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  • 1. Abdulla, Maysaa
    et al.
    Hollander, Peter
    Pandzic, Tatjana
    Mansouri, Larry
    Ednersson, Susanne Bram
    Andersson, Per-Ola
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fors, Maja
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Petersen, Helga Munch
    Asmar, Fazila
    Gronbaek, Kirsten
    Enblad, Gunilla
    Cavelier, Lucia
    Rosenquist, Richard
    Amini, Rose-Marie
    Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma2020In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 95, no 1, p. 57-67Article in journal (Refereed)
    Abstract [en]

    The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.

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  • 2.
    Abildgaard, Niels
    et al.
    Hematology Research Unit, Department of Hematology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
    Anttila, Pekka
    Comprehensive Cancer Center, Department of Hematology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
    Waage, Anders
    Department of Hematology, St Olav's University Hospital, Trondheim, Norway.
    Rubin, Katrine Hass
    Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
    Ørstavik, Sigurd
    Takeda Pharmaceuticals International AG, Oslo, Norway.
    Bent-Ennakhil, Nawal
    Takeda Pharmaceuticals International AG, Zurich, Switzerland.
    Gavini, François
    Takeda Pharmaceuticals International AG, Zurich, Switzerland.
    Ma, Yuanjun
    Parexel International, Stockholm, Sweden.
    Freilich, Jonatan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology. Parexel International, Stockholm, Sweden.
    Hansson, Markus
    Sahlgrenska Academy and Sahlgrenska University Hospital, Göteborg, Sweden.
    Real-world treatment patterns and outcomes for patients with multiple myeloma in Denmark, Finland and Sweden: An analysis using linked Nordic registries2024In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 201, article id 113921Article in journal (Refereed)
    Abstract [en]

    Aim: The Health outcomes and Understanding of MyelomA multi-National Study (HUMANS) was a large-scale, retrospective study conducted across Denmark, Finland and Sweden using linked data from national registries. We describe the characteristics, treatment patterns and clinical outcomes for patients with newly diagnosed multiple myeloma (NDMM) over 2010–2018.

    Methods: Patients with NDMM who received MM-specific, first-line treatments, were categorised by treatment (autologous stem cell transplantation [ASCT] or a combination chemotherapy regimen based on bortezomib, lenalidomide or melphalan-prednisolone-thalidomide).

    Results: 11,023 patients received treatment over 2010–2018. Time between diagnosis and treatment was shortest in Denmark (0.9 months), then Sweden (2.9 months) and Finland (4.6 months). Around one third of patients underwent ASCT. Lenalidomide-based regimens were prescribed to 23–28% of patients in Denmark and Finland, versus 12% in Sweden. Patients receiving lenalidomide had the longest wait for treatment, from 3.2 months (Denmark) to 12.1 months (Sweden). Treatment persistence was highest among patients receiving melphalan-prednisolone-thalidomide (7–8 months) in Finland and Sweden and lowest among those receiving bortezomib (3.5 months) in Finland. Overall survival (OS) was longest among patients with ASCT (7–10 years). Among patients receiving chemotherapy, OS (from diagnosis/treatment initiation), varied between cohorts. In a sensitivity analysis excluding patients with smouldering MM, OS decreased for all; for patients receiving bortezomib or lenalidomide, OS from diagnosis was 40–49 and 27–54 months, respectively.

    Conclusions: This population-based study of patients with NDMM receiving first-line MM-specific treatment, provides real-world data on treatment patterns and outcomes to complement data from randomised clinical trials.

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  • 3. Achouiti, A.
    et al.
    Vogl, T.
    Urban, Constantin
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hommes, T. J.
    van Zoelen, M. A.
    Florquin, S.
    Roth, J.
    van 't Veer, C.
    de Vos, A. F.
    van der Poll, T.
    Myeloid related protein (mrp) 8/14 contributes to an antibacterial host response against klebsiella (k.) pneumoniae2012In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no S1, p. 56-56Article in journal (Other academic)
  • 4. Acosta, Stefan
    et al.
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Current status on plasma biomarkers for acute mesenteric ischemia2012In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 33, no 4, p. 355-361Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 6. Andrews, Robert K.
    et al.
    Wolberg, Alisa
    Lip, Gregory Y. H.
    Eikelboom, John
    De Meyer, Simon F.
    Mast, Alan
    Flick, Matthew
    Urano, Tetsumei
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Cutler, Daniel
    Ju, Lining A.
    Zhu, Cheng
    Randi, Anna M.
    O'Donnell, James S.
    O'Brien, Sarah H.
    Fijnvandraat, Karin
    Shima, Midori
    Nathwani, Amit
    Luyendyk, Jim
    Vanhoorelbeke, Karen
    Barco, Stefano
    Chuansumrit, Ampaiwan
    Stanworth, Simon J.
    Curry, Nicola
    Del Rio, J. Mauricio
    Battinelli, Elisabeth M.
    Bos, Mettine H. A.
    Reinhardt, Christoph
    Peter, Karlheinz
    Gomez, Keith
    Danese, Elisa
    Rak, Janusz
    Flaumenhaft, Robert
    Di Paola, Jorge
    Nilsson, Susie
    Severin, Sonia
    Eto, Koji
    Hitchcock, Ian S.
    Ni, Heyu
    Despotovic, Jenny
    Boilard, Eric
    Rondina, Matthew
    Mangin, Pierre
    Hamilton, Justin R.
    Suzuki-Inoue, Katsue
    Tsukiji, Nagaharu
    Conway, Edward M.
    Maas, Coen
    Emsley, Jonas
    Jenne, Craig N.
    Fuchs, Tobias A.
    Weitz, Jeffrey
    Johnsen, Jill M.
    Rauova, Lubica
    Spyropoulos, Alex
    Goto, Shinya
    Verhamme, Peter
    Miranda, Sebastien
    Rodger, Marc
    Ni Ainle, Fionnuala
    Schreiber, Karen
    Thomas, Moumneh
    Le Gal, Gregoire
    Zentner, Dominica
    McLintock, Claire
    Magnusson, Maria
    Illustrated State-of-the-Art Capsules of the ISTH 2019 Congress in Melbourne, Australia: Plasminogen in wound healing2019In: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS, ISSN 2475-0379, Vol. 3, no 3, p. 431-497Article, review/survey (Refereed)
    Abstract [en]

    The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6-10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or 'Capsules' consisting of short text, three references and a figure, with topics including stroke, cancer-associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure-function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.

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

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

  • 8. Bager, Ninna
    et al.
    Juul-Dam, Kristian L
    Sandahl, Julie D
    Abrahamsson, Jonas
    Beverloo, Berna
    de Bont, Eveline S J M
    Ha, Shau-Yin
    Jahnukainen, Kirsi
    Jónsson, Ólafur G
    Kaspers, Gertjan L
    Kovalova, Zhanna
    Lausen, Birgitte
    De Moerloose, Barbara
    Norén-Nyström, Ulrika
    Umeå University Hospital.
    Palle, Josefine
    Saks, Kadri
    Zeller, Bernward
    Kjeldsen, Eigil
    Hasle, Henrik
    Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia: A NOPHO-DBH-AML study2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 183, no 4, p. 618-628Article in journal (Refereed)
    Abstract [en]

    Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.

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

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

  • 10. Berggren, Daniel Moreno
    et al.
    Folkvaljon, Yasin
    Engvall, Marie
    Sundberg, Johan
    Lambe, Mats
    Antunovic, Petar
    Garelius, Hege
    Lorenz, Fryderyk
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Lars
    Rasmussen, Bengt
    Lehmann, Sören
    Hellström-Lindberg, Eva
    Jädersten, Martin
    Ejerblad, Elisabeth
    Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, no 5, p. 614-627Article in journal (Refereed)
    Abstract [en]

    The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2.9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0.05) and for WPSS compared to IPSS (P=0.07). IPSS-R was superior to both IPSS and WPSS for patients aged <= 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.

