplant depression was associated with fewer days-alive-and-out-of-the hospital (means ratio [MR]=0.97; 95% CI, 0.95-0.99; P=0.004). There were 512 (13.5%) patients with Pre-transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre-transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98-1.34; P=0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97-0.99; P=0.002).

    CONCLUSION: Pre-transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre-transplant depression represent a population that is at risk for post-transplant complications.

  • 225.
    Eloranta, Sandra
    et al.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Brånvall, Elsa
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Celsing, Fredrik
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden..
    Papworth, Karin
    Norrlands Univ Hosp, Dept Oncol, Umea, Sweden..
    Ljungqvist, Maria
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ekström-Smedby, Karin
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden..
    Increasing incidence of primary central nervous system lymphoma but no improvement in survival in Sweden 2000-20132018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 1, p. 61-68Article in journal (Refereed)
    Abstract [en]

    Objectives: This study aims to characterize the epidemiology of immunocompetent Primary central nervous system lymphoma (PCNSL) diagnosed 2000-2013 in Sweden.

    Methods: Cases were identified in the population-based Swedish Lymphoma Register. Incidence per 100000 person-years and 95% confidence intervals (CI) were calculated, and PCNSL-specific survival was estimated using relative survival. Tests for temporal trends were performed using Poisson regression. Population incidence of all brain tumors was retrieved for comparison.

    Results: With 359 identified PCNSL cases (median age 66years), overall incidence was 0.26 (95% CI: 0.24-0.29) and the average annual increase 4% (P=.002). The increasing trend was primarily observed among elderly individuals (70+years). Similarly, an increase in incidence of all brain tumors was noted only among the elderly. There was no significant improvement in relative survival across the study period although, among fit patients (with Eastern Cooperative Oncology Group, EGOC 0), survival plateaued 6years after diagnosis.

    Conclusion: The increasing PCNSL incidence in the elderly was consistent with an increasing incidence of brain tumors of any type and may in part be attributable to improved diagnostics and reporting in this group. New treatment options have not yet translated into general survival improvements in a population-based setting, although the presence of long-term survivors among fit patients is encouraging.

  • 226.
    Enblad, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Karlsson, Hannah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gammelgård, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lövgren, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wikstrom, Kristina I.
    Karolinska Univ Hosp Huddinge, VECURA, Stockholm, Sweden.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Savoldo, Barbara
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dotti, Gianpietro
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Brenner, Malcolm K.
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia2018In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, no 24, p. 6185-6194Article in journal (Refereed)
    Abstract [en]

    Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19(+) B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy.

    Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array.

    Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14(+)CD33(+)HLA(-)DR(-)) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2.

    Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.

  • 227.
    Enblad, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Karlsson, Hannah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wikström, Kristina
    Karolinska Univ Hosp, VECURA, Stockholm, Sweden..
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Savoldo, Barbara
    Baylor Collage Med, Ctr Cell & Gene Therapy, Houston, TX USA..
    Brenner, Malcolm K.
    Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.;Houston Methodist Hosp, Houston, TX USA..
    Dotti, Gianpietro
    Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.;Houston Methodist Hosp, Houston, TX USA..
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Third Generation CD19-CAR T Cells for Relapsed and Refractory Lymphoma and Leukemia Report from the Swedish Phase I/IIa Trial2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 228.
    Engan, Harald K.
    et al.
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Ecotechnology and Sustainable Building Engineering. LHL Health Röros, Norwegian Heart and Lung Patient Organization, Oslo, Norway.
    Lodin-Sundström, Angelica
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Ecotechnology and Sustainable Building Engineering.
    Schagatay, Fanny
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Ecotechnology and Sustainable Building Engineering.
    Schagatay, Erika
    Mid Sweden University, Faculty of Human Sciences, Department of Health Sciences.
    The effect of climbing mount everest on spleen contraction and increase in hemoglobin concentration during breath holding and exercise2014In: High Altitude Medicine & Biology, ISSN 1527-0297, E-ISSN 1557-8682, Vol. 15, no 1, p. 52-57Article in journal (Refereed)
    Abstract [en]

    Release of stored red blood cells resulting from spleen contraction improves human performance in various hypoxic situations. This study determined spleen volume resulting from two contraction-evoking stimuli: breath holding and exercise before and after altitude acclimatization during a Mount Everest ascent (8848m). Eight climbers performed the following protocol before and after the climb: 5min ambient air respiration at 1370m during rest, 20min oxygen respiration, 20min ambient air respiration at 1370m, three maximal-effort breath holds spaced by 2min, 10min ambient air respiration, 5min of cycling at 100 W, and finally 10min ambient air respiration. We measured spleen volume by ultrasound and capillary hemoglobin (HB) concentration after each exposure, and heart rate (HR) and arterial oxygen saturation (Sao2) continuously. Mean (SD) baseline spleen volume was unchanged at 213 (101) mL before and 206 (52) mL after the climb. Before the climb, spleen volume was reduced to 184 (83) mL after three breath holds, and after the climb three breath holds resulted in a spleen volume of 132 (26) mL (p=0.032). After exercise, the preclimb spleen volume was 186 (89) mL vs. 112 (389) mL) after the climb (p=0.003). Breath hold duration and cardiovascular responses were unchanged after the climb. We concluded that spleen contraction may be enhanced by altitude acclimatization, probably reflecting both the acclimatization to chronic hypoxic exposure and acute hypoxia during physical work. © Copyright 2014, Mary Ann Liebert, Inc. 2014.

  • 229. 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, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    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, p. 115-208Article 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.

