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  • 101.
    Brekkan, Ari
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Berntorp, Erik
    Skane Univ Hosp, Clin Coagulat Res Unit, Malmo, Sweden.
    Jensen, Kirsten
    Skane Univ Hosp, Clin Coagulat Res Unit, Malmo, Sweden.
    Nielsen, Elisabet I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population Pharmacokinetics of Plasma-Derived Factor IX: Procedures for Dose Individualization2016In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 14, no 4, p. 724-732Article in journal (Refereed)
    Abstract [en]

    Background: Population pharmacokinetic (POPPK) models describing factor IX (FIX) activity levels in plasma, in combination with individual FIX measurements, may be used to individualize dosing in the treatment of hemophilia B. Objectives: The aim was to reevaluate a previously developed POPPK model for FIX activity and to explore the number and timing of FIX samples required in pharmacokinetic (PK) dose individualization. Methods: The POPPK model was reevaluated using an extended data set. Several sampling schedules, varying with respect to the timing and number of samples, were evaluated in a simulation study with relative dose errors compared between schedules. The performance of individually calculated doses was compared with commonly prescribed FIX doses with respect to the number of patients with a trough FIX activity > 0.01 U mL(-1). Results and conclusions: A three-compartment PK model best described the FIX activity levels. The number and timing of samples greatly influenced imprecision in dose prediction. Schedules with single samples taken on both day 2 and day 3 were identified as being convenient schedules with an acceptable performance level. Individually calculated doses performed better with respect to patient target attainment than a fixed 40 U kg(-1) dose regardless of how many samples were available to calculate individual doses. The results of this study suggest that PK dose tailoring with limited sampling may be applicable for plasma-derived FIX products.

  • 102.
    Brundin, Peik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Zhao, Chunyan
    Dahlman-Wright, Karin
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Gene Expression of Estrogen Receptors in Pbmc From Patients With Puumala-Virus Infection2012In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no 4, p. 355-359Article in journal (Refereed)
    Abstract [en]

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

  • 103. Bruzelius, M.
    et al.
    Bottai, M.
    Sabater-Lleal, M.
    Strawbridge, R. J.
    Bergendal, A.
    Silveira, A.
    Sundstrom, A.
    Kieler, H.
    Hamsten, A.
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska University Hospital Solna, Sweden; Karolinska Institutet, Sweden .
    Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no 2, p. 219-227Article in journal (Refereed)
    Abstract [en]

    BackgroundFamily history of venous thromboembolism (VTE) has been suggested to be more useful in risk assessment than thrombophilia testing. ObjectivesWe investigated established genetic susceptibility variants for association with VTE and evaluated a genetic risk score in isolation and combined with known trigger factors, including family history of VTE. Patients/MethodA total of 18 single nucleotide polymorphisms (SNPs) selected from the literature were genotyped in 2835 women participating in a Swedish nationwide case-control study (the ThromboEmbolism Hormone Study [TEHS]). Association with VTE was assessed by odds ratios (ORs) with 95% confidence interval (CI) using logistic regression. Clinical and genetic predictors that contributed significantly to the fit of the logistic regression model were included in the prediction models. SNP-SNP interactions were investigated and incorporated into the models if found significant. Risk scores were evaluated by calculating the area under the receiver-operating characteristics curve (AUC). ResultsSeven SNPs (F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446) with four SNP-SNP interactions contributed to the genetic risk score for VTE, with an AUC of 0.66 (95% CI, 0.64-0.68). After adding clinical risk factors, which included family history of VTE, the AUC reached 0.84 (95% CI, 0.82-0.85). The goodness of fit of the genetic and combined scores improved when significant SNP-SNP interaction terms were included. ConclusionPrediction of VTE in high-risk individuals was more accurate when a combination of clinical and genetic predictors with SNP-SNP interactions was included in a risk score.

  • 104. Bruzelius, M.
    et al.
    Iglesias, Maria Jesus
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hong, Mun-Gwan
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sanchez-Rivera, Laura
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gyorgy, B.
    Souto, J. C.
    Franberg, M.
    Fredolini, Claudia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Strawbridge, R. J.
    Holmström, M.
    Hamsten, A.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Silveira, A.
    Soria, J. M.
    Smadja, D. M.
    Butler, L. M.
    Schwenk, Jochen M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Morange, P. -E
    Trégouët, D. -A
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    PDGFB, a new candidate plasma biomarker for venous thromboembolism: Results from the VEREMA affinity proteomics study2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. e59-e66Article in journal (Refereed)
    Abstract [en]

    There is a clear clinical need for high-specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far, such markers have remained elusive. Utilizing affinity reagents from the Human Protein Atlas project and multiplexed immuoassays, we extensively analyzed plasma samples from 2 individual studies to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish ¡°Venous Thromboembolism Biomarker Study,¡± using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins. We identified significant associations between VTE occurrence and plasma levels of human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1), von Willebrand factor (VWF), glutathione peroxidase 3 (GPX3), and platelet-derived growth factor β (PDGFB). For replication, we profiled plasma samples of 580 cases and 589 controls from the French FARIVE study. These results confirmed the association of VWF and PDGFB with VTE after correction for multiple testing, whereas only weak trends were observed for HIVEP1 and GPX3. Although plasma levels of VWF and PDGFB correlated modestly (p ~ 0.30) with each other, they were independently associated with VTE risk in a joint model in FARIVE (VWF P < .001; PDGFB P 5 .002). PDGF was verified as the target of the capture antibody by immunocapture mass spectrometry and sandwich enzyme-linked immunosorbent assay. In conclusion, we demonstrate that high-throughput affinity plasma proteomic profiling is a valuable research strategy to identify potential candidate biomarkers for thrombosis-related disorders, and our study suggests a novel association of PDGFB plasma levels with VTE.

  • 105. Bruzelius, Maria
    et al.
    Iglesias, Maria Jesus
    Hong, Mun-Gwan
    Sanchez-Rivera, Laura
    Gyorgy, Beata
    Carlos Souto, Juan
    Frånberg, Mattias
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Karolinska Institutet, Sweden.
    Fredolini, Claudia
    Strawbridge, Rona J.
    Holmström, Margareta
    Hamsten, Anders
    Uhlén, Mathias
    Silveira, Angela
    Manuel Soria, Jose
    Smadja, David M.
    Butler, Lynn M.
    Schwenk, Jochen M.
    Morange, Pierre-Emmanuel
    Tregouet, David-Alexandre
    Odeberg, Jacob
    PDGFB, a new candidate plasma biomarker for venous thromboembolism: results from the VEREMA affinity proteomics study2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. E59-E66Article in journal (Refereed)
    Abstract [en]

    There is a clear clinical need for high-specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far, such markers have remained elusive. Utilizing affinity reagents from the Human Protein Atlas project and multiplexed immuoassays, we extensively analyzed plasma samples from 2 individual studies to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish Venous Thromboembolism Biomarker Study, using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins. We identified significant associations between VTE occurrence and plasma levels of human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1), von Willebrand factor (VWF), glutathione peroxidase 3 (GPX3), and platelet-derived growth factor beta (PDGFB). For replication, we profiled plasma samples of 580 cases and 589 controls from the French FARIVE study. These results confirmed the association of VWF and PDGFB with VTE after correction for multiple testing, whereas only weak trends were observed for HIVEP1 and GPX3. Although plasma levels of VWF and PDGFB correlated modestly (rho similar to 0.30) with each other, they were independently associated with VTE risk in a joint model in FARIVE (VWF P < .001; PDGFB P = .002). PDGF. was verified as the target of the capture antibody by immunocapture mass spectrometry and sandwich enzyme-linked immunosorbent assay. In conclusion, we demonstrate that high-throughput affinity plasma proteomic profiling is a valuable research strategy to identify potential candidate biomarkers for thrombosis-related disorders, and our study suggests a novel association of PDGFB plasma levels with VTE.

  • 106. Bruzelius, Maria
    et al.
    Strawbridge, Rona J.
    Tregouet, David-Alexandre
    Wiggins, Kerri L.
    Gertow, Karl
    Sabater-Lleal, Maria
    Ohrvik, John
    Bergendal, Annica
    Silveira, Angela
    Sundstrom, Anders
    Kieler, Helle
    Syvanen, Ann-Christine
    Smith, Nicholas L.
    Morange, Pierre-Emmanuel
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Coagulation Unit, Hematology Centre; Atherosclerosis Research Unit, Centre for Molecular Medicine Karolinska University Hospital Solna, Sweden.
    Hamsten, Anders
    Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 426-432Article in journal (Refereed)
    Abstract [en]

    Introduction: We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case-control study (n = 2753) from Sweden. Materials and Methods: 39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression. Results: Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n = 7181). Conclusions: It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.

  • 107. Bruzelius, Maria
    et al.
    Strawbridge, Rona J
    Trégouët, David-Alexandre
    Wiggins, Kerri L
    Gertow, Karl
    Sabater-Lleal, Maria
    Ohrvik, John
    Bergendal, Annica
    Silveira, Angela
    Sundström, Anders
    Kieler, Helle
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smith, Nicholas L
    Morange, Pierre-Emmanuel
    Odeberg, Jacob
    Hamsten, Anders
    Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 426-432Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case-control study (n=2753) from Sweden.

    MATERIALS AND METHODS:

    39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression.

    RESULTS:

    Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n=7181).

    CONCLUSIONS:

    It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.