  • 11.
    Berglund, Eva
    et al.
    Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Barbany, Gisela
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics, Karolinska University Hospital, Solna, Sweden.
    Orsmark-Pietras, Christina
    Department of Clinical Genetics and Pathology, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden; Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; Clinical Genomics Lund, Science for Life Laboratory, Lund University, Lund, Sweden.
    Fogelstrand, Linda
    Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Clinical Genomics Gothenburg, Science for Life Laboratory, University of Gothenburg, Gothenburg, Sweden.
    Abrahamsson, Jonas
    Clinical Sciences, Queen Silvias Childrens Hospital, Gothenburg, Sweden.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hallböök, Helene
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Höglund, Martin
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Lazarevic, Vladimir
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Levin, Lars-Åke
    Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Nordlund, Jessica
    Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Palle, Josefine
    Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Thangavelu, Tharshini
    Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Palmqvist, Lars
    Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Clinical Genomics Gothenburg, Science for Life Laboratory, University of Gothenburg, Gothenburg, Sweden.
    Wirta, Valtteri
    Department of Microbiology, Tumor and Cell Biology, Clinical Genomics Stockholm, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
    Cavelier, Lucia
    Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Fioretos, Thoas
    Department of Clinical Genetics and Pathology, Office for Medical Services, Division of Laboratory Medicine, Lund, Sweden; Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; Clinical Genomics Lund, Science for Life Laboratory, Lund University, Lund, Sweden.
    Rosenquist, Richard
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics, Karolinska University Hospital, Solna, Sweden.
    A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias2022In: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 9, article id 842507Article in journal (Refereed)
    Abstract [en]

    Background: Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed.

    Methods and Analysis: The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normal/germline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact.

    Discussion: Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care.

    Clinical Trial Registration: [https://doi.org/10.1186/ISRCTN66987142], identifier [ISRCTN66987142].

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  • 12.
    Bergman, Peter
    et al.
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Laboratory Medicine, Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
    Blennow, Ola
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Hansson, Lotta
    Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Mielke, Stephan
    Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Nowak, Piotr
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Huddinge, Infectious Diseases, Karolinska Institutet, Stockholm, Sweden.
    Chen, Puran
    Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden.
    Söderdahl, Gunnar
    Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Österborg, Anders
    Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Smith, C. I. Edvard
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Wullimann, David
    Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden.
    Vesterbacka, Jan
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Lindgren, Gustaf
    Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Blixt, Lisa
    Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Friman, Gustav
    Department of Transplantation, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Wahren-Borgström, Emilie
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Nordlander, Anna
    Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Gomez, Angelica Cuapio
    Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden.
    Akber, Mira
    Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden.
    Valentini, Davide
    Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Norlin, Anna-Carin
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Thalme, Anders
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Bogdanovic, Gordana
    Dept of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
    Muschiol, Sandra
    Dept of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, Peter
    Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden.
    Hober, Sophia
    Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden.
    Loré, Karin
    Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Chen, Margaret Sällberg
    Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Buggert, Marcus
    Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ljunggren, Hans-Gustaf
    Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ljungman, Per
    Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Medicine Huddinge, Hematology, Karolinska Institutet, Stockholm.
    Aleman, Soo
    Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Huddinge, Infectious Diseases, Karolinska Institutet, Stockholm, Sweden.
    Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial2021In: EBioMedicine, E-ISSN 2352-3964, Vol. 74, article id 103705Article in journal (Refereed)
    Abstract [en]

    Background: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls.

    Methods: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection.

    Findings: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively.

    Interpretation: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity.

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  • 13. Birgegård, Gunnar
    et al.
    Björkholm, Magnus
    Kutti, Jack
    Larfars, Gerd
    Löfvenberg, Eva
    Markevärn, Berit
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Merup, Mats
    Palmblad, Jan
    Mauritzson, Nils
    Westin, Jan
    Samuelsson, Jan
    Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders.2004In: Haematologica, ISSN 1592-8721, Vol. 89, no 5, p. 520-7Article in journal (Refereed)
  • 14.
    Björck, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Warfarin treatment quality in stroke prevention2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

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

    Methods

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

    Results

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

    Conclusions

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

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  • 15.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ek, Agnes
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Warfarin persistence among atrial fibrillation patients – why is treatment ended?2016In: Cardiovascular Therapeutics, ISSN 1755-5914, Vol. 34, no 6, p. 468-474Article in journal (Refereed)
    Abstract [en]

    Background and Aim

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

    Methods

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

    Results

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

    Conclusions

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

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  • 16.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Kadhim, Hayder
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Predictors for INR-control in a well-managed warfarin treatment setting2019In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 47, no 2, p. 227-232Article in journal (Refereed)
    Abstract [en]

    Warfarin is well studied in patients with non-valvular atrial fibrillation (AF). It has low complication rates for patients achieving individual Time in Therapeutic Range (iTTR)>70%. The risk scores SAMe-TT2R2 and PROSPER are designed to predict future TTR, but are derived from a heterogeneous population with generally low iTTR. The aim of this study was to evaluate predictors for high and low iTTR in an AF population in Sweden, where there is a generally good anticoagulation control. A retrospective register study based on Swedish warfarin dosing system AuriculA, including 28,011 AF patients starting treatment during 1 January 2006 to 31 December 2011. Complications and risk factors were analysed and related to iTTR. Mean age was 73.7 (SD +/- 9.5) years, with 42.0% women. Mean CHA(2)DS(2)-VASc score (SD) was 3.6 (+/- 1.7). For patients with iTTR<60% there were over three times higher prevalence of excessive alcohol consumption than for patients with iTTR>70% (3.7% vs. 1.1%). Previous stroke were more prevalent for patients with high than low iTTR (17.1% vs. 20.3%). Concomitant comorbidities were associated with increased risk of poor iTTR. In Swedish AF patients, excessive alcohol use is clearly associated with iTTR below 60%. Patients with previous stroke are more likely to get iTTR above 70%, unlike those with concomitant disorders who more often have poor anticoagulation control. The SAMe-TT2R2-score cannot be applied in Sweden.

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  • 17.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renlund, Henrik
    Svensson, Peter J
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Warfarin persistence among stroke patients with atrial fibrillation2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 4, p. 744-748Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 18.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sandén, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renlund, Henrik
    Svensson, Peter J
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 2, p. 216-220Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 19.
    Blaha, M.
    et al.
    Faculty Nemocnice Hradec Kralove, University Hospital Hradec Kralove, Hradec Králové, Czech Republic.
    Gasova, Z.
    Institute of Hematology and Blood Transfusion, UHKT, Prague, Czech Republic.
    Berlin, G.
    Dept Clinical Immunology and Transfusion Medicine, and Dpt Biomedical Clinical Science, Linköping University, Linköping, Sweden.
    Audzijoniene, J.
    Hematology, onkology and Transfusion Centre, University Hospital, Vilnius, Lithuania.
    Griskevicius, A.
    Hematology, onkology and Transfusion Centre, University Hospital, Vilnius, Lithuania.
    Dykes, J.
    Dept Hematology and Transfusion Medicine, University Lund, Lund, Sweden.
    Bhuiyanova, Z.
    Institute of Hematology and Blood Transfusion, UHKT, Prague, Czech Republic.
    Lanska, M.
    Faculty Nemocnice Hradec Kralove, University Hospital Hradec Kralove, Hradec Králové, Czech Republic.
    Eich, T.
    Dept Clinical Immunology and Transfusion Medicine, Uppsala Akademiska University Hospital, Uppsala, Sweden.
    Vrielink, H.
    Sanquin Blood Supply, Netherlands.
    Witt, V.
    Apheresis Centres, St. Anna Kinderspital/MUW, Vienna, Austria.
    Seval, G.C.
    Hematology, Ankara University School of Medicine, Ankara, Turkey.
    Ilhan, O.
    Hematology, Ankara University School of Medicine, Ankara, Turkey.
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Analysis of extracorporeal photopheresis within the frame of the WAA register2021In: Transfusion and apheresis science, ISSN 1473-0502, E-ISSN 1878-1683, Vol. 60, no 5, article id 103172Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate safety and if extracorporeal photopheresis (ECP) may change health criteria (HC) and quality of life (QoL).

    Material and method: 560 patients (33 % women) were treated with ECP for a total of 13,871 procedures during a 17-years period. Mean age was 48 years (±18, range 3−81 years). Self-estimation of QoL was graded: 0 (suicidal) up to 10 (best ever) and HC: 0 (Bed ridden, ICU condition) up to 10 (athletic). Adverse events were analyzed. ANOVA and paired comparisons were performed.

