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  • 1.
    Aardal-Eriksson, Elisabeth
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Mobäck, Caroline
    Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Jakobsson, Sandra
    Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Germany.
    Hoffmann, Johannes J. M. L.
    Abbott GmbH and Co KG, Germany.
    Iron depletion in blood donors - Have extended erythrocyte and reticulocyte parameters diagnostic utility?2015In: Transfusion and apheresis science, ISSN 1473-0502, E-ISSN 1878-1683, Vol. 53, no 1, p. 76-81Article in journal (Refereed)
    Abstract [en]

    Background: Blood donation is associated with iron depletion, but donor iron status is not usually investigated, as such tests are cumbersome and costly. It would therefore be desirable to have simple, fast and inexpensive tests that give information on a donors risk of developing iron depletion. In a pilot study we investigated whether novel erythrocyte and reticulocyte parameters can serve this goal. Methods: In regular blood donors extended red cell parameters were measured using the Abbott CELL-DYN Sapphire hematology analyzer and conventional biochemical tests of iron status. Donors were compared with a regionally matched group of non-donating controls. Results: In the controls, the reference ranges of extended RBC parameters were well comparable to published data. Donors had significantly more microcytic RBC than controls (median 0.9 vs 0.6%), lower serum ferritin concentration (median 43 vs 91 mg/L) and higher soluble transferrin receptor/ferritin index (median 1.60 vs 1.27). Overall 18-28% of the donors were iron depleted. Moreover, 3.3% of donors had iron-restricted erythropoiesis. Microcytic RBC and reticulocyte mean cell hemoglobin content predicted iron depletion with 70% and 64% sensitivities and specificities of 72% and 78%, respectively. When combined these two parameters increased the sensitivity to 82%. Conclusions: Our results in Swedish blood donors confirm a high prevalence of iron depletion, despite iron supplementation used by about half of the donors. Microcytic RBC and MCHr appeared to be helpful in identifying iron-depleted donors, who might benefit from iron supplementation. We recommend larger prospective investigations in order to confirm and extend the findings of this pilot study. (C) 2015 Elsevier Ltd. All rights reserved.

  • 2.
    Adoberg, Annika
    et al.
    North Estonia Med Ctr, Estonia.
    Paats, Joosep
    Tallinn Univ Technol, Estonia.
    Arund, Jurgen
    Tallinn Univ Technol, Estonia.
    Dhondt, Annemieke
    Ghent Univ Hosp, Belgium.
    Fridolin, Ivo
    Tallinn Univ Technol, Estonia.
    Glorieux, Griet
    Ghent Univ Hosp, Belgium.
    Holmar, Jana
    Tallinn Univ Technol, Estonia.
    Lauri, Kai
    Synlab Eesti OU, Estonia.
    Leis, Liisi
    North Estonia Med Ctr, Estonia.
    Luman, Merike
    North Estonia Med Ctr, Estonia; Tallinn Univ Technol, Estonia.
    Pilt, Kristjan
    Tallinn Univ Technol, Estonia.
    Uhlin, Fredrik
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Medicine Center, Department of Nephrology. Tallinn Univ Technol, Estonia.
    Tanner, Risto
    Tallinn Univ Technol, Estonia.
    Treatment with Paracetamol Can Interfere with the Intradialytic Optical Estimation in Spent Dialysate of Uric Acid but Not of Indoxyl Sulfate2022In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 14, no 9, article id 610Article in journal (Refereed)
    Abstract [en]

    Optical online methods are used to monitor the haemodialysis treatment efficiency of end stage kidney disease (ESKD) patients. The aim of this study was to analyse the effect of the administration of UV-absorbing drugs, such as paracetamol (Par), on the accuracy of optical monitoring the removal of uremic toxins uric acid (UA) and indoxyl sulfate (IS) during standard haemodialysis (HD) and haemodiafiltration (HDF) treatments. Nine patients received Par in daily dosages 1-4 g for 30 sessions. For 137 sessions, in 36 patients the total daily dosage of UV-absorbing drugs was less than 500 mg, and for 6 sessions 3 patients received additional UV-absorbing drugs. Par administration slightly affected the accuracy of optically assessed removal of UA expressed as bias between optically and laboratory-assessed reduction ratios (RR) during HD but not HDF employing UV absorbance of spent dialysate (p < 0.05) at 295 nm wavelength with the strongest correlation between the concentration of UA and absorbance. Corresponding removal of IS based on fluorescence at Ex280/Em400 nm during HD and HDF was not affected. Administration of UV-absorbing drugs may in some settings influence the accuracy of optical assessments in spent dialysate of the removal of uremic solutes during haemodialysis treatment of ESKD patients.

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  • 3.
    Ahlstrand, Erik
    et al.
    Orebro Univ, Sweden.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lindgren, Marie
    Kalmar Cty Hosp, Sweden.
    Pettersson, Helna
    NU Hosp Grp, Sweden.
    Liljeholm, Maria
    Univ Hosp Nouthern Sweden, Sweden.
    Ravn-Landtblom, Anna
    Karolinska Inst, Sweden; Stockholm South Hosp, Sweden.
    Scheding, Stefan
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Andreasson, Bjorn
    NU Hosp Grp, Sweden.
    Highly reduced survival in essential thrombocythemia and polycythemia vera patients with vascular complications during follow-up2020In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 104, no 3, p. 271-278Article in journal (Refereed)
    Abstract [en]

    Objective To explore the relative importance of risk factors, treatments, and blood counts for the occurrence of vascular complications and their impact on life expectancy in essential thrombocythemia (ET) and polycythemia vera (PV). Methods Nested case-control study within the Swedish MPN registry. From a cohort of 922 ET patients and 763 PV patients, 71 ET and 81 PV cases with vascular complications were compared with matched controls. Results Incidence of vascular complications was 2.0 and 3.4 events per 100 patient-years in ET and PV, respectively. At diagnosis, no significant risk factor differences were observed between cases and controls in neither of the diseases. At the time of vascular event, ET complication cases did not differ significantly from controls but in PV, cases had significantly higher WBCs and were to a lesser extent treated with anti-thrombotic and cytoreductive therapy. Life expectancy was significantly decreased in both ET and PV cases compared with controls. Conclusions The risk of vascular complications is high in both ET and PV, and these complications have a considerable impact on life expectancy. The protective effect of anti-thrombotic and cytoreductive therapy for vascular complications in PV underscores the importance of avoiding undertreatment.

  • 4.
    Ali Abdi, Abshir
    et al.
    East Africa University, Somalia.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Prevalence of common hereditary risk factors for thrombophilia in Somalia and identification of a novel Gln544Arg mutation in coagulation factor V2017In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 44, no 4, p. 536-543Article in journal (Refereed)
    Abstract [en]

    Thrombophilia, commonly manifested as venous thromboembolism (VTE), is a worldwide concern but little is known on its genetic epidemiology in many parts of the globe particularly in the developing countries. Here we employed TaqMan genotyping and pyrosequencing to evaluate the prevalence of known common nucleotide polymorphisms associated with thrombophilia in a Somali population in the Puntland region of Somalia. We also employed next generation sequencing (NGS) to investigate other genetic variants in a Somali patient with deep venous thrombosis (DVT). As expected, we found no existence of factor V Leiden (rs6025) and prothrombin G20210A (rs1799963) in the Somali population. The G allele of ABO [261G/delG] polymorphism (rs8176719) was found at a frequency of 29%, similar to that observed in other African populations. We found the lowest so far reported frequency of MTHFR C677T (rs1801133) polymorphism in the Somali population (T allele frequency 1.5%). A novel and deleterious single nucleotide variation in exon 11 of coagulation factor V (c.1631A amp;gt; G) causing Gln544Arg exchange in factor V was identified in a 29 years old Somali female with DVT. The same patient was heterozygous to VKORC1 Asp36Tyr polymorphism (rs61742245) that predisposes to warfarin resistance. In conclusion, this study shows that common hereditary factors for thromboembolism found in Caucasians are either less frequent or absent in the Somali population-similar to the situation in other Africans. NGS is possibly a better choice to detect genetic risk variants for thrombosis in this ethnic group.

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  • 5.
    Augustsson, Cecilia
    et al.
    Univ & Reg Labs Reg Skane, Sweden.
    Taxbro, Knut
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Strandberg, Karin
    Univ & Reg Labs Reg Skane, Sweden.
    Zetterberg, Eva
    Skane Univ Hosp, Sweden; Lund Univ, Sweden.
    A nonneutralizing antibody as cause of prothrombin deficiency in a patient with follicular lymphoma2024In: Clinical Case Reports, E-ISSN 2050-0904, Vol. 12, no 1, article id e8400Article in journal (Refereed)
    Abstract [en]

    Acquired inhibitors of blood coagulation are rare but of clinical importance. Prothrombin is a vitamin K-dependent protein, and acquired antibodies toward prothrombin are often associated with the presence of lupus anticoagulant. We describe a previously healthy 70-year-old man presenting with both hemorrhage and thrombosis as well as a prolonged prothrombin time. At arrival at the hospital, he was diagnosed with deep venous thrombosis, and an enlarged lymph node in the left groin was noted (revealed as follicular lymphoma grade 1 by biopsy). Prothrombin activity and antibody titer were followed for 5 months with 15 sampling time points to monitor the treatment outcome of the patient. Diagnostic work-up identified prothrombin deficiency as cause of bleeding. A nonneutralizing calcium-dependent antiprothrombin antibody was found, suspected to increase the clearance of prothrombin, which has previously only occasionally been reported. Lupus anticoagulant was ruled out and thrombosis was judged to be caused by a combination of malignant disease and stagnant venous flow following enlarged lymph nodes in the groin. This report illustrates how investigation of prolonged global coagulation tests, triggered the diagnosis of a rare but critical condition, immune-mediated prothrombin deficiency. The diagnosis is challenging and involves proper differential diagnosis. image

  • 6.
    Auvinen, Marja-Kaisa
    et al.
    Uppsala Univ Hosp, Sweden.
    Zhao, Jingcheng
    Karolinska Inst, Sweden.
    Lassen, Ewa
    Umea Univ Hosp, Sweden.
    Lubenow, Norbert
    Uppsala Univ Hosp, Sweden.
    Seger-Mollén, Agneta
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Watz, Emma
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Wikman, Agneta
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Edgren, Gustaf
    Karolinska Inst, Sweden; Soder Sjukhuset, Sweden.
    Patterns of blood use in Sweden from 2008 to 2017: A nationwide cohort study2020In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 60, no 11, p. 2529-2536Article in journal (Refereed)
    Abstract [en]

    Background Transfusion patterns in Sweden have not been characterized on a nationwide level. Study Design and Methods We conducted a nationwide descriptive cohort study in Sweden from 2008 to 2017. Data on blood donors, donations, component manufacture, transfusions, and transfused patients were extracted from Swedish portion of the Scandinavian Donations and Transfusions (SCANDAT3-S) database. Results A total of 708 436 patients received 5 587 684 red cell, plasma, or platelet transfusions during the study period. The age-standardized transfusion rate decreased markedly during the study period for red cell units (from 53 to 39 units/1000 persons) and plasma units (from 11 to 4.9 units/1000 persons), but remained relatively constant for platelet concentrates. The transfusion rate was 30%-40% higher in males than in females in the first year of life, and higher in males over 45 years than in females. Between age 20 and 45, the majority of red cells were transfused to female patients with obstetric indications, whereas trauma was the predominant indication for male contemporaries. In females over 80 years, the largest proportion of red cells were administered due to trauma. Overall, hematological patients received 36% of all platelet units. There were large regional differences in transfusion rates for red cell units, ranging from less than 30 to greater than 60/1000 persons. Conclusion Transfusion rates in Sweden remain high but have decreased strikingly during the study period - with the exception of platelet transfusions. Based on the available data, it is difficult to draw firm conclusions about whether transfusion rates can be further reduced.