  • 230.
    Engert, Andreas
    et al.
    University of Cologne, Germany.
    Balduini, Carlo
    IRCCS Policlin San Matteo Fdn, Italy.
    Brand, Anneke
    Leids University, Netherlands.
    Coiffier, Bertrand
    University of Lyon 1, France.
    Cordonnier, Catherine
    Hop University of Henri Mondor, France.
    Doehner, Hartmut
    University of Klinikum Ulm, Germany.
    Duyvene de Wit, Thom
    European Hematol Assoc, Netherlands.
    Eichinger, Sabine
    Medical University of Wien, Austria.
    Fibbe, Willem
    Leids University, Netherlands.
    Green, Tony
    Cambridge Institute Medical Research, England.
    de Haas, Fleur
    European Hematol Assoc, Netherlands.
    Iolascon, Achille
    University of Naples Federico II, Italy.
    Jaffredo, Thierry
    University of Paris 06, France.
    Rodeghiero, Francesco
    Osped San Bortolo, Italy.
    Salles, Gilles
    University of Lyon, France.
    Jacob Schuringa, Jan
    University of Groningen, Netherlands.
    Andre, Marc
    Catholic University of Louvain, Belgium.
    Andre-Schmutz, Isabelle
    University of Paris 05, France.
    Bacigalupo, Andrea
    Osped San Martino Genova, Italy.
    Bochud, Pierre-Yves
    University of Lausanne, Switzerland.
    den Boer, Monique
    Erasmus MC, Netherlands.
    Bonini, Chiara
    University of Milan, Italy.
    Camaschella, Clara
    San Raffaele Institute, Italy.
    Cant, Andrew
    Great North Childrens Hospital, England.
    Domenica Cappellini, Maria
    University of Milan, Italy.
    Cazzola, Mario
    University of Pavia, Italy.
    Lo Celso, Cristina
    Imperial Coll London, England.
    Dimopoulos, Meletios
    University of Athens, Greece.
    Douay, Luc
    University of Paris 06, France.
    Dzierzak, Elaine
    University of Edinburgh, Scotland.
    Einsele, Hermann
    University of Wurzburg, Germany.
    Ferreri, Andres
    Ist Science San Raffaele, Italy.
    De Franceschi, Lucia
    University of Verona, Italy.
    Gaulard, Philippe
    Hop Henri Mondor, France.
    Gottgens, Berthold
    University of Cambridge, England.
    Greinacher, Andreas
    University of Medical Greifswald, Germany; Ernst Moritz Arndt University of Greifswald, Germany.
    Gresele, Paolo
    University of Perugia, Italy.
    Gribben, John
    Queen Mary University of London, England.
    de Haan, Gerald
    University of Groningen, Netherlands.
    Hansen, John-Bjarne
    University of Tromso, Norway.
    Hochhaus, Andreas
    University of Klinikum Jena, Germany.
    Kadir, Rezan
    Royal Free Hospital, England.
    Kaveri, Srini
    Institute National Sante and Rech Med, France.
    Kouskoff, Valerie
    University of Manchester, England.
    Kuehne, Thomas
    University of Kinderspital Beider Basel, Switzerland.
    Kyrle, Paul
    Medical University of Wien, Austria.
    Ljungman, Per
    Karolinska Institute, Sweden.
    Maschmeyer, Georg
    Klinikum Ernst Von Bergmann, Germany.
    Mendez-Ferrer, Simon
    University of Cambridge, England.
    Milsom, Michael
    Deutsch Krebsforschungszentrum Neuenheimer Feld, Germany.
    Mummery, Christine
    Leids University, Netherlands.
    Ossenkoppele, Gert
    Vrije University of Amsterdam Medical Centre, Netherlands.
    Pecci, Alessandro
    University of Pavia, Italy.
    Peyvandi, Flora
    University of Milan, Italy.
    Philipsen, Sjaak
    Erasmus MC, Netherlands.
    Reitsma, Pieter
    Leids University, Netherlands.
    Maria Ribera, Jose
    Institute Catala Oncol, Spain.
    Risitano, Antonio
    University of Naples Federico II, Italy.
    Rivella, Stefano
    Weill Medical Coll, NY USA.
    Ruf, Wolfram
    Johannes Gutenberg University of Mainz, Germany.
    Schroeder, Timm
    Swiss Federal Institute Technology, Switzerland.
    Scully, Marie
    University of Coll London Hospital, England.
    Socie, Gerard
    Hop St Louis, France.
    Staal, Frank
    Leids University, Netherlands.
    Stanworth, Simon
    John Radcliffe Hospital, England.
    Stauder, Reinhard
    Medical University of Innsbruck, Austria.
    Stilgenbauer, Stephan
    University of Klinikum Ulm, Germany.
    Tamary, Hannah
    Schneider Childrens Medical Centre Israel, Israel.
    Theilgaard-Monch, Kim
    University of Copenhagen, Denmark.
    Lay Thein, Swee
    Kings Coll London, England.
    Tilly, Herve
    University of Rouen, France.
    Trneny, Marek
    Charles University of Prague, Czech Republic.
    Vainchenker, William
    Institute Gustave Roussy, France.
    Maria Vannucchi, Alessandro
    University of Florence, Italy.
    Viscoli, Claudio
    University of Genoa, Italy.
    Vrielink, Hans
    Sanquin Research, Netherlands.
    Zaaijer, Hans
    Sanquin Research, Netherlands.
    Zanella, Alberto
    Osped Maggiore Policlin, Italy.
    Zolla, Lello
    University of Tuscia, Italy.
    Jan Zwaginga, Jaap
    Leids University, Netherlands.
    Aguilar Martinez, Patricia
    Hop St Eloi, France.
    van den Akker, Emile
    Sanquin Research, Netherlands.
    Allard, Shubha
    Barts Health NHS Trust and NHS Blood and Transplant, England.
    Anagnou, Nicholas
    University of Athens, Greece.
    Andolfo, Immacolata
    University of Naples Federico II, Italy.
    Andrau, Jean-Christophe
    Institute Genet Molecular Montpellier, France.
    Angelucci, Emanuele
    Osp A Businco, Italy.
    Anstee, David
    NHSBT Blood Centre, England.
    Aurer, Igor
    University of Zagreb, Croatia.
    Avet-Loiseau, Herve
    Centre Hospital University of Toulouse, France.
    Aydinok, Yesim
    Ege University, Turkey.
    Bakchoul, Tamam
    University of Medical Greifswald, Germany.
    Balduini, Alessandra
    IRCCS Policlin San Matteo Fdn, Italy.
    Barcellini, Wilma
    Osped Maggiore Policlin, Italy.
    Baruch, Dominique
    University of Paris 05, France.
    Baruchel, Andre
    Hop University of Robert Dabre, France.
    Bayry, Jagadeesh
    Institute National Sante and Rech Med, France.
    Bento, Celeste
    Centre Hospital and University of Coimbra, Portugal.
    van den Berg, Anke
    University of Groningen, Netherlands.
    Bernardi, Rosa
    Ist Science San Raffaele, Italy.
    Bianchi, Paola
    Osped Maggiore Policlin, Italy.
    Bigas, Anna
    Institute Hospital del Mar Investgac Med, Spain.
    Biondi, Andrea
    University of Milano Bicocca, Italy.
    Bohonek, Milos
    Central Mil Hospital, Czech Republic.
    Bonnet, Dominique
    Francis Crick Institute, England.
    Borchmann, Peter
    University Hospital Cologne Int, Germany.
    Borregaard, Niels
    University of Copenhagen, Denmark.
    Braekkan, Sigrid
    University of Tromso, Norway.
    van den Brink, Marcel
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Brodin, Ellen
    University of Sykehuset Nordic Norge, Norway.
    Bullinger, Lars
    University of Klin Ulm, Germany.
    Buske, Christian
    University of Klinikum Ulm, Germany.
    Butzeck, Barbara
    European Federat Assoc Patients Haemochromatosis, France.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Campo, Elias
    University of Barcelona, Spain.
    Carbone, Antonino
    Centre Riferimento Oncol, Italy.
    Cervantes, Francisco
    University of Barcelona, Spain.
    Cesaro, Simone
    Policlin GB Rossi, Italy.
    Charbord, Pierre
    University of Paris 06, France.
    Claas, Frans
    Leids University, Netherlands.
    Cohen, Hannah
    Imperial Coll London, England.
    Conard, Jacqueline
    Hop Hotel Dieu, France.
    Coppo, Paul
    Hop St Antoine, France.
    Vives Corrons, Joan-Lluis
    University of Barcelona, Spain.
    da Costa, Lydie
    Hop Robert Debre, France.
    Davi, Frederic
    University of Paris 06, France.
    Delwel, Ruud
    Erasmus MC, Netherlands.
    Dianzani, Irma
    University of Turin, Italy.
    Domanovic, Dragoslav
    European Centre Disease Prevent and Control, Sweden.
    Donnelly, Peter
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Dovc Drnovsek, Tadeja
    Zavod RS Transfuzijsko Med, Slovenia.
    Dreyling, Martin
    University of Munich, Germany.
    Du, Ming-Qing
    University of Cambridge, England.
    Dufour, Carlo
    Ist Giannina Gaslini, Italy.
    Durand, Charles
    University of Paris 06, France.
    Efremov, Dimitar
    Int Centre Genet Engn and Biotechnol, Italy.
    Eleftheriou, Androulla
    Thalassaemia Int Fed, Cyprus.
    Elion, Jacques
    University of Paris Diderot, France.
    Emonts, Marieke
    Great North Childrens Hospital, England.
    Engelhardt, Monika
    University of Klinikum Freiburg, Germany.
    Ezine, Sophie
