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  • 51. Hammer, Anne Sofie Borg
    et al.
    Juul-Dam, Kristian
    Sandahl, Julie Damgaard
    Abrahamsson, Jonas
    Balwierz, Walentyna
    Guilmatre, Audrey
    Haltrich, Iren
    Jahnukainen, Kirsi
    Kolb, E. Anders
    Kovacs, Gabor
    Leverger, Guy
    Locatelli, Franco
    Masetti, Riccardo
    Norén-Nyström, Ulrika
    Umeå University.
    Raimondi, Susana C.
    Rasche, Mareike
    Reinhardt, Dirk
    Taki, Tomohiko
    Tomizawa, Daisuke
    Zeller, Bernward
    Hasle, Henrik
    Kjeldsen, Eigil
    Hypodiploidy in Childhood Acute Myeloid Leukemia: A Retrospective Cohort Study within the International Berlin-Frankfurt-Munster Study Group2018Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Artikkel i tidsskrift (Annet vitenskapelig)
  • 52. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur Gisli
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 20042012Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, nr 5, s. 978-984Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 53.
    Hernestål-Boman, Jenny
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Jansson, Jan-Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Eliasson, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nilsson, Torbjörn K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Johansson, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Individual PAI-1 increase over nine years relates differently in men and women to changes in anthropometric, glycaemic, inflammatory and lipid markers.Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

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

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

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

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

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

  • 54.
    Hernestål-Boman, Jenny
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Jansson, Jan-Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nilsson, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Eliasson, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Johansson, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Individual changes in fibrinolytic factors, von Willebrand factor, and C-reactive protein over a nine-year period.Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

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

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

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

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

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

  • 55. Hosnijeh, Fatemeh Saberi
    et al.
    Lan, Qing
    Rothman, Nathaniel
    Liu, Chin San
    Cheng, Wen-Ling
    Nieters, Alexandra
    Guldberg, Per
    Tjonneland, Anne
    Campa, Daniele
    Martino, Alessandro
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Krogh, Vittorio
    Tumino, Rosario
    Panico, Salvatore
    Masala, Giovanna
    Weiderpass, Elisabete
    Castano, Jose Maria Huerta
    Ardanaz, Eva
    Sala, Nuria
    Dorronsoro, Miren
    Quiros, J. Ramon
    Sanchez, Maria-Jose
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Ann Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Malm, Johan
    Borgquist, Signe
    Peeters, Petra H.
    Bueno-de-Mesquita, H. Bas
    Wareham, Nick
    Khaw, Kay-Tee
    Travis, Ruth C.
    Brennan, Paul
    Siddiq, Afshan
    Riboli, Elio
    Vineis, Paolo
    Vermeulen, Roel
    Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 4, s. 530-535Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 56. Ilander, M
    et al.
    Olsson-Strömberg, U
    Schlums, H
    Guilhot, J
    Brück, O
    Lähteenmäki, H
    Kasanen, T
    Koskenvesa, P
    Söderlund, S
    Höglund, M
    Markevärn, B
    Själander, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lotfi, K
    Dreimane, A
    Lübking, A
    Holm, E
    Björeman, M
    Lehmann, S
    Stenke, L
    Ohm, L
    Gedde-Dahl, T
    Majeed, W
    Ehrencrona, H
    Koskela, S
    Saussele, S
    Mahon, F-X
    Porkka, K
    Hjorth-Hansen, H
    Bryceson, Y T
    Richter, J
    Mustjoki, S
    Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia2017Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, nr 5, s. 1108-1116Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 57. Ilander, Mette Matilda
    et al.
    Olsson-Strömberg, Ulla
    Lahteenmaki, Hanna
    Tiina, Kasanen
    Koskenvesa, Perttu
    Söderlund, Stina
    Höglund, Martin
    Markevärn, Berit
    Själander, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lotfi, Kourosh
    Malm, Claes
    Lubking, Anna
    Ekblom, Marja
    Holm, Elena
    Bjoreman, Mats
    Lehmann, Soren
    Stenke, Leif
    Ohm, Lotta
    Majeed, Waleed
    Pfirrmann, Markus
    Muller, Martin C.
    Guilhot, Joelle
    Ehrencrona, Hans
    Hjorth-Hansen, Henrik
    Saussele, Susanne
    Mahon, Francois-Xavier
    Porkka, Kimmo
    Richter, Johan
    Mustjoki, Satu
    Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and Impaired Function of NK-Cells2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 21Artikkel i tidsskrift (Annet vitenskapelig)
  • 58. Ilander, Mette
    et al.
    Schlums, Heinrich
    Olsson-Stromberg, Ulla
    Lahteenmäki, Hanna
    Kasanen, Tiina
    Koskenvesa, Perttu
    Söderlund, Stina
    Höglund, Martin
    Markevärn, Berit
    Själander, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Lotfi, Kourosh
    Malm, Claes
    Lubking, Anna
    Ekblom, Marja
    Holm, Elena
    Björeman, Mats
    Lehmann, Soren
    Stenke, Leif
    Ohm, Lotta
    Majeed, Waleed
    Muller, Martin C
    Ehrencrona, Hans
    Hjorth-Hansen, Henrik
    Saussele, Susanne
    Mahon, Francois-Xavier
    Porkka, Kimmo
    Guilhot, Joelle
    Bryceson, Yenan
    Richter, Johan
    Mustjoki, Satu
    Mature, Adaptive-like CD56(DIM) NK Cells in Chronic Myeloid Leukemia Patients in Treatment Free Remission2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, nr 23Artikkel i tidsskrift (Annet vitenskapelig)
  • 59. Inaba, Hiroto
    et al.
    Zhou, Yinmei
    Abla, Oussama
    Adachi, Souichi
    Auvrignon, Anne
    Beverloo, H. Berna
    de Bont, Eveline
    Chang, Tai-Tsung
    Creutzig, Ursula
    Dworzak, Michael
    Elitzur, Sarah
    Fynn, Alcira
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Nordic Society for Pediatric Hematology and Oncology, Stockholm, Sweden.
    Hasle, Henrik
    Liang, Der-Cherng
    Lee, Vincent
    Locatelli, Franco
    Masetti, Riccardo
    De Moerloose, Barbara
    Reinhardt, Dirk
    Rodriguez, Laura
    Van Roy, Nadine
    Shen, Shuhong
    Taga, Takashi
    Tomizawa, Daisuke
    Yeoh, Allen E. J.
    Zimmermann, Martin
    Raimondi, Susana C.
    Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, nr 13, s. 1575-1584Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 60. Iolascon, Achille
    et al.
    Heimpel, Hermann
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Tamary, Hannah
    Congenital dyserythropoietic anemias: molecular insights and diagnostic approach2013Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 122, nr 13, s. 2162-2166Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 61. Jonsdottir, Gudbjörg
    et al.
    Lund, Sigrún H.
    Björkholm, Magnus
    Turesson, Ingemar
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Mailankody, Sham
    Blimark, Cecilie
    Hultcrantz, Malin
    Porwit, Anna
    Landgren, Ola
    Kristinsson, Sigurdur Y.
    Survival in multiple myeloma patients who develop second malignancies: a population-based cohort study2016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, nr 4, s. e145-e148Artikkel i tidsskrift (Fagfellevurdert)
  • 62. Karlsson, Lene
    et al.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hasle, Henrik
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Nyström, Ulrika Noren
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Palle, Josefine
    Tierens, Anne
    Zeller, Bernward
    Abrahamsson, Jonas
    Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia2017Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, nr 4, s. 592-602Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 63. Karlsson, Lene
    et al.
    Nyvold, Charlotte Guldborg
    Palmqvist, Lars
    Tierens, Anne
    Hasle, Henrik
    Lausen, Birgitte
    Jonsson, Olafur G.
    Juergensen, Gitte Wulff
    Ebbesen, Lene Hyldahl
    Kuchenbauer, Florian
    Forestier, Erik
    Umeå University, Sweden.
    Abrahamsson, Jonas
    Fogelstrand, Linda
    Quantification of Fusion Transcripts Reveals Slower Treatment Kinetics As Compared with Multiparameter Flow Cytometry during Induction Treatment of Acute Myeloid Leukemia in Children2018Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Artikkel i tidsskrift (Annet vitenskapelig)
  • 64. Kimby, Eva
    et al.
    Östenstad, Björn
    Brown, Peter de Nully
    Holte, Harald, Jr.
    Hagberg, Hans
    Erlanson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Linden, Ola
    Nordström, Marie
    Sundström, Christer
    Rituximab (R) in Combination with Interferon-a2a (IFN) Versus Single R in Patients with Follicular or Other CD20+Low-Grade (indolent) Lymphoma. Final Results From a Randomized Phase III Study From the Nordic Lymphoma Group2012Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, nr 21Artikkel i tidsskrift (Annet vitenskapelig)
  • 65.
    Kolar, Mallappa K
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Kingham, Paul J
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Novikova, Liudmila N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Wiberg, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Handkirurgi.
    Novikov, Lev N
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    The therapeutic effects of human adipose derived stem cells in a rat cervical spinal cord injury model2014Inngår i: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 23, nr 14, s. 1659-1674Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Spinal cord injury triggers a cascade of degenerative changes leading to cell death and cavitation. Severed axons fail to regenerate across the scar tissue and are only capable of limited sprouting. In this study we investigated the effects of adult human adipose derived stem cells (ASC) on axonal regeneration following transplantation into the injured rat cervical spinal cord. ASC did not induce activation of astrocytes in culture and supported neurite outgrowth from adult rat sensory DRG neurons. After transplantation into the lateral funiculus 1mm rostral and caudal to the cervical C3-C4 hemisection, ASC continued to express BDNF, VEGF and FGF-2 for 3 weeks but only in animals treated with cyclosporine A. Transplanted ASC stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone with some terminal arborisations reaching the caudal spinal cord. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure of the lesion scar with numerous astrocytic processes extended into the middle of the trauma zone in a chain-like pattern and in close association with regenerating axons. The density of the astrocytic network was also significantly decreased. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the activity of OX42-positive microglial cells was markedly reduced. However, ASC did not support recovery of forelimb function. The results suggest that transplanted ASC can modify the structure of the glial scar and stimulate axonal sprouting.