  • 7.
    Baliakas, Panagiotis
    et al.
    Uppsala Univ, Sweden.
    Tesi, Bianca
    Karolinska Univ Hosp, Sweden.
    Wartiovaara-Kautto, Ulla
    Helsinki Univ Hosp, Finland.
    Stray-Pedersen, Asbjorg
    Oslo Univ Hosp, Norway.
    Friis, Lone Smidstrup
    Copenhagen Univ Hosp, Denmark.
    Dybedal, Ingunn
    Oslo Univ Hosp, Norway.
    Hovland, Randi
    Haukeland Hosp, Norway.
    Jahnukainen, Kirsi
    Helsinki Univ Hosp, Finland.
    Raaschou-Jensen, Klas
    Odense Univ Hosp, Denmark.
    Ljungman, Per
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Rustad, Cecilie F.
    Oslo Univ Hosp, Norway.
    Lautrup, Charlotte K.
    Aalborg Univ Hosp, Denmark.
    Kilpivaara, Outi
    Univ Helsinki, Finland; Univ Helsinki, Finland.
    Kittang, Astrid Olsnes
    Haukeland Hosp, Norway.
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Denmark.
    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.
    Hellstrom-Lindberg, Eva
    Karolinska Univ Hosp, Sweden.
    Andersen, Mette K.
    Copenhagen Univ Hosp, Denmark.
    Nordic Guidelines for Germline Predisposition to Myeloid Neoplasms in Adults: Recommendations for Genetic Diagnosis, Clinical Management and Follow-up2019In: HemaSphere, E-ISSN 2572-9241, Vol. 3, no 6, article id UNSP e321Article in journal (Refereed)
    Abstract [en]

    Myeloid neoplasms (MNs) with germline predisposition have recently been recognized as novel entities in the latest World Health Organization (WHO) classification for MNs. Individuals with MNs due to germline predisposition exhibit increased risk for the development of MNs, mainly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Setting the diagnosis of MN with germline predisposition is of crucial clinical significance since it may tailor therapy, dictate the selection of donor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), determine the conditioning regimen, enable relevant prophylactic measures and early intervention or contribute to avoid unnecessary or even harmful medication. Finally, it allows for genetic counseling and follow-up of at-risk family members. Identification of these patients in the clinical setting is challenging, as there is no consensus due to lack of evidence regarding the criteria defining the patients who should be tested for these conditions. In addition, even in cases with a strong suspicion of a MN with germline predisposition, no standard diagnostic algorithm is available. We present the first version of the Nordic recommendations for diagnostics, surveillance and management including considerations for allo-HSCT for patients and carriers of a germline mutation predisposing to the development of MNs.

  • 8.
    Banch Clausen, Frederik
    et al.
    Copenhagen Univ Hosp, Denmark; Natl Univ Singapore, Singapore.
    Barrett, Angela Natalie
    Copenhagen Univ Hosp, Denmark; Natl Univ Singapore, Singapore.
    Nyström, Sofia N. (Contributor)
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine. Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology.
    Noninvasive fetal RHD genotyping to guide targeted anti-D prophylaxis-an external quality assessment workshop2019In: Vox Sanguinis, ISSN 0042-9007, E-ISSN 1423-0410, Vol. 114, no 4, p. 386-393Article in journal (Refereed)
    Abstract [en]

    Background and Objectives Fetal RHD genotyping of cell-free fetal DNA from RhD-negative pregnant women can be used to guide targeted antenatal and postnatal anti-D prophylaxis for the prevention of RhD immunization. To assure the quality of clinical testing, we conducted an external quality assessment workshop with the participation of 28 laboratories. Materials and Methods Aliquots of pooled maternal plasma were sent to each laboratory. One sample was positive, and the second sample was negative for fetal RHD, verified by pre-workshop testing using quantitative real-time PCR (qPCR) analysis of RHD exons 4, 5, 7 and 10. Plasma samples were shipped at room temperature. A reporting scheme was supplied for data collection, including questions regarding the methodological setup, results and clinical recommendations. Different methodological approaches were used, all employing qPCR with a total of eight different combinations of RHD exon targets. The samples were tested blindly. Results Fetal RHD genotyping was performed with no false-negative and no false-positive results. One inconclusive result was reported for the RHD-positive sample, and four inconclusive results were reported for the RHD-negative sample. All clinical conclusions were satisfactory. Conclusion This external quality assessment workshop demonstrates that despite the different approaches taken to perform the clinical assays, fetal RHD genotyping is a reliable laboratory assay to guide targeted use of Rh prophylaxis in a clinical setting.

  • 9.
    Baudet, Anna
    et al.
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden; Department of Haematopoietic Stem Cell Transplantation Lund University Lund Sweden .
    Ek, Fredrik
    Department of Chemical Biology and Therapeutics Lund University Lund Sweden.
    Davidsson, Josef
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Soneji, Shamit
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Olsson, Roger
    Department of Chemical Biology and Therapeutics Lund University Lund Sweden.
    Magnusson, Mattias
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden.
    Cammenga, Jörg
    Department of Molecular Medicine and Gene Therapy Lund University Lund Sweden;Department of Chemical Biology and Therapeutics Lund University Lund Sweden .
    Juliusson, Gunnar
    Department of Haematopoietic Stem Cell Transplantation Lund University Lund Sweden; Departments of Haematology Skanes University Hospital Lund University Lund Sweden.
    Small molecule screen identifies differentiation-promoting compounds targeting genetically diverse acute myeloid leukaemia2016In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 175, no 2, p. 342-346Article in journal (Other academic)
  • 10.
    Bergemalm, Daniel
    et al.
    Department of Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Ramström, Sofia
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry. Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Örebro University, Örebro.
    Kardeby, Caroline
    Cardiovascular Research Centre, School of Medical Sciences, Örebro University, Örebro.
    Hultenby, Kjell
    Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm.
    Eremo, Anna Göthlin
    Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro.
    Sihlbom, Carina
    Proteomics Core Facility, University of Gothenburg, Gothenburg.
    Bergström, Jörgen
    Proteomics Core Facility, University of Gothenburg, Gothenburg.
    Palmblad, Jan
    Departments of Medicine and Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm.
    Åström, Maria
    Department of Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Platelet proteome and function in X-linked thrombocytopenia with thalassemia and in silico comparisons with gray platelet syndrome2021In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 106, no 11, p. 2947-2959Article in journal (Refereed)
    Abstract [en]

    In X-linked thrombocytopenia with thalassemia (XLTT; OMIM 314050), caused by the mutation p.R216Q in exon 4 of the GATA1 gene, male hemizygous patients display macrothrombocytopenia, bleeding diathesis and a ß-thalassemia trait. Herein, we describe findings in two unrelated Swedish XLTT families with a bleeding tendency exceeding what is expected from the thrombocytopenia. Blood tests revealed low P-PAI-1 and P-factor 5, and elevated S-thrombopoietin levels. Transmission electron microscopy showed diminished numbers of platelet a- and dense granules. The proteomes of isolated blood platelets from 5 male XLTT patients, compared to 5 gender- and age matched controls, were explored. Quantitative mass spectrometry showed alterations of 83 proteins (fold change =±1.2, q< .05). Of 46 downregulated proteins, 39 were previously reported to be associated with platelet granules. Reduced protein levels of PTGS1 and SLC35D3 were validated in megakaryocytes of XLTT bone marrow biopsies by immunohistochemistry. Platelet function testing by flow cytometry revealed low dense- and a-granule release and fibrinogen binding in response to ligation of receptors for ADP, the thrombin receptor PAR4 and the collagen receptor GPVI. Significant reductions of a number of a-granule proteins overlapped with a previous platelet proteomics investigation in the inherited macrothrombocytopenia gray platelet syndrome (GPS). In contrast, Ca2+ transporter proteins that facilitate dense granule release were downregulated in XLTT but upregulated in GPS. Ingenuity Pathway Analysis showed altered Coagulation System and Protein Ubiquitination pathways in the XLTT platelets. Collectively, the results revealed protein and functional alterations affecting platelet a- and dense granules in XLTT, probably contributing to bleeding.

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  • 11.
    Berggren, Daniel Moreno
    et al.
    Uppsala Univ, Sweden.
    Garelius, Hege
    Sahlgrens Univ Hosp, Sweden.
    Willner Hjelm, Petter
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Nilsson, Lars
    Skane Univ Hosp, Sweden.
    Rasmussen, Bengt
    Orebro Univ, Sweden.
    Weibull, Caroline E.
    Karolinska Inst, Sweden.
    Lambe, Mats
    Karolinska Inst, Sweden; Reg Canc Ctr Cent Sweden, Sweden.
    Lehmann, Soren
    Uppsala Univ, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hellstrom-Lindberg, Eva
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Jadersten, Martin
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Ejerblad, Elisabeth
    Uppsala Univ, Sweden.
    Therapy-related MDS dissected based on primary disease and treatment-a nationwide perspective2023In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 37, p. 1103-1112Article in journal (Refereed)
    Abstract [en]

    In this population-based study, we aimed to characterize and compare subgroups of therapy-related Myelodysplastic syndromes (t-MDS) and define the implications of type of previous treatment and primary disease. We combined data from MDS patients, diagnosed between 2009 and 2017 (n = 2705), in the nationwide Swedish MDS register, with several health registers. Furthermore, using matched population controls, we investigated the prevalence of antecedent malignancies in MDS patients in comparison with the general population. This first ever nationwide study on t-MDS confirms a shorter median survival for t-MDS compared to de novo MDS (15.8 months vs 31.1 months, p < 0.001). T-MDS patients previously treated with radiation only had disease characteristics with a striking resemblance to de novo-MDS, in sharp contrast to patients treated with chemotherapy who had a significantly higher risk profile. IPSS-R and the WHO classification differentiated t-MDS into different risk groups. As compared with controls, MDS patients had a six-fold increased prevalence of a previous hematological malignancy but only a 34% increased prevalence of a previous solid tumor. T-MDS patients with a previous hematological malignancy had a dismal prognosis, due both to mortality related to their primary disease and to high-risk MDS.