    University of Paris 05, France.
    Falkenburg, Fred
    Leids University, Netherlands.
    Favier, Remi
    Hop Enfants A Trousseau, France.
    Federico, Massimo
    University of Modena and Reggio Emilia, Italy.
    Fenaux, Pierre
    Hop St Louis, France.
    Fitzgibbon, Jude
    Queen Mary University of London, England.
    Flygare, Johan
    Lund University, Sweden.
    Foa, Robin
    University of Roma La Sapienza, Italy.
    Forrester, Lesley
    University of Edinburgh, Scotland.
    Galacteros, Frederic
    Hop University of Henri Mondor, France.
    Garagiola, Isabella
    University of Milan, Italy.
    Gardiner, Chris
    University of Oxford, England.
    Garraud, Olivier
    University of St Etienne, France.
    van Geet, Christel
    Katholieke University of Leuven, Belgium.
    Geiger, Hartmut
    University of Klinikum Ulm, Germany.
    Geissler, Jan
    CML Advocates Network, Switzerland.
    Germing, Ulrich
    University of Klinikum Dusseldorf, Germany.
    Ghevaert, Cedric
    University of Cambridge, England.
    Girelli, Domenico
    Institute Cochin, France.
    Godeau, Bertrand
    Hop University of Henri Mondor, France.
    Goekbuget, Nicola
    University of Klinikum Frankfurt, Germany.
    Goldschmidt, Hartmut
    University of Klinikum Heidelberg, Germany.
    Goodeve, Anne
    University of Sheffield, England.
    Graf, Thomas
    Centre Genom Regulat, Spain.
    Graziadei, Giovanna
    University of Milan, Italy.
    Griesshammer, Martin
    Muhlenkreisklin, Germany.
    Gruel, Yves
    Hop Trousseau, France.
    Guilhot, Francois
    University of Poitiers, France.
    von Gunten, Stephan
    University of Bern, Switzerland.
    Gyssens, Inge
    University of Hasselt, Belgium.
    Halter, Jorg
    University of Spital Basel, Switzerland.
    Harrison, Claire
    Guys and St Thomas, England.
    Harteveld, Cornelis
    Leids University, Netherlands.
    Hellstrom-Lindberg, Eva
    Karolinska Institute, Sweden.
    Hermine, Olivier
    University of Paris 05, France.
    Higgs, Douglas
    University of Oxford, England.
    Hillmen, Peter
    University of Leeds, England.
    Hirsch, Hans
    University of Basel, Switzerland.
    Hoskin, Peter
    Mt Vernon Hospital, England.
    Huls, Gerwin
    University of Groningen, Netherlands.
    Inati, Adlette
    Lebanese American University, Lebanon.
    Johnson, Peter
    University of Southampton, England.
    Kattamis, Antonis
    University of Athens, Greece.
    Kiefel, Volker
    University of Medical Rostock, Germany.
    Kleanthous, Marina
    Cyprus School Molecular Med, Cyprus.
    Klump, Hannes
    University of Klinikum Essen, Germany.
    Krause, Daniela
    Georg Speyer Haus Institute Tumorbiol and Expt Therapy, Germany.
    Kremer Hovinga, Johanna
    University of Bern, Switzerland.
    Lacaud, Georges
    University of Manchester, England.
    Lacroix-Desmazes, Sebastien
    Institute National Sante and Rech Med, France.
    Landman-Parker, Judith
    Hop Armand Trousseau, France.
    LeGouill, Steven
    University of Nantes, France.
    Lenz, Georg
    University of Klinikum Munster, Germany.
    von Lilienfeld-Toal, Marie
    University of Klinikum Jena, Germany.
    von Lindern, Marieke
    Sanquin Research, Netherlands.
    Lopez-Guillermo, Armando
    Hospital Clin Barcelona, Spain.
    Lopriore, Enrico
    Leiden University of Medical Centre, Netherlands.
    Lozano, Miguel
    University of Barcelona, Spain.
    MacIntyre, Elizabeth
    University of Paris 05, France.
    Makris, Michael
    Royal Hallamshire Hospital, England; University of Sheffield, England.
    Mannhalter, Christine
    Medical University of Wien, Austria.
    Martens, Joost
    Radboud University of Nijmegen, Netherlands.
    Mathas, Stephan
    Charite University of Medical Berlin, Germany.
    Matzdorff, Axel
    Caritasclin Saarbrucken, Germany.
    Medvinsky, Alexander
    University of Edinburgh, Scotland.
    Menendez, Pablo
    University of Barcelona, Spain.
    Rita Migliaccio, Anna
    Mt Sinai Hospital, NY 10029 USA.
    Miharada, Kenichi
    Lund University, Sweden.
    Mikulska, Malgorzata
    University of Genoa, Italy.
    Minard, Veronique
    Institute Gustave Roussy, France.
    Montalban, Carlos
    MD Anderson Cancer Centre Madrid, Spain.
    de Montalembert, Mariane
    Necker Enfants Malades University Hospital, France.
    Montserrat, Emili
    Hospital Clin Barcelona, Spain.
    Morange, Pierre-Emmanuel
    Aix Marseille University, France.
    Mountford, Joanne
    University of Glasgow, Scotland.
    Muckenthaler, Martina
    University of Klinikum Heidelberg, Germany.
    Mueller-Tidow, Carsten
    University of Klinikum Halle, Germany.
    Mumford, Andrew
    University of Bristol, England.
    Nadel, Bertrand
    University of Mediterranee, France.
    Navarro, Jose-Tomas
    Institute Catala Oncol, Spain.
    el Nemer, Wassim
    INSERM, France.
    Noizat-Pirenne, France
    Etab Francais Sang, France.
    OMahony, Brian
    European Haemophilia Consortium, Belgium.
    Oldenburg, Johannes
    University of Klinikum Bonn, Germany.
    Olsson, Martin
    Lund University, Sweden.
    Oostendorp, Robert
    Technical University of Munich, Germany.
    Palumbo, Antonio
    University of Turin, Italy.
    Passamonti, Francesco
    Osp Circolo and Fdn Macchi, Italy.
    Patient, Roger
    University of Oxford, England.
    Peffault de Latour, Regis
    NIH, MD 20892 USA.
    Pflumio, Francoise
    Institute Rech Radiobiol Cellulaire and Molecular IRCM, France.
    Pierelli, Luca
    University of Roma La Sapienza, Italy.
    Piga, Antonio
    University of Turin, Italy.
    Pollard, Debra
    Royal Free Hospital, England.
    Raaijmakers, Marc
    Erasmus MC, Netherlands.
    Radford, John
    University of Manchester, England.
    Rambach, Ralf
    DLH, Germany.
    Koneti Rao, A.
    Temple University of School Med, PA USA.
    Raslova, Hana
    University of Paris Sud, France.
    Rebulla, Paolo
    Ops Maggiore, Italy.
    Rees, David
    Kings Coll Hospital London, England.
    Ribrag, Vincent
    Institute Gustave Roussy, France.
    Rijneveld, Anita
    Erasmus MC, Netherlands.
    Rinalducci, Sara
    University of Tuscia, Italy.
    Robak, Tadeusz
    University of Medical Lodz, Poland.
    Roberts, Irene
    University of Oxford, England.
    Rodrigues, Charlene
    Great North Childrens Hospital, England.
    Rosendaal, Frits
    Leids University, Netherlands.
    Rosenwald, Andreas
    University of Wurzburg, Germany.
    Rule, Simon
    Derriford Hospital, England.
    Russo, Roberta
    University of Naples Federico II, Italy.
    Saglio, Guiseppe
    University of Turin, Italy.
    Sanchez, Mayka
    IJC, Spain.
    Scharf, Ruediger E.
    University of Dusseldorf, Germany.
    Schlenke, Peter
    Medical University of Graz, Austria.
    Semple, John
    St Michaels Hospital, Canada.
    Sierra, Jorge
    Hospital Santa Creu I Sant Pau, Spain.
    So-Osman, Cynthia
    Sanquin Research, Netherlands.
    Manuel Soria, Jose
    Hospital Santa Creu I Sant Pau, Spain.
    Stamatopoulos, Kostas
    Institute Appl Bioscience, Greece.
    Stegmayr, Bernd
    Umeå University, Sweden.
    Stunnenberg, Henk
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Swinkels, Dorine
    Radboud University of Nijmegen Medical Centre, Netherlands.
    Pedro Taborda Barata, Joao
    University of Lisbon, Portugal.
    Taghon, Tom
    University of Ghent, Belgium.
    Taher, Ali
    Amer University of Beirut Medical Centre, Lebanon.
    Terpos, Evangelos
    National and Kapodistrian University of Athes, Greece.
    Daniel Tissot, Jean
    University of Lausanne, Switzerland.
    Touw, Ivo
    Erasmus MC, Netherlands.
    Toye, Ash
    University of Bristol, England.
    Trappe, Ralf
    Charite University of Medical Berlin, Germany.
    Unal, Sule
    Hacettepe University, Turkey.
    Vaulont, Sophie
    Institute Cochin, France.
    Viprakasit, Vip
    Mahidol University, Thailand.
    Vitolo, Umberto
    University of Turin, Italy.
    van Wijk, Richard
    University of Medical Centre Utrecht, Netherlands.
    Wojtowicz, Agnieszka
    CHU Vaudois, Switzerland.
    Zeerleder, Sacha
    Sanquin Research, Netherlands.
    Zieger, Barbara
    University of Klinikum Freiburg, Germany.
    The European Hematology Association Roadmap for European Hematology Research: a consensus document2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, p. 115-208Article 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.