    Results: Patients were treated due to graft versus host disease (GVHD, n = 317), skin lymphoma (n = 70), solid organ transplants (n = 47), skin diseases (n = 20) and other diseases (n = 106). Adverse events (AEs) were registered in 5.4 % of the first treatments and in 1.2 % of the subsequent procedures. Severe AEs were present in 0.04 % of all procedures. No patient died due to the procedure. Tingling and stitching were the most common AE. For those with GVHD an improvement was noticed within approximately 10 procedures of ECP in the severity stage, QoL (from a mean of 6.1 to 6.8, p < 0.002) and the HC (6.1 -> 6.4, p < 0.014) and improved further with added procedures.

    Conclusion: Photopheresis is an established therapy with few side effects. The present study of soft variables indicate that GVHD shows benefits upon ECP within approximately 10 procedures in regard to the severity of mainly skin GVHD, and lower baseline levels of HC and QoL.

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  • 20.
    Bonnard, Åsa
    et al.
    Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Medical Unit of ENT, Hearing and Balance, Karolinska University Hospital, Stockholm, Sweden; Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Berglin, Cecilia Engmér
    Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Medical Unit of ENT, Hearing and Balance, Karolinska University Hospital, Stockholm, Sweden.
    Wincent, Josephine
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
    Eriksson, Per Olof
    Medical Unit of ENT, Hearing and Balance, Karolinska University Hospital, Stockholm, Sweden; Department of Surgical Sciences, Otorhinolaryngology, Uppsala University Hospital, Uppsala, Sweden.
    Westman, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Feychting, Maria
    Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Mogensen, Hanna
    Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    The risk of cholesteatoma in individuals with first-degree relatives surgically treated for the disease2023In: JAMA Otolaryngology - Head and Neck Surgery, ISSN 2168-6181, E-ISSN 2168-619X, Vol. 149, no 5, article id ooi230002Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE:  Cholesteatoma in the middle ear is not regarded as a hereditary disease, but case reports of familial clustering exist in the literature, as well as observed familial cases in the clinical work. However, the knowledge regarding cholesteatoma as a hereditary disease is lacking in the literature. OBJECTIVE To assess the risk of cholesteatoma in individuals with a first-degree relative surgically treated for the same disease.

    DESIGN, SETTING, AND PARTICIPANTS: In this nested case-control study in the Swedish population between 1987 and 2018 of first-time cholesteatoma surgery identified from the Swedish National Patient Register, 2 controls per case were randomly selected from the population register through incidence density sampling, and all first-degree relatives for cases and controls were identified. Data were received in April 2022, and analyses were conducted between April and September 2022.

    EXPOSURE: Cholesteatoma surgery in a first-degree relative.

    MAIN OUTCOMES AND MEASURES: The main outcome was first-time cholesteatoma surgery. The association between having a first-degree relative with cholesteatoma and the risk of cholesteatoma surgery in the index persons was estimated by odds ratios (ORs) and 95% CIs through conditional logistic regression analysis.

    RESULTS: Between 1987 and 2018, 10 618 individuals with a first-time cholesteatoma surgery (mean [SD] age at surgery, 35.6 [21.5] years; 6302 [59.4%] men) were identified in the Swedish National Patient Register. The risk of having a cholesteatoma surgery was almost 4 times higher in individuals having a first-degree relative surgically treated for the disease (OR, 3.9; 95% CI, 3.1-4.8), but few cases were exposed overall. Among the 10 105 cases with at least 1 control included in the main analysis, 227 (2.2%) had at least 1 first-degree relative treated for cholesteatoma, while the corresponding numbers for controls were 118 of 19 553 control patients (0.6%). The association was stronger for individuals under the age of 20 years at first surgery (OR, 5.2; 95% CI, 3.6-7.6) and for a surgery involving the atticus and/or mastoid region (OR, 4.8; 95% CI, 3.4-6.2). There was no difference in the prevalence of having a partner with cholesteatoma between cases and controls (10 cases [0.3%] and 16 controls [0.3%]; OR, 0.92; 95% CI, 0.41-2.05), which implies that increased awareness does not explain the association.

    CONCLUSIONS AND RELEVANCE:  In this Swedish case-control study using nationwide register data with high coverage and completeness, the findings suggest that the risk of cholesteatoma in the middle ear is strongly associated with a family history of the condition. Family history was nevertheless quite rare and can therefore only explain a limited number of all cases; these families could be an important source for information regarding the genetic background for cholesteatoma disease.

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  • 21.
    Borg Hammer, Anne Sofie
    et al.
    Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
    Løvvik Juul-Dam, Kristian
    Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
    Damgaard Sandahl, Julie
    Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
    Abrahamsson, Jonas
    Children's Cancer Center, Queen Silvia's Children's Hospital, Göteborg, Sweden.
    Czogala, Malgorzata
    Department of Pediatric Oncology and Hematology, Jagiellonian University Medical College, Institute of Pediatrics, Krakow, Poland.
    Delabesse, Emmanuelle
    Toulouse-Oncopole, Laboratoire d'Hématologie Secteur Génétique des Hémopathies, Toulouse, France.
    Haltrich, Iren
    2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
    Jahnukainen, Kirsi
    New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Kolb, E. Anders
    Nemours/Alfred I. DuPont Hospital for Children, DE, Wilmington, United States.
    Kovács, Gábor
    2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
    Leverger, Guy
    Hopital Armand Trousseau, Assistance Publique-Hopitaux de Paris, Service d'Hematologie et d'Oncologie Pediatrique, Paris, France.
    Locatelli, Franco
    Department of Pediatric Haematology/Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Catholic University of the Sacred Heart, Rome, Italy.
    Masetti, Riccardo
    Dipartimento di Scienze Mediche e Chirurgiche, Pediatric Oncology and Hematology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Raimondi, Susana C.
    St Jude Children's Research Hospital, TN, Memphis, United States.
    Rasche, Mareike
    Department of Pediatric Hematology-Oncology, Pediatrics III, University Hospital of Essen, Essen, Germany.
    Reinhardt, Dirk
    Department of Pediatric Hematology-Oncology, Pediatrics III, University Hospital of Essen, Essen, Germany.
    Taki, Tomohiko
    Faculty of Health Sciences, Laboratory of Clinical Hematology, Department of Medical Technology, Kyorin University, Mitaka, Japan.
    Tomizawa, Daisuke
    Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
    Zeller, Bernward
    Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway.
    Hasle, Henrik
    Department of Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
    Kjeldsen, Eigil
    Department of Hematology, Hemodiagnostic Laboratory, Aarhus University Hospital, Aarhus, Denmark.
    Hypodiploidy has unfavorable impact on survival in pediatric acute myeloid leukemia: An I-BFM Study Group collaboration2023In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 7, no 6, p. 1045-1055Article in journal (Refereed)
    Abstract [en]

    Hypodiploidy, defined as modal numbers (MNs) 45 or lower, has not been independently investigated in pediatric acute myeloid leukemia (AML) but is a well-described high-risk factor in pediatric acute lymphoblastic leukemia. We aimed to characterize and study the prognostic impact of hypodiploidy in pediatric AML. In this retrospective cohort study, we included children below 18 years of age with de novo AML and a hypodiploid karyotype diagnosed from 2000 to 2015 in 14 childhood AML groups from the International Berlin-Frankfurt-Münster (I-BFM) framework. Exclusion criteria comprised constitutional hypodiploidy, monosomy 7, composite karyotype, and t(8;21) with concurring sex chromosome loss. Hypodiploidy occurred in 81 patients (1.3%) with MNs, 45 (n = 66); 44 (n = 10) and 43 (n = 5). The most frequently lost chromosomes were chromosome 9 and sex chromosomes. Five-year event-free survival (EFS) and overall survival (OS) were 34% and 52%, respectively, for the hypodiploid cohort. Children with MN≤44 (n = 15) had inferior EFS (21%) and OS (33%) compared with children with MN = 45 (n = 66; EFS, 37%; OS, 56%). Adjusted hazard ratios (HRs) were 4.9 (P = .001) and 6.1 (P = .003). Monosomal karyotype or monosomy 9 had particular poor OS (43% and 15%, respectively). Allogeneic stem cell transplantation (SCT) in first complete remission (CR1) (n = 18) did not mitigate the unfavorable outcome of hypodiploidy (adjusted HR for OS was 1.5; P = .42). We identified pediatric hypodiploid AML as a rare subgroup with an inferior prognosis even in the patients treated with SCT in CR1.