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  • 12.
    Berlin, Gösta
    et al.
    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.
    Cherif, Honar
    Akademiska sjukhuset - Hematologiska kliniken Uppsala, Sweden Akademiska sjukhuset - Hematologiska kliniken Uppsala, Sweden.
    Knutson, Folke
    Akademiska sjukhuset - Klinisk immunologi och transfusionsmedicin Uppsala, Sweden Akademiska sjukhuset - Klinisk immunologi och transfusionsmedicin Uppsala, Sweden.
    Mattsson, Jonas
    Karolinska Universitetssjukhuset - Centrum för allogen stamcellstransplantation Stockholm, Sweden .
    Axdorph Nygell, Ulla
    Karolinska Universitetssjukhuset - Klinisk immunologi och transfusionsmedicin Stockholm, Sweden .
    Granulocyttransfusion bör övervägas vid neutropeni och allvarlig infektion [Granulocyte transfusion – when and how should it be used?]2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115, article id EXUUArticle, review/survey (Refereed)
    Abstract [en]

    There are no randomized controlled trials proving the clinical benefit of granulocyte transfusions. However, clinical experience and a number of case studies suggest that granulocyte transfusions may be life-saving in certain situations. In our opinion granulocyte transfusions should be considered for patients with profound neutropenia and severe, life-threatening infection not responding to antibiotic or antifungal therapy. Since the clinical effect seems to be dose-dependent, the granulocyte concentrate should contain a large number of cells, which usually means that the donor should be mobilized with steroids and G-CSF. Regular blood donors as well as relatives to the patient can be used for granulocyte donations with apheresis technique after information of the process. Granulocyte transfusion should be given daily as long as the indication remains. The clinical efficacy of the transfusions should be evaluated daily.

  • 13.
    Berlin, Gösta
    et al.
    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.
    Cherif, Honar
    Akademiska sjukhuset - Hematologiska kliniken Uppsala, Sweden Akademiska sjukhuset - Hematologiska kliniken Uppsala, Sweden.
    Knutson, Folke
    Akademiska sjukhuset - Klinisk immunologi och transfusionsmedicin Uppsala, Sweden Akademiska sjukhuset - Klinisk immunologi och transfusionsmedicin Uppsala, Sweden.
    Mattsson, Jonas
    Karolinska Universitetssjukhuset - Centrum för allogen stamcellstransplantation Stockholm, Sweden Karolinska Universitetssjukhuset - Centrum för allogen stamcellstransplantation Stockholm, Sweden.
    Axdorph Nygell, Ulla
    Karolinska Universitetssjukhuset - Klinisk immunologi och transfusionsmedicin Stockholm, Sweden Karolinska Universitetssjukhuset - Klinisk immunologi och transfusionsmedicin Stockholm, Sweden.
    Replik gällande granulocyttransfusion: Rekommendationerna är väl underbyggda2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115Article in journal (Refereed)
  • 14.
    Biloglav, Andrea
    et al.
    Lund Univ, Sweden.
    Olsson-Arvidsson, Linda
    Lund Univ, Sweden; Dept Clin Genet and Pathol, Sweden.
    Theander, Johan
    Skane Univ Hosp, Sweden.
    Behrendtz, Mikael
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
    Castor, Anders
    Skane Univ Hosp, Sweden.
    Johansson, Bertil
    Lund Univ, Sweden; Dept Clin Genet and Pathol, Sweden.
    SFPQ-ABL1-positive B-cell precursor acute lymphoblastic leukemias2020In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 59, no 9, p. 540-543Article in journal (Refereed)
    Abstract [en]

    In recent years, a subgroup of B-cell precursor acute lymphoblastic leukemia (BCP ALL) without an established abnormality ("B-other") has been shown to be characterized by rearrangements of ABL1, ABL2, CSF1R, or PDGFRB (a.k.a. ABL-class genes). Using FISH with probes for these genes, we screened 55 pediatric and 50 adult B-other cases. Three (6%) of the adult but none of the childhood B-other cases were positive for ABL-class aberrations. RT-PCR and sequencing confirmed a rare SFPQ-ABL1 fusion in one adult B-other case with t(1;9)(p34;q34). Only six SFPQ-ABL1-positive BCP ALLs have been reported, present case included. A review of these shows that all harbored fusions between exon 9 of SFPQ and exon 4 of ABL1, that the fusion is typically found in adolescents/younger adults without hyperleukocytosis, and that IKZF1 deletions are recurrent. The few patients not treated with tyrosine kinase inhibitors (TKIs) and/or allogeneic stem cell transplantation relapsed, strengthening the notion that TKI should be added to the therapy of SFPQ-ABL1-positive BCP ALL.

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  • 15.
    Birgegard, Gunnar
    et al.
    Uppsala Univ, Sweden.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ahlstrand, Erik
    Orebro Univ, Sweden.
    Ejerblad, Elisabeth
    Uppsala Univ, Sweden.
    Enevold, Christian
    Copenhagen Univ Hosp, Denmark.
    Ghanima, Waleed
    Ostfold Hosp, Norway.
    Hasselbalch, Hans
    Zealand Univ Hosp, Denmark.
    Nielsen, Claus H.
    Zealand Univ Hosp, Denmark.
    Knutsen, Havar
    Ulleval Hosp, Norway.
    Pedersen, Ole B.
    Naestved Hosp, Denmark.
    Sorensen, Anders
    Copenhagen Univ Hosp, Denmark; Zealand Univ Hosp, Denmark.
    Andreasson, Bjorn
    NU Hosp Grp, Sweden.
    Inflammatory functional iron deficiency common in myelofibrosis, contributes to anaemia and impairs quality of life. From the Nordic MPN study Group2019In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 102, no 3, p. 235-240Article in journal (Refereed)
    Abstract [en]

    Objectives The study investigates the hypothesis that inflammation in myelofibrosis (MF) like in myeloma and lymphoma, may disturb iron distribution and contribute to anaemia. Methods A cross-sectional study of 80 MF and 23 ET patients was performed. Results About 35% of anaemic MF patients had functional iron deficiency (FID) with transferrin saturation amp;lt;20 and normal or elevated S-ferritin (amp;lt;500 mu g/L). In ET, FID was rare. In MF patients with FID, 70.6% were anaemic, vs 29.4% in patients without FID (P = 0.03). Hepcidin was significantly higher in MF patients with anaemia, including transfusion-dependent patients, 50.6 vs 24.4 mu g/L (P = 0.01). There was a significant negative correlation between Hb and inflammatory markers in all MF patients: IL-2, IL-6 and TNF-alpha, (P amp;lt; 0.01-0.03), LD (P = 0.004) and hepcidin (P = 0.03). These correlations were also seen in the subgroup of anaemic MF patients (Table ). Tsat correlated negatively with CRP (P amp;lt; 0.001). Symptom burden was heavier in MF patients with FID, and MPN-SAF quality of life scores correlated with IL-6 and CRP. Conclusions The inflammatory state of MF disturbs iron turnover, FID is common and contributes to anaemia development and impairment of QoL. Anaemic MF patients should be screened for FID.

  • 16.
    Bjerrum, Ole Weis
    et al.
    Rigshosp, Denmark.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ghanima, Waleed
    Univ Oslo, Norway; Univ Oslo, Norway.
    Kauppila, Marjut
    Turku Univ Hosp, Finland.
    Andersen, Christen Lykkegaard
    Rigshosp, Denmark; Roskilde Hosp, Denmark.
    Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms-Clinical practice among Nordic specialists2018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 5, p. 475-478Article in journal (Refereed)
    Abstract [en]

    Background: Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) have higher risks of developing thromboembolisms compared to the general population. International guidelines on the management of MPNs therefore include recommendations concerning thromboembolism prophylaxis. In clinical practice, strict adherence to guidelines may be challenging and dependent on factors such as physician experience, outpatient clinic setting, and access to therapy; however, no data exist on physician adherence or patient compliance to thromboembolism prophylaxis in MPNs. Objectives: The Nordic Myeloproliferative Neoplasm Study Group (NMPN) performed a survey among Nordic hematology specialists with the aim of documenting the implementation of international recommendations in a region of Northern Europe with similar healthcare systems. Results: The study showed that Nordic specialists managed their patients in accordance with international guidelines concerning medical intervention, but to a lesser degree regarding the management of additional cardiovascular risk factors. The survey also drew attention to the common clinical dilemma of combining antiaggregatory agents with vitamin K antagonists (VKA), or novel oral anticoagulants (NOAC), as well as phlebotomy limits in female polycythemia vera patients. Conclusions: The results of this study highlight the importance of considering all risk factors for thrombosis and an optimal collaboration with the primary healthcare sector.

  • 17.
    Björnsson, Jon Mar
    et al.
    Lund University, Department of Molecular Medicine.
    Larsson, Nina
    Lund University, Department of Molecular Medicine.
    Brun, Ann C. M.
    Lund University, Department of Molecular Medicine.
    Andersson, Elisabet
    Lund University, Department of Molecular Medicine.
    Lundström, Patrik
    Lund University, Department of Molecular Medicine.
    Larsson, Jonas
    Lund University, Department of Molecular Medicine.
    Repetowska, Ewa
    Lund University, Department of Molecular Medicine.
    Ehinger, Mats
    Lund University, Department of Molecular Medicine.
    Humphries, R. Keith
    University of British Columbia, Department of Medicine.
    Karlsson, Stefan
    Lund University, Department of Molecular Medicine.
    Reduced proliferative capacity of hematopoietic stem cells deficient in hoxb3 and hoxb42003In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 23, no 11, p. 3872-3883Article in journal (Refereed)
    Abstract [en]

    Several homeobox transcription factors, such as HOXB3 and HOXB4, have been implicated in regulation of hematopoiesis. In support of this, studies show that overexpression of HOXB4 strongly enhances hematopoietic stem cell regeneration. Here we find that mice deficient in both Hoxb3 and Hoxb4 have defects in endogenous hematopoiesis with reduced cellularity in hematopoietic organs and diminished number of hematopoietic progenitors without perturbing lineage commitment. Analysis of embryonic day 14.5 fetal livers revealed a significant reduction in the hematopoietic stem cell pool, suggesting that the reduction in cellularity observed postnatally is due to insufficient expansion during fetal development. Primitive Lin(-) Scal(+) c-kit(+) hematopoietic progenitors lacking Hoxb3 and Hoxb4 displayed impaired proliferative capacity in vitro. Similarly, in vivo repopulating studies of Hoxb3/Hoxb4-deficient hematopoietic cells resulted in lower repopulating capability compared to normal littermates. Since no defects in homing were observed, these results suggest a slower regeneration of mutant HSC. Furthermore, treatment with cytostatic drugs demonstrated slower cell cycle kinetics of hematopoietic stem cells deficient in Hoxb3 and Hoxb4, resulting in increased tolerance to antimitotic drugs. Collectively, these data suggest a direct physiological role of Hoxb4 and Hoxb3 in regulating stem cell regeneration and that these genes are required for maximal proliferative response.