  • 231.
    Englund, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Rostgaard, K.
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen S, Denmark..
    Eloranta, S.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kuusk, T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Brown, P. de Nully
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Kamper, P.
    Aarhus Univ Hosp, Dept Haematol, Aarhus, Denmark..
    Smedby, K. E.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Hjalgrim, H.
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen S, Denmark..
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hjalgrim, L. Lyngsie
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen S, Denmark.;Rigshosp, Dept Paediat Haematol & Oncol, Child & Youth Clin, Copenhagen, Denmark..
    Hodgkin Lymphoma In Children, Adolescents And Young Adults-A Comparative Study Of Clinical Presentation And Treatment Outcome2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 36-36Article in journal (Other academic)
  • 232.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Studies of New Signal Transduction Modulators in Acute Myeloid Leukemia2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute myeloid leukemia (AML) is a life-threatening malignant disorder with dismal prognosis. AML is characterized by frequent genetic changes involving tyrosine kinases, normally acting as important mediators in many basic cellular processes. Due to the overexpression and frequent mutations of the FMS-like receptor tyrosine kinase 3 (FLT3) in AML, this tyrosine kinase receptor has become one of the most sought after targets in AML drug development.

    In this thesis, we have used a combination of high-throughput screens, direct target interaction assays and sequential cellular screens, including primary patient samples, as an approach to discover new targeted therapies. Gefitinib, a previously known inhibitor of epidermal growth factor receptor and the two novel tyrosine kinase inhibitors AKN-032 and AKN-028, have been identified as compounds with cytotoxic activity in AML.