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  • 22.
    Borssen, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Cullman, Inger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sundstrom, Christer
    Porwit, Anna
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup2011In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, no 12, p. 1144-1151Article in journal (Refereed)
    Abstract [en]

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

  • 23.
    Borssén, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schmiegelow, Kjeld
    Åsberg, Ann E.
    Kanerva, Jukka
    Madsen, Hans O.
    Marquart, Hanne
    Heyman, Mats
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Paediatrics, University Hospital of Trondheim, Norway.
    DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, p. 1185-1192Article in journal (Refereed)
    Abstract [en]

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

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  • 24.
    Borssén, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nordlund, Jessica
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Flaegstad, Trond
    Jónsson, Ólafur Gísli
    Frost, Britt-Marie
    Palle, Josefine
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Heyman, Mats
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lönnerholm, Gudmar
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia2018In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 31Article in journal (Refereed)
    Abstract [en]

    Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.

    Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.

    Results: Among the 137 patients that later relapsed, patients with a CIMP-profile (n = 42) at initial diagnosis had an inferior overall survival (pOS(5years) 33%) compared to CIMP+ patients (n = 95, pOS(5years) 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.

    Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.

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  • 25. Brandefors, Lena
    et al.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindh, Jack
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundqvist, Kristina
    Kimby, Eva
    Prognostic factors and primary treatment for Waldenstrom macroglobulinemia: a Swedish Lymphoma Registry study2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 183, no 4, p. 564-577Article in journal (Refereed)
    Abstract [en]

    We present a nationwide prospective Swedish registry-based study of Waldenstrom macroglobulinaemia (WM), that focuses on incidence and survival in relation to clinical prognostic factors and primary systemic therapies. A total of 1511 patients with WM and lymphoplasmocytic lymphoma (LPL) were registered in the Swedish Lymphoma Registry (SLR) between 1 January 2000 and 31 December 2014. The age-adjusted incidence of WM/LPL was 11.5 per million persons per year, three times higher than the reported incidence worldwide. Medical records were retrieved for 1135 patients (75%). A retrospective review showed that 981 (86.1%) of these patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analysed further. The overall survival (OS) improved between two periods - 2000-2006 and 2007-2014 - with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and haemoglobin <= 115 g/l for patients receiving therapy 0-3 months after diagnosis, and age, poor performance status, haemoglobin <= 115 g/l, and female sex in "watch and wait" patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival.

  • 26.
    Brandefors, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sander, Birgitta
    Department of Laboratory Medicine, Department of Pathology, Karolinska Institute, Stockholm, Sweden.
    Lundqvist, Kristina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kimby, Eva
    Department of Haematology, Karolinska Institute, Stockholm, Sweden.
    Clinical characteristic and outcome of lymphoplasmacytic lymphoma of non-Waldenstrom macroglobulinemia type: A Swedish lymphoma registry study2022In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 196, no 6, p. 1362-1368Article in journal (Refereed)
    Abstract [en]

    Lymphoplasmacytic lymphoma (LPL) not fulfilling the WHO diagnostic criteria (2017) for Waldenstrom’s macroglobulinemia (WM) (named non-WM LPL) is a rare disease and only a few systematic studies have been published. Here, we present a population-based study of non-WM LPL focusing on diagnostic difficulties, patient characteristics, and outcome. From 1511 patients included in the Swedish Lymphoma Registry 1 Jan 2000 – 31 Dec 2014 with a diagnosis of WM/LPL, we could confirm the diagnosis of non-WM LP in only 33 patients. The median age at diagnosis was 69 years. A paraprotein was found in most (IgG in 54%, IgA in 15%) and 12% of the cases were non-secretory. Compared with the WM patients, the non-WM LPL patients were younger, had more adverse prognostic factors such as elevated LDH, anaemia, and lymphocytosis at diagnosis. In addition, the non-WM LPL patients more often were symptomatic and received treatment at diagnosis. The overall survival (OS) did not significantly differ between the non-WM LPL and WM groups (P = 0.247), with a median survival time of 71 and 96 months, respectively. To conclude, we found differences in clinical features between WM and non-WM LPL, but no difference in survival.

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  • 27.
    Brundin, Peik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, Huddinge, Stockholm, Sweden.
    Zhao, Chunyan
    Dahlman-Wright, Karin
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Gene Expression of Estrogen Receptors in Pbmc From Patients With Puumala-Virus Infection2012In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no 4, p. 355-359Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 29. Buitenkamp, Trudy
    et al.
    Izraeli, Shai
    Zimmermann, Martin
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Heerema, Nyla A.
    van den Heuvel, Marry M.
    Pieters, Rob
    de Haas, Valerie
    Silverman, Lewis B.
    Schmiegelow, Kjeld
    Liang, Der-Cherng
    Horibe, Keizo
    Arico, Maurizio
    Cazzaniga, Giovanni
    Basso, Giuseppe
    Rabin, Karen R.
    Schrappe, Martin
    Cario, Gunnar
    Mann, Georg
    Mondelaers, Veerle
    Lammens, Tim
    Cave, Helene
    Stark, Batia
    Moorman, Anthony V.
    Vora, Ajay J.
    Hunger, Stephen
    Pui, Ching-Hon
    Mullighan, Charles G.
    Manabe, Atsushi
    Escherich, Gabriele
    Kowalczyk, Jerzy
    Whitlock, James A.
    Zwaan, Christian M.
    Acute Lymphoblastic Leukemia in children with Down Syndrome: A report from the Ponte Di Legno Study Group2011In: 53rd ASH Annual Meeting and Exposition, December 10-13, 2011: Program: Oral and Poster AbstractsSession: 612. Acute Lymphoblastic Leukemia - Biology and Pathophysiology: Poster III Monday, December 12, 2011, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center), American Society of Hematology , 2011, Vol. 118, no 21Conference paper (Refereed)
  • 30. Buus, Terkild Brink
    et al.
    Willerslev-Olsen, Andreas
    Fredholm, Simon
    Blumel, Edda
    Nastasi, Claudia
    Gluud, Maria
    Hu, Tengpeng
    Lindahl, Lise M.
    Iversen, Lars
    Fogh, Hanne
    Gniadecki, Robert
    Litvinov, Ivan V.
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Clinical Research Center, Lund University, Malmö, Sweden.
    Bonefeld, Charlotte Menne
    Geisler, Carsten
    Christensen, Jan Praysgaard
    Krejsgaard, Thorbjorn
    Litman, Thomas
    Woetmann, Anders
    Odum, Niels
    Single-cell heterogeneity in Sézary syndrome2018In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 2, no 16, p. 2115-2126Article in journal (Refereed)
    Abstract [en]

    Sezary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.

  • 31. Caruso, Christina
    et al.
    Guruprasad, Puneeth
    Mannino, Robert G.
    Zhang, Hanqing
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Josephson, Cassandra D.
    Roback, John D.
    Lam, Wilbur A.
    Integrated Microfluidic Automated Particle Tracking Enables High-Throughput Cell Deformability Cytometry for Red Cell Disorders2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Article in journal (Other academic)
  • 32. Cesaro, Simone
    et al.
    Marsh, Judith
    Tridello, Gloria
    Rovò, Alicia
    Maury, Sebastien
    Montante, Barbara
    Masszi, Tamás
    Van Lint, Maria Teresa
    Afanasyev, Boris
    Iriondo Atienza, Arturo
    Bierings, Marc
    Carbone, Cecilia
    Doubek, Michael
    Lanino, Edoardo
    Sarhan, Mahmoud
    Risitano, Antonio
    Steinerova, Katerina
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Pegoraro, Anna
    Passweg, Jakob
    Retrospective survey on the prevalence and outcome of prior autoimmune diseases in patients with aplastic anemia reported to the registry of the European group for blood and marrow transplantation.2010In: Acta Haematologica, ISSN 0001-5792, E-ISSN 1421-9662, Vol. 124, no 1, p. 19-22Article in journal (Refereed)
    Abstract [en]