  • 18.
    Blimark, Cecilie Hveding
    et al.
    Univ Gothenburg, Sweden; Skane Univ Hosp, Sweden.
    Turesson, Ingemar
    Skåne University Hospital, Lund-Malmö, Sweden.
    Genell, Anna
    Western Sweden Hlth Care Reg, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Björkstrand, Bo
    Karolinska Inst, Sweden.
    Carlson, Kristina
    Uppsala Univ Hosp, Sweden.
    Forsberg, Karin
    Umeå Univ Hosp, Sweden.
    Juliusson, Gunnar
    Lund Univ, Sweden.
    Linder, Olle
    Örebro Univ Hosp, Sweden.
    Mellqvist, Ulf-Henrik
    Univ Gothenburg, Sweden; Skane Univ Hosp, Sweden; Boras Hosp, Sweden.
    Nahi, Hareth
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Kristinsson, Sigurdur Y.
    Karolinska Inst, Sweden; Univ Iceland, Iceland; Karolinska Univ Hosp, Sweden.
    Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish Myeloma Registry2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 3, p. 506-513Article in journal (Refereed)
    Abstract [en]

    Epidemiology and outcome of myeloma are mainly reported from large university centers and collaborative groups, and do not represent real-world patients. The Swedish Myeloma Registry is a prospective population-based registry documenting characteristics, treatment and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose of improving disease management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first-line treatment in patients diagnosed up to 2014, with a follow up until December 2016. We present age-adjusted incidence, patients characteristics at baseline, treatment, response, and survival. Baseline data were available with a 97% coverage in 4904 patients (median age 71 years, males 70 years, females 73 years; 72% were 65 years or older), and at 1-year follow up in 3558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100,000 inhabi-ants per year. Among initially symptomatic patients (n= 3988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients aged up to 66 years, and to 22% of patients aged 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first-line treatment, rising from 31% in 2008 to 81% in 2014. In active myeloma, the median relative survival of patients aged 65 years or under was 7.7 years, and 3.4 years in patients aged 66 years and over. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (Pamp;lt;0.05), and with a significantly higher survival, with a Hazard Ratio (HR) of 0.84 (95% CI: 0.77-0.92; Pamp;lt;0.05). There was a small, but significant survival benefit in patients treated at university hospitals (HR 0.93; 95% CI: 0.87-0.99; Pamp;lt;0.05). We report here on a near complete real-world population of myeloma patients during an 8-year period; a period in which newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden is comparable to other large registry studies, and responses and survival improved during the study period.

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  • 19.
    Blomqvist, Anders
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Prostaglandin E-2 Production by Brain Endothelial Cells and the Generation of Fever2023In: DNA and Cell Biology, ISSN 1044-5498, E-ISSN 1557-7430, Vol. 42, no 3, p. 107-112Article in journal (Refereed)
    Abstract [en]

    We recently demonstrated that prostaglandin production in brain endothelial cells is both necessary and sufficient for the generation of fever during systemic immune challenge. I here discuss this finding in light of the previous literature and point to some unresolved issues.

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  • 20.
    Cantù, Claudio
    et al.
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Bosè, Francesca
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy / Department of Immunology, INGM-National Institute of Molecular Genetics, Milan, Italy.
    Bianchi, Paola
    Haematology Unit 2, Unit of Physiopathology of Anaemia, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy.
    Reali, Eva
    Department of Immunology, INGM-National Institute of Molecular Genetics, Milan, Italy.
    Colzani, Maria Teresa
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Cantù, Ileana
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Barbarani, Gloria
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Ottolenghi, Sergio
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Witke, Walter
    Institut of Genetics, University of Bonn, Bonn, Germany.
    Spinardi, Laura
    Scientific Direction, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy.
    Ronchi, Antonella Ellena
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Defective Erythroid Maturation In Gelsolin Mutant Mice2012In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 97, no 7, p. 980-988Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: During late differentiation, erythroid cells undergo profound changes involving actin filament remodeling. One of the proteins controlling actin dynamics is gelsolin, a calcium-activated actin filament severing and capping protein. Gelsolin-null (Gsn(-/-)) mice generated in a C57BL/6 background are viable and fertile.1

    DESIGN AND METHODS: We analyzed the functional roles of gelsolin in erythropoiesis by: (i) evaluating gelsolin expression in murine fetal liver cells at different stages of erythroid differentiation (using reverse transcription polymerase chain reaction analysis and immunohistochemistry), and (ii) characterizing embryonic and adult erythropoiesis in Gsn(-/-) BALB/c mice (morphology and erythroid cultures).

    RESULTS: In the context of a BALB/c background, the Gsn(-/-) mutation causes embryonic death. Gsn(-/-) embryos show defective erythroid maturation with persistence of circulating nucleated cells. The few Gsn(-/-) mice reaching adulthood fail to recover from phenylhydrazine-induced acute anemia, revealing an impaired response to stress erythropoiesis. In in vitro differentiation assays, E13.5 fetal liver Gsn(-/-) cells failed to undergo terminal maturation, a defect partially rescued by Cytochalasin D, and mimicked by administration of Jasplakinolide to the wild-type control samples.

    CONCLUSIONS: In BALB/c mice, gelsolin deficiency alters the equilibrium between erythrocyte actin polymerization and depolymerization, causing impaired terminal maturation. We suggest a non-redundant role for gelsolin in terminal erythroid differentiation, possibly contributing to the Gsn(-/-) mice lethality observed in mid-gestation.

  • 21.
    Carlstrom, Karl E.
    et al.
    Karolinska Inst, Sweden.
    Ewing, Ewoud
    Karolinska Inst, Sweden.
    Granqvist, Mathias
    Karolinska Inst, Sweden.
    Gyllenberg, Alexandra
    Karolinska Inst, Sweden.
    Aeinehband, Shahin
    Karolinska Inst, Sweden.
    Enoksson, Sara Lind
    Karolinska Univ Hosp, Sweden.
    Checa, Antonio
    Karolinska Inst, Sweden.
    Badam, Tejaswi
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering. Univ Skovde, Sweden.
    Huang, Jesse
    Karolinska Inst, Sweden.
    Gomez-Cabrero, David
    Univ Publ Nevarra UPNA, Spain.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Al Nimer, Faiez
    Karolinska Inst, Sweden.
    Wheelock, Craig E.
    Karolinska Inst, Sweden.
    Kockum, Ingrid
    Karolinska Inst, Sweden.
    Olsson, Tomas
    Karolinska Inst, Sweden.
    Jagodic, Maja
    Karolinska Inst, Sweden.
    Piehl, Fredrik
    Karolinska Inst, Sweden.
    Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes2019In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 3081Article in journal (Refereed)
    Abstract [en]

    Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

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  • 22.
    Christensen, Mathilde Egelund
    et al.
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Siersma, Volkert
    Univ Copenhagen, Denmark.
    Kriegbaum, Margit
    Univ Copenhagen, Denmark.
    Lind, Bent Struer
    Univ Copenhagen, Denmark; Copenhagen Univ Hosp, Denmark.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ostgard, Lene Sofie Granfeldt
    Odense Univ Hosp, Denmark; Aarhus Univ, Denmark.
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Andersen, Christen Lykkegaard
    Copenhagen Univ Hosp, Denmark; Univ Copenhagen, Denmark.
    Monocytosis in primary care and risk of haematological malignancies2023In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609Article in journal (Refereed)
    Abstract [en]

    Monocytosis (>= 0.5 x 10(9)/L in peripheral blood) is the hallmark of chronic myelomonocytic leukaemia (CMML) but may be present in a spectrum of diseases including other haematological malignancies. In the primary care sector, monocytosis is a relatively common finding, but its predictive value for haematological malignancy is unknown. We included 663 184 adult primary care patients from the greater Copenhagen area with one or more differential cell counts registered between 2000 and 2016 and followed them in the extensive nationwide Danish health data registers for 3 years after blood sampling. We used logistic regression to model the risk of haematological malignancy and death following monocytosis. Monocytosis was associated with an increased risk of all types of haematological malignancy with the greatest relative risk increase observed in CMML with an OR of 105.22 (95% confidence interval: 38.27-289.30). Sustained monocytosis (at least two requisitions in 3 months) further increased CMML risk, although the diagnosis was still very rare, that is, observed in only 0.1% of these individuals. Outside the haematological setting, the absolute risk of haematological malignancy associated with monocytosis is low and haematological malignancy should mainly be suspected when monocytosis is sustained or the clinical presentation raises suspicion of malignancy.

  • 23.
    Czerw, Tomasz
    et al.
    Maria Sklodowska Curie Natl Res Inst Oncol, Poland.
    Iacobelli, Simona
    Tor Vergata Univ, Italy.
    Malpassuti, Vittoria
    Tor Vergata Univ, Italy.
    Koster, Linda
    EBMT Data Off, Netherlands.
    Kroeger, Nicolaus
    Univ Hosp Eppendorf, Germany.
    Robin, Marie
    Univ Paris, France.
    Maertens, Johan
    Univ Hosp Gasthuisberg, Belgium.
    Chevallier, Patrice
    CHU Nantes, France.
    Watz, Emma
    Karolinska Univ Hosp, Sweden.
    Poire, Xavier
    Clin Univ St Luc, Belgium.
    Snowden, John A.
    Sheffield Teaching Hosp NHS Trust, England.
    Kuball, Jurgen
    Univ Med Ctr, Netherlands.
    Kinsella, Francesca
    Univ Hosp Birmingham NHS Trust, England.
    Blaise, Didier
    Inst Paoli Calmettes, France.
    Remenyi, Peter
    Del Pesti Centrumkorhaz, Hungary.
    Mear, Jean-Baptiste
    Ctr Hosp Univ Rennes, France.
    Cammenga, Jörg
    Linköping University, Department of Biomedical and Clinical Sciences, 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.
    Rubio, Marie Therese
    CHRU BRABOIS, France.
    Maury, Sebastien
    Hop Henri Mondor, France.
    Daguindau, Etienne
    Hop Jean Minjoz, France.
    Finnegan, Damian
    Belfast City Hosp, North Ireland.
    Hayden, Patrick
    St James Hosp, Ireland.
    Carlos Hernandez-Boluda, Juan
    Univ Valencia, Spain.
    McLornan, Donal
    Guys & St Thomas NHS Fdn Trust, England; Univ Coll London Hosp, England.
    Yakoub-Agha, Ibrahim
    Univ Lille, France.
    Impact of donor-derived CD34+infused cell dose on outcomes of patients undergoing allo-HCT following reduced intensity regimen for myelofibrosis: a study from the Chronic Malignancies Working Party of the EBMT2022In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 57, p. 261-270Article in journal (Refereed)
    Abstract [en]

    The optimal CD34 + cell dose in the setting of RIC allo-HCT for myelofibrosis (MF) remains unknown. We retrospectively analyzed 657 patients with primary or secondary MF transplanted with use of peripheral blood (PB) stem cells after fludarabine/melphalan or fludarabine/busulfan RIC regimen. Median patient age was 58 (range, 22-76) years. Donors were HLA-identical sibling (MSD) or unrelated (UD). Median follow-up was 46 (2-194) months. Patients transplanted with higher doses of CD34 + cells (>7.0 x 10(6)/kg), had an increased chance of achievement of both neutrophil (hazard ratio (HR), 1.46; P < 0.001) and platelet engraftment (HR, 1.43; P < 0.001). In a model with interaction, for patients transplanted from a MSD, higher CD34 + dose was associated with improved overall survival (HR, 0.63; P = 0.04) and relapse-free survival (HR, 0.61; P = 0.02), lower risk of non-relapse mortality (HR, 0.57; P = 0.04) and higher rate of platelet engraftment. The combined effect of higher cell dose and UD was apparent only for higher neutrophil and platelet recovery rate. We did not document any detrimental effect of high CD34 + dose on transplant outcomes. More bulky splenomegaly was an adverse factor for survival, engraftment and NRM. Our analysis suggests a potential benefit for MF patients undergoing RIC PB-allo-HCT receiving more than 7.0 x 10(6)/kg CD34 + cells.