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

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

  • 109. Buitenkamp, Trudy
    et al.
    Izraeli, Shai
    Zimmermann, Martin
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Heerema, Nyla A.
    van den Heuvel, Marry M.
    Pieters, Rob
    de Haas, Valerie
    Silverman, Lewis B.
    Schmiegelow, Kjeld
    Liang, Der-Cherng
    Horibe, Keizo
    Arico, Maurizio
    Cazzaniga, Giovanni
    Basso, Giuseppe
    Rabin, Karen R.
    Schrappe, Martin
    Cario, Gunnar
    Mann, Georg
    Mondelaers, Veerle
    Lammens, Tim
    Cave, Helene
    Stark, Batia
    Moorman, Anthony V.
    Vora, Ajay J.
    Hunger, Stephen
    Pui, Ching-Hon
    Mullighan, Charles G.
    Manabe, Atsushi
    Escherich, Gabriele
    Kowalczyk, Jerzy
    Whitlock, James A.
    Zwaan, Christian M.
    Acute Lymphoblastic Leukemia in children with Down Syndrome: A report from the Ponte Di Legno Study Group2011In: 53rd ASH Annual Meeting and Exposition, December 10-13, 2011: Program: Oral and Poster AbstractsSession: 612. Acute Lymphoblastic Leukemia - Biology and Pathophysiology: Poster III Monday, December 12, 2011, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center), American Society of Hematology , 2011, Vol. 118, no 21Conference paper (Refereed)
  • 110.
    Burbano, X.
    et al.
    University of Miami School of Medicine, Division of Disease Prevention, Department of Psychiatry and Behavioral Sciences, Miami, FL, United States.
    Miguez, M. J.
    University of Miami School of Medicine, Division of Disease Prevention, Department of Psychiatry and Behavioral Sciences, Miami, FL, United States.
    Lecusay, Robert
    University of Miami School of Medicine, Division of Disease Prevention, Department of Psychiatry and Behavioral Sciences, Miami, FL, United States.
    Rodriguez, A.
    University of Miami School of Medicine, Department of Medicine, Miami, FL, United States.
    Ruiz, P.
    University of Miami School of Medicine, Department of Medicine, Miami, FL, United States.
    Morales, G.
    University of Miami School of Medicine, Division of Disease Prevention, Department of Psychiatry and Behavioral Sciences, Miami, FL, United States.
    Castillo, G.
    University of Miami School of Medicine, Division of Disease Prevention, Department of Psychiatry and Behavioral Sciences, Miami, FL, United States.
    Baum, M.
    Florida International University, College of Health Dietetics and Nutrition, Miami, FL, United States.
    Shor-Posner, G.
    University of Miami School of Medicine, Division of Disease Prevention, Department of Psychiatry and Behavioral Sciences, Miami, FL, United States.
    Thrombocytopenia in HIV-infected drug users in the HAART era2001In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 12, no 8, p. 456-461Article in journal (Refereed)
    Abstract [en]

    The present case-control study compared 26 HIV+ drug users having persistent thrombocytopenia (TCP< 150 000/mm(3)) with 54 available age, gender and HIV CDC classification matched controls with normal platelet counts. Participants were followed longitudinally over a 2-year period (1998-2000), and hematological alterations evaluated in relationship to antiretroviral treatment, drug use and nutritional (selenium) status. Demographic information and medical history, including antiretroviral treatment were obtained. Blood was drawn for complete cell blood count, T lymphocytes and viral load. Sixty-nine percent of the individuals with persistent TCP and 49% of the controls were receiving antiretrovirals. At baseline, no significant differences in CD4 existed between the two groups. Over time, CD4 cell count declined in the cases (P = 0.05) and a significantly higher proportion of the cases (38%) developed AIDS (CD4< 200 cell/mm(3)), as compared to the controls (18%, P = 0.004). A high risk for development of thrombocytopenia was observed with specific drug use (heroin 2.96 times, P = 0.0007), selenium levels below 145 mug/l (6 times, P = 0.008), and abnormal liver enzyme (SGOT) levels (2 times, P = 0.002). Together, these results indicate a number of factors that may be sensitive predictors of thrombocytopenia, which, despite antiretroviral treatment, appears to be related to more rapid disease progression in drug users.

  • 111.
    Burke, Michael J.
    et al.
    Med Coll Wisconsin, Dept Pediat, Div Hematol Oncol Blood & Marrow Transplant, Milwaukee, WI 53226 USA.;Childrens Hosp Wisconsin, Milwaukee, WI 53226 USA..
    Verneris, Michael R.
    Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA..
    Le Rademacher, Jennifer
    Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA.;Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA..
    He, Wensheng
    Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA..
    Abdel-Azim, Hisham
    Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90033 USA..
    Abraham, Allistair A.
    Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Blood & Marrow Transplantat, Washington, DC 20010 USA..
    Auletta, Jeffery J.
    Nationwide Childrens Hosp, Div Hematol Oncol Bone Marrow Transplantat & Infe, Columbus, OH USA..
    Ayas, Mouhab
    King Faisal Specialist Hosp & Res Ctr, Dept Pediat Hematol Oncol, Riyadh, Saudi Arabia..
    Brown, Valerie I.
    Penn State Hershey Childrens Hosp, Dept Pediat, Div Pediat Oncol Hematol, Hershey, PA USA.;Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Hershey, PA 17033 USA..
    Cairo, Mitchell S.
    New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA..
    Chan, Ka Wah
    Texas Transplant Inst, Dept Pediat, San Antonio, TX USA..
    Diaz Perez, Miguel A.
    Hosp Infantil Univ Nino Jesus, Dept Hematol Oncol, Madrid, Spain..
    Dvorak, Christopher C.
    Univ Calif San Francisco, Dept Pediat, Med Ctr, San Francisco, CA USA..
    Egeler, R. Maarten
    Hosp Sick Children, Dept Hematol Oncol, Toronto, ON M5G 1X8, Canada..
    Eldjerou, Lamis
    Univ Florida, Dept Pediat, Gainesville, FL USA..
    Frangoul, Haydar
    Vanderbilt Univ, Dept Pediat, Div Hematol Oncol, Sch Med, Nashville, TN USA..
    Guilcher, Gregory M. T.
    Alberta Childrens Prov Gen Hosp, Sect Paediat Oncol & Blood & Marrow Transplant, Calgary, AB, Canada..
    Hayashi, Robert J.
    Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, St Louis, MO 63110 USA..
    Ibrahim, Ahmed
    Makassed Gen Hosp, Dept Hematol Oncol, Beiruit, Lebanon..
    Kasow, Kimberly A.
    Univ N Carolina, Dept Pediat, Div Hematol Oncol, Chapel Hill, NC USA..
    Leung, Wing H.
    St Jude Childrens Res Hosp, Div Bone Marrow Transplantat, Memphis, TN 38105 USA..
    Olsson, Richard F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden.
    Pulsipher, Michael A.
    Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90033 USA..
    Shah, Niketa
    Mayo Clin Arizona, Dept Pediat, Div Hematol Oncol, Phoenix, AZ USA.;Phoenix Childrens Hosp, Phoenix, AZ USA..
    Shah, Nirali N.
    Natl Canc Inst NIH, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD USA..
    Thiel, Elizabeth
    Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA..
    Talano, Julie-An
    Med Coll Wisconsin, Dept Pediat, Div Hematol Oncol Blood & Marrow Transplant, Milwaukee, WI 53226 USA.;Childrens Hosp Wisconsin, Milwaukee, WI 53226 USA..
    Kitko, Carrie L.
    Vanderbilt Univ, Dept Pediat, Stem Cell Transplant Program, Nashville, TN USA..
    Transplant Outcomes for Children with T Cell Acute Lymphoblastic Leukemia in Second Remission: A Report from the Center for International Blood and Marrow Transplant Research2015In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 21, no 12, p. 2154-2159Article in journal (Refereed)
    Abstract [en]

    Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P =.005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted. (c) 2015 American Society for Blood and Marrow Transplantation.

  • 112.
    Bäcklin, Christofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Machine Learning Based Analysis of DNA Methylation Patterns in Pediatric Acute Leukemia2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in the Nordic countries. Recent evidence indicate that DNA methylation (DNAm) play a central role in the development and progression of the disease.

    DNAm profiles of a collection of ALL patient samples and a panel of non-leukemic reference samples were analyzed using the Infinium 450k methylation assay. State-of-the-art machine learning algorithms were used to search the large amounts of data produced for patterns predictive of future relapses, in vitro drug resistance, and cytogenetic subtypes, aiming at improving our understanding of the disease and ultimately improving treatment.

    In paper I, the predictive modeling framework developed to perform the analyses of DNAm dataset was presented. It focused on uncompromising statistical rigor and computational efficiency, while allowing a high level of modeling flexibility and usability. In paper II, the DNAm landscape of ALL was comprehensively characterized, discovering widespread aberrant methylation at diagnosis strongly influenced by cytogenetic subtype. The aberrantly methylated regions were enriched for genes repressed by polycomb group proteins, repressively marked histones in healthy cells, and genes associated with embryonic development. A consistent trend of hypermethylation at relapse was also discovered. In paper III, a tool for DNAm-based subtyping was presented, validated using blinded samples and used to re-classify samples with incomplete phenotypic information. Using RNA-sequencing, previously undetected non-canonical aberrations were found in many re-classified samples. In paper IV, the relationship between DNAm and in vitro drug resistance was investigated and predictive signatures were obtained for seven of the eight therapeutic drugs studied. Interpretation was challenging due to poor correlation between DNAm and gene expression, further complicated by the discovery that random subsets of the array can yield comparable classification accuracy. Paper V presents a novel Bayesian method for multivariate density estimation with variable bandwidths. Simulations showed comparable performance to the current state-of-the-art methods and an advantage on skewed distributions.

    In conclusion, the studies characterize the information contained in the aberrant DNAm patterns of ALL and assess its predictive capabilities for future relapses, in vitro drug sensitivity and subtyping. They also present three publicly available tools for the scientific community to use.

  • 113.
    Bäcklin, Christofer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    DNA methylation-based prediction of in vitro drug resistance in primary pediatric acute lymphoblastic leukemia patient samplesManuscript (preprint) (Other academic)
  • 114.
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Molecular Genetic and DNA Methylation Profiling of Chronic Lymphocytic Leukaemia: A Focus on Divergent Prognostic Subgroups and Subsets2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Advancements in prognostication have improved the subdivision of chronic lymphocytic leukaemia (CLL) into diverse prognostic subgroups. In CLL, IGHV unmutated and IGHV3-21 genes are associated with a poor-prognosis, conversely, IGHV mutated genes with a favourable outcome. The finding of multiple CLL subsets expressing ‘stereotyped’ B-cell receptors (BCRs) has suggested a role for antigen(s) in leukemogenesis. Patients belonging to certain stereotyped subsets share clinical and biological characteristics, yet limited knowledge exists regarding the genetic and epigenetic events that may influence their clinical behaviour. This thesis aimed to, further investigate Swedish IGHV3-21-utilising patients, screen for genetic and DNA-methylation events in CLL subgroups/subsets and study DNA methylation over time and within different CLL compartments.