  • 66. Kozlowski, Piotr
    et al.
    Åström, Maria
    Ahlberg, Lucia
    Bernell, Per
    Hulegårdh, Erik
    Hägglund, Hans
    Karlsson, Karin
    Markuszewska-Kuczynska, Alicja
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Tomaszewska-Toporska, Beata
    Smedmyr, Bengt
    Hallbook, Helene
    High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003-20072012Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 97, nr 9, s. 1414-1421Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background A minority of patients with adult acute lymphoblastic leukemia who relapse are rescued. The aim of this population-based study was to assess the results of reinduction treatment and allogeneic stem cell transplantation in patients in second complete remission.

    Design and Methods Between 2003-2007, 76 adults (<66 years) with relapsed acute lymphoblastic leukemia (Burkitt's leukemia excluded) were prospectively reported to The Swedish Adult Acute Leukemia Registry and later evaluated.

    Results Reinduction with: (i) mitoxantrone, etoposide, and cytarabine (MEA); (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor (FLAG-Asp); and (iii) cytarabine, betamethasone, cyclophosphamide, daunorubicin, and vincristine (ABCDV) resulted in complete remission in 6/9 (67%), 10/16 (63%) and 9/21 (43%) of the patients, respectively. Allogeneic stem cell transplantation was performed during second complete remission in 29 patients. Multivariate analysis regarding overall survival after relapse revealed that age over 35 years at diagnosis and relapse within 18 months were negative prognostic factors. Overall survival rates at 3 and 5 years were 22% (95% CI: 13-32) and 15% (95% CI: 7-24). Of 19 patients less than 35 years at diagnosis who underwent allogeneic stem cell transplantation in second remission, ten (53%) are still alive at a median of 5.5 years (range, 4.2-8.3) after relapse, whereas all patients over 35 years old at diagnosis have died.

    Conclusions Allogeneic stem cell transplantation remains the treatment of choice for young adults with relapsed acute lymphoblastic leukemia. Both (i) mitoxantrone, etoposide, and cytarabine and (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor seem effective as reinduction treatments and should be further evaluated. New salvage strategies are needed, especially for patients over 35 years old at diagnosis.

  • 67. Kristinsson, Sigurdur Y
    et al.
    Björkholm, Magnus
    Goldin, Lynn R
    Blimark, Cecilie
    Mellqvist, Ulf-Henrik
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Turesson, Ingemar
    Landgren, Ola
    Patterns of hematologic malignancies and solid tumors among 37,838 first-degree relatives of 13,896 patients with multiple myeloma in Sweden.2009Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 125, nr 9, s. 2147-2150Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There are emerging data to suggest a role for genetic factors in the pathogenesis of multiple myeloma (MM). Based on small numbers, certain solid tumors have been reported to occur more frequently among blood relatives of patients with MM. Using population-based data, we assessed risks for hematologic malignancies, monoclonal gammopathy of undetermined significance (MGUS), and solid tumors among first-degree relatives of patients with MM. We included 13,896 patients with MM and 54,365 matched controls. Also we identified first-degree relatives of patients with MM (n = 37,838) and controls (n = 151,068). Using a marginal survival model, we estimated relative risks (RRs) and 95% confidence intervals (CIs) for hematologic and solid tumors among family members of patients with MM and controls as measures of familial aggregation. Compared with relatives of controls, relatives of patients with MM had an increased risk of developing MM (RR = 2.1; 95% CI 1.6-2.9), MGUS (2.1; 1.5-3.1), acute lymphoblastic leukemia (ALL) (2.1; 1.0-4.2), any solid tumor (1.1; 1.0-1.1) and bladder cancer (1.3; 1.0-1.5). No significantly increased risk was found for other hematologic or solid malignancies. Our findings support a role for a shared susceptibility (genetic, environmental or both) that predisposes to MM, MGUS, ALL and bladder cancer.

  • 68. Kristinsson, Sigurdur Y
    et al.
    Tang, Min
    Pfeiffer, Ruth M
    Björkholm, Magnus
    Blimark, Cecilie
    Mellqvist, Ulf-Henrik
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Turesson, Ingemar
    Landgren, Ola
    Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study2010Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 116, nr 15, s. 2651-2655Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients with multiple myeloma (MM) have an increased risk of fractures. On the basis of small numbers, patients with monoclonal gammopathy of undetermined significance (MGUS) have been reported to have an increased fracture risk. Using population-based data from Sweden, we assessed the risks of fractures in 5326 MGUS patients diagnosed from 1958 to 2006, compared with 20 161 matched controls. MGUS patients had an increased risk of any fracture at 5 (hazard ratio [HR] = 1.74; 95% confidence interval [CI], 1.58-1.92) and 10 (HR = 1.61; 95% CI, 1.49-1.74) years. The risk was significantly higher for axial (skull, vertebral/pelvis, and sternum/costae) compared with distal (arm and leg) fractures (P < .001). On the basis of 10 years of follow-up, there was an increased risk of vertebral/pelvic (HR = 2.37; 95% CI, 2.02-2.78), sternal/costae (HR = 1.93; 95% CI, 1.5-2.48), arm (HR = 1.23; 95% CI, 1.06-1.43), leg (HR = 1.40; 95% CI, 1.26-1.56), and other/multiple fractures (HR = 4.25; 95% CI, 3.29-5.51). Risks for fractures did not differ by isotype or M protein concentration at diagnosis. MGUS patients with (versus without) fractures had no excess risk of MM or Waldenström macroglobulinemia. Our results suggest that bone alterations are present in early myelomagenesis. Our findings may have implications for the development of better prophylaxis for bone disease in MGUS, and they provide novel clues on pathogenesis of MM bone disease.