  • 24.
    Czerw, Tomasz
    et al.
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Labopin, Myriam
    Hop St Antoine, France; INSERM, France; University of Paris 06, France.
    Schmid, Christoph
    University of Munich, Germany.
    Cornelissen, Jan J.
    Erasmus University, Netherlands.
    Chevallier, Patrice
    CHU Nantes, France.
    Blaise, Didier
    Institute J Paoli I Calmettes, France.
    Kuball, Juergen
    University of Medical Centre, Netherlands.
    Vigouroux, Stephane
    Hop Haut Leveque, France.
    Garban, Frederic
    Hop A Michallon, France.
    Lioure, Bruno
    Nouvel Hop Civil, France.
    Fegueux, Nathalie
    CHU Lapeyronie, France.
    Clement, Laurence
    Centre Hospital University of CHU Nancy, France.
    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.
    Maertens, Johan
    University Hospital Gasthuisberg, Belgium.
    Guillerm, Gaelle
    CHU Morvan, France.
    Bordessoule, Dominique
    CHRU Limoges, France.
    Mohty, Mohamad
    Hop St Antoine, France; INSERM, France; University of Paris 06, France.
    Nagler, Arnon
    Hop St Antoine, France; Chaim Sheba Medical Centre, Israel.
    High CD3+and CD34+peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia - an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation2016In: Oncotarget, E-ISSN 1949-2553, Vol. 7, no 19, p. 27255-27266Article in journal (Refereed)
    Abstract [en]

    Inconsistent results have been reported regarding the influence of graft composition on the incidence of graft versus host disease (GVHD), disease control and survival after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell transplantation (allo-PBSCT). These discrepancies may be at least in part explained by the differences in disease categories, disease status at transplant, donor type and conditioning. The current retrospective EBMT registry study aimed to analyze the impact of CD3+ and CD34+ cells dose on the outcome of RIC allo-PBSCT in patients with acute myelogenous leukemia (AML) in first complete remission, allografted from HLA-matched unrelated donors (10 of 10 match). We included 203 adults. In univariate analysis, patients transplanted with the highest CD3+ and CD34+ doses (above the third quartile cut-off point values, amp;gt;347 x 10amp;lt;^amp;gt;6/kg and amp;gt;8.25 x 10amp;lt;^amp;gt;6/kg, respectively) had an increased incidence of grade III-IV acute (a) GVHD (20% vs. 6%, P = .003 and 18% vs. 7%, P = .02, respectively). There was no association between cellular composition of grafts and transplant-related mortality, AML relapse, incidence of chronic GVHD and survival. Neither engraftment itself nor the kinetics of engraftment were affected by the cell dose. In multivariate analysis, CD3+ and CD34+ doses were the only adverse predicting factors for grade III-IV aGVHD (HR = 3.6; 95% CI: 1.45-9.96, P = .006 and 2.65 (1.07-6.57), P = .04, respectively). These results suggest that careful assessing the CD3+ and CD34+ graft content and tailoring the cell dose infused may help in reducing severe acute GVHD risk without negative impact on the other transplantation outcomes.

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  • 25.
    Derolf, Asa
    et al.
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Juliusson, Gunnar
    Skane Univ Hosp, Sweden.
    Benson, Lina
    Epidemiol and Reg Oncol Ctr Stockholm, Sweden.
    Floisand, Yngvar
    Oslo Univ Hosp, Norway.
    Lazarevic, Vladimir
    Skane Univ Hosp, Sweden.
    Antunovic, Petar
    Linköping University, Department of Biomedical and Clinical Sciences, 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.
    Mollgard, Lars
    Sahlgrens Univ Hosp, Sweden.
    Lehmann, Soren
    Uppsala Univ, Sweden.
    Uggla, Bertil
    Orebro Univ Hosp, Sweden.
    Wahlin, Anders
    Umea Univ, Sweden.
    Hoglund, Martin
    Uppsala Univ, Sweden.
    Deneberg, Stefan
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Letter: Decreasing early mortality in acute myeloid leukaemia in Sweden 1997-2014: improving performance status is a major contributing factor in BRITISH JOURNAL OF HAEMATOLOGY, vol 188, issue 1, pp 187-1912020In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 188, no 1, p. 187-191Article in journal (Other academic)
    Abstract [en]

    n/a

  • 26.
    Diallo, Idrissa
    et al.
    CHU Quebec, Canada; Univ Laval, Canada.
    Benmoussa, Abderrahim
    CHU Quebec, Canada; Univ Laval, Canada.
    Laugier, Jonathan
    CHU Quebec, Canada; Univ Laval, Canada.
    Osman, Abdimajid
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Hitzler, Walter E.
    Johannes Gutenberg Univ Mainz, Germany.
    Provost, Patrick
    CHU Quebec, Canada; Univ Laval, Canada.
    Platelet Pathogen Reduction Technologies Alter the MicroRNA Profile of Platelet-Derived Microparticles2020In: Frontiers in Cardiovascular Medicine, E-ISSN 2297-055X, Vol. 7, article id 31Article in journal (Refereed)
    Abstract [en]

    Despite improvements in donor screening and increasing efforts to avoid contamination and the spread of pathogens in clinical platelet concentrates (PCs), the risks of transfusion-transmitted infections remain important. Relying on an ultraviolet photo activation system, pathogen reduction technologies (PRTs), such as Intercept and Mirasol, utilize amotosalen, and riboflavin (vitamin B2), respectively, to mediate inactivation of pathogen nucleic acids. Although they are expected to increase the safety and prolong the shelf life of clinical PCs, these PRTs might affect the quality and function of platelets, as recently reported. Upon activation, platelets release microparticles (MPs), which are involved in intercellular communications and regulation of gene expression, thereby mediating critical cellular functions. Here, we have used small RNA sequencing (RNA-Seq) to document the effect of PRT treatment on the microRNA profiles of platelets and derived MPs. PRT treatment did not affect the microRNA profile of platelets. However, we observed a specific loading of certain microRNAs into platelet MPs, which was impaired by treatment with Intercept or its Additive solution (SSP+). Whereas, Intercept had an impact on the microRNA profile of platelet-derived MPs, Mirasol did not impact the microRNA profile of platelets and derived MPs, compared to non-treated control. Considering that platelet MPs are able to transfer their microRNA content to recipient cells, and that this content may exert biological activities, those findings suggest that PRT treatment of clinical PCs may modify the bioactivity of the platelets and MPs to be transfused and argue for further investigations into PRT-induced changes in clinical PC content and function.

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  • 27.
    Dolinska, Monika
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Cai, Huan
    Karolinska Institute, Stockholm, Sweden.
    Mansson, Alma
    Karolinska Institute, Stockholm, Quebec, Sweden.
    Shen, Jingyi
    Karolinska Institute, Stockholm, Sweden.
    Xiao, Pingnan
    Karolinska Institute, Stockholm, Sweden.
    Bouderlique, Thibault
    Karolinska, Sweden.
    Li, Xidan
    Karolinska Institute, Stockholm, Alabama, Sweden.
    Leonard, Elory
    Karolinska Institute, Stockholm, Sweden.
    Chang, Marcus
    Karolinska Institute, Stockholm, Sweden.
    Gao, Yuchen
    Karolinska Institute, Stockholm, Sweden.
    Medina Giménez, Juan Pablo
    Karolinska Institute, Stockholm, Sweden.
    Kondo, Makoto
    Karolinska, Sweden.
    Sandhow, Lakshmi
    Karolinska Institute, Stockholm, Sweden.
    Johansson, Anne-Sofie
    Karolinska Institutet, Huddinge, Sweden.
    Deneberg, Stefan
    Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Söderlund, Stina
    Uppsala University Hospital.
    Jädersten, Martin
    Karolinska Institutet, Stockholm, Sweden.
    Ungerstedt, Johanna S
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Armenia.
    Tobiasson, Magnus
    Karolinska Institute, Stockholm, Sweden.
    Östman, Arne
    Karolinska Institute, Stockholm, Sweden.
    Mustjoki, Satu
    University of Helsinki, Helsinki, Finland.
    Stenke, Leif
    Dept of Hematology, Stockholm, Sweden.
    Le Blanc, Katarina
    Karolinska Institutet, Stockholm, Sweden.
    Hellstrom-Lindberg, Eva S
    Karolinska Institutet, Stockholm, Sweden.
    Lehmann, Sören
    Karolinska, Sweden.
    Ekblom, Marja
    Lund Stem Cell Center, Lund, Sweden.
    Olsson-Strömberg, Ulla
    University Hospital, Uppsala, Sweden.
    Sigvardsson, Mikael
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
    Qian, Hong
    Karolinska Institute, Stockholm, Sweden.
    Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option2023In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 142, no 1, p. 73-89Article in journal (Refereed)
    Abstract [en]

    Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.

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  • 28.
    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, Health care Center 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. Division of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Sweden.
    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.

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  • 29.
    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. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Strandberg, Maria
    Sundsvall Hosp, Sweden.
    Osterborg, Anders
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hansson, Lotta
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    First-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.

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  • 30. Order onlineBuy this publication >>
    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.

    List of papers
    1. Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability
    Open this publication in new window or tab >>Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability
    2006 (English)In: Journal of Stem Cells, ISSN 1556-8539, Vol. 1, no 4, p. 247-257Article in journal (Refereed) Published
    Abstract [en]

    Self-renewal is a prerequisite for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow throughout adult life. Cytokines are mainly providing pro-survival signals of HSC, whereas low oxygen levels (hypoxia) were recently shown to influence self-renewal. In contrast, the effects on other progenitor cell types is not clear. In the present work, we have analyzed whether hypoxia has any effects on mouse multipotent progenitors. When bone marrow-derived Lin-Sca1+c-kit+ (LSK) cells were kept in hypoxic cultures (1% O2 ) for 4 days together with cytokines, the numbers of colony forming high-proliferative progenitors (HPP-CFC) and precursors for cobble-stone forming cells (CAFC) were increased compared to normoxic conditions. A similar effect was seen with pre-CFCmulti from unfractionated bone marrow, whereas more committed progenitors (CFU-GM) were expanded better in normoxia compared to hypoxia. The observed increase in numbers of primitive colony-forming progenitor cells was associated with maintenance of the c-kit/Sca-1 phenotype and a preferential expansion of immature  blast-like appearing cells. The results suggest that a major function of hypoxia is to regulate differentiation by increased self-renewal. Furthermore, in cultures of limited cytokine supply, survival of the stem cell-like cell line FDCP-mix was increased during hypoxia. Thus, hypoxia allows for better survival and self-renewal of multipotent progenitors and HSCs from adult bone marrow. Such culture conditions may have beneficial clinical implications for ex vivo purposes and may improve the yields of stem cells and early progenitors.