    In paper I, IGHV gene sequencing of 337 CLL patients from a Swedish population-based cohort revealed a lower (6.5%) IGHV3-21 frequency relative to previous Swedish hospital-based studies (10.1-12.7%). Interestingly, this frequency remained higher compared to other Western CLL (2.6-4.1%) hospital-based cohorts. Furthermore, we confirmed the poor-outcome for IGHV3-21 patients to be independent of mutational and stereotypy status.

    In paper II, genomic events in stereotyped IGHV3-21-subset #2, IGHV4-34-subset #4 and subset #16 and their non-stereotyped counterparts were investigated via SNP arrays (n=101). Subset #2 and non-subset #2 carried a higher frequency of events compared to subset #4. A high frequency of del(11q) was evident in IGHV3-21 patients particularly subset #2 cases, which may partially explain their poor-prognosis. In contrast, the lower prevalence of aberrations and absence of poor-prognostic alterations may reflect the inherent low-proliferative disease seen in subset #4 cases.

    In papers III and IV, differential methylation profiles in IGHV mutated and IGHV unmutated patients were identified using DNA-methylation microarrays. CLL prognostic genes (CLLU1, LPL), tumor-suppressor genes (TSGs) (ABI3, WISP3) and genes belonging to TGF-ß and NF-kB/TNFR1 pathways were differentially methylated between the subgroups. Additionally, the re-expression of methylated TSGs by use of methyl and deacetyl inhibitors was demonstrated. Interestingly, analysis of patient-paired diagnostic/follow-up samples and patient-matched lymph node (LN) and peripheral blood (PB) cases revealed global DNA methylation to be relatively stable over time and remarkably similar within the different compartments.

    Altogether, this thesis provides insight into the aberrant genomic and DNA methylation events in divergent CLL subgroups. Moreover this thesis helps distinguish the extent to which DNA methylation changes with respect to time and microenvironment in CLL.

  • 115.
    Cahill, Nicola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Jansson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Ryan, Fergus
    Ekström-Smedby, Karin
    Geisler, Christian
    Juliusson, Gunnar
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    IGHV3-21 Gene Frequency in a Swedish Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia2012In: Clinical Lymphoma, Myeloma & Leukemia, ISSN 2152-2650, E-ISSN 2152-2669, Vol. 12, no 3, p. 201-206Article in journal (Refereed)
    Abstract [en]

    The IGHV3-21 gene has been shown to be overrepresented in Scandinavian patients with chronic lymphocytic leukemia (CLL). By investigating a population-based cohort of 337 Swedish patients with CLL, a lower (6.5%) IGHV3-21 frequency was determined relative to our previous hospital-based studies (10.1%-12.7%), yet this frequency remained higher compared to other Western CLL cohorts (2.6%-4.1%). Furthermore, we confirmed the poor outcome for patients with IGHV3-21 to be independent of mutational and stereotypy status. Background: Scandinavian patients with CLL have shown an overrepresentation of the poor-prognostic IGHV3-21 gene. Furthermore, approximately 50% of patients with IGHV3-21 carry stereotyped B-cell receptors, which implicate antigen selection in leukemogenesis. These patients have also been reported to have shorter time to progression than patients with nonstereotyped IGHV3-21. Materials and Methods: To investigate the IGHV3-21 frequency and the clinical impact of IGHV3-21 stereotypy, 337 newly diagnosed Swedish CLL patients from a population-based cohort were analyzed. Results: Interestingly, the IGHV3-21 frequency was indeed lower (6.5%) in this indolent patient cohort than in our previous hospital-based cohort studies (10.1%-12.7%). Hence, a selection bias of more-aggressive cases rendered a higher proportion of IGHV3-21 cases in our original studies. Nevertheless, the Swedish IGHV3-21 frequency still remained higher when compared with other larger European or American studies (2.6%-4.1%). Finally, we confirmed the poor outcome for IGHV3-21 patients to be independent of mutational status and found stereotypy to have no impact on survival or time to treatment. Conclusion: The Swedish geographic bias in IGHV3-21 gene frequency was validated albeit at a lower frequency than previously reported. Moreover, no prognostic value could be attributed to IGHV3-21 stereotype status.

  • 116.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Carrero, Juan-Jesús
    Stenvinkel, Peter
    Bottai, Matteo
    Barany, Peter
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Endostatin, Cathepsin S, and Cathepsin L, and Their Association with Inflammatory Markers and Mortality in Patients Undergoing Hemodialysis2015In: Blood Purification, ISSN 0253-5068, E-ISSN 1421-9735, Vol. 39, no 4, p. 259-265Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIMS: Although both endostatin and cathepsins S have been associated with higher mortality, data in patients with end-stage renal disease (ESRD) are scarce.

    METHODS: A longitudinal cohort study of 207 prevalent patients undergoing hemodialysis.

    RESULTS: Cathepsins S and L were associated with soluble receptors for tumor necrosis factor (sTNFR1 and sTNFR2, rho between 0.28 and 0.43, p < 0.001 for all). Weaker or absent associations between endostatin, cathepsins S and L were seen with other inflammatory biomarkers, that is, CRP, interleukin 6, pentraxin 3, and TNF. In Cox and Laplace regression models adjusted for age, sex, dialysis vintage, and diabetes: standard deviation increments of endostatin was associated with a lower mortality (hazard ratio 0.75, 95% confidence interval (CI) 0.57-0.98), and with 6.8 months longer median survival.

    CONCLUSIONS: The high levels of endostatin, cathepsins S and L, and their associations with sTNFR1 and sTNFR2 warrant further studies exploring mortality, and the angiogenic and inflammatory pathways in ESRD.

  • 117.
    Cesaro, Simone
    et al.
    Azienda Osped Univ Integrata, Paediat Haematol & Oncol, Verona, Italy..
    de latour, Regis Peffault
    Univ Paris 07, Dept Haematol, BMT, Hop St Louis, Paris, France..
    Tridello, Gloria
    Azienda Osped Univ Integrata, Paediat Haematol & Oncol, Verona, Italy..
    Pillon, Marta
    Dipartimento Pediat, Clin Oncoematol Pediat, Padua, Italy..
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Fagioli, Franca
    Regina Margherita Hosp, Paediat Haematol, Turin, Italy..
    Jouet, Jean-Pierre
    Hop Claude Huriez Serv Malad Sang, Lille, France..
    Koh, Mickey B. C.
    St George Hosp, Dept Haematol, London, England..
    Panizzolo, Irene Sara
    Azienda Osped Univ Integrata, Paediat Haematol & Oncol, Verona, Italy..
    Kyrcz-Krzemien, Slawomira
    Med Univ Silesia, Univ Dept Haematol, Katowice, Poland.;BMT, Katowice, Poland..
    Maertens, Johan
    Univ Hosp Gasthuisberg, Dept Haematol, Leuven, Belgium..
    Rambaldi, Alessandro
    Osped Riuniti Bergamo, Div Ematol, Bergamo, Italy..
    Strahm, Brigitte
    Univ Med Ctr, Dept Paediat & Adolescent Med, Paediat Haematol & Oncol, Freiburg, Germany..
    Blaise, Didier
    Inst Paoli Calmettes, Ctr Rech Cancerol Marseille, Programme Transplantat & Therapie Cellulaire, Marseille, France..
    Maschan, Alexei
    Fed Res Ctr Paediat Haematol Oncol & Immunol, Moscow, Russia..
    Marsh, Judith
    Kings Coll London, Kings Coll Hosp, Dept Haematol Med, London, England..
    Dufour, Carlo
    Inst G Gaslini, Paediat Haematol, Genoa, Italy..
    Second allogeneic stem cell transplant for aplastic anaemia: a retrospective study by the severe aplastic anaemia working party of the European society for blood and marrow transplantation2015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 171, no 4, p. 606-614Article in journal (Refereed)
    Abstract [en]

    We analysed the outcome of a second allogeneic haematopoietic stem cell transplant (alloHSCT) in 162 patients reported to the European Society for Blood and Marrow Transplantation between 1998 and 2009. Donor origin was a sibling in 110 and an unrelated donor in 52 transplants, respectively. The stem cell source was bone marrow in 31% and peripheral blood in 69% of transplants. The same donor as for the first alloHSCT was used in 81% of transplants whereas a change in the choice of stem cell source was reported in 56% of patients, mainly from bone marrow to peripheral blood. Neutrophil and platelet engraftment occurred in 85% and 72% of patients, after a median time of 15 and 17days, respectively. Grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 21% and 37% of patients, respectively. Graft failure (GF) occurred in 42 patients (26%). After a median follow-up of 3.5years, the 5-year overall survival (OS) was 60.7%. In multivariate analysis, the only factor significantly associated with a better outcome was a Karnofsky/Lansky score 80 (higher OS). We conclude that a second alloHSCT is feasible rescue option for GF in SAA, with a successful outcome in 60% of cases.