  • 69. Kristinsson, Sigurdur Y
    et al.
    Tang, Min
    Pfeiffer, Ruth M
    Björkholm, Magnus
    Goldin, Lynn R
    Blimark, Cecilie
    Mellqvist, Ulf-Henrik
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Turesson, Ingemar
    Landgren, Ola
    Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study.2012Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 97, nr 6, s. 854-858Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    No comprehensive evaluation has been conducted to assess the risk of viral and bacterial infections among patients with monoclonal gammopathy of undetermined significance. Using population-based data from Sweden, we estimated risk of infections among 5,326 MGUS patients compared to 20,161 matched controls. Patients with monoclonal gammopathy of undetermined significance had a 2-fold increased risk (P<0.05) of developing any infection at 5 and 10 years of follow-up. More specifically, patients with monoclonal gammopathy of undetermined significance had an increased risk (P<0.05) of bacterial infections (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis), and viral infections (influenza and herpes zoster). Patients with monoclonal gammopathy of undetermined significance with M-protein concentrations >2.5 g/dL at diagnosis had highest risks of infections; however, the risk was also increased (P<0.05) among those with concentrations <0.5 g/dL. Patients with monoclonal gammopathy of undetermined significance who developed infections had no excess risk of developing multiple myeloma. Our findings provide novel clues for the mechanisms behind infections in patients with plasma cell dyscrasias, and may have clinical implications.

  • 70. Kuchinskaya, E
    et al.
    Heyman, M
    Grandér, D
    Linderholm, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Centre of Haematology, Karolinska Institutet, Stockholm, Sweden.
    Söderhäll, S
    Zaritskey, A
    Nordgren, A
    Porwit-Macdonald, A
    Zueva, E
    Pawitan, Y
    Corcoran, M
    Nordenskjöld, M
    Blennow, Elisabeth
    Children and adults with acute lymphoblastic leukaemia have similar gene expression profiles2005Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 74, nr 6, s. 466-480Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: To compare the gene expression pattern in children and adults with acute lymphoblastic leukaemia (ALL) in order to improve our understanding of the difference in disease biology and prognosis.

    METHODS: The gene expression profiles in diagnostic samples from 29 children and 15 adults with ALL were analysed using the oligonucleotide chip Hu95ver2a, produced by Affymetrix.

    RESULTS: Unsupervised hierarchical cluster analysis revealed that, in spite of differences in outcome, patients clustered irrespective of age, first by T-cell or B-precursor immunophenotype, and second by cytogenetic changes within the B-precursor group. The expression pattern analysis allowed the reclassification of some samples into the proper cytogenetic group. We also showed that separate clustering of samples with the BCR/ABL translocation could be explained by different breakpoint regions in the BCR. No significant difference in gene expression was observed between samples with and without CDKN2A deletion within the B-precursor group. Analysis of different age groups revealed a similarity in expression profiles when infants with the MLL translocation and adults over 40 yr of age were compared irrespective of karyotype.

    CONCLUSIONS: In spite of the difference in clinical outcome, the gene expression pattern in children and adults with ALL is very similar and is primarily dependent on immunophenotype and cytogenetic aberrations. However, when age groups are compared, the expression patterns of infants and adults over 40 show a remarkable similarity.

  • 71.
    Kyrk, Tobias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Bechara, Alex
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Skagerlind, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Stegmayr, Bernd
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Heparin and albumin as part of the priming solution limits exposure to anticoagulation during hemodialysis: in vitro studies2014Inngår i: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 37, nr 10, s. 734-740Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Hemodialysis patients who are subject to increased risk of hemorrhage may need specific dialysis regimes to avoid bleeding. The aim of this study was to determine in vitro which of various anticoagulation options were most beneficial.

    Materials and method: 60 in vitro hemodialyses (HD) were performed in parallel using blood from healthy donors. The dialysis circuits were rinsed with either 1 L of 0.9% NaCl alone (n = 6), or with 1 L saline and the addition of either 5 mL 20% albumin (Alb, n = 6), 5,000 U of heparin (Hep, n = 6), Hep and Alb in combination (HA, n = 30), 20,000 U of Hep and Alb (4H-A, n = 6), and finally Hep and 20 mL 20% albumin (H-4A, n = 6). The blood was recirculated for a maximum of 192 min. Clotting was graded.

    Results: A 192 min dialysis was completed with all series of HA, 4H-A, and H-4A, all with a slight grade of clotting. In contrast to the above settings (p = 0.002, Fisher's test), a total clotting of the dialysis circuit occurred for all series using the NaCl rinsing alone (median time to stop: 21, range: 18-27 min, p = 0.026 compared to the HA setting) and for the Alb rinsing (median 26, range: 19-35 min, p = 0.028).

    Conclusions: Priming using HA, Hep, 4H-A, and H-4A reduced clotting and allowed 192 min of HD. Clinical studies need to confirm these data in vivo.

  • 72. Labaf, Ashkan
    et al.
    Grzymala-Lubanski, Bartosz
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Internal Medicine, General Hospital in Sundsvall, Sundsvall, Sweden.
    Stagmo, Martin
    Lövdahl, Susanna
    Wieloch, Mattias
    Själander, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Internal Medicine, General Hospital in Sundsvall, Sundsvall, Sweden.
    Svensson, Peter J.
    Thromboembolism, major bleeding and mortality in patients with mechanical heart valves: a population-based cohort study2014Inngår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, nr 2, s. 354-359Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Low incidences of thromboembolism (TE) and bleeding in patients with mechanical heart valves (MHV) have previously been reported. This study assesses the incidence of and clinical risk factors predicting TE, major bleeding and mortality in a clinical setting. Methods and results: All 546 patients undergoing anticoagulation treatment due to MHV replacement at hospitals in Malmo and Sundsvall in Sweden were monitored during 2008-2011 and the incidence of TE, major bleeding and mortality was prospectively followed. There were 398, 122 and 26 patients in the aortic group (AVR), mitral (MVR) group and the combined aortic/mitral valve group respectively. The incidence of TE was 1.8 and 2.2 per 100 patient-years in the AVR group MVR group respectively. The corresponding incidences of bleeding were 4.4 and 4.6, respectively. Independent predictor of thromboembolism was vascular disease (Odds ratio {OR}: 4.2; 95% CI: 1.0-17.4). Predictor of bleeding was previous bleeding (OR: 2.7; 95% CI: 1.4-5.3). Independent predictors of mortality was age (Hazard ratio {HR}: 1.03; 95% CI: 1.00-1.05), hypertension (HR: 2.4; 95% CI: 1.3-4.5), diabetes (HR: 2.4; 95% CI: 1.3-4.3) and alcohol overconsumption (HR: 5.2; 95% CI: 1.7-15.9). Standardized mortality/morbidity ratio for mortality and AMI was 0.99 (95% CI: 0.8-1.2) and 0.87 (95% CI: 0.5-1.2) respectively. Conclusion: The incidence of TE and major bleeding in this unselected clinical population exceeds that of previously reported retrospective and randomized trials. Despite this, mortality is equal to that of the general population.

  • 73. Labaf, Ashkan
    et al.
    Själander, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Stagmo, Martin
    Svensson, Peter J
    INR variability and outcomes in patients with mechanical heart valve prosthesis2015Inngår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, nr 6, s. 1211-1215Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The quality of treatment with warfarin is mainly assessed by the time in therapeutic range (TTR) in patients with mechanical heart valve prosthesis (MHV). Our aim was to evaluate if International Normalized Ratio (INR) variability predicted a combined endpoint of thromboembolism, major bleeding and death better than TTR.