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

  • 33.
    Christensen, Sarah Friis
    et al.
    Department of Hematology Zealand University Hospital, Roskilde, Denmark.
    Svingel, Lise Skovgaard
    Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
    Kjærsgaard, Anders
    Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
    Stenling, Anna
    Novartis Sverige AB, Kista, Sweden.
    Darvalics, Bianka
    Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
    Paulsson, Björn
    Novartis Sverige AB, Kista, Sweden.
    Andersen, Christen Lykkegaard
    Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Denmark; The Research Unit for General Practice and Section of General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
    Christiansen, Christian Fynbo
    Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
    Stentoft, Jesper
    Department of Hematology Aarhus University Hospital, Aarhus, Denmark.
    Starklint, Jørn
    Department of Hematology, Holstebro Hospital, Holstebro, Denmark.
    Severinsen, Marianne Tang
    Department of Hematology Aalborg University Hospital, Aalborg, Denmark.
    Clausen, Mette Borg
    Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Denmark.
    Hilsøe, Morten Hagemann
    Department of Hematology, Hospital South West Jutland, Esbjerg, Denmark.
    Hasselbalch, Hans Carl
    Department of Hematology, Zealand University Hospital, Roskilde, Denmark.
    Frederiksen, Henrik
    Department of Hematology Odense University Hospital, Odense, Denmark.
    Mikkelsen, Ellen Margrethe
    Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
    Bak, Marie
    Department of Hematology Zealand University Hospital, Roskilde, Denmark; Department of Hematology Copenhagen University Hospital, Rigshospitalet, Denmark.
    Healthcare resource utilization in patients with myeloproliferative neoplasms: A Danish nationwide matched cohort study2022In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609Article in journal (Refereed)
    Abstract [en]

    Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.

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  • 34.
    Christensen, Sarah Friis
    et al.
    Department of Hematology, Zealand University Hospital, Roskilde, Denmark.
    Svingel, Lise Skovgaard
    Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark.
    Kjærsgaard, Anders
    Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark.
    Stenling, Anna
    Novartis, Kista, Sweden.
    Paulsson, Björn
    Novartis, Kista, Sweden.
    Andersen, Christen Lykkegaard
    Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark.
    Christiansen, Christian Fynbo
    Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark.
    Stentoft, Jesper
    Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
    Starklint, Jørn
    Department of Hematology, Holstebro Hospital, Holstebro, Denmark.
    Severinsen, Marianne Tang
    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark;Department of Hematology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
    Clausen, Mette Borg
    Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark.
    Hilsøe, Morten Hagemann
    Department of Hematology, Hospital of South West Jutland, Esbjerg, Denmark.
    Frederiksen, Henrik
    Department of Hematology, Odense University Hospital, Odense, Denmark.
    Hasselbalch, Hans C.
    Department of Hematology, University of Copenhagen, Zealand University Hospital, Roskilde, Denmark.
    Bak, Marie
    Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark;Department of Hematology, Zealand University Hospital, Roskilde, Denmark.
    Mikkelsen, Ellen Margrethe
    Department of Clinical Epidemiology, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark.
    Labor Market Attachment in Patients with Myeloproliferative Neoplasms: A Nationwide Matched Cohort Study2021In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 138, no Suppl 1, article id 3627Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Myeloproliferative neoplasms (MPNs) are characterized by a substantial symptom burden, risk of debilitating complications (e.g., thrombosis), and increased comorbidity. Recently, three comprehensive questionnaire studies (Mesa 2016, Harrison 2017, Jingbo 2018) have reported a high impact of MPNs on patients' ability to work. However, no registry-based studies have assessed labor market attachment (LMA) of MPN patients and matched nonMPN comparisons.

    AIM: To assess the pre- and post-diagnostic LMA of MPN patients and matched nonMPN comparisons.

    METHODS: We conducted a descriptive, registry-based nationwide cohort study, using data from the Danish National Chronic Myeloid Neoplasia Registry including all Danish MPN patients diagnosed between January 2010 and December 2016. Population-based cohorts of nonMPN comparisons were constructed by 1:10 matching on age, sex, level of education, and region of residence. Data on LMA were retrieved from the Danish Register for Evaluation of Marginalization, which holds information on all public transfer payments in Denmark. Data were linked using the unique civil registration number, which identifies all Danish citizens. The LMA endpoints were defined for each individual as working (not receiving any type of transfer payment), unemployed, receiving transfer payment for either sick leave, disability pension, age pension, or other health-related benefits (e.g., wage-subsidized employment). We assessed LMA weekly for each individual from two years before diagnosis until death, emigration, or two years after the diagnosis. For each cohort, we presented LMA as proportions with 95% confidence intervals (CIs), as well as the proportion of individuals who died during follow-up.

    RESULTS: The study included 3,342 MPN patients (1,140 essential thrombocythemia [ET]; 1,109 polycythemia vera [PV]; 533 myelofibrosis [MF]; and 560 unspecified MPN [MPN-U]) and 32,737 nonMPN comparisons (11,181 nonET; 10,873 nonPV; 5,217 nonPMF; and 5,466 nonMPN-U). The median age at time of diagnosis was: ET 67 years (interquartile range [IQR], 55-76); PV, 69 years (IQR, 61-77); PMF, 73 years (IQR, 66-79); and MPN-U, 72 years (IQR, 63-80).

    At time of MPN diagnosis, the majority of MPN patients and nonMPN comparisons received age pension (range: ET, 52.1% [95% CI, 49.2-55.0] to nonMF, 70.3% [95% CI, 69.1-71.6]). The proportions working were: ET, 35.1% (95% CI, 32.3-37.9) vs. nonET, 37.3% (95% CI, 36.5-38.2); PV, 22.6% (95% CI, 20.2-25.1) vs. nonPV, 30.8% (95% CI, 29.9-31.7); MF, 23.8% (95% CI, 20.2-27.4) vs. nonMF, 23.6% (95% CI, 22.5-24.8); and MPN-U, 22.1% (95% CI,18.7- 25.6) vs. nonMPN-U, 27.8% (95% CI, 26.6-29.0). Across MPN subtypes, a larger proportion of patients than comparisons were on sick leave: ET, 3.5% (95% CI, 2.4-4.6) vs. nonET, 1.3% (95% CI, 1.1-1.5); PV, 5.5% (95% CI, 4.2-6.8) vs. nonPV, 0.9% (95% CI, 0.7-1.1); MF (not applicable due to small numbers) vs. nonMF, 0.6% (95% CI, 0.4-0.8); and MPN-U, 3.0% (95% CI, 1.6- 4.5) vs. nonMPN-U, 1.0% (95% CI, 0.7-1.3). Regarding disability pension, the proportions ranged from 4.1% (95% CI, 2.4-5.8) to 5.0% (95% CI, 3.7-6.3) among patients and from 3.1% (95% CI, 2.6-3.6) to 4.7% (95% CI, 4.3-5.1) among comparisons. For both MPN patients and nonMPN comparisons, few were unemployed (≤3.3%) or received other health-related benefits (≤1.6%).

    Two years preceding diagnosis, the proportion of PV and MPN-U patients working was slightly lower than the matched comparisons: PV, 31.0% (95% CI, 28.4-33.8) vs. nonPV, 34.3% (95% CI, 33.5-35.2) and MPN-U, 28.2% (95% CI, 24.6-32.1) vs. nonMPN-U, 32.0% (95% CI, 30.7-33.2), while this difference was not observed between ET and MF patients and their respective comparisons.

    From two years before to two years after diagnosis, we observed slightly larger reductions in the proportion working among MPN patients than among comparisons. Among MPN patients, the proportion on sick leave including other health-related benefits, increased during the study period, while it remained unchanged among comparisons. The proportion of patients and comparisons on disability pension remained stable.

    CONCLUSION: Overall, our findings showed that Danish patients with ET, PV, MF, and MPN-U had slightly impaired LMA already two years before diagnosis and up to two years after diagnosis. Thus, fewer patients were working and more patients transferred to sick leave compared with matched individuals without MPN.