    AKN-028 is a potent inhibitor of FLT3 with an IC50 value of 6 nM in an enzyme assay, but also displaying in vitro activity in a variety of primary AML samples, irrespective of FLT3 mutation status or quantitative FLT3 expression. AKN-028 shows a sequence dependent in vitro synergy when combined with standard cytotoxic agents cytarabine or daunorubicin, with better efficacy when cells are exposed to standard chemotherapy simultaneously or for 24 hours prior to adding AKN-028. Antagonism is observed when cells are pre-treated with AKN-028, possibly explained by the cell cycle arrest induced by the compound. In vivo cytotoxic activity and good oral bioavailability have made AKN-028 a candidate drug for clinical studies and the compound is presently investigated in an international two-part multicenter phase I/II study.

    Results from microarray studies performed to further elucidate the mechanism of action of AKN-028, revealed significantly altered gene expression induced by AKN-028 in both AML cell lines and in primary AML cells, with an enrichment of the Myc pathway among the downregulated genes.

    Furthermore, tyrosine kinase activity profiling shows a dose-dependent kinase inhibition by AKN-028 in all AML samples tested. Interestingly, cells with a high overall kinase activity were more sensitive to AKN-028. Provided conformation in a larger set of samples, kinase activity profiling may give useful information in individualizing treatment of patients with AML.

  • 233.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 367-368Article in journal (Other academic)
  • 234.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Ekholm, C
    Jenmalm Jensen, A
    Löthgren, A
    Lehmann, F
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Parrow, V
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia2012In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 2, p. e81-Article in journal (Refereed)
    Abstract [en]

    Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).

  • 235.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hilhorst, Riet
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson Kultima, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    de Wijn, Rik
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Parrow, Vendela
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia2014In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 87, no 2, p. 284-291Article in journal (Refereed)
    Abstract [en]

    AKN-028 is a novel tyrosine kinase inhibitor with preclinical activity in acute myeloid leukemia (AML), presently undergoing investigation in a phase I/II study. It is a potent inhibitor of the FMS-like kinase 3 (FLT3) but shows in vitro activity in a wide range of AML samples. In the present study, we have characterized the effects of AKN-028 on AML cells in more detail. AKN-028 induced a dose-dependent G(0)/arrest in AML cell line MV4-11. Treatment with AKN-028 caused significantly altered gene expression in all AML cell types tested (430 downregulated, 280 upregulated transcripts). Subsequent gene set enrichment analysis revealed enrichment of genes associated with the proto-oncogene and cell cycle regulator c-Myc among the downregulated genes in both AKN-028 and midostaurin treated cells. Kinase activity profiling in AML cell lines and primary AML samples showed that tyrosine kinase activity, but not serine/threonine kinase activity, was inhibited by AKN-028 in a dose dependent manner in all samples tested, reaching approximately the same level of kinase activity. Cells sensitive to AKN-028 showed a higher overall tyrosine kinase activity than more resistant ones, whereas serine/threonine kinase activity was similar for all primary AML samples. In summary, AKN-028 induces cell cycle arrest in AML cells, downregulates Myc-associated genes and affect several signaling pathways. AML cells with high global tyrosine kinase activity seem to be more sensitive to the cytotoxic effect of AKN-028 in vitro.