    METHODS AND RESULTS: We included 394 patients at one center with MHV during 2008-2011 with adverse events and death followed prospectively. TTR 2.0-4.0 and log-transformed INR variability was calculated for all patients. In order to make comparisons between the measures, the gradient of the risk per one standard deviation (SD) was assessed. INR variability performed equal as TTR 2.0-4.0 per one SD unit adjusted for covariates, hazard ratio (HR) 1.30 (95% CI 1.1-1.5) and 0.71 (95% CI 0.6-0.8) respectively for the combined endpoint, and performed better for mortality HR 1.47 (95% CI 1.1-1.9) and 0.70 (95% CI 0.6-0.8). INR variability was categorized into high and low group and TTR into tertiles. High variability within the low and high TTR, had a HR 2.0 (95% CI 1.7-3.6) and 2.2 (95% CI 1.1-4.1) respectively, of the combined endpoint compared to the low variability/high TTR group. INR values <2.0 greatly increased the rate of thromboembolism whereas the rate of major bleeding increased moderately between INR 3.0 and 4.0 and increased substantially after INR >4.0.

    CONCLUSION: The INR variability is an equal predictor as TTR of the combined endpoint of thromboembolism, major bleeding and death, and adds important information on top of TTR in patients with MHV.

  • 74. Lampinen, Maria
    et al.
    Fredricsson, Annika
    Vessby, Johan
    Martinez, Johana Fernandez
    Wanders, Alkwin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rorsman, Fredrik
    Carlson, Marie
    Downregulated eosinophil activity in ulcerative colitis with concomitant primary sclerosing cholangitis2018Inngår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 104, nr 1, s. 173-183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Primary sclerosing cholangitis (PSC) is a chronic bile duct inflammation strongly connected to ulcerative colitis (UC). PSC is associated with an increased risk of colon cancer, but the link between the intestinal and the bile duct inflammation is still unknown. Also, the involvement of intestinal immune cells in the pathogenesis of PSC remains to be determined. The eosinophil granulocyte is one of the immune cells implicated in the inflammatory process of ulcerative colitis. This study was performed to determine how the accumulation and activation of intestinal eosinophils may differ between UC with and without concomitant PSC, and how this may be influenced by the cytokine/chemokine profile of the intestinal compartment. Eosinophils from peripheral blood and multiple parts of the colon were analyzed by flow cytometry. The intestinal level of inflammatory mediators was assessed using a multiplex proximity extension assay and a quantitative immunoassay. We found that colonic eosinophils were more abundant in both UC and PSC-UC compared with controls, but that their expression of activation markers was significantly increased in UC only. The colonic level of pro-inflammatory cytokines was increased in active UC but not in PSC-UC. In conclusion, we show for the first time that eosinophil activation phenotype discriminates between UC and PSC-UC, and that this may depend on the local cytokine profile of the colonic mucosa. Lower expression of activation markers on eosinophils in UC with concomitant PSC may depend on the local protein profile of the colonic mucosa.

  • 75. Landgren, Ola
    et al.
    Kristinsson, Sigurdur Y
    Goldin, Lynn R
    Caporaso, Neil E
    Blimark, Cecilie
    Mellqvist, Ulf-Henrik
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Björkholm, Magnus
    Turesson, Ingemar
    Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden.2009Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 114, nr 4, s. 791-795Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.

  • 76. Lanza, Francesco
    et al.
    Campioni, Diana C.
    Hellmann, Andrzej
    Milone, Giuseppe
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Walewski, Jan
    Spedini, Pierangelo
    Fiamenghi, Cristina
    Cuneo, Antonio
    Knopinska, Wanda
    Swierkowska-Czeneszew, Monica
    Petriz, Jordi
    Fruehauf, Stefan
    Farge, Dominique
    Mohty, Mohamad
    Passweg, Jacob
    Ruuto, Tapani
    Madrigal, Alejandro
    Johnsen, Hans E.
    Individual Quality Assessment of Autografting by Probability Estimation for Clinical Endpoints: A Prospective Validation Study from the European Group for Blood and Marrow Transplantation2013Inngår i: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 19, nr 12, s. 1670-1676Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The aim of supportive autografting is to reduce the side effects from stem cell transplantation and avoid procedure-related health disadvantages for patients at the lowest possible cost and resource expenditure. Economic evaluation of health care is becoming increasingly important. We report clinical and laboratory data collected from 397 consecutive adult patients (173 non-Hodgkin lymphoma, 30 Hodgkin lymphoma, 160 multiple myeloma, 7 autoimmune diseases, and 28 acute leukemia) who underwent their first autologous peripheral blood stem cell transplantation (PBSCT). We considered primary endpoints evaluating health economic efficacy (eg, antibiotic administration, transfusion of blood components, and time in hospital), secondary endpoints evaluating toxicity (in accordance with Common Toxicity Criteria), and tertiary endpoints evaluating safety (le, the risk of regimen-related death or disease progression within the first year after PBSCT). A time-dependent grading of efficacy is proposed with day 21 for multiple myeloma and day 25 for the other disease categories (depending on the length of the conditioning regimen) as the acceptable maximum time in hospital, which together with antibiotics, antifungal, or transfusion therapy delineates four groups: favorable (<= 7 days on antibiotics and no transfusions; <= 21 [25] days in hospital), intermediate (from 7 to 10 days on antibiotics and <3 transfusions, <= 21 to 25 days in hospital or >= 7 days on antibiotics and no transfusions; from 21 to 30 days [25 to 34] in hospital), unfavorable (>7 days on antibiotics, >3 but <6 transfusions; >30/34 days in hospital after transplantation), and very unfavorable (>10 days on antibiotics, >6 transfusions; >30 to 34 days in hospital). The multivariate analysis showed that (1) PBSC harvests of >= 4 x 10(6)/kg CD34 + cells in 1 apheresis procedure were associated with a favorable outcome in all patient categories except acute myelogenous leukemia and acute lymphoblastic leukemia (P = .001), (2) >= 5 x 10(6)/kg CD34 + cells infused predicted better transplantation outcome in all patient categories (P < .0001) except acute myelogenous leukemia and acute lymphoblastic leukemia, (3) 1 or 2 aphereses (P = .001) predicted good outcome, (4) toxicity increased with higher graft volume reinfused (>500 mL) (P = .002), and (5) patients with a central venous catheter during both collection and infusion of PBSC had a more favorable outcome post-PBSCT than peripheral access (P = .007). The type of mobilization regimen did not affect the outcome of auto-PBSCT. The present study identified predictive variables, which may be useful in future individual pretransplantation probability evaluations with the goal to improve supportive care. (C) 2013 American Society for Blood and Marrow Transplantation.

  • 77. Larfors, Gunnar
    et al.
    Sandin, Fredrik
    Richter, Johan
    Själander, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Stenke, Leif
    Lambe, Mats
    Höglund, Martin
    The impact of socio-economic factors on treatment choice and mortality in chronic myeloid leukaemia2017Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, nr 4, s. 398-406Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To evaluate the influence of socio-economic variables on treatment selection and survival of patients with chronic myeloid leukaemia (CML).

    METHODS: Using information available in population-based Swedish registries, we evaluated indices of health, education and economy from the 980 patients in the Swedish CML register diagnosed between 2002 and 2012. Apart from internal comparisons, five age-, gender- and region-matched control subjects per patient served as control cohort. Median follow-up time from CML diagnosis was 4.8 years.

    RESULTS: Among patients with CML, low personal or household income, short education, living alone, poor performance status and high age (>60 years) were significantly associated with an inferior survival (in univariate analyses). However, similar findings were noted also in the matched control group, and in comparisons adjusted for calendar year, age and performance status, socio-economic variables were not significantly associated with CML survival. Meanwhile, both education and income were independently linked to TKI treatment overall and to upfront treatment with second-generation TKIs.

    CONCLUSIONS: In conclusion, socio-economic conditions were associated with survival in the studied CML cohort but these associations could be explained by differences at baseline. Meanwhile, socio-economic conditions appeared to influence treatment choice.