  • 35. Christensen, Sarah
    et al.
    Svingel, Lise
    Kjærsgaard, Anders
    Stenling, Anna
    Novartis Sverige AB, Kista, Sweden.
    Darvalics, Bianka
    Paulsson, Björn
    Andersen, Christen
    Christiansen, Christian
    Hasselbalch, Hans
    Stentoft, Jesper
    Starklint, Jørn
    Severinsen, Marianne
    Clausen, Mette
    Hilsøe, Morten
    Frederiksen, Henrik
    Mikkelsen, Ellen
    Bak, Marie
    Healthcare resource utilization in patients with myeloproliferative neoplasms: a nationwide matched cohort study2021In: HemaSphere, ISSN 2572-9241, Vol. 5, no S2, p. 529-530, article id EP1107Article in journal (Refereed)
    Abstract [en]

    Background: Myeloproliferative neoplasms (MPNs) are associated with severe complications and a substantial symptom burden – frequently emerging several years before diagnosis. Due to the chronic nature ofthe diseases, MPN patients have a lifelong need for treatment and care. However, only few studies have assessed MPN healthcare resource utilization (HRU) compared with matched cohorts, and no detailed assessments of HRU in the years preceding MPN diagnosis exist.

    Aims: To assess the pre- and post-diagnostic HRU of MPN patients compared with matched cohorts of nonMPN comparisons.

    Methods: We conducted this descriptive, register-based nationwide cohort study, utilizing data from the Danish National Chronic Myeloid Neoplasia Registry on all MPN patients diagnosed between January 2010 and December 2016, and data on HRU from the Danish National Patient Registry and the Danish National Health Service Registry. Populationbased cohorts of nonMPN comparisons were constructed by 1:10 matchingon age, sex, level of education, and region of residence. Data were linkedusing the unique civil registration number, which identifies all Danish citizens. HRU was summarized over each year for all cohorts from twoyears before date of MPN diagnosis and until emigration, death, or endof study (31 December 2017). HRU was calculated as annual number ofhealthcare contacts (inpatient days, outpatient consultations, treatmentsand examinations, and general practitioner [GP] visits) divided by person-years at risk and compared using rate ratios with 95% CI.

    Results: The study population included 3,342 MPN patients (1,140 essential thrombocythemia [ET]; 1,109 polycythemia vera [PV]; 533 primary myelofibrosis [PMF]; and 560 unspecified MPN [MPN-U]) and 32,737 nonMPN comparisons (11,181 nonET; 10,873 nonPV; 5,217 nonPMF; and 5,466 nonMPN-U). The median age was 67 (ET), 69 (PV), 73 (PMF), and 72 years (MPN-U), and the mean follow-up was 3.8 (ET), 3.8(PV), 3.1 (PMF), and 3.3 years (MPN-U). A total of 750 (22.4%) MPNpatients and 4,627 (14.1%) nonMPN comparisons died during follow-up.In nearly all years of follow-up, MPN patients had a higher HRU thannonMPN comparisons (Figure, rate ratio>1). Rate ratios for outpatientconsultations were largest at the time of diagnosis: ET, 2.7 (95%CI, 2.6-2.9); PV, 3.4 (95%CI, 3.2-3.6); PMF, 4.0 (95%CI, 3.7-4.4); and MPN-U,3.7 (95%CI, 3.4-4.0). For most MPN subtypes, rate ratios also peaked attime of diagnosis for treatment and examinations. In contrast, the largest rate ratio for PV was in the last year of follow-up: 3.5 (95%CI, 2.8-4.3). Across MPN subtypes, rate ratios for GP visits varied from 1.0 to1.5 during follow-up without any considerable fluctuations. Interestingly, increased rate ratios for inpatients days were evident 2 years before diagnosis: ET, 1.8 (95%CI, 1.7-1.9); PV, 1.3, (95%CI, 1.2-1.3); PMF, 1.4(95%CI, 1.2-1.5); and MPN-U, 1.7 (95%CI, 1.6-1.9). During follow-up,notable increases in rate ratios were observed, e.g., PMF 3.0 (95%CI 2.4-3.6) and PV 3.8 (95%CI 3.0-4.8) in year 5 and 7, respectively.

    Summary/Conclusion: Overall, compared with matched nonMPN comparisons, MPN patients had a higher HRU throughout the study period. This was consistent across MPN subtypes and HRU measures. Within the limitations of small numbers toward end of follow-up and lack ofmatching on comorbidity, our findings confirmed a consistent HRU burden after MPN diagnosis. Equally important, our study revealed substantial increases in HRU two years before MPN diagnosis, warrantingfurther exploration of the pre-diagnostic period, including the potentialbenefits of early detection.

  • 36.
    Christiansson, Lisa
    et al.
    Uppsala, Sweden.
    Söderlund, Stina
    Uppsala, Sweden.
    Mangsbo, Sara
    Uppsala, Sweden.
    Hjorth-Hansen, Henrik
    Trondheim, Norway.
    Höglund, Martin
    Uppsala, Sweden.
    Markevärn, Berit
    Department of Hematology, Norrland University Hospital, Umeå, Sweden.
    Richter, Johan
    Lund, Sweden.
    Stenke, Leif
    Stockholm, Sweden.
    Mustjoki, Satu
    Helsinki, Finland.
    Loskog, Angelica
    Uppsala, Sweden.
    Olsson-Strömberg, Ulla
    Uppsala, Sweden.
    The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses2015In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 5, p. 1181-1191Article in journal (Refereed)
    Abstract [en]

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

  • 37.
    Clay-Gilmour, Alyssa
    et al.
    Arnold School of Public Health, Department of Epidemiology & Biostatistics, University of South Carolina, SC, Columbia, United States.
    Chattopadhyay, Subhayan
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Hildebrandt, Michelle A. T.
    Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, TX, Houston, United States.
    Thomsen, Hauke
    GeneWerk GmbH, Im Neuenheimer Feld 582, Heidelberg, Germany; Center for Primary Health Care Research, Lund University, Malmo, Sweden.
    Weinhold, Niels
    Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
    Vodicka, Pavel
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
    Vodickova, Ludmila
    Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Albertov 4, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
    Hoffmann, Per
    Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Biomedicine, University of Basel, Basel, Switzerland.
    Nöthen, Markus M.
    Institute of Human Genetics, University of Bonn, Bonn, Germany.
    Jöckel, Karl-Heinz
    Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany.
    Schmidt, Börge
    Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany.
    Langer, Christian
    Department of Internal Medicine III, University of Ulm, Ulm, Germany.
    Hajek, Roman
    Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Ohlsson, Claes
    Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Späth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Houlston, Richard
    Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
    Goldschmidt, Hartmut
    Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; National Centre of Tumor Diseases, Heidelberg, Germany.
    Manasanch, Elisabet E.
    Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, TX, Houston, United States.
    Norman, Aaron
    Division of Computational Genomics, Mayo Clinic, MN, Rochester, United States.
    Kumar, Shaji
    Division of Hematology, Mayo Clinic Rochester Mayo Clinic, MN, Rochester, United States.
    Rajkumar, S. Vincent
    Division of Hematology, Mayo Clinic Rochester Mayo Clinic, MN, Rochester, United States.
    Slager, Susan
    Division of Computational Genomics, Mayo Clinic, MN, Rochester, United States; Division of Hematology, Mayo Clinic Rochester Mayo Clinic, MN, Rochester, United States.
    Försti, Asta
    Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
    Vachon, Celine M.
    Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, MN, Rochester, United States.
    Hemminki, Kari
    Biomedical Center, Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg, Germany.
    Genome-wide meta-analysis of monoclonal gammopathy of undetermined significance (MGUS) identifies risk loci impacting IRF-62022In: Blood Cancer Journal, E-ISSN 2044-5385, Vol. 12, no 4, article id 60Article in journal (Refereed)
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  • 38.
    Cova, Giovanni
    et al.
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
    Taroni, Chiara
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
    Deau, Marie-Céline
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
    Cai, Qi
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
    Mittelheisser, Vincent
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
    Philipps, Muriel
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
    Jung, Matthieu
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France; Plateforme GenomEast, Infrastructure France Génomique, Illkirch, France.
    Cerciat, Marie
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France; Plateforme GenomEast, Infrastructure France Génomique, Illkirch, France.
    Le Gras, Stéphanie
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France; Plateforme GenomEast, Infrastructure France Génomique, Illkirch, France.
    Thibault-Carpentier, Christelle
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France; Plateforme GenomEast, Infrastructure France Génomique, Illkirch, France.
    Jost, Bernard
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France; Plateforme GenomEast, Infrastructure France Génomique, Illkirch, France.
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Thornton, Angela M.
    Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Bethesda, United States.
    Shevach, Ethan M.
    Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MD, Bethesda, United States.
    Kirstetter, Peggy
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
    Kastner, Philippe
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France; Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
    Chan, Susan
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1258, Illkirch, France; Centre National de la Recherche Scientifique (CNRS), UMR7104, Illkirch, France; Université de Strasbourg, Illkirch, France.
    Helios represses megakaryocyte priming in hematopoietic stem and progenitor cells2021In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 218, no 10, article id e20202317Article in journal (Refereed)
    Abstract [en]

    Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte gene expression program in cells as early as the stem cell stage. Helios binding promotes chromatin compaction, notably at the regulatory regions of platelet-specific genes recognized by the Gata2 and Runx1 transcriptional activators, implicated in megakaryocyte priming. Helios null HSPCs are biased toward the megakaryocyte lineage at the expense of the lymphoid and partially resemble cells of aging animals. We propose that Helios acts as a guardian of HSPC pluripotency by continuously repressing the megakaryocyte fate, which in turn allows downstream lymphoid priming to take place. These results highlight the importance of negative and positive priming events in lineage commitment.