  • 236.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lennartsson, Andreas
    Karolinska Inst, Stockholm, Sweden.
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Epigenetic aberrations in acute myeloid leukemia: Early key events during leukemogenesis2015In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 43, no 8, p. 609-624Article in journal (Refereed)
    Abstract [en]

    As a result of the introduction of new sequencing technologies, the molecular landscape of acute myeloid leukemia (AML) is rapidly evolving. From karyotyping, which detects only large genomic aberrations of metaphase chromosomes, we have moved into an era when sequencing of each base pair allows us to define the AML genome at highest resolution. This has revealed a new complex landscape of genetic aberrations where addition of mutations in epigenetic regulators has been one of the most important contributions to the understanding of the pathogenesis of AML. These findings, together with new insights into epigenetic mechanisms, have placed dysregulated epigenetic mechanisms at the forefront of AML development. Not only have several new mutations in genes directly involved in epigenetic regulatory mechanisms been discovered, but also previously well-known gene fusions have been found to exert aberrant effects through epigenetic mechanisms. In addition, mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1 have recently been found to be the earliest known events during AML evolution and to be present as preleukemic lesions before the onset of AML. In this article, we review epigenetic changes in AML also in relation to what is known about their mechanism of action and their prognostic role.

  • 237.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Osterros, Albin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hassan, Sadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Repositioning of Quinacrine for Treatment of Acute Myeloid Leukemia2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 238.
    Eriksson, Mia
    et al.
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Peña-Martínez, Pablo
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Ramakrishnan, Ramprasad
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Chapellier, Marion
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Högberg, Carl
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Glowacki, Gabriella
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Orsmark-Pietras, Christina
    Department of Clinical Genetics, Lund University, Lund, Sweden.
    Velasco-Hernández, Talía
    Department of Molecular Hematology, Lund University, Lund, Sweden.
    Lazarevic, Vladimir Lj
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Juliusson, Gunnar
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Mulloy, James C
    Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
    Richter, Johan
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Fioretos, Thoas
    Department of Clinical Genetics, Lund, Sweden.
    Ebert, Benjamin L.
    Division of Hematology, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, USA.
    Järås, Marcus
    Department of Clinical Genetics, Lund, Sweden.
    Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NF?B-dependent differentiation of AML cells2017In: Blood advances, ISSN 2473-9529, Vol. 1, no 23, p. 2046-2057Article in journal (Refereed)
    Abstract [en]

    Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+CD38-cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 inMLL-AF9-driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NF?B-dependent manner. By using murineTrp53 -/- MLL-AF9AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murineAML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined toMLL-rearranged AML. We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects. Ex vivo Pam3CSK4 treatment inhibited murine and human leukemia-initiating cells, whereas murine normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected. Consistent with these findings, primary human AML cells across several genetic subtypes of AML were more vulnerable for TLR1/TLR2 activation relative to normal human HSPCs. In theMLL-AF9AML mouse model, treatment with Pam3CSK4 provided proof of concept for in vivo therapeutic efficacy. Our results demonstrate that TLR1 and TLR2 are upregulated on primitive AML cells and that agonistic targeting of TLR1/TLR2 forces AML cells into apoptosis by p38 MAPK-dependent activation of Caspase 3, and differentiation by activating NF?B, thus revealing a new putative strategy for therapeutically targeting AML cells.

  • 239.
    Eriksson, Oskar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hegde, Geeta
    Human Prot Atlas Project, Lab Surgpath, Mumbai Site, Bombay, Maharashtra, India..
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Navani, Sanjay
    Human Prot Atlas Project, Lab Surgpath, Mumbai Site, Bombay, Maharashtra, India..
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A stromal cell population in the large intestine identified by tissue factor expression that is lost during colorectal cancer progression2016In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 116, no 6, p. 1050-1059Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is a major cause of morbidity and mortality, and the composition of the tumour stroma is a strong predictor of survival in this cancer type. Tissue factor (TF) functions as the trigger of haemostasis together with its ligand coagulation factor VII/ VIIa, and TF expression has been found in tumour cells of colorectal tumours. However, TF expression in the CRC tumour stroma or its relationship to patient outcome has not yet been studied. To address this question we developed and validated a specific anti-TF antibody using standardised methods within the Human Protein Atlas project. We used this antibody to investigate TF expression in normal colorectal tissue and CRC using immunofluorescence and immunohistochemistry in two patient cohorts. TF was strongly expressed in a cell population immediately adjacent to the colorectal epithelium. These TF-positive cells were ACTA2-negative but weakly vimentin-positive, defining a specific population of pericryptal sheath cells. In colorectal tumours, TF-positive sheath cells were progressively lost after the adenoma-to-carcinoma transition, demonstrating downregulation of this source of TF in CRC. Furthermore, loss of sheath cell TF was significantly associated with poor overall and disease-specific survival in rectal but not colon cancers. In conclusion, we demonstrate that TF is a marker of a specific cell population in the large intestine, which is lost during CRC progression. Our results highlight the role of the tumour stroma in this cancer type and suggest TF to be a potential prognostic biomarker in rectal cancers through the identification of pericryptal sheath cells.

  • 240.
    Eriksson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hedge, G.
    Navani, S.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Cross-talk between tissue factor and EPHA2 in cancer: potentiation of ligand-dependent EPHA2-signaling in vitro and co-expression in human colorectal cancer specimens2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 111-111, article id OR046Article in journal (Other academic)
  • 241. Erlinge, David
    et al.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Duvvuru, Suman
    Jakubowski, Joseph A.
    Wagner, Henrik
    Varenhorst, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Tantry, Udaya S.
    Brown, Patricia B.
    Small, David
    Moser, Brian A.
    Sundseth, Scott S.
    Walker, Joseph R.
    Winters, Kenneth J.
    Gurbel, Paul A.
    Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease2014In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 111, no 5, p. 943-950Article in journal (Refereed)
    Abstract [en]