  • 118. Cesaro, Simone
    et al.
    Marsh, Judith
    Tridello, Gloria
    Rovò, Alicia
    Maury, Sebastien
    Montante, Barbara
    Masszi, Tamás
    Van Lint, Maria Teresa
    Afanasyev, Boris
    Iriondo Atienza, Arturo
    Bierings, Marc
    Carbone, Cecilia
    Doubek, Michael
    Lanino, Edoardo
    Sarhan, Mahmoud
    Risitano, Antonio
    Steinerova, Katerina
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Pegoraro, Anna
    Passweg, Jakob
    Retrospective survey on the prevalence and outcome of prior autoimmune diseases in patients with aplastic anemia reported to the registry of the European group for blood and marrow transplantation.2010In: Acta Haematologica, ISSN 0001-5792, E-ISSN 1421-9662, Vol. 124, no 1, p. 19-22Article in journal (Refereed)
    Abstract [en]

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

  • 119. Chaireti, R.
    et al.
    Lindahl, T. L.
    Bremme, K.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Inflammatory and endothelial markers and their relations to the haemostatic potential during the menstrual cycle2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 614-614, article id PO292-TUEArticle in journal (Other academic)
  • 120.
    Chatzilari, Elisavet
    et al.
    CERTH, Inst Informat Technol, Thessaloniki, Greece..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Xochelli, Aliki
    Ctr Res & Technol Hellas, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Maronidis, Anastasios
    CERTH, Inst Informat Technol, Thessaloniki, Greece..
    Vardi, Anna
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Douka, Vassiliki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Iskas, Michail
    George Papanicolaou Gen Hosp, Hematol BMT Unit, Thessaloniki, Greece..
    Karavalakis, George
    G Papanicolaou Hosp, BMT Unit, Dept Hematol, Thessaloniki, Greece..
    Papalexandri, Apostolia
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Niemann, Carsten
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Montillo, Marco
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Haematol, Milan, Italy..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Davi, Frederic
    Hop La Pitie Salpetriere, Dept Biol Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Stavroyianni, Niki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Hadzidimitriou, Anastasia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nikolopoulos, Spiros
    CERTH, Inst Informat Technol, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Kompatsiaris, Yannis
    CERTH, Inst Informat Technol, Thessaloniki, Greece..
    Personalized Modeling of Disease Evolution in CLL: Does Statistical Significance Translate into Predictive Accuracy?2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 121.
    Chen, Y-B
    et al.
    Massachusetts Gen Hosp, Yawkey 9E 9052 55 Fruit St, Boston, MA 02114 USA..
    Wang, T.
    Med Coll Wisconsin, Ctr Int Blood, Marrow Transplant Res, Dept Med, Milwaukee, WI USA.;Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI USA..
    Hemmer, M. T.
    Med Coll Wisconsin, Ctr Int Blood, Marrow Transplant Res, Dept Med, Milwaukee, WI USA..
    Brady, C.
    Natl Marrow Donor Program Be Match, Ctr Int Blood, Marrow Transplant Res, Minneapolis, MN USA..
    Couriel, D. R.
    Marrow Transplant Program, Utah Blood, Salt Lake City, UT USA..
    Alousi, A.
    Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Stem Cell Transplantat, Houston, TX 77030 USA..
    Pidala, J.
    H Lee Moffitt Canc Ctr & Res Inst, Res Inst, Tampa, FL USA..
    Urbano-Ispizua, A.
    Univ Barcelona, IDIBAPS, Hosp Clin, Barcelona, Spain.;Univ Barcelona, Inst Res Josep Carreras, Dept Hematol, Hosp Clin, Barcelona, Spain..
    Choi, S. W.
    Univ Michigan, Ann Arbor, MI 48109 USA..
    Nishihori, T.
    H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA..
    Teshima, T.
    Univ Hosp, Fukuoka, Japan..
    Inamoto, Y.
    Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan..
    Wirk, B.
    Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA..
    Marks, D. I.
    Univ Hosp Bristol NHS Trust, Adult Bone Marrow Transplant, Bristol, Avon, England..
    Abdel-Azim, H.
    Univ So Calif, Keck Sch Med, Marrow Transplantat, Div Hematol Oncol & Blood, Los Angeles, CA 90033 USA..
    Lehmann, L.
    Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA..
    Yu, L.
    Louisiana State Univ, Med Ctr, Div Hematol Oncol, Childrens Hosp,Ctr Canc & Blood Disorders,HSC, New Orleans, LA USA..
    Bitan, M.
    Tel Aviv Sourasky Med Ctr, Tel Aviv, Dept Pediat Hematol Oncol, Tel Aviv, Israel..
    Cairo, M. S.
    New York Med Coll, Div Pediat Hematol Oncol, Stem Cell Transplantat, Dept Pediat, Valhalla, NY USA..
    Qayed, M.
    Emory Univ, Sch Med, Dept Pediat, Atlanta, GA, Australia..
    Salit, R.
    Fred Hutchinson Canc Res Ctr, Seattle, WA USA..
    Gale, R. P.
    Imperial Coll London, Hematol Res Ctr, Div Expt Med, Dept Med, London, England..
    Martino, R.
    Hosp Santa Creu St Pau, Div Clin Hematol, Barcelona, Spain..
    Jaglowski, S.
    Ohio State Univ, Med Ctr, Div Hematol, Columbus, OH 43210 USA..
    Bajel, A.
    Royal Melbourne Hosp City Campus, Melbourne, Australia..
    Savani, B.
    Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Dept Med, Nashville, TN USA..
    Frangoul, H.
    Vanderbilt Univ, Sch Med, Div Hematol Oncol, Dept Pediat, Nashville, TN USA..
    Lewis, I. D.
    Royal Adelaide Hosp, Haematol & Bone Marrow Transplant Unit, Adelaide, SA, Australia..
    Storek, J.
    Univ Calgary, Dept Med, Calgary, AB, Canada..
    Askar, M.
    Baylor Univ, Med Ctr, Dallas, TX USA..
    Kharfan-Dabaja, M. A.
    H Lee Mofitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA..
    Aljurf, M.
    King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia..
    Ringden, O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Div Therapeut Immunol, Dept Lab Med, Stockholm, Sweden..
    Reshef, R.
    Columbia Univ, Med Ctr, Blood & Marrow Transplantat Program, Columbia Ctr Translat Immunol, New York, NY USA..
    Olsson, R. F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Div Therapeut Immunol, Dept Lab Med, Stockholm, Sweden..
    Hashmi, S.
    Mayo Clin Rochester, Rochester, MN USA..
    Seo, S.
    Nat Canc Res Ctr, East Hosp, Kashiwa, Chiba, Japan..
    Spitzer, T. R.
    MacMillan, M. L.
    Univ Minnesota, Med Ctr, Minneapolis, MN USA..
    Lazaryan, A.
    Univ Minnesota, Med Ctr, Div Hematol Oncol, Dept Med, Minneapolis, MN USA..
    Spellman, S. R.
    Arora, M.
    Cutler, C. S.
    Dana Farber Canc Inst, Ctr Hematol Oncol, Dept Med Oncol, Boston, MA USA..
    GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes2017In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 52, no 3, p. 400-408Article in journal (Refereed)
    Abstract [en]

    Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (>= 18 years) = 810, double (< 18 years) = 594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

  • 122. Cherif, Honar
    et al.
    Greinacher, Andreas
    Lubenow, Norbert
    Patient was wrongly diagnosed and repeatedly treated for immune thrombocytopenia for 50 years2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115, article id EY3IArticle in journal (Refereed)
    Abstract [sv]

    We report on a patient with inherited macrothrombocytopenia, MYH9 related disease (MYH9-RD). The patient was wrongly diagnosed and repeatedly treated for immune thrombocytopenia (ITP) for nearly 50 years. Cases of misdiagnosed MYH9-RD and other hereditary thrombocytopenias have been described previously. Typical clinical features such as renal failure and/or progressive loss of hearing should give grounds to suspect hereditary thrombocytopenia. Initial laboratory diagnosis can start with a simple blood smear followed by immunohistochemistry and genotyping. Therapy with thrombopoietin receptor agonists may be beneficial in selected cases of MYH9-RD. ITP treatments including splenectomy are not indicated and may cause harm.

  • 123.
    Cherif, Honar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Karlsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Combination treatment with an erythropoiesis-stimulating agent and intravenous iron alleviates anaemia in patients with hereditary haemorrhagic telangiectasia2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 4, p. 350-353Article in journal (Refereed)
    Abstract [en]

    Background

    Patients with hereditary haemorrhagic telangiectasia (HHT) suffer from recurrent epistaxis and bleeding from gastrointestinal telangiectasias that occur despite otherwise normal haemostasis and result in iron deficiency anaemia with increasing severity. In advanced disease, anaemia may be severe, be irresponsive to iron supplementation, and may lead to red blood cell transfusion dependency.

    Methods

    We conducted a retrospective study at our Centre for Osler's Disease to evaluate the effectiveness of adding an erythropoiesis-stimulating agent (ESA) to intravenous iron supplementation in the management of anaemic HHT patients. Blood values and treatment parameters were collected for nine months before combination therapy (iron supplementation only) and 12 months during combination therapy (iron supplementation plus ESA).

    Results

    Four patients received intravenous iron and an ESA with mean weekly doses of 126 mg and 17,300 units (U), respectively. Mean haemoglobin improved significantly during combination therapy, from 106 g/L to 119 g/L (p < 0.001).

    Conclusion

    Anaemia can be alleviated in patients with HHT who are irresponsive to intravenous iron supplementation, by addition of an ESA. The proposed mechanism behind the iron irresponsiveness is that the anaemia is caused by a combination of recurrent haemorrhage and anaemia of chronic disease.

  • 124.
    Christensen, Kjeld
    et al.
    Orebro Univ Hosp, Dept Cardiol, Orebro, Sweden.;Linnaeus Univ, Linnaeus Ctr Biomat Chem, SE-39182 Kalmar, Sweden..
    Kozarcanin, Huda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, SE-39182 Kalmar, Sweden..
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, SE-39182 Kalmar, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, SE-39182 Kalmar, Sweden..
    Evidence of contact activation in patients suffering from ST-elevation myocardial infarction2016In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 141, p. 158-162Article in journal (Refereed)
    Abstract [en]

    Introduction: Factor (F) XIIa is an attractive target for anticoagulation in arterial thrombosis. The aim of this study is to investigate the degree of involvement of the contact system in cardiac infarctions. Methods and patients: 165 patients suffering from ST-elevation myocardial infarction (STEMI) and 100 healthy controls were included in the study. Samples were drawn at admission before percutaneous intervention (PCI), 1-3 days post-percutaneous intervention (PCI) and, in one-third of the patients, 3 months after PCI. In order to investigate the degree of Factor XII (FXII) activation, changes in FXIIa/AT and FXIIa/C1INH complex levels were quantified by ELISA. Results: FXIIa/AT levels at admission (0.89 +/- 0.50; p < 0.01) were significantly higher than those in normal individuals (0.39 +/- 0.28), but the levels after 1-3 days (0.33 +/- 0.33; p < 0.05) were essentially normalized. In contrast, the FXII/C1INH levels at admission (1.40 +/- 0.72; p < 0.001) and after 1-3 days (0.83 +/- 0.59; p < 0.001) were both significantly higher than those in normal individuals (0.40 +/- 0.30). FXIIa/AT and FXIIa/C1INH complexes at admission (p < 0.001; p < 0.001) and after 1-3 days (p < 0.02; p < 0.001) were significantly different from those at 3 months. No significant differences were observed when the data were stratified for patency (open/closed culprit lesions). Conclusion: Both FXIIa/AT and FXIIa/C1INH complexes were significantly increased and reflected the activation of FXII in STEMI patients at admission. In particular, FXIIa/AT complex elevations support the hypothesis that clot propagation-mediated FXII activation had occurred, and this activation may be a target for anticoagulation in patients with cardiac infarction. Based on previous studies, the FXIIa/C1INH complex levels were primarily interpreted to reflex endothelial cell activation.