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  • 39.
    Dahlén, Torsten
    et al.
    Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden; Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
    Edgren, Gustaf
    Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden; Department of Cardiology, Södersjukhuset, Stockholm, Sweden.
    Ljungman, Per
    Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Huddinge, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Flygt, Hjalmar
    Department of Medical Science and Division of Hematology, University Hospital, Uppsala, Sweden.
    Richter, Johan
    Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden.
    Olsson-Strömberg, Ulla
    Department of Medical Science and Division of Hematology, University Hospital, Uppsala, Sweden.
    Wadenvik, Hans
    Section of Hematology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Dreimane, Arta
    Department of Hematology, Linköping University Hospital, Linköping, Sweden.
    Myhr-Eriksson, Kristina
    Department of Hematology, Sunderby Hospital, Luleå, Sweden.
    Zhao, Jingcheng
    Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Höglund, Martin
    Department of Medical Science and Division of Hematology, University Hospital, Uppsala, Sweden.
    Stenke, Leif
    Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Adverse outcomes in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: Follow-up of patients diagnosed 2002–2017 in a complete coverage and nationwide agnostic register study2022In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 97, no 4, p. 421-430Article in journal (Refereed)
    Abstract [en]

    Tyrosine kinase inhibitors (TKIs) have profoundly improved the clinical outcome for patients with chronic myeloid leukemia (CML), but their overall survival is still subnormal and the treatment is associated with adverse events. In a large cohort-study, we assessed the morbidity in 1328 Swedish CML chronic phase patients diagnosed 2002–2017 and treated with TKIs, as compared to that in carefully matched control individuals. Several Swedish patient registers with near-complete nationwide coverage were utilized for data acquisition. Median follow-up was 6 (IQR, 3–10) years with a total follow-up of 8510 person-years for the full cohort. Among 670 analyzed disease categories, the patient cohort showed a significantly increased risk in 142 while, strikingly, no category was more common in controls. Increased incidence rate ratios/IRR (95% CI) for more severe events among patients included acute myocardial infarction (AMI) 2.0 (1.5–2.6), heart failure 2.6 (2.2–3.2), pneumonia 2.8 (2.3–3.5), and unspecified sepsis 3.5 (2.6–4.7). When comparing patients on 2nd generation TKIs vs. imatinib in a within-cohort analysis, nilotinib generated elevated IRRs for AMI (2.9; 1.5–5.6) and chronic ischemic heart disease (2.2; 1.2–3.9), dasatinib for pleural effusion (11.6; 7.6–17.7) and infectious complications, for example, acute upper respiratory infections (3.0; 1.4–6.0). Our extensive real-world data reveal significant risk increases of severe morbidity in TKI-treated CML patients, as compared to matched controls, particularly for 2nd generation TKIs. Whether this increased morbidity may also translate into increased mortality, thus preventing CML patients to achieve a normalized overall survival, needs to be further explored.

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  • 40.
    D'Ambrosi, Silvia
    et al.
    Department of Neurosurgery, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; and.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wurdinger, Thomas
    Department of Neurosurgery, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; and.
    Platelets and tumor-associated RNA transfer2021In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 137, no 23, p. 3181-3191Article in journal (Refereed)
    Abstract [en]

    Until recently, the nucleic acid content of platelets was considered to be fully determined by their progenitor megakaryocyte. However, it is now well understood that additional mediators (eg, cancer cells) can intervene, thereby influencing the RNA repertoire of platelets. Platelets are highly dynamic cells that are able to communicate and influence their environment. For instance, platelets have been involved in various steps of cancer development and progression by supporting tumor growth, survival, and dissemination. Cancer cells can directly and/or indirectly influence platelet RNA content, resulting in tumor-mediated "education" of platelets. Alterations in the tumor-educated platelet RNA profile have been described as a novel source of potential biomarkers. Individual platelet RNA biomarkers as well as complex RNA signatures may be used for early detection of cancer and treatment monitoring. Here, we review the RNA transfer occurring between cancer cells and platelets. We explore the potential use of platelet RNA biomarkers as a liquid biopsy biosource and discuss methods to evaluate the transcriptomic content of platelets.

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

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

  • 43. Derolf, Asa
    et al.
    Juliusson, Gunnar
    Benson, Lina
    Floisand, Yngvar
    Lazarevic, Vladimir
    Antunovic, Petar
    Mollgard, Lars
    Lehmann, Soren
    Uggla, Bertil
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hoglund, Martin
    Deneberg, Stefan
    Decreasing early mortality in acute myeloid leukaemia in Sweden 1997-2014: improving performance status is a major contributing factor2020In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 188, no 1, p. 187-191Article in journal (Refereed)
  • 44. Doma, Eszter
    et al.
    Mayer, Isabella Maria
    Brandstoetter, Tania
    Maurer, Barbara
    Grausenburger, Reinhard
    Menzl, Ingeborg
    Zojer, Markus
    Hoelbl-Kovacic, Andrea
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Heller, Gerwin
    Kollmann, Karoline
    Sexl, Veronika
    A robust approach for the generation of functional hematopoietic progenitor cell lines to model leukemic transformation2021In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 5, no 1, p. 39-53Article in journal (Refereed)
    Abstract [en]

    Studies of molecular mechanisms of hematopoiesis and leukemogenesis are hampered by the unavailability of progenitor cell lines that accurately mimic the situation in vivo. We now report a robust method to generate and maintain LSK (Lin-, Sca-1+, c-Kit+) cells, which closely resemble MPP1 cells. HPCLSKs reconstitute hematopoiesis in lethally irradiated recipient mice over >8 months. Upon transformation with different oncogenes including BCR/ABL, FLT3-ITD, or MLL-AF9, their leukemic counterparts maintain stem cell properties in vitro and recapitulate leukemia formation in vivo. The method to generate HPCLSKs can be applied to transgenic mice, and we illustrate it for CDK6-deficient animals. Upon BCR/ABLp210 transformation, HPCLSKs Cdk6-/- induce disease with a significantly enhanced latency and reduced incidence, showing the importance of CDK6 in leukemia formation. Studies of the CDK6 transcriptome in murine HPCLSK and human BCR/ABL+ cells have verified that certain pathways depend on CDK6 and have uncovered a novel CDK6-dependent signature, suggesting a role for CDK6 in leukemic progenitor cell homing. Loss of CDK6 may thus lead to a defect in homing. The HPCLSK system represents a unique tool for combined in vitro and in vivo studies and enables the production of large quantities of genetically modifiable hematopoietic or leukemic stem/progenitor cells.