    Place, publisher, year, edition, pages
    Nova Science Publishers, Inc., 2006
    Keywords
    Hematopoiesis, Stem cells, Progenitor, Hypoxia, Survival, Self-renewal
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17713 (URN)
    Note

    Original Publication: Pernilla Eliasson, Richard Karlsson and Jan-Ingvar Jönsson, Hypoxia Expands Primitive Hematopoietic Progenitor Cellsfrom Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability, 2006, Journal of Stem Cells, (1), 4, 247-257. https://www.novapublishers.com/catalog/editorial.php?products_id=3730 Copyright: Nova Science Publishers https://www.novapublishers.com/

    Available from: 2009-04-16 Created: 2009-04-16 Last updated: 2018-05-29Bibliographically approved
    2. Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture
    Open this publication in new window or tab >>Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture
    Show others...
    2010 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 38, no 4, p. 301-310Article in journal (Refereed) Published
    Abstract [en]

    Objective. Recent evidence suggests that hematopoietic stem cells (HSCs) in the bone marrow (BM) are located in areas where the environment is hypoxic. Although previous studies have demonstrated positive effects by hypoxia, its role in HSC maintenance has not been fully elucidated, neither has the molecular mechanisms been delineated. Here, we have investigated the consequence of in vitro incubation of HSCs in hypoxia prior to transplantation and analyzed the role of hypoxia-inducible factor (HIF)-1 alpha. Materials and Methods. HSC and progenitor populations isolated from mouse BM were cultured in 20% or 1% O-2, and analyzed for effects on cell cycle, expression of cyclin-dependent kinase inhibitors genes, and reconstituting ability to lethally irradiated mice. The involvement of HIF-1 alpha was studied using methods of protein stabilization and gene silencing. Results. When long-term FLT3(-)CD34(-)Lin(-)Sca-1(+)c-Kit(+) (LSK) cells were cultured in hypoxia, cell numbers were significantly reduced in comparison to normoxia. This was due to a decrease in proliferation and more cells accumulating in G(0). Moreover, the proportion of HSCs with long-term engraftment potential was increased. Whereas expression of the cyclin-dependent kinase inhibitor genes p21(cip1), p27(Kip1), and p57(Kip2) increased in LSK cells by hypoxia, only p21(cip1) was upregulated in FLT3(-)CD34(-)LSK cells. We could demonstrate that expression of p27(KiP1) and p57(Kip2) was dependent of HIF-1 alpha. Surprisingly, overexpression of constitutively active HIF-1 alpha or treatment with the HIF stabilizer agent FG-4497 led to a reduction in HSC reconstituting ability. Conclusions. Our results imply that hypoxia, in part via HIF-1 alpha, maintains HSCs by decreasing proliferation and favoring quiescence.

    Place, publisher, year, edition, pages
    Elsevier, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-54780 (URN)10.1016/j.exphem.2010.01.005 (DOI)000276054300005 ()
    Note

    Original Publication: Pernilla Eliasson, Matilda Rehn, Petter Hammar, Peter Larsson, Oksana Sirenko, Lee A Flippin, Jorg Cammenga and Jan-Ingvar Jönsson, Hypoxia mediates low cell-cycle activity and increases the proportion of long-term reconstituting hematopoietic stem cells during in vitro culture, 2010, EXPERIMENTAL HEMATOLOGY, (38), 4, 301-310. http://dx.doi.org/10.1016/j.exphem.2010.01.005 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/

    On the day of the defence date the title of this article was "Hypoxia, via hypoxia-inducible factor (HIF)-1, mediates low cell cycle activity and preserves the engraftment potential of mouse hematopoietic stem cells" and one of the authors is no longer included in the article.

    When finally published online the title of this article changed name to Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture.

    Available from: 2010-04-09 Created: 2010-04-09 Last updated: 2024-01-10Bibliographically approved
    3. Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability
    Open this publication in new window or tab >>Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    A balanced regulation of the ability of hematopoietic stem cells (HSCs) to undergo self-renewal and give rise to new blood cells is crucial for blood homeostasis. Recent studies utilizing genetically modified mice have demonstrated that reactive oxygen species (ROS) damage cellular functions and decrease the lifespan of long-term (LT) HSCs. These LT-HSCs are predominately located in a low-oxygen, or hypoxic, niche, essential for maintaining stem cell capacities. Here, we show that hypoxic culturing rescues HSCs from oxidative stress-induced cell death. Hypoxia inducible factor (HIF)-1 and its target gene pyruvate dehydrogenase kinase 1 (PDK1) were both crucial for survival and long term repopulating ability of HSCs, but less important for hypoxic resistance towards oxidative stress. Moreover, hypoxia increased the expression of Foxo3a, a transcription factor important in adaption to stress stimuli. In conclusion, hypoxia protects LT-HSCs from oxidative stress, possibly by multiple mechanisms, where Foxo3a is likely to play a central role.

    Keywords
    Hematopoiesis, Stem cells, Progenitor, Hypoxia, Hypoxia-inducible factor 1 alpha, oxidative stress, Puruvate dehydrogenase kinase 1
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-52941 (URN)
    Available from: 2010-01-13 Created: 2010-01-13 Last updated: 2018-10-08
    4. BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.
    Open this publication in new window or tab >>BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.
    Show others...
    2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 10, p. 2302-2311Article in journal (Refereed) Published
    Abstract [en]

    Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD–mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapototic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras–mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition.

     

    Place, publisher, year, edition, pages
    Washington, D.C: The American Society of Hematology, 2009
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-52728 (URN)10.1182/blood-2008-07-167023 (DOI)
    Available from: 2010-01-11 Created: 2010-01-11 Last updated: 2018-01-12
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    Live and Let Die : Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells
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  • 31.
    El-Serafi, Ahmed
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Suez Canal Univ, Egypt.
    He, Rui
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Zheng, Wenyi
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Benkossou, Fadwa
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Oerther, Sandra
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Zhao, Ying
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Mellgren, Karin
    Sahlgrens Univ Hosp, Sweden.
    Gustafsson, Britt
    Karolinska Inst, Sweden.
    Heilmann, Carsten
    Natl Univ Hosp, Denmark.
    Kanerva, Jukka
    HUS Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Lotfi, Kourosh
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology.
    Toporski, Jacek
    Skane Univ Hosp, Sweden.
    Sundin, Mikael
    Karolinska Inst, Sweden; Astrid Lindgren Childrens Hosp, Sweden.
    Hoglund, Martin
    Uppsala Univ, Sweden.
    Mattsson, Jonas
    Univ Toronto, Canada; Princess Margaret Canc Ctr, Canada; Karolinska Inst, Sweden.
    El-Serafi, Ibrahim
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Inst, Sweden; Port Said Univ, Egypt.
    Hassan, Moustapha
    Karolinska Inst, Sweden; Karolinska Univ Hosp Huddinge, Sweden; Karolinska Univ Hosp Huddinge, Sweden.
    Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study2021In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 56, p. 807-817Article in journal (Refereed)
    Abstract [en]

    Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.

  • 32.
    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.

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  • 33.
    Engvall, Marie
    et al.
    Uppsala Univ, Sweden.
    Karlsson, Ylva
    Uppsala Univ, Sweden.
    Kuchinskaya, Ekaterina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Jörnegren, Åsa
    Örebro Univ Hosp, Sweden.
    Mathot, Lucy
    Uppsala Univ, Sweden.
    Pandzic, Tatjana
    Uppsala Univ, Sweden.
    Palle, Josefine
    Uppsala Univ, Sweden.
    Ljungström, Viktor
    Uppsala Univ, Sweden.
    Cavelier, Lucia
    Uppsala Univ, Sweden.
    Lindberg, Eva Hellström
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Cammenga, Jörg
    Linköping University, Department of Biomedical and Clinical Sciences, 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.
    Baliakas, Panagiotis
    Uppsala Univ, Sweden.
    Familial platelet disorder due to germline exonic deletions in RUNX1: a diagnostic challenge with distinct alterations of the transcript isoform equilibrium2022In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 63, no 10, p. 2311-2320Article in journal (Refereed)
    Abstract [en]

    Germline pathogenic variants in RUNX1 are associated with familial platelet disorder with predisposition to myeloid malignancies (FPD/MM) with intragenic deletions in RUNX1 accounting for almost 7% of all reported variants. We present two new pedigrees with FPD/MM carrying two different germline RUNX1 intragenic deletions. The aforementioned deletions encompass exons 1-2 and 9-10 respectively, with the exon 9-10 deletion being previously unreported. RNA sequencing of patients carrying the exon 9-10 deletion revealed a fusion with LINC00160 resulting in a change in the 3 sequence of RUNX1. Expression analysis of the transcript isoform demonstrated altered RUNX1a/b/c ratios in carriers from both families compared to controls. Our data provide evidence on the impact of intragenic RUNX1 deletions on transcript isoform expression and highlight the importance of routinely performing copy number variant analysis in patients with suspected MM with germline predisposition.

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  • 34.
    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 , E-ISSN 2473-9537, 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.

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  • 35.
    Flygt, Hjalmar
    et al.
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Sandin, Fredrik
    Reg Canc Ctr, Sweden.
    Dahlen, Torsten
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lubking, Anna
    Skane Univ Hosp, Sweden.
    Markevarn, Berit
    Univ Hosp, Sweden.
    Myhr-Eriksson, Kristina
    Sunderby Hosp, Sweden.
    Olsson, Karin
    Reg Canc Ctr, Sweden.
    Olsson-Stromberg, Ulla
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Sjalander, Anders
    Umea Univ, Sweden.
    Soderlund, Stina
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Sweden.
    Wadenvik, Hans
    Sahlgrens Univ Hosp, Sweden.
    Stenke, Leif
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Hoglund, Martin
    Univ Hosp, Sweden; Univ Hosp, Sweden.
    Richter, Johan
    Skane Univ Hosp, Sweden.
    Successful tyrosine kinase inhibitor discontinuation outside clinical trials - data from the population-based Swedish chronic myeloid leukaemia registry2021In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 193, no 5, p. 915-921Article in journal (Refereed)
    Abstract [en]

    Clinical trials show that tyrosine kinase inhibitor (TKI) treatment can be discontinued in selected patients with chronic myeloid leukaemia (CML). Although updated CML guidelines support such procedure in clinical routine, data on TKI stopping outside clinical trials are limited. In this retrospective study utilising the Swedish CML registry, we examined TKI discontinuation in a population-based setting. Out of 584 patients diagnosed with chronic-phase CML (CML-CP) in 2007-2012, 548 had evaluable information on TKI discontinuation. With a median follow-up of nine years from diagnosis, 128 (23%) discontinued TKI therapy (>= 1 month) due to achieving a DMR (deep molecular response) and 107 (20%) due to other causes (adverse events, allogeneic stem cell transplant, pregnancy, etc). Among those stopping in DMR, 49% re-initiated TKI treatment (median time to restart 4 center dot 8 months). In all, 38 patients stopped TKI within a clinical study and 90 outside a study. After 24 months 41 center dot 1% of patients discontinuing outside a study had re-initiated TKI treatment. TKI treatment duration pre-stop was longer and proportion treated with second-generation TKI slightly higher outside studies, conceivably affecting the clinical outcome. In summary we show that TKI discontinuation in CML in clinical practice is common and feasible and may be just as successful as when performed within a clinical trial.