  • 125.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Jönelid, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    The change of the amount of circulating microparticles and their association to the general atherosclerotic burden after acute coronary syndrome2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 214-214, article id OR312Article in journal (Other academic)
  • 126.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Myeloid-Derived Suppressor Cells and Other Immune Escape Mechanisms in Chronic Leukemia2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, a minute chromosome that leads to the creation of the fusion gene BCR/ABL and the transcription of the fusion protein BCR/ABL in transformed cells. The constitutively active tyrosine kinase BCR/ABL confers enhanced proliferation and survival on leukemic cells. CML has in only a few decades gone from being a disease with very bad prognosis to being a disease that can be effectively treated with oral tyrosine kinase inhibitors (TKIs). TKIs are drugs inhibiting BCR/ABL as well as other tyrosine kinases. In this thesis, the focus has been on the immune system of CML patients, on immune escape mechanisms present in untreated patients and on how these are affected by TKI therapy. We have found that newly diagnosed, untreated CML patients exert different kinds of immune escape mechanisms. Patients belonging to the Sokal high-risk group had higher levels of myeloid-derived suppressor cells (MDSCs) as well as high levels of the programmed death receptor 1 (PD-1)-expressing cytotoxic T cells compared to control subjects. Moreover, CML patients had higher levels of myeloid cells expressing the ligand for PD-1, PD-L1. CML patients as well as patients with B cell malignacies had high levels of soluble CD25 in blood plasma. In B cell malignacies, sCD25 was found to be released from T regulatory cells (Tregs). Treatment with the TKIs imatinib or dasatinib decreased the levels of MDSCs in peripheral blood. Tregs on the other hand increased during TKI therapy. The immunostimulatory molecule CD40 as well as NK cells increased during therapy, indicating an immunostimulatory effect of TKIs. When evaluating immune responses, multiplex techniques for quantification of proteins such as cytokines and chemokines are becoming increasingly popular. With these techniques a lot of information can be gained from a small sample volume and complex networks can be more easily studied than when using for example the singleplex ELISA. When comparing different multiplex platforms we found that the absolute protein concentration measured by one platform rarely correlated with the absolute concentration measured by another platform. However, relative quantification was better correlated.

  • 127.
    Christiansson, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Markevarn, Berit
    Norrland Univ Hosp, Dept Hematol, Umea, Sweden..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Coagulat, Lund, Sweden..
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Mustjoki, Satu
    Univ Helsinki, Dept Med, Div Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses2015In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 5, p. 1181-1191Article in journal (Refereed)
    Abstract [en]

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

  • 128.
    Christiansson, Lisa
    et al.
    Uppsala, Sweden.
    Söderlund, Stina
    Uppsala, Sweden.
    Mangsbo, Sara
    Uppsala, Sweden.
    Hjorth-Hansen, Henrik
    Trondheim, Norway.
    Höglund, Martin
    Uppsala, Sweden.
    Markevärn, Berit
    Department of Hematology, Norrland University Hospital, Umeå, Sweden.
    Richter, Johan
    Lund, Sweden.
    Stenke, Leif
    Stockholm, Sweden.
    Mustjoki, Satu
    Helsinki, Finland.
    Loskog, Angelica
    Uppsala, Sweden.
    Olsson-Strömberg, Ulla
    Uppsala, Sweden.
    The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses2015In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 5, p. 1181-1191Article in journal (Refereed)
    Abstract [en]

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

  • 129.
    Cornell, Robert F.
    et al.
    Vanderbilt Univ, Med Ctr, Dept Med, Div Hematol Oncol, Nashville, TN USA..
    Bachanova, Veronika
    Univ Minnesota, Med Ctr, Bone & Marrow Transplant Program, Minneapolis, MN 55455 USA..
    D'Souza, Anita
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Woo-Ahn, Kwang
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA.;Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA..
    Martens, Michael
    Med Coll Wisconsin, Dept Oncol, Milwaukee, WI 53226 USA..
    Huang, Jiaxing
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Al-Homsi, A. Samer
    Spectrum Hlth, Blood & Marrow Transplant, Grand Rapids, MI USA..
    Chhabra, Saurabh
    Med Univ South Carolina, Dept Med, Charleston, SC USA..
    Copelan, Edward
    Carolinas HealthCare Syst, Levine Canc Inst, Dept Hematol Oncol & Blood Disorders, Charlotte, NC USA..
    Diaz, Miguel-Angel
    Hosp Infanta Univ Nino Jesus, Dept Hematol Oncol, Madrid, Spain..
    Freytes, Cesar O.
    Texas Transplant Inst, San Antonio, TX USA..
    Gale, Robert Peter
    Imperial Coll London, Dept Med, Div Expt Med, Hematol Res Ctr, London, England..
    Ganguly, Siddhartha
    Univ Kansas, Med Ctr, Blood & Marrow Transplantat, Div Hematol & Oncol, Kansas City, KS 66103 USA..
    Hamadani, Mehdi
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Hildebrandt, Gerhard
    Univ Kentucky, Div Hematol & Blood & Marrow Transplantat, Markey Canc Ctr, Lexington, KY USA..
    Kamble, Rammurti T.
    Baylor Coll Med, Div Hematol & Oncol, Ctr Cell & Gene Therapy, Houston, TX 77030 USA..
    Kharfan-Dabaja, Mohamed
    H Lee Moffitt Canc & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA..
    Kindwall-Keller, Tamila
    Univ Virginia Hlth Syst, Div Hematol Oncol, Charlottesville, VA USA..
    Lazarus, Hillard M.
    Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA..
    Marks, David I.
    Univ Hosp Bristol NHS Trust, Adult Bone Marrow Transplant, Bristol, Avon, England..
    Nishihori, Taiga
    H Lee Moffitt Canc & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA..
    Olsson, Richard F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Div Therapeut Immunol, Dept Lab Med, Stockholm, Sweden..
    Saad, Ayman
    Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA..
    Usmani, Saad
    Carolinas HealthCare Syst, Levine Canc Inst, Dept Hematol Oncol & Blood Disorders, Charlotte, NC USA..
    Vesole, David H.
    Hackensack UMC, John Theurer Canc Ctr, Hackensack, NJ USA..
    Yared, Jean
    Univ Maryland, Dept Med, Blood & Marrow Transplantat Program, Div Hematol Oncol,Greenebaum Canc Ctr, Baltimore, MD 21201 USA..
    Mark, Tomer
    Weill Cornell Med Coll, Dept Med, New York, NY USA..
    Nieto, Yago
    Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA..
    Hari, Parameswaran
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Allogeneic Transplantation for Relapsed Waldenström Macroglobulinemia and Lymphoplasmacytic Lymphoma2017In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 23, no 1, p. 60-66Article in journal (Refereed)
    Abstract [en]

    Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and IgM production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients who received adult alloHCT for WM/LPL. Data were obtained from the Center for International Blood and Marrow Transplant Research database (2001 to 2013). Patients received myeloablative (n = 67) or reduced-intensity conditioning (RIC; n = 67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n = 18) failed prior autologous HCT. About half (n = 82, 57%) had chemosensitive disease at the time of transplantation, whereas 22% had progressive disease. Rates of progression-free survival, overall survival, relapse, and nonrelapse mortality at 5 years were 46%, 52%, 24%, and 30%, respectively. Patients with chemosensitive disease and better pretransplant disease status experienced significantly superior overall survival. There were no significant differences in progression-free survival based on conditioning (myeloablative, 50%, versus RIC, 41%) or graft source. Conditioning intensity did not impact treatment-related mortality or relapse. The most common causes of death were primary disease and graft-versus-host disease (GVHD). AlloHCT yielded durable survival in select patients with WM/LPL. Strategies to reduce mortality from GVHD and post-transplant relapse are necessary to improve this approach.

  • 130. Cornell, Robert F
    et al.
    D'Souza, Anita
    Kassim, Adetola A
    Costa, Luciano J
    Innis-Shelton, Racquel D
    Zhang, Mei-Jie
    Huang, Jiaxing
    Abidi, Muneer
    Aiello, Jack
    Akpek, Gorgun
    Bashey, Asad
    Bashir, Qaiser
    Cerny, Jan
    Comenzo, Raymond
    Diaz, Miguel Angel
    Freytes, César
    Gale, Robert Peter
    Ganguly, Siddhartha
    Hamadani, Mehdi
    Hashmi, Shahrukh
    Holmberg, Leona
    Hossain, Nasheed
    Kamble, Rammurti T
    Kharfan-Dabaja, Mohamed
    Kindwall-Keller, Tamila
    Kyle, Robert
    Kumar, Shaji
    Lazarus, Hillard
    Lee, Cindy
    Maiolino, Angelo
    Marks, David I
    Meehan, Kenneth
    Mikhael, Joe
    Nath, Rajneesh
    Nishihori, Taiga
    Olsson, Richard F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Ramanathan, Muthalagu
    Saad, Ayman
    Seo, Sachiko
    Usmani, Saad
    Vesole, David
    Vij, Ravi
    Vogl, Dan
    Wirk, Baldeep M
    Yared, Jean
    Krishnan, Amrita
    Mark, Tomer
    Nieto, Yago
    Hari, Parameswaran
    Maintenance versus Induction Therapy Choice on Outcomes after Autologous Transplantation for Multiple Myeloma2017In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 23, no 2, p. 269-277Article in journal (Refereed)
    Abstract [en]

    Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving "upfront" AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post-transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transplant therapy had significantly improved 3-year PFS versus no post-transplant therapy (55% versus 39%, P = .0001). This benefit was most evident in patients not achieving at least a complete response post-AHCT (P = .005). In patients receiving upfront AHCT, the choice of induction regimen (doublet or triplet therapies) appears to be of lower impact than use of post-transplant therapy.