  • 78.
    Larsson, Anders
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Hult, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Idrottsmedicin.
    Nilsson, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Olsson, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Oldenborg, Per-Arne
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Red blood cells with elevated cytoplasmic Ca2+ are primarily taken up by splenic marginal zone macrophages and CD207+dendritic cells2016Inngår i: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 56, nr 7, s. 1834-1844Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The normal red blood cell (RBC) life span may be significantly reduced when RBCs are stored under blood bank conditions, resulting in a reduced 24-hour survival after transfusion. The damage of stored RBCs is probably multifactorial as stored RBCs share features of both senescence and suicidal RBC death (eryptosis). Since an increased intracellular Ca2+ concentration ([Ca2+](i)) is one key feature of eryptosis, we here investigated if stored human RBCs had increased [Ca2+](i) and the mechanisms behind uptake of such RBCs in a murine model.

    STUDY DESIGN AND METHODS: The intracellular Ca2+ content of RBCs was determined using the Ca2+ probe Fluo-3 and flow cytometry. In vivo uptake of Ca2+ ionophore-treated murine RBCs (Ca2+-RBCs) was investigated in recipient mice, using flow cytometry and immunohistochemical analysis.

    RESULTS: A small fraction of human RBCs accumulated [Ca2+](i) during storage for up to 42 days under blood bank conditions. In a murine model, where fresh or Ca2+-RBCs were transfused, Ca2+-RBCs were mainly trapped by MARCO+ splenic marginal zone macrophages and CD11c+ CD207+ dendritic cells (DCs) within 1 hour after transfusion. In marked contrast, freshly transfused RBCs aging normally in circulation were cleared much slower and preferentially by F4/80+ red pulp macrophages. CD47 on the Ca2+-RBCs did not affect their clearance by splenic phagocytic cells.

    CONCLUSIONS: A small fraction of RBCs accumulate [Ca2+](i) during storage, and in a murine model such RBCs are recognized by splenic macrophages and DCs in ways similar to what has been reported for nucleated apoptotic cells.

  • 79. Lazarevic, Vladimir Lj
    et al.
    Remberger, Mats
    Hägglund, Hans
    Hallböök, Helene
    Juliusson, Gunnar
    Kimby, Eva
    Malm, Claes
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Omar, Hamdy
    Johansson, Jan-Erik
    Myeloablative allogeneic stem cell transplantation for lymphoblastic lymphoma in Sweden: a retrospective study.2011Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 86, nr 8, s. 709-710Artikkel i tidsskrift (Fagfellevurdert)
  • 80. Lehmann, Soren
    et al.
    Lazarevic, Vladimir
    Hörstedt, Ann-Sofi
    Hulegårdh, Erik
    Nilsson, Christer
    Antunovic, Petar
    Derolf, Åsa Rangert
    Möllgård, Lars
    Uggla, Bertil
    Vennström, Lovisa
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Höglund, Martin
    Stockelberg, Dick
    Juliusson, Gunnar
    Poor Outcome in Secondary Acute Myeloid Leukemia (AML): A First Report From the Population-Based Swedish Acute Leukemia Registry2012Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, nr 21Artikkel i tidsskrift (Annet vitenskapelig)
  • 81. Lehmann, Sören
    et al.
    Ravn, S
    Carlsson, L
    Antunovic, P
    Deneberg, S
    Möllgård, L
    Rangert Derolf, Å
    Stockelberg, D
    Tidefelt, U
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Wennström, L
    Högberg, M
    Juliusson, G
    Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry2011Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 25, nr 7, s. 1128-1134Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our knowledge about acute promyelocytic leukemia (APL) patients is mainly based on data from clinical trials, whereas population-based information is scarce. We studied APL patients diagnosed between 1997 and 2006 in the population-based Swedish Adult Acute Leukemia Registry. Of a total of 3897 acute leukemia cases, 3205 (82%) had non-APL acute myeloid leukemia (AML) and 105 (2.7%) had APL. The incidence of APL was 0.145 per 100 000 inhabitants per year. The median age at the time of diagnosis was 54 years; 62% were female and 38% male. Among younger APL patients, female sex predominated (89% of patients <40 years). Of the 105 APL patients, 30 (29%) died within 30 days (that is, early death (ED)) (median 4 days) and 28 (26%) within 14 days from diagnosis. In all, 41% of the EDs were due to hemorrhage; 35% of ED patients never received all-trans-retinoic acid treatment. ED rates increased with age but more clearly with poor performance status. ED was also associated with high white blood cells, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count. Of non-ED patients, 97% achieved complete remission of which 16% subsequently relapsed. In total, 62% are still alive at 6.4 years median follow-up. We conclude that ED rates remain very high in an unselected APL population.

  • 82.
    Liljeholm, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Congenital Dyserythropoietic Anemia type III (CDA III): diagnostics, genetics and morbidity2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The Congenital Dyserythropoietic Anemias (CDA) are rare hereditary hemolytic disorders with large bi- to multi-nucleated erythroblasts in the bone marrow. Hemolysis is negative in a direct antiglobulin test (DAT). Based on morphology and clinical picture, three major forms of CDAs, type I, II, and III have been defined. CDA III, dominantly inherited, constitutes the rarest type with a majority of cases belonging to a family in Västerbotten, Sweden. The genetic background of CDA I and CDA II has been linked to mutations in CDAN1 and SEC23B respectively. The mutation of CDA III has been linked to 15q22 in earlier studies.

    In this project we have defined the causative genetic lesion in two families with CDA III. The novel mutation KIF23 c.2747C>G (p.P916R) was shown to segregate with CDA III in the Swedish and American CDA III families and was absent in 356 healthy controls. KIF23 encodes mitotic kinesin-like protein 1 (MKLP1), which plays a central role in the last step of cytokinesis. RNAi-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, resulting in increasing number of bi-nuclear cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23, encoding MKLP1, a conserved mitotic kinesin crucial for cytokinesis.

    Flow cytometry with eosin-5´-maleimide (EMA), anti-CD55 and anti-CD59 is commonly used when investigating non-autoimmune hemolytic anemias. Reduced fluorescence of EMA, typically detected in hereditary spherocytosis, is also seen in CDA II, while reduction of CD55 and CD59 characterizes paroxysmal nocturnal hemoglobinuria (PNH). We studied the flow cytometric profile of EMA, CD55, and CD59 on erythrocytes in CDA III. We found no abnormality of the erythrocyte membrane in CDA III and concluded that standard flow cytometry cannot be used to discriminate between CDA III and normal controls.

    In CDA I and CDA II a majority of patients, including those who are not transfusion dependent, suffer from iron overload, which, according to earlier studies, is not the case in CDA III. We found that individuals of the Västerbotten CDA III family carry mutations in the hemochromatosis (HFE) gene. Three CDA III patients with heterozygous or compound HFE mutations need treatment with phlebotomy due to iron overload. One of them carries heterozygous H63D mutation, which is not reported to lead to iron overload by itself in otherwise healthy individuals. We propose that molecular genetic testing of the HFE gene is indicated in all patients with CDA, including CDA III.

  • 83.
    Liljeholm, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grönlund, Elisabeth
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Sandström, Herbert
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Erythrocyte Flow Cytometric Analysis in Congenital Dyserythropoietic Anemia Type III-Evaluation of Eosin-5´-Maleimide, CD55, and CD592013Inngår i: Journal of Blood Disorders & Transfusion, ISSN 2155-9864, Vol. 121, nr 23, s. 4791-4799Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Flow cytometry with eosin-5´-maleimide (EMA), anti-CD55 and anti-CD59 is commonly used when investigating non-autoimmune hemolytic anemias. Reduced fluorescence of EMA, typically detected in hereditary spherocytosis is also seen in congenital dyserythropoietic anemia type II (CDA II). Reduction of CD55 and CD59 characterizes paroxysmal nocturnal hemoglobinuria (PNH). We studied the flow cytometric profile of EMA, CD55 and CD59 on erythrocytes in congenital dyserythropoietic anemia type III (CDA III). 