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  • 45. Ekberg, Jenny
    et al.
    Holm, Caroline
    Jalili, Sara
    Richter, Johan
    Anagnostaki, Lola
    Landberg, Göran
    Persson, Jenny L.
    Division of Pathology, Department of LaboratoryMedicine, Lund University, University Hospital, Malmö, Sweden.
    Expression of cyclin A1 and cell cycle proteins in hematopoietic cells and acute myeloid leukemia and links to patient outcome2005In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 75, no 2, p. 106-115Article in journal (Refereed)
    Abstract [en]

    Abnormal expression of several key regulators essential for G1/S transitions has been implicated in tumorigenesis. A critical role of cyclin A1 in the development of acute myeloid leukemia (AML) has previously been demonstrated in transgenic mice. Our present study focused on the expression and prognostic significance of cyclin A1 and a panel of cell cycle regulatory proteins including cyclin A2, cyclin B1, cyclin E, CDK1, CDK2, p21 and p27 in bone marrow samples from 40 patients with AML. Freshly isolated CD34+ hematopoietic cells and bone marrow samples from 10 healthy donors were also assessed for cell type- and subcellular-specific expression of the cell cycle regulatory proteins. The level of cyclin A1 expression was the only factor that showed a significant correlation with patient outcome. In log-rank test stratified by levels of cyclin A1 expression, patients with high levels of cyclin A1 had significantly worse overall survival (OS) (P = 0.012) compared to those with low levels. Further, patients with high levels of cyclin A1 had significantly lower disease-free survival (DFS) (P = 0.028). Multivariate analysis indicated that cyclin A1 protein expression was an independent prognostic factor for predicting DFS (P = 0.035) and OS (P = 0.045). No correlation between cyclin A1 expression and age was found. However, expression of cyclin A2, cyclin B1, cyclin E, CDK1, CDK2, p21 and p27 did not show prognostic significance in these AML patients.

  • 46.
    Enblom, Anneli
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Andréasson, Björn
    NU Hospital Group, Uddevalla, Sweden.
    Holmberg, Henrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Liljeholm, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Erythrocytosis, thrombocytosis, and rate of recurrent thromboembolic event: a population based cohort study2023In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 110, no 6, p. 608-617Article in journal (Refereed)
    Abstract [en]

    Introduction: The management to reduce risk of thromboembolic complications in polycythemia vera and essential thrombocythemia are well established, but for other conditions with elevated hemoglobin, hematocrit, or platelets there are no consensus regarding treatment and follow up.

    Aims: To assess frequency of elevated blood values in patients with thromboembolic event, how many of these should be investigated further regarding myeloproliferative neoplasm and if the risk of recurrent event is depending on underlying condition.

    Methods: Retrospective cohort study of 3931 adult patients in the county of Norrbotten, Sweden, with thromboembolism during 2017 and 2018.

    Results: Of the 3931 patients, 1195 had either elevated Hb, HCT, or platelets fulfilling the 2016 revised WHO criteria for PV and ET, and out of these 411 should be evaluated regarding underlying myeloproliferative neoplasms. Unexplained thrombocytosis and secondary erythrocytosis were associated with the highest rate of recurrent event as well as the most inferior restricted mean survival time.

    Conclusion: Elevated blood values are common in patients with thromboembolic event and the high risk of recurrent event and inferior restricted mean survival time in patients with unexplained thrombocytosis and secondary erythrocytosis implicates the importance of finding and managing the underlying condition.

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  • 47.
    Enblom, Anneli
    et al.
    Department of Internal Medicine, Sunderby hospital, Luleå, Sweden.
    Girodon, Francois
    Service d'hématologie Biologique, CHU de Dijon, Dijon, France.
    Bak, Marie
    Department of Hematology, Roskilde hospital, Roskilde, Denmark.
    Hersby, Ditte
    Department of Hematology, Roskilde hospital, Roskilde, Denmark.
    Jooste, Valérie
    Registre Bourguignon des Cancers Digestifs, INSERM UMR 866 - CHU Dijon Bourgogne - Université Bourgogne Franche-Comté, Dijon, France.
    Hasselbalch, Hans
    Department of Hematology, Roskilde hospital, Roskilde, Denmark.
    Johansson, Peter
    Hematology and Coagulation section, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Andreasson, Björn
    NU hospital group, Uddevalla Hospital, Uddevalla, Sweden.
    A retrospective analysis of the impact of treatments and blood counts on survival and the risk of vascular events during the course of polycythaemia vera2017In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 177, no 5, p. 800-805Article in journal (Refereed)
    Abstract [en]

    Vascular and non-vascular complications are common in patients with polycythaemia vera. This retrospective study of 217 patients with polycythaemia vera aimed to determine whether blood counts with respect to different treatments influenced the complication rate and survival. We found that 78 (36%) patients suffered from at least one complication during follow-up. Older age and elevated lactate dehydrogenase at diagnosis were found to be risk factors for vascular complications. When the vascular complication occurred, 41% of the patients with a complication had elevated white blood cells (WBC) compared with 20% of patients without a complication (P = 0·042). Patients treated with hydroxycarbamide (HC; also termed hydroxyurea) experienced significantly fewer vascular complications (11%) than patients treated with phlebotomy only (27%) (P = 0·013). We also found a survival advantage for patients treated with HC, when adjusted for age, gender and time period of diagnosis (Hazard ratio for phlebotomy-treated patients compared to HC-treated patients at 5 years was 2·42, 95% confidence interval 1·03-5·72, P = 0·043). Concerning survival and vascular complications, HC-treated patients who needed at least one phlebotomy per year were not significantly different from HC-treated patients with a low phlebotomy requirement. We conclude that complementary phlebotomy in HC-treated patients in order to maintain the haematocrit, is safe.

  • 48.
    Enblom, Anneli
    et al.
    Sunderby Hospital, Luleå, Sweden.
    Lindskog, Emma
    Hasselbalch, Hans
    Hersby, Ditte
    Bak, Marie
    Tetu, Jennifer
    Girodon, François
    Andréasson, Björn
    High rate of abnormal blood values and vascular complications before diagnosis of myeloproliferative neoplasms2015In: European journal of internal medicine, ISSN 0953-6205, E-ISSN 1879-0828, Vol. 26, no 5, p. 344-347Article in journal (Refereed)
    Abstract [en]

    Background: Vascular complications occurring before the diagnosis of myeloproliferative neoplasms (MPN) in 612 patients from four centers in Sweden, Denmark and France were retrospectively studied.

    Results: Vascular complications were observed in 151 (25%) of the 612 patients. Of these, 66% occurred during the two years preceding diagnosis. The majority of events were thromboembolic (95%), and included myocardial infarction (n = 46), ischemic stroke (n = 43), transient ischemic attack (TIA) (n = 22), deep vein thrombosis/pulmonary embolism (n = 19), splanchnic vein thrombosis (n = 7), and peripheral embolism (n = 7). Bleeding was observed in only 7 (5%) of the 151 patients with vascular events (3 with intracranial bleeding, 2 with epistaxis and 2 with gastrointestinal bleeding). Full blood counts obtained at least 3 months prior to the MPN diagnosis showed that 269 (44%) had abnormal blood values, fulfilling the diagnostic criteria for MPN. During the time from the abnormal blood test to the diagnosis of MPN, 50 patients suffered from a vascular complication.

    Conclusion: We therefore conclude that a large proportion of MPN patients suffer severe thromboembolic complications prior to diagnosis. If MPN were diagnosed earlier, a large proportion of these events might be prevented. An MPN should always be suspected and ruled out in patients with unexplained elevated hematocrit, leukocyte and/or platelet counts.

  • 49.
    Enblom-Larsson, Anneli
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Renlund, Henrik
    Uppsala Clinical Research Centre Uppsala University, Uppsala, Sweden.
    Andréasson, Björn
    NU Hospital Group, Uddevalla, Sweden.
    Holmberg, Henrik
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Liljeholm, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Thromboembolic events, major bleeding and mortality in essential thrombocythaemia and polycythaemia vera: a matched nationwide population-based study2024In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141Article in journal (Refereed)
    Abstract [en]

    Thromboembolic events and bleeding are known complications in essential thrombocythaemia (ET) and polycythaemia vera (PV). Using multiple Swedish health care registers, we assessed the rate of arterial and venous events, major bleeding, all-cause stroke and all-cause mortality in ET and PV compared to matched controls. For each patient with ET (n = 3141) and PV (n = 2604), five matched controls were randomly selected. In total, 327 and 405 arterial or venous events were seen in the group of ET and PV patients respectively. Compared to corresponding controls, the rate of venous thromboembolism, major bleeding and all-cause mortality per 100 treatment years was significantly increased among both ET (0.63, 0.79 and 3.70) and PV patients (0.94, 1.20 and 4.80). The PV patients also displayed a significantly higher rate of arterial events and all-cause stroke compared to controls. When dividing the cohort into age groups, we found a significantly higher rate of arterial and venous events in all age groups of PV patients, and the rate of all-cause mortality was significantly higher in both ET and PV patients in all ages above the age of 50. This study confirms that PV and ET are diseases truly marked by thromboembolic complications and bleeding.

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

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

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