  • 131.
    Czerw, Tomasz
    et al.
    Maria Sklodowska Curie Mem Cancer Centre, Poland; Institute Oncol, Poland.
    Labopin, Myriam
    Hop St Antoine, France; INSERM, France; University of Paris 06, France.
    Schmid, Christoph
    University of Munich, Germany.
    Cornelissen, Jan J.
    Erasmus University, Netherlands.
    Chevallier, Patrice
    CHU Nantes, France.
    Blaise, Didier
    Institute J Paoli I Calmettes, France.
    Kuball, Juergen
    University of Medical Centre, Netherlands.
    Vigouroux, Stephane
    Hop Haut Leveque, France.
    Garban, Frederic
    Hop A Michallon, France.
    Lioure, Bruno
    Nouvel Hop Civil, France.
    Fegueux, Nathalie
    CHU Lapeyronie, France.
    Clement, Laurence
    Centre Hospital University of CHU Nancy, France.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Maertens, Johan
    University Hospital Gasthuisberg, Belgium.
    Guillerm, Gaelle
    CHU Morvan, France.
    Bordessoule, Dominique
    CHRU Limoges, France.
    Mohty, Mohamad
    Hop St Antoine, France; INSERM, France; University of Paris 06, France.
    Nagler, Arnon
    Hop St Antoine, France; Chaim Sheba Medical Centre, Israel.
    High CD3+and CD34+peripheral blood stem cell grafts content is associated with increased risk of graft-versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia - an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 19, p. 27255-27266Article in journal (Refereed)
    Abstract [en]

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

  • 132. Dahlen, Torsten
    et al.
    Edgren, Gustaf
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lambe, Mats
    Bjorkholm, Magnus
    Sandin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sjalander, Anders
    Richter, Johan
    Ohm, Lotta
    Back, Magnus
    Stenke, Leif
    Increased Risk of Cardiovascular Events Associated with TKI Treatment in Chronic Phase Chronic Myeloid Leukemia. Data from Swedish Population-Based Registries2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 133.
    Dahlin, J. S.
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Ungerstedt, J. S.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Grootens, J.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Sander, B.
    Karolinska Inst, Karolinska Univ Hosp, Div Pathol, Dept Lab Med, Stockholm, Sweden..
    Guelen, T.
    Karolinska Univ, Huddinge Hosp, Dept Resp Dis & Allergy, Stockholm, Sweden..
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Uppsala Hosp, Sect Hematol, Uppsala, Sweden..
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Karolinska Univ Hosp, Dept Med, Stockholm, Sweden..
    Detection of circulating mast cells in advanced systemic mastocytosis2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 9, p. 1954-+Article in journal (Refereed)
  • 134.
    Dahlin, Joakim S.
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ekoff, Maria
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Grootens, Jennine
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ungerstedt, Johanna S.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden.
    KIT signaling is dispensable for human mast cell progenitor development2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 130, no 16, p. 1785-1794Article in journal (Refereed)
    Abstract [en]

    Human hematopoietic progenitors are generally assumed to require stem cell factor (SCF) and KIT signaling during differentiation for the formation of mast cells. Imatinib treatment, which inhibits KIT signaling, depletes mast cells in vivo. Furthermore, the absence of SCF or imatinib treatment prevents progenitors from developing into mast cells in vitro. However, these observations do not mean that mast cell progenitors require SCF and KIT signaling throughout differentiation. Here, we demonstrate that circulating mast cell progenitors are present in patients undergoing imatinib treatment. In addition, we show that mast cell progenitors from peripheral blood survive, mature, and proliferate without SCF and KIT signaling in vitro. Contrary to the prevailing consensus, our results show that SCF and KIT signaling are dispensable for early mast cell development.

  • 135.
    Dahlin, Joakim S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Öhrvik, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lineage- CD34hi CD117int/hi FcϵRI+ cells in human blood constitute a rare population of mast cell progenitors2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, no 4, p. 383-391Article in journal (Refereed)
    Abstract [en]

    Mast cells are rare tissue-resident immune cells that are involved in allergic reactions, and their numbers are increased in the lungs of asthmatics. Murine lung mast cells arise from committed bone marrow-derived progenitors that enter the blood circulation, migrate through the pulmonary endothelium, and mature in the tissue. In humans, mast cells can be cultured from multipotent CD34(+) progenitor cells. However, a population of distinct precursor cells that give rise to mast cells has remained undiscovered. To our knowledge, this is the first report of human lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) progenitor cells, which represented only 0.0053% of the isolated blood cells in healthy individuals. These cells expressed integrin β7 and developed a mast cell-like phenotype, although with a slow cell division capacity in vitro. Isolated lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) blood cells had an immature mast cell-like appearance and expressed high levels of many mast cell-related genes as compared with human blood basophils in whole-transcriptome microarray analyses. Furthermore, serglycin, tryptase, and carboxypeptidase A mRNA transcripts were detected by quantitative RT-PCR. Altogether, we propose that the lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) blood cells are closely related to human tissue mast cells and likely constitute an immediate precursor population, which can give rise to predominantly mast cells. Furthermore, asthmatics with reduced lung function had a higher frequency of lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) blood mast cell progenitors than asthmatics with normal lung function.

  • 136. Dalin, Martin G.
    et al.
    Engström, Pär G.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ivarsson, Emil G.
    Unneberg, Per
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Schaufelberger, Maria
    Gilljama, Thomas
    Andersson, Bert
    Bergo, Martin O.
    Massive parallel sequencing questions the pathogenic role of missense variants in dilated cardiomyopathy2017In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 228, p. 742-748Article in journal (Refereed)
    Abstract [en]

    Background: Germline genetic variants are an important cause of dilated cardiomyopathy (DCM). However, recent sequencing studies have revealed rare variants in DCM-associated genes also in individuals without known heart disease. In this study, we investigate variant prevalence and genotype-phenotype correlations in Swedish DCM patients, and compare their genetic variants to those detected in reference cohorts. Methods and results: We sequenced the coding regions of 41 DCM-associated genes in 176 unrelated patients with idiopathic DCM and found 102 protein-altering variants with an allele frequency of <0.04% in reference cohorts; the majority were missense variants not previously described in DCM. Fifty-five (31%) patients had one variant, and 24 (14%) patients had two or more variants in the analysed genes. Detection of genetic variants in any gene, and in LMNA, MYII7 or TTN alone, was associated with early onset disease and reduced transplant-free survival. As expected, nonsense and frameshift variants were more common in DCM patients than in healthy individuals of the reference cohort 1000 Genomes Europeans. Surprisingly however, the prevalence, conservation and pathogenicity scores, and localization of missense variants were similar in DCM patients and healthy reference individuals. Conclusion: To our knowledge, this is the first study to identify correlations between genotype and prognosis when sequencing a large number of genes in unselected DCM patients. The similar distribution of missense variants in DCM patients and healthy reference individuals questions the pathogenic role of many variants, and suggests that results from genetic testing of DCM patients should be interpreted with caution.

  • 137. d'Amore, Francesco
    et al.
    Relander, Thomas
    Lauritzsen, Grete F.
    Jantunen, Esa
    Hagberg, Hans
    Anderson, Harald
    Holte, Harald Jr.
    Osterborg, Anders
    Merup, Mats
    Brown, Peter de Nully
    Kuittinen, Outi
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ostenstad, Bjorn
    Fagerli, Unn-Merete
    Gadeberg, Ole
    Sundstrom, Christer
    Delabie, Jan
    Rafkiaer, Elisabeth
    Vornanen, Martine
    Toldbod, Helle
    High-dose chemotherapy and autologuos stem cell transplantation in previously untreated peripheral T-Cell Lymphoma: Final analysis of a large prospective multicenter study (NLG-T-01)2011In: 53rd ASH Annual Meeting and Exposition: Session: 731. Clinical Allogeneic and Autologous Transplantation - Results: Myeloma, Lymphomas and Multiple Sclerosis ; Monday, December 12, 2011: 7:00 AM Douglas Pavilion C (Manchester Grand Hyatt San Diego), washington, USA: American Society of Hematology , 2011, Vol. 118, no 21, p. 155-156Conference paper (Refereed)
  • 138.
    Danielsson, Signe
    et al.
    Medicinska kliniken, Universitetssjukhuset Örebro, Örebro, Sweden.
    Merup, Mats
    Hematologiskt centrum, Karolinska universitetssjukhuset, Huddinge, Sweden.
    Olsson, Lovisa A.
    Laboratoriemedicinska länskliniken/klinisk kemi, Universitetssjukhuset, Örebro, Sweden.
    Palmblad, Jan
    Hematologiskt centrum, Karolinska universitetssjukhuset, Huddinge, Sweden; Institutionen för medicin, Karolinska institutet, Stockholm, Sweden.
    Åström, Maria
    Medicinska kliniken, Universitetssjukhuset Örebro, Örebro, Sweden.
    X-bunden trombocytopeni med talassemi i två svenska familjer: Överväg hereditära orsaker till trombocytopeni och benmärgsfibros2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 34-35, p. 1474-7Article in journal (Other academic)
  • 139.
    Dantonello, Tobias M
    et al.
    Paediatrics 5 (oncology, hematology, immunology), Olgahospital Klinikum Stuttgart, Germany.
    Stark, Monika
    Paediatrics 5 (oncology, hematology, immunology), Olgahospital Klinikum Stuttgart, Germany.
    Timmermann, Beate
    Fuchs, Jörg
    Selle, Barbara
    Linderkamp, Christin
    Handgretinger, Rupert
    Hagen, Rudolf
    Feuchtgruber, Simone
    Kube, Stefanie
    Kosztyla, Daniel
    Kazanowska, Bernarda
    Ladenstein, Ruth
    Niggli, Felix
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Bielack, Stefan S
    Klingebiel, Thomas
    Koscielniak, Ewa
    Paediatrics 5 (oncology, hematology, immunology), Olgahospital Klinikum Stuttgart, Germany.
    Tumour volume reduction after neoadjuvant chemotherapy impacts outcome in localised embryonal rhabdomyosarcoma2015In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 62, no 1, p. 16-23Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Response (tumour volume reduction) to induction chemotherapy has been used to stratify secondary local and systemic treatment of Intergroup Rhabdomyosarcoma Study Group III (IRSG-III) embryonal rhabdomyosarcoma (RME) in consecutive CWS-trials. To evaluate its actual impact we studied response-related treatment and outcomes.