    Methods: Erythrocytes from 16 CDA III positive individuals, 14 CDA III negative relatives and three normal controls per assay were studied with flow cytometry after EMA staining. Flow cytometry after anti-CD55 and anti- CD59 was performed on erythrocytes from 12 CDA III positive and 7 CDA III negative relatives with one normal control per assay. 

    Results: CDA III - erythrocytes exhibited marginally stronger fluorescence after EMA-staining than normal controls. Correlation between EMA fluorescence and erythrocyte volume was confirmed. CDA III subjects did not differ from normal controls concerning CD55 and CD59. 

    Conclusion: The results of the present study indicate no abnormality of the erythrocyte membrane in CDA III and show that standard flow cytometry cannot be used to discriminate between CDA III and normal controls. 

  • 84.
    Liljeholm, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Vikberg, Ann-Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Sandström, Herbert
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Congenital Dyserythropoietic Anemia Type III and Primary Hemochromatosis; Coexistence of Mutations in KIF23 and HFE.2016Inngår i: Journal of Hematology and Blood Disorders, Vol. 1, nr 2, artikkel-id 203Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Congenital dyserythropoietic anemia type III (CDA III) can be caused by mutation in KIF23. CDA III differs from CDA I and II in the sense that secondary hemochromatosis has not been reported. However, we have observed elevated serum ferritin in a CDA III family. Since primary hemochromatosis is common in Northern Europe we decided to screen the family for HFE mutations.

    Aim: Study clinical appearance and prevalence of HFE gene mutations, C282Y and H63D, in a CDA III family. 

    Methods: DNA from 37 CDA III patients and 21 non-affected siblings was genotyped. Iron status from EDTA plasma was measured in 32 of the CDA III patients and 18 of the non-affected siblings.

    Results: Out of 37 CDA III patients, 18 carried heterozygous HFE mutations and six were compound heterozygotes. Out of 21 CDA III negative siblings, nine had heterozygous HFE mutations, two were homozygous (one H63D and one C282Y), and two were compound heterozygous. None of the patients with wt HFE, regardless of CDA III status, suffered from iron overload. Four patients with HFE mutations needed treatment with phlebotomy to normalize ferritin and transferrin iron saturation; one CDA III negative patient with homozygous C282Y, two CDA III patients with heterozygous HFE mutations and one CDA III case with compound heterozygosity.

    Conclusion: HFE mutations were found in 65 % of CDA III patients and in 62 % of their CDA III negative siblings. Heterozygous HFE mutation, C282Y and even H63D, can cause iron overload when occurring concomitantly with CDA III.

  • 85.
    Liljeholm, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Vikberg, Ann-Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Congenital dyserythropoietic anemia type III and primary hemochromatosis; coexistence of mutations in KIF23 and HFE2015Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, s. 594-594Artikkel i tidsskrift (Annet vitenskapelig)
  • 86.
    Lind, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Determinants of adverse events during oral anticoagulant treatment2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Treament with oral anticoagulation is highly effective in reducing the burden of thromboembolic complications in several clinical conditions. The number of patients receiving oral anticoagulation is growing steadily. InSwedenabout 1.5 percent of the population receives treatment. Although the treatment is highly effective in preventing thromboembolic complications, it is also associated with a substantial increase in the risk of bleeding. In clinical practice every physician has to balance the potential benefit of treatment against the risk of bleeding complications in the individual patient.

    To aid in this decision making, risk scores addressing the likelihood of thromboembolic events, as well as the risk of bleeding complications, have been developed. These scores are imperfect and, to some degree limited by the fact that the risk factors predictive of thromboembolic events are also often associated with bleeding complications. The addition of biomarkers has the potential to increase the predictive ability of risk scores and further enhance the net benefit of oral anticoagulant treatment in the individual patient. In this thesis several potential biomarkers for thromoboembolic and haemorrhagic complications of anticoagulant therapy have been investigated in a longitudinal cohort study of 719 patients with a median follow-up time of 4.2 years.

    Thrombomodulin is a key component in the generation of activated protein C and hence, a coagulation inhibitor. Conversely, it is also a key component in the inhibition of fibrinolysis by activation of trombin-activated fibrinolysis inhibitor. In warfarin-treated patients we demonstrate that thrombomodulin predicts an increased risk of bleeding complications, but not cardiovascular events. Thus, thrombomodulin has potential as a biomarker specifically for bleeding complications.

    Von Willebrand factor plays a central and intricate role in the aggregation of platelets and low levels of VWF have been associated with bleeding as a manifestation of von Willebrand’s disease. In our study we noted that high levels of von Willebrand factor predict an increased risk of cardiovascular as well as all-cause mortality, possibly as an expression of endothelial dysfunction. We also noted that high levels of WVF seem to be associated with serious bleeding complications.

    Decreased renal function is usually measured by an increase in the levels of creatinine and cystatin C, or a decrease in the calculated glomerular filtration rate. A decrease in kidney function is regarded as a marker of an increased risk of bleeding complications. We investigated all the mentioned markers of kidney function and no association with bleeding complications became apparent. However, a clear association between a decrease in kidney function and mortality was noted. Our findings indicate that the emphasis on impaired kidney function as a risk marker needs to be shifted from bleeding complications toward thromboembolic events.

    Fibrinolysis is important in containing coagulation and several constituents of the fibrinolytic pathway have been shown to predict cardiovascular events and mortality. We found that fibrinolytic factors seem to predict cardiovascular events in patients with oral anticoagulation and that D-dimer also predicts bleeding complications.

    In conclusion, we have found several biomarkers which exhibit different predictive abilities in patients with oral anticoagulation. It is likely that biomarkers, either alone, in combination, or as ancillary components of risk scores, can contribute to improved risk stratification in patients with oral anticoagulation.

  • 87.
    Lind, Marcus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Jansson, Jan-Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nilsson, Torbjörn K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Järvholm, Lisbeth Slunga
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Johansson, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Cystatin C and creatinine as markers of bleeding complications, cardiovascular events and mortality during oral anticoagulant treatment2013Inngår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 132, nr 2, s. E77-E82Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Impaired kidney function has been linked to both ischemic events as well as bleeding complications in several clinical conditions. Our aim was to investigate if cystatin C, creatinine and calculated glomerular filtration rate (eGFR) were related to future risk of bleeding complications, cardiovascular events or all-cause mortality during oral anticoagulant treatment.

    Materials and methods: In a cohort study, 719 patients on long-term vitamin K antagonist (VKA) treatment were followed for a mean of 4.2 years. Blood sampling was taken at inclusion and patients were followed prospectively. Cystatin C and creatinine were analysed and eGFR was calculated. All medical records were reviewed. Major bleeding events, myocardial infarctions, strokes, arterial emboli, and deaths were recorded and classified.

    Results: After adjustment for age, no association between cystatin C, creatinine or eGFR and major bleeding was found. Cystatin C was independently associated with cardiovascular events (hazard ratio 1.50 (95% CI: 1.27-1.77)) and all-cause mortality (hazard ratio 1.62 (95% CI: 1.38-1.90)). Creatinine was only associated with all-cause mortality, while eGFR was not associated with any of the outcomes.

    Conclusions: Our findings underscore the superiority of cystatin C as a marker of cardiovascular risk compared to creatinine or eGFR. VKA-treated patients with increased cystatin C levels should be considered to be at an increased risk of cardiovascular events, and not bleeding complications.