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  • 36.
    Flygt, Hjalmar
    et al.
    Univ Uppsala Hosp, Sweden; Univ Uppsala Hosp, Sweden.
    Söderlund, Stina
    Univ Uppsala Hosp, Sweden; Univ Uppsala Hosp, Sweden.
    Stentoft, Jesper
    Aarhus Univ Hosp, Denmark.
    Richter, Johan
    Skane Univ Hosp, Sweden.
    Koskenvesa, Perttu
    Univ Helsinki, Finland; Univ Helsinki, Finland.
    Mustjoki, Satu
    Univ Helsinki, Finland; Univ Helsinki, Finland; Univ Helsinki, Finland; Univ Helsinki, Finland.
    Majeed, Waleed
    Stavanger Univ Hosp, Norway.
    Lubking, Anna
    Skane Univ Hosp, Sweden.
    Dreimane, Arta
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Markevarn, Berit
    Umea Univ Hosp, Sweden.
    Stenke, Leif
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Myhr Eriksson, Kristina
    Sunderby Hosp, Sweden.
    Gjertsen, Bjorn Tore
    Haukeland Hosp, Norway.
    Gedde-Dahl, Tobias
    Natl Hosp Norway, Norway.
    Dimitrijevic, Andreja
    Odense Univ Hosp, Denmark.
    Udby, Lene
    Zealand Univ Hosp, Denmark.
    Olsson-Strömberg, Ulla
    Univ Uppsala Hosp, Sweden; Univ Uppsala Hosp, Sweden.
    Hjorth-Hansen, Henrik
    St Olavs Hosp Trondheim, Norway; Norwegian Univ Sci & Technol, Norway.
    Long-term tolerability and efficacy after initial PegIFN-alpha addition to dasatinib in CML-CP: Five-year follow-up of the NordCML007 study2021In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 107, no 6, p. 617-623Article in journal (Refereed)
    Abstract [en]

    Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-alpha in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-alpha (PegIFN-alpha) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 mu g/wk of PegIFN-alpha was added and increased to 25 mu g/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-alpha to DAS shows good long-term efficacy without increased toxicity.

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  • 37.
    Friesen, C.
    et al.
    UNIV HEIDELBERG,CHILDRENS HOSP,W-6900 HEIDELBERG,GERMANY .
    Herr, I.
    UNIV HEIDELBERG,CHILDRENS HOSP,W-6900 HEIDELBERG,GERMANY .
    Los, Marek Jan
    GERMAN CANC RES CTR,DIV MOLEC ONCOL,D-69120 HEIDELBERG,GERMANY.
    Debatin, K. M.
    GERMAN CANC RES CTR,DIV MOLEC ONCOL,D-69120 HEIDELBERG,GERMANY.
    Drug induced cytotoxicity in leukemia cells involves the CD95 (APO-1/FAS) pathway of apoptosis1996In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 93, p. 367-367Article in journal (Refereed)
  • 38.
    Frödin, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Fomichov, Victoria
    Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Juliusson, G.
    Lund University, Sweden; Lund University, Sweden.
    Börjeson, Sussanne
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health.
    Frequent and long-term follow-up of health-related quality of life following allogeneic haematopoietic stem cell transplantation2015In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 24, no 6, p. 898-910Article in journal (Refereed)
    Abstract [en]

    Health-related quality of life (HRQL) was evaluated in 94 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative (MAC, n=18) or reduced intensity conditioning (RIC, n=76). HRQL was assessed with the EORTC QLQ C-30 during the inpatient period as well as during the following 3years, i.e. at baseline and 12 times thereafter. Functional status and global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first 3weeks, particularly appetite loss, nausea and vomiting, diarrhoea and fatigue. It took at least 1year for HRQL to return to the baseline level. The only function that improved significantly 3years after HSCT was role function. Patients treated with MAC experienced significantly worse HRQL at baseline than patients treated with RIC, as well as more pain, sleep disturbance and appetite loss in weeks 3 and 4. Patients with extensive chronic graft-versus-host disease experienced reduced HRQL. These results provide a clinically useful overview of patients HRQL during and after HSCT and indicate when they require increased support. The results demonstrate the importance of close follow-ups during the first year after HSCT to improve preventive or supportive interventions.

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  • 39.
    Fulda, S.
    et al.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    Friesen, C.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Benedict, M.
    UNIV MICHIGAN,SCH MED,DEPT PATHOL,ANN ARBOR,MI.
    Nunez, G.
    UNIV MICHIGAN,SCH MED,DEPT PATHOL,ANN ARBOR,MI.
    Peter, M. E.
    UNIV ULM, CHILDRENS HOSP, ULM, GERMANY .
    Debatin, K. M.
    GERMAN CANC RES CTR,D-6900 HEIDELBERG,GERMANY.
    CD95 (APO-1/Fas)- and p53-independent apoptosis by betulinic acid involves mitochondrial alterations and activation of caspases.1997In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 90, no 10, p. 2207-2207Article in journal (Refereed)
  • 40.
    Garcia Gonzalez, Javier
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Hernandez, Frank J
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Nuclease activity: an exploitable biomarker in bacterial infections2022In: Expert Review of Molecular Diagnostics, ISSN 1473-7159, E-ISSN 1744-8352, Vol. 22, no 3, p. 265-294Article in journal (Refereed)
    Abstract [en]

    Introduction In the increasingly challenging field of clinical microbiology, diagnosis is a cornerstone whose accuracy and timing are crucial for the successful management, therapy, and outcome of infectious diseases. Currently employed biomarkers of infectious diseases define the scope and limitations of diagnostic techniques. As such, expanding the biomarker catalog is crucial to address unmet needs and bring about novel diagnostic functionalities and applications. Areas covered This review describes the extracellular nucleases of 15 relevant bacterial pathogens and discusses the potential use of nuclease activity as a diagnostic biomarker. Articles were searched for in PubMed using the terms: nuclease, bacteria, nuclease activity or biomarker. For overview sections, original and review articles between 2000 and 2019 were searched for using the terms: infections, diagnosis, bacterial, burden, challenges. Informative articles were selected. Expert opinion Using the catalytic activity of nucleases offers new possibilities compared to established biomarkers. Nucleic acid activatable reporters in combination with different transduction platforms and delivery methods can be used to detect disease-associated nuclease activity patterns in vitro and in vivo for prognostic and diagnostic applications. Even when these patterns are not obvious or of unknown etiology, screening platforms could be used to identify new disease reporters.

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  • 41.
    Gauert, Anton
    et al.
    Charite Univ Med Berlin, Germany.
    Olk, Nadine
    Charite Univ Med Berlin, Germany.
    Pimentel-Gutierrez, Helia
    Charite Univ Med Berlin, Germany; German Canc Res Ctr, Germany.
    Astrahantseff, Kathy
    Charite Univ Med Berlin, Germany.
    Jensen, Lasse
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Eggert, Angelika
    Charite Univ Med Berlin, Germany; German Canc Res Ctr, Germany.
    Eckert, Cornelia
    Charite Univ Med Berlin, Germany; German Canc Res Ctr, Germany.
    Hagemann, Anja I. H.
    Charite Univ Med Berlin, Germany.
    Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia2020In: Cancers, ISSN 2072-6694, Vol. 12, no 7, article id 1883Article in journal (Refereed)
    Abstract [en]

    Only half of patients with relapsed B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) currently survive with standard treatment protocols. Predicting individual patient responses to defined drugs prior to application would help therapy stratification and could improve survival. With the purpose to aid personalized targeted treatment approaches, we developed a human-zebrafish xenograft (ALL-ZeFiX) assay to predict drug response in a patient in 5 days. Leukemia blast cells were pericardially engrafted into transiently immunosuppressedDanio rerioembryos, and engrafted embryos treated for the test case, venetoclax, before single-cell dissolution for quantitative whole blast cell analysis. Bone marrow blasts from patients with newly diagnosed or relapsed BCP-ALL were successfully expanded in 60% of transplants in immunosuppressed zebrafish embryos. The response of BCP-ALL cell lines to venetoclax in ALL-ZeFiX assays mirrored responses in 2D cultures. Venetoclax produced varied responses in patient-derived BCP-ALL grafts, including two results mirroring treatment responses in two refractory BCP-ALL patients treated with venetoclax. Here we demonstrate proof-of-concept for our 5-day ALL-ZeFiX assay with primary patient blasts and the test case, venetoclax, which after expanded testing for further targeted drugs could support personalized treatment decisions within the clinical time window for decision-making.

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  • 42.
    Grahn, Tan Hooi Min
    et al.
    Lund Univ Hosp, Sweden.
    Niroula, Abhishek
    Lund Univ, Sweden.
    Vegvari, Akos
    Karolinska Inst, Sweden.
    Oburoglu, Leal
    Lund Univ Hosp, Sweden.
    Pertesi, Maroulio
    Lund Univ, Sweden.
    Warsi, Sarah
    Lund Univ Hosp, Sweden.
    Safi, Fatemeh
    Lund Univ Hosp, Sweden.
    Miharada, Natsumi
    Lund Univ Hosp, Sweden.
    Garcia, Sandra C.
    Univ Calif Los Angeles, CA USA.
    Siva, Kavitha
    Lund Univ Hosp, Sweden.
    Liu, Yang
    Lund Univ Hosp, Sweden.
    Rörby, Emma
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Bjorn
    Lund Univ, Sweden.
    Zubarev, Roman A.
    Karolinska Inst, Sweden.
    Karlsson, Stefan
    Lund Univ Hosp, Sweden.
    S100A6 is a critical regulator of hematopoietic stem cells2020In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 34, p. 3323-3337Article in journal (Refereed)
    Abstract [en]

    The fate options of hematopoietic stem cells (HSCs) include self-renewal, differentiation, migration, and apoptosis. HSCs self-renewal divisions in stem cells are required for rapid regeneration during tissue damage and stress, but how precisely intracellular calcium signals are regulated to maintain fate options in normal hematopoiesis is unclear. S100A6 knockout (KO) HSCs have reduced total cell numbers in the HSC compartment, decreased myeloid output, and increased apoptotic HSC numbers in steady state. S100A6KO HSCs had impaired self-renewal and regenerative capacity, not responding to 5-Fluorouracil. Our transcriptomic and proteomic profiling suggested that S100A6 is a critical HSC regulator. Intriguingly, S100A6KO HSCs showed decreased levels of phosphorylated Akt (p-Akt) and Hsp90, with an impairment of mitochondrial respiratory capacity and a reduction of mitochondrial calcium levels. We showed that S100A6 regulates intracellular and mitochondria calcium buffering of HSC upon cytokine stimulation and have demonstrated that Akt activator SC79 reverts the levels of intracellular and mitochondrial calcium in HSC. Hematopoietic colony-forming activity and the Hsp90 activity of S100A6KO are restored through activation of the Akt pathway. We show that p-Akt is the prime downstream mechanism of S100A6 in the regulation of HSC self-renewal by specifically governing mitochondrial metabolic function and Hsp90 protein quality.

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  • 43.
    Gregers, Jannie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. University of Copenhagen Hospital, Denmark.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. KTH Royal Institute Technology, Sweden; National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Christensen, I. J.
    Rigshosp, Denmark.
    Dalhoff, K.
    Bispebjerg Hospital, Denmark.
    Schroeder, H.
    University Hospital Skejby, Denmark.
    Carlsen, N.
    Odense University Hospital, Denmark.
    Rosthoej, S.
    University Hospital Aalborg, Denmark.
    Lausen, B.
    University of Copenhagen, Denmark.
    Schmiegelow, K.
    University of Copenhagen, Denmark; University of Copenhagen, Denmark.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia2015In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 15, no 4, p. 372-379Article in journal (Refereed)
    Abstract [en]

    The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P = 0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P = 0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P = 0.01/P less than 0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT ( P = 0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G greater than A may be a new possible predictive marker for outcome in childhood ALL.