    PROCEDURE: Patients with IRSG-III RME <21 years and non-response (NR, <33% volume reduction) in five consecutive CWS-trials were analysed and compared with partial responders (PAR, ≥33% reduction). The NR was reviewed and sub-classified as Objective Response (OR, <0%-33% reduction) or Stable/Progressive Disease (SPD).

    RESULTS: Fifty-nine of 529 patients had NR (n = 34 OR, n = 25 SPD). Primary risk-factors including age, tumour size, and TN-classification did not differ between NR and PAR groups but NR had more patients with unfavourable sites comparatively (P = 0.04). There were no differences in primary risk-factors between OR and SPD. Significant factors associated with poor outcome in multivariate analysis were NR, TN-classification, age >10 years, tumour size >5 cm and therapy in older trials. After response assessment n = 24 NR continued to receive induction chemotherapy, n = 32 received other combinations and n = 3 no further chemotherapy. Forty-two non-responders were irradiated, and the tumours were completely resected in n = 20. After a median follow-up of 8 years, 34 NR are alive. Seventeen of 21 failures leading to disease-related deaths were locoregional. The five-year overall survival rate (OS) was 76 ± 4% for PAR, 79 ± 14% for OR, but only 40 ± 19% for SPD (P < 0.001).

    CONCLUSION: Response to induction chemotherapy appears to be an important surrogate marker of poor outcome in patients with SPD largely due to ineffective local control.

  • 140. Darzentas, N.
    et al.
    Hadzidimitriou, A.
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hatzi, K.
    Josefsson, P.
    Laoutaris, N.
    Moreno, C.
    Anagnostopoulos, A.
    Jurlander, J.
    Tsaftaris, A.
    Chiorazzi, N.
    Belessi, C.
    Ghia, Paolo
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Davi, F.
    Stamatopoulos, K.
    A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence2010In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 24, no 1, p. 125-132Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is uniquely characterized by the existence of subsets of cases with quasi-identical, 'stereotyped' B-cell receptors (BCRs). Herein we investigate this stereotypy in 2662 patients with CLL, the largest series yet, using purpose-built bioinformatics methods based on sequence pattern discovery. Besides improving the identification of 'stereotyped' cases, we demonstrate that CLL actually consists of two different categories, based on the BCR repertoire, with important biological and ontogenetic differences. The first ( approximately 30% of cases) shows a very restricted repertoire and is characterized by BCR stereotypy (clustered cases), whereas the second includes cases with heterogeneous BCRs (nonclustered cases). Eleven major CLL clusters were identified with antigen-binding sites defined by just a few critically positioned residues, regardless of the actual immunoglobulin (IG) variable gene used. This situation is closely reminiscent of the receptors expressed by cells participating in innate immune responses. On these grounds, we argue that whereas CLL cases with heterogeneous BCRs likely derive from the conventional B-cell pool, cases with stereotyped BCRs could derive from progenitor cells evolutionarily adapted to particular antigenic challenges, perhaps intermediate between a true innate immune system and the conventional adaptive B-cell immune system, functionally similar to what has been suggested previously for mouse B1 cells.

  • 141.
    De Caterina, Raffaele
    et al.
    Univ G DAnnunzio, Chieti, Italy.;Fdn Toscana G Monasterio, Pisa, Italy..
    Husted, Steen
    Univ Aarhus, Aarhus, Denmark..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Andreotti, Felicita
    Univ Cattolica Sacro Cuore, I-00168 Rome, Italy..
    Arnesen, Harald
    Oslo Univ Hosp Ulleval, Oslo, Norway.;Univ Oslo, Oslo, Norway..
    Bachmann, Fedor
    Univ Lausanne, Lausanne, Switzerland..
    Baigent, Colin
    Univ Oxford, Oxford, England..
    Collet, Jean-Philippe
    Grp Hosp Pitie Salpetriere, INSERM, UMRS ICAN 1166, F-75634 Paris, France..
    Halvorsen, Sigrun
    Oslo Univ Hosp Ulleval, Oslo, Norway.;Univ Oslo, Oslo, Norway..
    Huber, Kurt
    Wilhelminenhosp, Vienna, Austria..
    Jespersen, Jorgen
    Univ Southern Denmark, Esbjerg, Denmark..
    Kristensen, Steen Dalby
    Aarhus Univ Hosp, DK-8000 Aarhus, Denmark..
    Lip, Gregory Y. H.
    Univ Birmingham, City Hosp, Inst Cardiovasc Sci, Birmingham, W Midlands, England..
    Morais, Joao
    Hosp Santo Andre, Leiria, Portugal..
    Rasmussen, Lars Hvilsted
    Aalborg Univ, Aalborg, Denmark..
    Ricci, Fabrizio
    Univ G DAnnunzio, Chieti, Italy.;Fdn Toscana G Monasterio, Pisa, Italy..
    Sibbing, Dirk
    Univ Munich, Klinikum Univ Munchen, Med Klin & Poliklin 1, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Storey, Robert F.
    Univ Sheffield, Sheffield, S Yorkshire, England..
    ten Berg, Jurrien
    St Antonius Hosp, Nieuwegein, Netherlands..
    Verheugt, Freek W. A.
    Onze Lieve Vrouw Hosp, Amsterdam, Netherlands..
    Weitz, Jeffrey I.
    McMaster Univ, Hamilton, ON, Canada.;Thrombosis & Atherosclerosis Res Inst, Hamilton, ON, Canada..
    Oral anticoagulants in coronary heart disease (Section IV) Position paper of the ESC Working Group on Thrombosis - Task Force on Anticoagulants in Heart Disease2016In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 115, no 4, p. 685-711Article in journal (Refereed)
    Abstract [en]

    Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients, most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel. Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice.

  • 142. de Miranda, Noel F. C. C.
    et al.
    Georgiou, Konstantinos
    Chen, Longyun
    Wu, Chenglin
    Gao, Zhibo
    Zaravinos, Apostolos
    Lisboa, Susana
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Teixeira, Manuel R.
    Zeng, Yixin
    Peng, Roujun
    Pan-Hammarstrom, Qiang
    Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 16, p. 2544-2553Article in journal (Refereed)
    Abstract [en]

    Next-generation sequencing studies on diffuse large B-cell lymphomas (DLBCLs) have revealed novel targets of genetic aberrations but also high intercohort heterogeneity. Previous studies have suggested that the prevalence of disease subgroups and cytogenetic profiles differ between Western and Asian patients. To characterize the coding genome of Chinese DLBCL, we performed whole-exome sequencing of DNA derived from 31 tumors and respective peripheral blood samples. The mutation prevalence of B2M, CD70, DTX1, LYN, TMSB4X, and UBE2A was investigated in an additional 105 tumor samples. We discovered 11 novel targets of recurrent mutations in DLBCL that included functionally relevant genes such as LYN and TMSB4X. Additional genes were found mutated at high frequency (>= 10%) in the Chinese cohort including DTX1, which was the most prevalent mutation target in the Notch pathway. We furthermore demonstrated that mutations in DTX1 impair its function as a negative regulator of Notch. Novel and previous unappreciated targets of somatic mutations in DLBCL identified in this study support the existence of additional/alternative tumorigenic pathways in these tumors. The observed differences with previous reports might be explained by the genetic heterogeneity of DLBCL, the germline genetic makeup of Chinese individuals, and/or exposure to distinct etiological agents.

  • 143. den Hollander, J
    et al.
    Rimpi, Sara
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Doherty, JR
    Rudelius, M
    Buck, A
    Hoellein, A
    Kremer, M
    Graf, N
    Scheerer, M
    Hall, MA
    Goga, A
    von Bubnoff, N
    Duyster, J
    Peschel, C
    Cleveland, JL
    Nilsson, Jonas A
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Keller, U
    Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 116, no 9, p. 1498-1505Article in journal (Refereed)
    Abstract [en]

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

  • 144.
    Deneberg, Stefan
    et al.
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Guardiola, Philippe
    Inserm, Angers, France; Service des Maladies du Sang, Centre Hospitalier Universitaire, Angers, France.
    Lennartsson, Andreas
    Institute for Biomedicine and Nutrition, NOVUM, Karolinska Institutet, Stockholm, Sweden.
    Qu, Ying
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Gaidzik, Verena E.
    Department of Internal Medicine III, University Hospital, Ulm, Germany.
    Blanchet, Odile
    Inserm, Angers, France; Laboratoire d Hematologie, Centre Hospitalier Universitaire, Angers, France.
    Karimi, Mohsen
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Bengtzén, Sofia
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Nahi, Hareth
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Uggla, Bertil
    Örebro University, School of Medical Sciences. Department of Hematology, Örebro University Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Hematology, Örebro University Hospital, Örebro, Sweden.
    Höglund, Martin
    Department of Hematology, Uppsala University Hospital, Uppsala, Sweden.
    Paul, Christer
    Department of Internal Medicine/Hematology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Ekwall, Karl
    Institute for Biomedicine and Nutrition, NOVUM, Karolinska Institutet, Stockholm, Sweden.
    Döhner, Konstanze
    Department of Internal Medicine III, University Hospital, Ulm, Germany.
    Lehmann, Sören
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 20, p. 5573-5582Article in journal (Refereed)
    Abstract [en]

    Cytogenetically normal acute myeloid leukemia (CN-AML) comprise between forty and fifty percent of all adult acute myeloid leukemia (AML) cases. In this clinically diverse group molecular aberrations such as FLT3ITD, NPM1 and CEBPA mutations recently have added to the prognostic accuracy. Aberrant DNA methylation is a hallmark of cancer including AML. We investigated in total 118 CN-AML samples in a test and a validation cohort for genome-wide promoter DNA methylation with Illumina Methylation Bead arrays and compared them to normal myeloid precursors and global gene expression. IDH and NPM1 mutations were associated with different methylation patterns (p=0.0004 and 0.04, respectively). Genome-wide methylation levels were elevated in IDH mutated samples (p=0.006). We observed a negative impact of DNA methylation on transcription. Genes targeted by Polycomb group (PcG) proteins and genes associated with bivalent histone marks in stem cells showed increased aberrant methylation in AML (p<0.0001). Furthermore, high methylation levels of PcG target genes were independently associated with better progression free (OR 0.47, p=0.01) and overall survival (OR 0.36, p=0.001). In summary, genome wide methylation patterns show preferential methylation of PcG targets with prognostic impact in CN-AML.