  • 88.
    Lindberg, Fredrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Björck, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Rasmussen, Ib
    Nyman, Rickard
    Bergqvist, David
    Low frequency of phlebographic deep vein thrombosis after laparoscopic cholecystectomy: a pilot study2006Inngår i: Clinical and applied thrombosis/hemostasis, ISSN 1076-0296, E-ISSN 1938-2723, Vol. 12, nr 4, s. 421-426Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To investigate the rate of deep vein thrombosis (DVT) after laparoscopic surgery, 50 patients underwent bilateral phlebography 7-11 days after laparoscopic cholecystectomy (LC). All received thromboembolism prophylaxis, either low molecular weight heparin (LMWH) or dextran. Three patients were converted to open cholecystectomy. D-dimer was investigated preoperatively, on day 1 and on the day of phlebography. One asymptomatic DVT was found. One phlebogram was incomplete. Seven phlebograms were not optimal but of sufficient quality to rule out DVT. The frequency of DVT was thus 1 of 49 or 2.0% (95% confidence interval, 0-6.0%). No anticoagulants were prescribed after discharge. No patient developed late thromboembolic complications. D-dimer values increased significantly at day 1 and were further increased at the time of phlebography. The frequency of phlebographical DVTs thus seems to be low despite prophylaxis of questionable efficacy. The D-dimer values, however, suggest that the effects of LC on coagulation/fibrinolysis have a duration of longer than 1 week.

  • 89.
    Lorenz, Fryderyk
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Klimkowska, Monika
    Pawłowicz, Ewa
    Brustad, Agnes Bulanda
    Erlanson, Martin
    Machaczka, Maciej
    Clinical characteristics, therapy response, and outcome of 51 adult patients with hematological malignancy-associated hemophagocytic lymphohistiocytosis: a single institution experience2018Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 59, nr 8, s. 1840-1850Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hemophagocytic lymphohistiocytosis (HLH) is an underdiagnosed but life-threatening syndrome of hyperinflammation often occurring in adults with hematological malignancies (hM-HLH). The aim of the study was to describe clinical characteristics, therapy response, and outcome of adults with hM-HLH. The study included 51 adults with hM-HLH aged 23–84 years. Hyperferritinemia ≥500 µg/L was present in 96% of patients. The serum concentration of sIL-2Rα ≥ 2400 U/mL was revealed in 94% of patients. Twenty-three patients (45%) responded to therapy and achieved remission of HLH. The probability of overall survival (OS) at 6, 12, 24, and 60 months after HLH diagnosis were 42, 20, 15, and 15%, respectively. Patients with HLH during chemotherapy showed longer OS (median 124 days) than the patients who had HLH solely attributed to malignancy (median 65 days), but this difference was not statistically significant. Awareness of HLH in lymphoid and myeloid malignancies is crucial for improved survival.

  • 90.
    Lorenz, Fryderyk
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Pawlowicz, E.
    Bjorkvall, C. Kampe
    Brustad, A. Bulanda
    Machaczka, M.
    HYPERFERRITINEMIA AND SERUM INFLAMMATORY CYTOKINES IN ADULTS WITH GAUCHER DISEASE TYPE 12016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, nr S1, s. 580-581, artikkel-id E1403Artikkel i tidsskrift (Annet vitenskapelig)
  • 91.
    Lorenz, Fryderyk
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Pawlowicz, Ewa
    Klimkowska, Monika
    Beshara, Soheir
    Brustad, Agnes Bulanda
    Skotnicki, Aleksander B.
    Wahlin, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Machaczka, Maciej
    Ferritinemia and serum inflammatory cytokines in Swedish adults with Gaucher disease type 12018Inngår i: Blood Cells, Molecules & Diseases, ISSN 1079-9796, E-ISSN 1096-0961, Vol. 68, s. 35-42Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. Patients and methods: The study included 16 adults with GD1 aged 20-86 years. All but one patient carried at least one allele with the c.1226A > G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden. Results: Hyperferritinemia was present in 81% of patients. There was no correlation between hyperferritinemia and patient's gender, spleen status, or clinical status. Hepcidin was discrepantly low in relation to ferritin levels. TNF-alpha was moderately increased in 5 of 11 patients; 2 patients with the highest TNF-alpha concentrations showed mildly elevated IL-6 levels. The concentrations of IL-1 beta, IL-8, and IL-10 were normal in all patients. Upon treatment, ferritinemia ameliorated but S-ferritin levels did not normalize. The increased TNF-alpha level however, normalized in all treated patients, reaching the lowest values after 2 years of therapy and continued to be stable during the remaining 2 years of follow-up. Conclusions: Hyperferritinemia is a frequent finding in GD1 in Sweden. The relatively low hepcidin levels reveal a distorted relationship between hepcidin and ferritin in GD1. Therapy has the potential to not only ameliorate hyperferritinemia but to also normalize the serum TNF-alpha concentration in GD1. 

  • 92. Lourda, Magda
    et al.
    Akefeldt, Selma Olsson
    Gavhed, Desiree
    Clausen, Niels
    Hjalmars, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Sabel, Magnus
    Tazi, Abdellatif
    Arico, Maurizio
    Delprat, Christine
    Svensson, Mattias
    Henter, Jan-Inge
    Production by blood monocytes is tightly related to the degree of activity of Langerhans cell histiocytosis2014Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, nr 11, s. 2135-2135Artikkel i tidsskrift (Annet vitenskapelig)
  • 93. Machaczka, M.
    et al.
    Lorenz, Fryderyk
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Pawlowicz, E.
    Gajewski, M.
    Wolan, M.
    Klimkowska, M.
    Hyperferritinemia and serum inflammatory cytokines in 71 adults with newly diagnosed hemophagocytic lymphohistiocytosis associated with hematological malignancy2017Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, s. 761-761Artikkel i tidsskrift (Annet vitenskapelig)
  • 94.
    Mahmood, Dana
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nilsson, Solveig
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Olivecrona, Gunilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi.
    Stegmayr, Bernd
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lipoprotein lipase activity is favoured by peritoneal dialysis compared to hemodialysis2014Inngår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 74, nr 4, s. 296-300Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. The lipoprotein lipase (LPL) pool is reduced by 50% in patients on hemodialysis (HD). LPL release by tinzaparin has not been investigated for peritoneal dialysis (PD). Therefore, the aim of this study was to investigate if tinzaparin differently alters the pool of LPL and triglyceride levels of patients on HD versus PD. Materials and methods. Thirty-two patients on chronic PD or HD were matched to nearest age and gender. In order to release and thereby estimate the endothelial pool of LPL, all patients received a bolus of tinzaparin (75 units/kg). Blood samples were drawn for analysis of LPL activity and triglycerides (TG) between the groups. Results. The peak level of LPL released at 40 min after tinzaparin was similar in PD and HD patients. At 180 min, a slightly higher median level of LPL activity was noted in the PD patients (6.1 mU/mL (n = 6) versus 3.4 mU/mL (n = 16), p = 0.005). The TG concentration in plasma at 40 min was reduced relatively more in the PD patients than in the HD patients (p < 0.05). At 180 min, TG had returned to start levels in HD patients while they were still lowered in PD patients. Conclusions. The negative effect of uraemia on the LPL pool in HD patients, known from other studies, here is shown to be similar in PD patients. Tinzaparin administration releases the LPL pool during each HD but does not cause an exhaustion of the LPL system over time. In contrast to HD, the LPL pool is not altered during PD.

  • 95.
    Mahmood, Dana
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Stegmayr, Bernd
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Haemodialysis with Tinzaparin Versus Dialysate Citrate as Anticoagulation2018Inngår i: Blood Purification, ISSN 0253-5068, E-ISSN 1421-9735, Vol. 46, nr 3, s. 257-263Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Anticoagulation with citrate-containing haemodialysate (cHD) is an alternative to tinzaparin haemodialysate (tHD). The study investigated whether cHD would differ when changed from tHD. The same 18 patients were their own controls followed up with cHD for 5 months. LDL-cholesterol decreased at the end of a cHD session (p = 0.01). Neutrophils (p = 0.013) and monocytes (p = 0.007) dropped more during a cHD session. During the follow-up period of cHD, approximately 50% needed additional tinzaparin. Before the cHD session could start, there was a lower total cholesterol at 2 weeks (p = 0.014) and LDL-cholesterol at 1 month (p = 0.011) versus an increase of LDL at 5 months (p = 0.02). Only patients without additional tinzaparin had a reduction of C-reactive protein (CRP) at 2 months of cHD (p < 0.05) but not later. Solely cHD seems possible only in half of the patients. A greater reduction in granulocytes and monocytes during cHD indicates a more extensive blood membrane interaction, while CRP may be lower.