    We compared results obtained with the Nanosphere Verigene (R) System, a novel point-of-care (POC) genetic test capable of analysing 11, CYP2C19 variants within 3 hours, to an established, validated genotyping method (Affymetrix (TM) DMET+; reference assay) for identifying extensive and reduced metabolisers of clopidogrel. Based on genotyping, patients (N=82) with stable coronary artery disease on clopidogrel 75 mg daily were defined as extensive metabolisers (*1/*1, *1/*17,*17/*17), reduced metabolisers (*1/*2,*1/*8,*2/*2,*2/*3), or of indeterminate metaboliser status (*2/*17). Pharmacokinetic exposure to clopidogrel's active metabolite and pharmacodynamic measures with P2Y12 reaction units (PRU) (VerifyNow (R) P2Y12 assay), and VASP PRI (PRI) were also assessed. There was a 99.9% overall; concordance of marker-level data between the Nanosphere Verigene and DMET+ systems in identifying the CYP2C19 variants and 100% agreement in classifying the patients as extensive (n=59) or reduced metabolisers (n=15). Extensive metabolisers had significantly higher active metabolite exposure than reduced metabolisers (LS means 12.6 ng*h/ml vs 7.7 ng*h/ml; p<0.001). Extensive metabolisers also had lower PRU (LS means 158 vs 212; p=0.003) and VASP PRI (LS means 48% vs 63%, p=0.01) compared to reduced metabolisers. Rates of high on-treatment platelet reactivity were higher in reduced metabolisers compared to extensive metabolisers (VASP PRI >= 50%: 79% vs 47%; PRU >235: 33% vs 16%). The Nanosphere Verigene CBS system identified 11 CYP2C19 alleles in less than 3 hours with a high degree of accuracy when compared to a conventional method, and was further validated against pharmacokinetic and pharmacodynamic phenotypes.

  • 242.
    Ermert, David
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Niemiec, Maria Joanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Röhm, Marc
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Glenthøj, Andreas
    Department of Hematology, National University Hospital, Copenhagen, Denmark..
    Borregaard, Niels
    Department of Hematology, National University Hospital, Copenhagen, Denmark..
    Urban, Constantin F.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Candida albicans escapes from mouse neutrophils2013In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 94, no 2, p. 223-236Article in journal (Refereed)
    Abstract [en]

    Candida albicans, the most commonly isolated human fungal pathogen, is able to grow as budding yeasts or filamentous forms, such as hyphae. The ability to switch morphology has been attributed a crucial role for the pathogenesis of C. albicans. To mimic disseminated candidiasis in humans, the mouse is the most widely used model organism. Neutrophils are essential immune cells to prevent opportunistic mycoses. To explore potential differences between the rodent infection model and the human host, we compared the interactions of C. albicans with neutrophil granulocytes from mice and humans. We revealed that murine neutrophils exhibited a significantly lower ability to kill C. albicans than their human counterparts. Strikingly, C. albicans yeast cells formed germ tubes upon internalization by murine neutrophils, eventually rupturing the neutrophil membrane and thereby, killing the phagocyte. On the contrary, growth and subsequent escape of C. albicans are blocked inside human neutrophils. According to our findings, this blockage in human neutrophils might be a result of higher levels of MPO activity and the presence of α-defensins. We therefore outline differences in antifungal immune defense between humans and mouse strains, which facilitates a more accurate interpretation of in vivo results.

  • 243.
    Eshoj, Henrik Rode
    et al.
    Odense Univ Hosp, Dept Hematol, Qual Life Res Ctr, Odense, Denmark; Odense Univ Hosp, OPEN Odense Patient Data Explorat Network, Odense, Denmark.
    Nielsen, Lene Kongsgaard
    Odense Univ Hosp, Dept Hematol, Qual Life Res Ctr, Odense, Denmark.
    Schjesvold, Fredrik
    Oslo Univ Hosp, Dept Hematol, Oslo, Norway.
    Abildgaard, Niels
    Odense Univ Hosp, Dept Hematol, Qual Life Res Ctr, Odense, Denmark.
    Nahi, Hareth
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
    Andersen, Niels Frost
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark.
    Vangsted, Annette Juul
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Helleberg, Carsten
    Herlev Hosp, Dept Hematol, Herlev, Denmark.
    Frølund, Ulf Christian
    Zealand Univ Hosp, Dept Hematol, Roskilde, Denmark.
    Axelsson, Per
    Helsingborg Hosp, Dept Hematol, Helsingborg, Sweden.
    Stromberg, Olga
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
    Blimark, Cecilie
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Waage, Anders
    St Olays Hosp NTNU, Dept Hematol, Trondheim, Norway.
    Remes, Kari
    Turku Univ Hosp, Dept Hematol, Turku, Finland.
    Peceliunas, Valdas
    Vilnius Univ Hosp, Dept Hematol, Vilnius, Lithuania.
    Guldbrandsen, Nina
    Oslo Univ Hosp, Dept Hematol, Oslo, Norway.
    Hansson, Markus
    Skane Univ Hosp, Dept Hematol, Lund, Sweden.
    Gregersen, Henrik
    Aalborg Univ Hosp, Dept Hematol, Aalborg, Denmark.
    Health-related quality of life in multiple myeloma patients with first relapse treated with Carfilzomib-based re-induction and salvage autologous stem cell transplantation: data from a Nordic phase II trial2018In: Quality of Life Research, ISSN 0962-9343, E-ISSN 1573-2649, Vol. 27, no Supplement 1, p. S137-S137Article in journal (Other academic)
  • 244.
    Eskelund, Christian Winther
    et al.
    Rigshosp, Dept Hematol, Copenhagen, Denmark;Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Albertsson-Lindblad, Alexandra
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden.
    Kolstad, Arne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Raty, Riikka
    Helsinki Univ Hosp, Dept Hematol, Helsinki, Finland.
    Pedersen, Lone Bredo
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Geisler, Christian Hartmann
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Jerkeman, Mats
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden.
    Gronbaek, Kirsten
    Rigshosp, Dept Hematol, Copenhagen, Denmark;Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Lenalidomide plus bendamustine-rituximab does not overcome the adverse impact of TP53 mutations in mantle cell lymphoma2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 11, p. E541-E543Article in journal (Other academic)
  • 245.
    Espinet Sola, B.
    et al.
    Hosp Mar, Barcelona, Spain..
    Baliakas, P.
    Inst Hosp Mar Invest Med Imim, Barcelona, Spain..
    Puiggros, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Xochelli, A.
    Hosp Mar, Barcelona, Spain..
    Sutton, L-A
    Inst Hosp Mar Invest Med Imim, Barcelona, Spain..
    Nguyen-Khac, F.
    Certh, Inst Appl Biosci, Thessaloniki, Greece..
    Gardiner, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Plevova, K.
    Hop La Pitie Salpetriere, Paris, France..
    Ortega, M.
    Royal Bornemouth Hosp, Bornemouth, England..
    Collado, R.
    Masaryk Univ, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Gonzalez, T.
    Hosp Univ Vall Dhebron, Barcelona, Spain..
    Granada, I
    Consorcio Hosp Gen Univ, Valencia, Spain..
    Luno, E.
    Fdn Publ Galega Med Xenom, Santiago De Compostela, Spain..
    Kotaskova, J.
    Hosp Badalona Germans Trias & Pujol, Inst Recerca Josep Carreras, Badalona, Spain..
    Davis, Z.
    Hosp Univ Cent Asturias, Oviedo, Spain..
    Anagnostopoulos, A.
    Masaryk Univ, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Strefford, J.
    Royal Bornemouth Hosp, Bornemouth, England..
    Pospisilova, S.
    G Papanicolaou Hosp, Thessaloniki, Greece..
    Davi, F.
    Univ Southampton, Southampton SO9 5NH, Hants, England..
    Athanasiadou, A.
    Masaryk Univ, Brno, Czech Republic..
    Rosenquist, R.
    Hop La Pitie Salpetriere, Paris, France..
    Oscier, D.
    G Papanicolaou Hosp, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Royal Bornemouth Hosp, Bornemouth, England..
    Clinical- Biological Characterization Of The Patients With Llc And Trisomy 12 That Exhibit Additional Trisomies: Importance Of The Accompanying Alterations2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 67-67Article in journal (Other academic)
  • 246. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjorn
    Nahi, Hareth
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype2014In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 167, no 5, p. 671-680Article in journal (Refereed)
    Abstract [en]

    Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199G>A, 1236C>T, 2677G>T/A and 3435C>T, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0.017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0.039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236C>T and 2677G>T may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.

  • 247. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjörn
    Nahi, Hareth
    Hermanson, Monica
    Rosenquist, Richard
    Höglund, Martin
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Gréen, Henrik
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lotfi, Kourosh
    Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5 '-nucleotidase2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 12, p. 1001-1006Article in journal (Refereed)
    Abstract [en]

    De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A> C rs2072671 and 2451C> T rs532545), 50-nucleotidase (cN-II 7A> G rs10883841), and deoxycytidine kinase (DCK 30UTR 948T> C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and 2451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P< 0.001 and 5 vs. 23 months, P50.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P50.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML.

  • 248. Falk, Ingrid Jakobsen
    et al.
    Willander, Kerstin
    Chaireti, Roza
    Lund, Johan
    Nahi, Hareth
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Green, Henrik
    Lotfi, Kourosh
    Söderkvist, Peter
    TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome2015In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 94, no 4, p. 355-362Article in journal (Refereed)
    Abstract [en]

    BackgroundTP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of mouse double minute 2 (MDM2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. Experimental designWe investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2(SNP309) on treatment outcome and overall survival (OS) in 189 Swedish acute myeloid leukemia patients. The genetic analyses were performed using SSCA and direct sequencing (for mutations in exon 5-8 of TP53) and Pyrosequencing (for the MDM2(SNP309)). ResultsWe found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (P<0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, P<0.001) and reduced OS (2 and 16months, respectively, P<0.001). In TP53wt patients with high or intermediate risk cytogenetic aberrations, the MDM2(SNP309) conferred an impaired outcome, with patients carrying the alternative G-allele having shorter OS compared with T/T patients (median 9 vs. 50months, P=0.020). ConclusionsOur results show that TP53mut analysis and MDM2(SNP309) genotyping may be useful tools for prognostication, risk stratification, and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

  • 249.
    Fang, Xiaotian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Hultqvist, Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Meier, Silvio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    A small bispecific antibody-based construct based on bapineuzumab as a PET tracer for amyloid beta pathology in brain2017In: Meeting abstractArticle in journal (Other academic)
  • 250.
    Faxälv, Lars
    et al.
    Linköping University, Linköping, Sweden.
    Boknäs, Niklas
    Linköping University, Linköping, Sweden.
    Ström, Jakob O.
    Linköping University, Linköping, Sweden.
    Tengvall, Pentti
    Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Theodorsson, Elvar
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Linköping University, Linköping, Sweden.
    Putting polyphosphates to the test: evidence against platelet-induced activation of factor XII2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, no 23, p. 3818-3824Article in journal (Refereed)
    Abstract [en]

    The recent claim that stimulated platelets activate the intrinsic pathway of coagulation by the release of polyphosphates has been considered a breakthrough in hemostasis research. In little more than 3 years, the original publication by Müller et al has been cited >100 times. However, none of the citing articles has sought to independently validate this potentially paradigm-shifting concept. To this end, we performed extensive experimentation in vitro and in vivo in an attempt to verify the claim that factor XII (FXII) is primarily activated by stimulated platelets. In contrast to the original assertion, platelet-derived polyphosphates were found to be weak activators of FXII, with a FXIIa-generating activity of <10% compared with equivalent concentrations of kaolin. Using different coagulation assays, it was shown that platelet contribution to whole blood coagulation was unrelated to the generation of activated FXII in vitro. Additionally, key results used to verify the hypothesis in the original study in vivo were found to be irreproducible. We conclude that platelet-derived polyphosphates are not physiologically relevant activators of FXII.

2345678 201 - 250 of 965
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