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  • 44.
    Hagglund, Hans
    et al.
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Yavuz, Akif Selim
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Dreimane, Arta
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Malm, Claes
    Linköping University, Department of Biomedical and Clinical Sciences, 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.
    Sundin, Anders
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Sander, Birgitta
    Karolinska Inst, Sweden.
    Nilsson, Gunnar
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Graft-versus-mastocytosis effect after donor lymphocyte infusion: Proof of principle2021In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 106, no 2, p. 290-293Article in journal (Refereed)
    Abstract [en]

    Advanced systemic mastocytosis is a relatively rare entity where allogeneic stem cell transplantation can lead to the cure of the disease in selected patients. Delayed incomplete responses with graft-versus-mastocytosis effect were published in a few cases. In this particular patients report, we describe the direct evidence and potency of graft-versus-mastocytosis effect of donor lymphocyte infusions in a patient with systemic mastocytosis with associated hematological neoplasm (SM-AHN). In a 53-year-old female patient, an allogeneic stem cell transplantation after conventional induction treatment was performed for transformed acute myeloid leukemia (AML) during the course of polycythemia vera. After 6 years of remission period of AML and PV, the patient developed aleukemic mast cell leukemia and JAK2-positive myeloproliferative neoplasm (SM-AHN). We were able to achieve a sustained complete remission of SM-AHN lasting for 6 years with only donor lymphocyte infusions in a status of mixed chimerism. The patient is in a good clinical condition and remission. The potent graft-versus-mastocytosis effect in this patient resembles the favorable effect of donor lymphocyte infusions in relapsing chronic myeloid leukemia patients after transplantation. This patient is, to our knowledge, the first case showing the proof of principle of graft-versus-mastocytosis effect.

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  • 45.
    Hayden, Patrick J.
    et al.
    St James Hosp, Ireland.
    Iacobelli, Simona
    Tor Vergata Univ Rome, Italy.
    Antonio Perez-Simon, Jose
    Hosp Univ Virgen Rocio, Spain; Univ Seville, Spain.
    van Biezen, Anja
    Leiden EBMT Data Off, Netherlands.
    Minnema, Monique
    Univ Med Ctr Utrecht, Netherlands.
    Niittyvuopio, Riitta
    HUCH Comprehens Canc Ctr, Finland.
    Schoenland, Stefan
    Heidelberg Univ, Germany.
    Meijer, Ellen
    Vrije Univ Amsterdam Med Ctr, Netherlands.
    Blaise, Didier
    Marseille Inst Paoli Calmettes, France.
    Milpied, Noel
    CHU Bordeaux, France.
    Marquez-Malaver, Francisco J.
    Hosp Univ Virgen Rocio, Spain; Univ Seville, Spain.
    Veelken, Joan Hendrik
    Leiden Univ, Netherlands.
    Maertens, Johan
    Univ Hosp Gasthuisberg, Belgium.
    Michallet, Mauricette
    Ctr Hosp Lyon Sud, 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.
    NGuyen, Stephanie
    Hop La Pitie Salpetriere, France.
    Niederwieser, Dietger
    Univ Hosp Leipzig, Germany.
    Hunault-Berger, Mathilde
    CHRU Angers, France.
    Bourhis, Jean Henri
    Gustave Roussy Inst Cancerol, France.
    Passweg, Jakob
    Univ Hosp Basel, Switzerland.
    Bermudez, Arancha
    FEA Serv Hematol, Spain.
    Chalandon, Yves
    Hop Univ Geneve, Switzerland; Univ Geneva, Switzerland.
    Yakoub-Agha, Ibrahim
    Hop Claude Huriez, France.
    Garderet, Laurent
    Hosp St Antoine, France.
    Kroeger, Nicolaus
    Univ Hosp Eppendorf, Germany.
    Conditioning-based outcomes after allogeneic transplantation for myeloma following a prior autologous transplant (1991-2012) on behalf of EBMT CMWPIn: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609Article in journal (Refereed)
    Abstract [en]

    Objectives The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma-reduced intensity conditioning (RIC), non-myeloablative (NMA), myeloablative conditioning (MAC) or Auto-AlloHCT-on outcomes in patients who had had a prior autologous transplant. Methods A retrospective analysis of the EBMT database (1991-2012) was performed. Results A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto-Allo transplants. At a median follow-up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%-47%), 45% (95% CI 32%-57%), 19% (95% CI 6%-32%) and 34% (95% CI 17%-51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P = .004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P amp;lt; .001) but not after 2002 (HR = 1.2, P = .276). Conclusion From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.

  • 46.
    Hedbrant, Johan
    et al.
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering.
    Bjorne, Assar
    Specialisttandvården, Lasarettet Ystad.
    Ny mätmetod för käkmuskulaturen kan finna orsaken till tinnitus: Slutrapport Nutek 92-119041997Report (Other academic)
    Abstract [sv]

    Tinnitus är en åkomma som i lindrigare eller allvarligare former drabbar 17% av västvärldens befolkning. Ca 85 000 svenskar har tinnitus på invalidiserande nivå. Förutom mänskligt lidande orsakar tinnitus samhällskostnader på ca 1.5 miljard kr årligen. Orsaken är till största delen okänd.

    Vissa tecken tyder på ett samband mellan tinnitus och funktionsstörning i en käkmuskel. Några olika icke–invasiva metoder för mätning av muskelstörning i M Pterygoideus Lateralis har utvärderas. Två av dessa är intressanta för fortsatta studier.

    Termografi användes för att diagnosticera muskelstörningar på ytligt liggande muskler. Vi såg åtskilliga varma områden på ytliga käk– och nackmuskler på de patienter som hade käkledsstörningar, samt möjligen tecken på onormal värme från M Pterygoideus Lateralis. Mätförhållandena var dock ej ideala.

    En metod att mäta EMG med adaptiv noise cancelling provades. EMG från en ryggmuskel, stört av en “EKG–signal” från hjärtat användes. Metoden fungerade bra. Fortsatt metodutveckling på t.ex. ryggmuskler borde göras.

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  • 47.
    Hellberg, Sandra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Köpsén, Mattias
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kockum, Ingrid
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Olsson, Tomas
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Håkansson, Irene
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    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.
    Dynamic Response Genes in CD4+T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis2016In: Cell Reports, E-ISSN 2211-1247, Vol. 16, no 11, p. 2928-2939Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.

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  • 48.
    Hellström Lindberg, Eva
    et al.
    Karolinska institutet, Sverige; Karolinska universitetssjukhuset, Sverige.
    Cavelier, Lucia
    Uppsala universitet och Akademiska sjukhuset, Uppsala, Sverige.
    Cammenga, Jörg
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Andersson, Per-Ola
    Göteborgs universitet, Sverige; Södra Älvsborgs sjukhus, Borås, Sverige.
    Fioretos, Thoas
    Lunds universitet, Sverige; Skånes universitetsjukhus, Sverige.
    Rosenquist, Richard
    Karolinska institutet, Sverige; Karolinska universitetssjukhuset, Sverige.
    Precisionsmedicin standard vid flera hematologiska sjukdomar: Genpanelsekvensering viktig för diagnos och riktad behandling [Precision diagnostics and therapy in hematological malignancies]2021In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 118Article, review/survey (Refereed)
    Abstract [en]

    Precision diagnostics and therapy have been implemented rather early in clinical hematology due to the easy accessibility of blood and bone marrow, allowing not only for consecutive genetic analysis at diagnosis, remission and relapse, but also for culturing these cells and testing new drugs in vitro. One contributing factor has also been the relatively low number of »driver« mutations in hematologic malignancies and that some of them are gain of function mutations that are relatively easy to target by drugs. Examples of this development are ABL1-, JAK2-, and FLT3-inhibitors for the treatment of chronic myeloid leukemia, myeloproliferative neoplasms, and acute myeloid leukemia, respectively. More recently, gene panel sequencing has been introduced in clinical routine to identify genetic alterations with diagnostic, prognostic and predictive impact, and more sensitive techniques to monitor minimal residual disease are emerging. Whole genome and transcriptome sequencing are currently evaluated as the next diagnostic tool. Finally, a large number of targeted therapies are currently under development and/or undergoing clinical trials.

  • 49.
    Hjorth, Maria
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dandu-Bazon, Nicolae
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping.
    Mellergård, Johan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Neurologiska kliniken i Linköping.
    Treatment effects of fingolimod in multiple sclerosis: Selective changes in peripheral blood lymphocyte subsets2020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 2, article id e0228380Article in journal (Refereed)
    Abstract [en]

    Background Treatment with fingolimod reduces inflammation in multiple sclerosis (MS) by inhibiting lymphocyte egress from lymph nodes. We aimed to map, in detail, the alterations in peripheral blood lymphocyte subpopulations in relation to clinical outcome in MS patients treated with fingolimod. Methods Paired blood samples from relapsing-remitting MS patients (n = 19) were collected before and after one year of treatment with fingolimod (0.5 mg/day). Absolute counts and relative proportions of a broad set of T- B- and NK-cell subsets were analyzed by flow cytometry. Blood samples from 18 healthy controls were used for baseline comparisons. Results Treatment with fingolimod markedly decreased the absolute numbers of all major lymphocyte subsets, except for NK cells. The reduction was most pronounced within the T helper (Th) and B cell populations (p < 0.001). By phenotyping differentiation status of T cells, dramatic reductions within the naive and central memory (CM) cell populations were found (p < 0.001), while a less pronounced reduction was observed among effector memory (EM) cells (p < 0.001). The numbers of regulatory T cells (Tregs) were also decreased (p < 0.001), but to a lesser extent than other T cell populations, resulting in a relative preservation of Tregs with a memory phenotype (p = 0.002). Conclusions Our results confirm that fingolimod therapy markedly reduces lymphocyte counts in peripheral blood of MS patients. Subgroup analysis of T cells showed that naive and CM Th cells were the most profoundly affected and that memory Tregs were relatively preserved.

  • 50.
    Hjorth-Hansen, H.
    et al.
    St Olavs Hospital, Norway; Norwegian University of Science and Technology NTNU, Norway.
    Stentoft, J.
    Aarhus University Hospital, Denmark.
    Richter, J.
    Skåne University Hospital, Sweden.
    Koskenvesa, P.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Hoeglund, M.
    University of Uppsala Hospital, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Porkka, K.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Gedde-Dahl, T.
    Oslo University Hospital, Norway.
    Gjertsen, B. T.
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Gruber, F. X.
    University Hospital North Norway, Norway.
    Stenke, L.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Eriksson, K. M.
    Sunderbysjukhuset, Sweden.
    Markevarn, B.
    Umeå University Hospital, Sweden.
    Lubking, A.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden.
    Vestergaard, H.
    Odense University Hospital, Denmark.
    Udby, L.
    Roskilde Hospital, Denmark.
    Bjerrum, O. W.
    University of Copenhagen Hospital, Denmark.
    Persson, I.
    Uppsala University, Sweden.
    Mustjoki, S.
    University of Helsinki, Finland; Helsinki University Hospital, Sweden; University of Helsinki, Finland.
    Olsson-Stromberg, U.
    University of Uppsala Hospital, Sweden.
    Safety and efficacy of the combination of pegylated interferon-alpha 2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 9, p. 1853-1860Article in journal (Refereed)
    Abstract [en]

    Dasatinib (DAS) and interferon-a have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-alpha 2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 mu g/week and it increased to 25 mu g/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR4 was achieved by 46% and MR4.5 by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS +/- PegIFN is warranted.

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