  • 96.
    Mauerer, Katja
    et al.
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Zahrieh, David
    Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Gorgun, Gullu
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Li, Aihong
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Zhou, Jianbiao
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Ansén, Sascha
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Rassenti, Laura Z
    CLL Research Consortium, University of California San Diego, CA, USA.
    Gribben, John G
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Immunoglobulin gene segment usage, location and immunogenicity in mutated and unmutated chronic lymphocytic leukaemia2005Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 129, nr 4, s. 499-510Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mutational status of the variable region of the immunoglobulin heavy chain gene (IgV(H)) is an important prognostic marker in B-cell chronic lymphocytic leukaemia (B-CLL), with mutated patients having improved outcome. To examine the impact of mutational status on V(H), D(H), and J(H) gene segment location and immunogenicity, we analysed 375 IgH sequences from 356 patients with B-CLL. Although V(H) and D(H) gene usage was different in mutated compared to unmutated patients, there was no impact of gene location on frequency of use or clinical outcome. Surprisingly, somatic mutations did not increase the immunogenicity of the Ig, as assessed by predicted binding affinity of Ig-derived peptides to major histocompatibility Class I and Class II molecules. Even excluding patients using V(H)1-69, cases using the V(H)1 gene family had a poor outcome. Both mutated and unmutated CLL patients demonstrated evidence of antigen selection. The worst outcome was seen in the subset of 14 unmutated patients with similar HCDR3 amino acid sequence using V(H)1-69, D(H)3-3 and J(H)6, suggesting an antigen-driven process modulating the clinical course.

  • 97. Meeths, Marie
    et al.
    Chiang, Samuel C. C.
    Wood, Stephanie M.
    Entesarian, Miriam
    Schlums, Heinrich
    Bang, Benedicte
    Nordenskjold, Edvard
    Björklund, Caroline
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jakovljevic, Gordana
    Jazbec, Janez
    Hasle, Henrik
    Holmqvist, Britt-Marie
    Rajic, Ljubica
    Pfeifer, Susan
    Rosthoj, Steen
    Sabel, Magnus
    Salmi, Toivo T.
    Stokland, Tore
    Winiarski, Jacek
    Ljunggren, Hans-Gustaf
    Fadeel, Bengt
    Nordenskjold, Magnus
    Henter, Jan-Inge
    Bryceson, Yenan T.
    Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D2011Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, nr 22, s. 5783-5793Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies. (Blood. 2011;118(22):5783-5793)

  • 98. Meinderts, Sanne M.
    et al.
    Oldenborg, Per-Arne
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Beuger, Boukje M.
    Klei, Thomas R. L.
    Johansson, Johanna
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Kuijpers, Taco W.
    Matozaki, Takashi
    Huisman, Elise J.
    De Haas, Masja
    Van den Berg, Timo K.
    Van Bruggen, Robin
    Human and murine splenic neutrophils are potent phagocytes of IgG-opsonized red blood cells2017Inngår i: Blood Advances, ISSN 2473-9529, Vol. 1, nr 14, s. 875-886Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Red blood cell (RBC) clearance is known to occur primarily in the spleen, and is presumed to be executed by red pulp macrophages. Erythrophagocytosis in the spleen takes place as part of the homeostatic turnover of RBCs to remove old RBCs. It can be strongly promoted by immunoglobulin G (IgG) opsonization of RBCs, a condition that can occur as a consequence of autoantibody or alloantibody formation. The purpose of our study was to investigate which phagocytes are involved in IgG-mediated RBC clearance in the human spleen. We developed a highly specific in vitro assay to monitor RBC phagocytosis in total human splenocytes. Surprisingly, we have found that whereas homeostatic clearance of RBCs is primarily a task for splenic macrophages, neutrophils and, to a lesser extent, also monocytes can be a major factor in clearance of IgG-opsonized RBCs. Erythrophagocytosis by neutrophils is strongly dependent on the degree of opsonization of the RBCs. Additionally, the process is enhanced after blocking the "do not eat me" signal CD47 on the opsonized RBCs, which binds signal regulatory protein a, a myeloid inhibitory receptor that restricts phagocytosis. Moreover, RBCs isolated from autoimmune hemolytic anemia patients, opsonized by auto-IgGs, were shown to be readily phagocytosed by neutrophils. Finally, priming of neutrophils by inflammatory mediators such as tumor necrosis factor a and lipopolysaccharide further increases the magnitude of erythrophagocytosis. Collectively, our data suggest that neutrophils contribute significantly to the phagocytosis of antibody-opsonized RBCs, especially under inflammatory conditions. This indicates a hereto unanticipated contribution of neutrophils in RBC phagocytosis, especially under pathological conditions such as alloimmunization or autoimmunization.

  • 99. Mellqvist, Ulf-Henrik
    et al.
    Gimsing, Peter
    Hjertner, Oyvind
    Lenhoff, Stig
    Laane, Edward
    Remes, Kari
    Steingrimsdottir, Hlif
    Abildgaard, Niels
    Ahlberg, Lucia
    Blimark, Cecilie
    Dahl, Inger Marie
    Forsberg, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Gedde-Dahl, Tobias
    Gregersen, Henrik
    Gruber, Astrid
    Guldbrandsen, Nina
    Haukas, Einar
    Carlson, Kristina
    Kvam, Ann Kristin
    Nahi, Hareth
    Lindas, Roald
    Andersen, Niels Frost
    Turesson, Ingemar
    Waage, Anders
    Westin, Jan
    Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial2013Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, nr 23, s. 4647-4654Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the >= VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

  • 100. Moorman, AV
    et al.
    Raimondi, SC
    Pui, CH
    Baruchel, A
    Biondi, A
    Carroll, AJ
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Gaynon, PS
    Harbott, J
    Harms, DO
    Heerema, N
    Pieters, R
    Schrappe, M
    Silverman, LB
    Vilmer, E
    Harrison, CJ
    No prognostic effect of additional chromosomal abnormalities in children with acute lymphoblastic leukemia and 11q23 abnormalities2005Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 19, nr 4, s. 557-563Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study characterized the additional chromosomal abnormalities (ACA) associated with 11q23 rearrangements in 450 infants and children with acute lymphoblastic leukemia ( ALL) and examined the impact of these ACA on survival. Overall, 213 (47%) cases had ACA but the incidence varied according to patient age and 11q23 subgroup. Infants and patients with t(4; 11)(q21; q23) had the lowest incidence of ACA (50/182 (27%) and 57/216 (26%) respectively), whereas patients with del( 11)( q23) had the highest incidence (66/93 (71%)). Del( 11)( q23) abnormalities were heterogeneous and occasionally secondary to t( 9; 22)(q34; q11.2). Thus, patients with del( 11)( q23) comprised a separate biological entity, which was clearly distinct from those with an 11q23 translocation. The most frequent specific ACA were trisomy X ( n = 38), abnormal 12p ( n = 32), abnormal 9p ( n = 28) and del( 6q) ( n = 19). The presence of ACA did not change the 5 year event-free survival estimates among children (56% (95% CI 46 - 65%) vs 62% (54 - 69%)) or infants (22% ( 15 - 29%) vs 18% ( 9 - 29%)), nor when the different 11q23 subgroups were analyzed separately. This study has conclusively demonstrated that there is no prognostic effect of secondary chromosomal changes in association with 11q23 abnormalities in childhood ALL. However, characterization of these ACA is important to determine their potential role in initiation of MLL driven leukemogenesis.

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