  • 145.
    Deneberg, Stefan
    et al.
    Karolinska Univ Hosp, Ctr Hematol, Stockholm, Sweden.;Karolinska Inst, Inst Med, Stockholm, Sweden..
    Lundin, Ebba
    Karolinska Univ Hosp, Ctr Hematol, Stockholm, Sweden..
    Lazarevic, Vladimir
    Skane Univ Hosp, Dept Hematol, Lund, Sweden..
    Benson, Lina
    Karolinska Inst, Dept Clin Sci & Educ, Stockholm, Sweden..
    Uggla, Bertil
    Orebro Univ Hosp, Med, Orebro, Sweden..
    Antunovic, Petar
    Linkoping Univ Hosp, Hematol, S-58185 Linkoping, Sweden..
    Mollgard, Lars
    Sahlgrens Univ Hosp, Dept Hematol, Gothenbourg, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Juliusson, Gunnar
    Skane Univ Hosp, Dept Hematol, Lund, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Derolf, Asa Rangert
    Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Reasons for Decreasing Early Mortality in Acute Myeloid Leukemia: An Epidemiological Study from the Swedish Acute Leukemia Registry2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 146.
    Deol, Abhinav
    et al.
    Wayne State Univ, Karmanos Canc Inst, Dept Oncol, 4100 John R,4 HWCRC, Detroit, MI 48201 USA..
    Sengsayadeth, Salyka
    Vanderbilt Univ, Med Ctr, Nashville, TN USA..
    Ahn, Kwang Woo
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA.;Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA..
    Wang, Hai-Lin
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Aljurf, Mahmoud
    King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia..
    Antin, Joseph Harry
    Dana Farber Canc Inst, Dept Med Oncol, Ctr Hematol Oncol, Boston, MA 02115 USA..
    Battiwalla, Minoo
    NHLBI, Hematol Branch, Bethesda, MD 20892 USA..
    Bornhauser, Martin
    Carl Gustav Carus Univ Hosp, Dresden, Germany..
    Cahn, Jean-Yves
    Univ Hosp, Dept Hematol, Grenoble, France..
    Camitta, Bruce
    Med Coll Wisconsin, Midwest Ctr Canc & Blood Disorders, Milwaukee, WI 53226 USA.;Childrens Hosp Wisconsin, Milwaukee, WI 53201 USA..
    Chen, Yi-Bin
    Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA..
    Cutler, Corey S.
    Dana Farber Canc Inst, Dept Med Oncol, Ctr Hematol Oncol, Boston, MA 02115 USA..
    Gale, Robert Peter
    Imperial Coll London, Dept Med, Div Expt Med, Hematol Res Ctr, London, England..
    Ganguly, Siddhartha
    Univ Kansas, Med Ctr, Div Hematol & Oncol, Blood & Marrow Transplantat, Kansas City, KS 66103 USA..
    Hamadani, Mehdi
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Inamoto, Yoshihiro
    Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan..
    Jagasia, Madan
    Vanderbilt Univ, Med Ctr, Nashville, TN USA..
    Kamble, Rammurti
    Baylor Coll Med, Ctr Cell & Gene Therapy, Div Hematol & Oncol, Houston, TX 77030 USA..
    Koreth, John
    Dana Farber Canc Inst, Dept Med Oncol, Ctr Hematol Oncol, Boston, MA 02115 USA..
    Lazarus, Hillard M.
    Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA..
    Liesveld, Jane
    Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA..
    Litzow, Mark R.
    Mayo Clin, Div Hematol, Rochester, NY USA.;Mayo Clin, Transplant Ctr, Rochester, NY USA..
    Marks, David I.
    Univ Hosp Bristol Natl Hlth Serv Trust, Pediat Bone Marrow Transplant, Bristol, Avon, England..
    Nishihori, Taiga
    H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA..
    Olsson, Richard F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Div Therapeut Immunol, Dept Lab Med, Stockholm, Sweden..
    Reshef, Ran
    Columbia Univ, Med Ctr, Blood & Marrow Transplantat Program, New York, NY USA.;Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY USA..
    Rowe, Jacob M.
    Shaare Zedek Med Ctr, Dept Hematol, Jerusalem, Israel..
    Saad, Ayman A.
    Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA..
    Sabloff, Mitchell
    Univ Ottawa, Dept Med, Div Hematol, Ottawa, ON, Canada.;Ottawa Hosp, Res Inst, Ottawa, ON, Canada..
    Schouten, Harry C.
    Acad Hosp Maastricht, Dept Hematol, Maastricht, Netherlands..
    Shea, Thomas C.
    Univ North Carolina Hlth Care, Dept Med, Div Hematol & Oncol, Chapel Hill, NC USA..
    Soiffer, Robert J.
    Dana Farber Canc Inst, Dept Med Oncol, Ctr Hematol Oncol, Boston, MA 02115 USA..
    Uy, Geoffrey L.
    Washington Univ, Sch Med, Div Oncol, St Louis, MO USA..
    Waller, Edmond K.
    Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA..
    Wiernik, Peter H.
    Our Lady Mercy Med Ctr, Bronx, NY USA..
    Wirk, Badeep
    Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA..
    Woolfrey, Ann E.
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA..
    Bunjes, Donald
    Ulm Univ Hosp, Dept Internal Med 3, Ulm, Germany..
    Devine, Steven
    Ohio State Univ, Dept Internal Med, Comprehens Canc Ctr James, Columbus, OH 43210 USA..
    de Lima, Marcos
    Univ Hosp Case Med Ctr, Seidman Canc Ctr, Dept Med, Cleveland, OH USA..
    Sandmaier, Brenda M.
    Univ Washington, Div Med Oncol, Seattle, WA 98195 USA.;Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA..
    Weisdorf, Dan
    Natl Marrow Donor Program Be Match, Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA..
    Khoury, Hanna Jean
    Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA..
    Saber, Wael
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Does FLT3 Mutation Impact Survival After Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia?: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis2016In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 122, no 19, p. 3005-3014Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT). METHODS: Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes. RESULTS: In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20). CONCLUSIONS: The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors.

  • 147.
    Dhanraj, Santhosh
    et al.
    Univ Toronto, Inst Med Sci, Toronto, ON, Canada.;Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Gunja, Sethu Madhava Rao
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Deveau, Adam P.
    IWK Hlth Ctr, Dept Pediat, Halifax, NS, Canada..
    Nissbeck, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Boonyawat, Boonchai
    Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Coombs, Andrew J.
    IWK Hlth Ctr, Dept Pediat, Halifax, NS, Canada..
    Renieri, Alessandra
    Univ Siena, Med Genet, I-53100 Siena, Italy..
    Mucciolo, Mafalda
    Univ Siena, Med Genet, I-53100 Siena, Italy..
    Marozza, Annabella
    Univ Siena, Med Genet, I-53100 Siena, Italy..
    Buoni, Sabrina
    Univ Siena, Pediat Neurol, Siena, Italy..
    Turner, Lesley
    Mem Univ Newfoundland, Discipline Genet, St John, NF, Canada..
    Li, Hongbing
    Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Jarrar, Ameer
    IWK Hlth Ctr, Dept Pediat, Halifax, NS, Canada..
    Sabanayagam, Mathura
    Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Kirby, Melanie
    Hosp Sick Children, Dept Pediat, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada..
    Shago, Mary
    Hosp Sick Children, Dept Paediat, Lab Med, Cytogenet Lab, Toronto, ON, Canada..
    Pinto, Dalila
    Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Psychiat, New York, NY USA.;Mt Sinai Sch Med, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr, Dept Genet & Genom Sci, New York, NY USA..
    Berman, Jason N.
    Dalhousie Univ, IWK Hlth Ctr, Pediat, Microbiol & Immunol, Halifax, NS, Canada..
    Scherer, Stephen W.
    Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada..
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Dror, Yigal
    Univ Toronto, Inst Med Sci, Toronto, ON, Canada.;Hosp Sick Children, Genet & Genome Biol Program, Toronto, ON, Canada.;Hosp Sick Children, Dept Pediat, Div Hematol Oncol, Marrow Failure & Myelodysplasia Program, Toronto, ON M5G 1X8, Canada..
    Bone Marrow Failure and Developmental Delay Caused By Mutations in Poly(A)-Specific Ribonuclease2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 148. Dignass, Axel U
    et al.
    Gasche, Christoph
    Bettenworth, Dominik
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Danese, Silvio
    Gisbert, Javier P
    Gomollon, Fernando
    Iqbal, Tariq
    Katsanos, Konstantinos
    Koutroubakis, Ioannis
    Magro, Fernando
    Savoye, Guillaume
    Stein, Jürgen
    Vavricka, Stephan
    European Consensus on the Diagnosis and Management of Iron Deficiency and Anaemia in Inflammatory Bowel Diseases2015In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 9, no 3, p. 211-222Article in journal (Refereed)
  • 149.
    Dolinska, Monika
    et al.
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Klang, Johannis
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Xiao, Pingnan
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Durgaryan, Andranik
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Sandhow, Lakshmi
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Johansson, Anne-Sofie
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Kondo, Makoto
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Deneberg, Stefan
    Karolinska Univ Hosp, Ctr Hematol, Stockholm, Sweden..
    Ungerstedt, Johanna
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Le Blanc, Katarina
    Karolinska Inst, Lab Med Clin Immunol, Stockholm, Sweden..
    Stenke, Leif
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Ekblom, Marja
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Lehmann, Soren
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Qian, Hong
    Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med, Stockholm, Sweden..
    Phenotypic and Functional Alterations of Bone Marrow Mesenchymal Stem and Progenitor Cells in Chronic Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 150.
    Dolinska, Monika
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Piccini, Alexandre
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Wong, Wan Man
    Lund Univ, Dept Lab Med, Lund, Sweden..
    Gelali, Eleni
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Johansson, Anne-Sofie
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Klang, Johannis
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Xiao, Pingnan
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Yektaei-Karin, Elham
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Strömberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Clin Chem & Hematol, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland..
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ekblom, Marja
    Lund Univ, Dept Lab Med, Lund, Sweden..
    Qian, Hong
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, SE-14186 Stockholm, Sweden..
    Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34 (+)CD38(-) stem and progenitor cells in chronic myeloid leukemia2017In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 490, no 2, p. 378-384Article in journal (Refereed)
    Abstract [en]

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

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