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  • 101.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Besses, C.
    Hosp del Mar, IMIM, Dept Haematol, Barcelona, Spain..
    Griesshammer, M.
    Johannes Wesling Med Ctr, Hematol & Oncol, Minden, Germany..
    Gugliotta, L.
    St Orsola Malpighi Hosp, Dept Haematol, L&A Seragnoli, Bologna, Italy..
    Harrison, C.
    Guys & St Thomas NHS Fdn Trust, Dept Haematol, London, England..
    Hamdani, M.
    Shire Pharmaceut, Global Biometr, Wayne, PA USA..
    Achenbach, H.
    Shire AG, Res & Dev, Eysins, Switzerland..
    Kiladjian, J-J
    Hop St Louis, APHP, Ctr Invest Clin, Paris, France..
    Treatment of high risk ET: data from the EXELS study2016In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 44, p. S7-S8Article in journal (Other academic)
  • 102.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Besses, Carlos
    Griesshammer, Martin
    Gugliotta, Luigi
    Harrison, Claire N.
    Hamdani, Mohamed
    Achenbach, Heinrich
    Kiladjian, Jean-Jacques
    Treatment of Essential Thrombocythemia in Europe: An Observational Study of 3649 High-Risk Patients in Exels2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 103.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Besses, Carlos
    Griesshammer, Martin
    Gugliotta, Luigi
    Harrison, Claire N
    Hamdani, Mohamed
    Wu, Jingyang
    Achenbach, Heinrich
    Kiladjian, Jean-Jacques
    Treatment of essential thrombocythemia in Europe: a prospective long-term observational study of 3649 high-risk patients in the Evaluation of Anagrelide Efficacy and Long-term Safety study2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 1, p. 51-60Article in journal (Refereed)
    Abstract [en]

    Evaluation of Anagrelide (Xagrid (R)) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia patients treated with cytoreductive therapy. The primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: anagrelide (Xagrid (R)) (n=804), other cytoreductive therapy (n=2666), or anagrelide + other cytoreductive therapy (n=141). The median age was 56 vs. 70 years for anagrelide vs. other cytoreductive therapy. Event rates (patients with events/100 patient-years) were 1.62 vs. 2.06 for total thrombosis and 0.15 vs. 0.53 for venous thrombosis. Anagrelide was more commonly associated with hemorrhage (0.89 vs. 0.43), especially with anti-aggregatory therapy (1.35 vs. 0.33) and myelofibrosis (1.04 vs. 0.30). Other cytoreductive therapies were more associated with acute leukemia (0.28 vs. 0.07) and other malignancies (1.29 vs. 0.44). Post hoc multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age >= 65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age >= 65, time since diagnosis, and platelet count increase. Safety analysis reflected published data, and no new safety concerns for anagrelide were found. Live births occurred in 41/54 pregnancies (76%).

  • 104. Birgegård, Gunnar
    et al.
    Björkholm, Magnus
    Kutti, Jack
    Larfars, Gerd
    Löfvenberg, Eva
    Markevärn, Berit
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Merup, Mats
    Palmblad, Jan
    Mauritzson, Nils
    Westin, Jan
    Samuelsson, Jan
    Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders.2004In: Haematologica, ISSN 1592-8721, Vol. 89, no 5, p. 520-7Article in journal (Refereed)
  • 105.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Folkvaljon, Folke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Fac Life Sci & Med, London, England.
    Besses, Carlos
    Hosp del Mar, IMIM, Dept Haematol, Barcelona, Spain.
    Griesshammer, Martin
    Johannes Wesling Med Ctr, Hematol & Oncol, Minden, Germany.
    Gugliotta, Luigi
    St Orsola Malpighi Hosp, Dept Haematol L&A Seragnoli, Bologna, Italy.
    Wu, Jingyang
    Shire Pharmaceut, Global Biometr, Lexington, MA USA.
    Achenbach, Heinrich
    Shire GmbH, Res & Dev, Zug, Switzerland.
    Kiladjian, Jean-Jacques
    St Louis Hosp, APHP, Clin Invest Ctr, Paris, France.
    Harrison, Claire N.
    Guys & St Thomas NHS Fdn Trust, Dept Haematol, London, England.
    Leukemic transformation and second cancers in 3649 patients with high-risk essential thrombocythemia in the EXELS study2018In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 74, p. 105-109Article in journal (Refereed)
    Abstract [en]

    EXELS, a post-marketing observational study, is the largest prospective study of high-risk essential thrombocythemia (ET) patients, with an observation time of 5 years. EXELS found higher event rates of acute leukemia transformation in patients treated with hydroxycarbamide (HC). In the current analysis, we report age-adjusted rates of malignant transformation from 3460 EXELS patients exposed to HC, anagrelide (ANA), or both. At registration, 481 patients had ANA treatment without HC exposure, 2305 had HC without ANA exposure, and 674 had been exposed to both. Standard incidence ratios (SIRs) were calculated using data from the Cancer Incidence in Five Continents database to account for differences in age-, gender-, and country-specific background rates. SIRs for acute myelogenous leukemia (AML) were high in ET patients. SIRs for AML were high in HC-treated patients, but AML was rare in ANA-treated patients; no cases of AML were found in patients only treated with ANA. No statistically significant difference was seen between SIRs for ANA and HC treatment for AML or skin cancer. SIRs for other cancers were similar in the HC and ANA groups and close to 1, indicating little difference in risk. Although statistically inconclusive, this study strengthens concerns regarding possible leukemogenic risk with HC treatment. (NCT00202644)

  • 106.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Folkvaljon, Y.
    Reg Canc Ctr, Uppsala, Sweden..
    Garmo, H.
    Reg Canc Ctr, Uppsala, Sweden..
    Besses, C.
    Hosp Mar IMIM, Dept Haematol, Barcelona, Spain..
    Griesshammer, M.
    Johannes Wesling Med Ctr, Hematol & Oncol, Minden, Germany..
    Gugliotta, L.
    St Orsola Malpighi Hosp, Dept Haematol L&A Seragnoli, Bologna, Italy..
    Harrison, C.
    Guys & St Thomas NHS Fdn Trust, Dept Haematol, London, England..
    Hamdani, M.
    Shire Pharmaceut, Global Biometr, Lexington, MA USA..
    Wu, J.
    Shire Pharmaceut, Global Biometr, Lexington, MA USA..
    Achenbach, H.
    Shire GmbH, Res & Dev, Zug, Switzerland..
    Kiladjian, J. J.
    Hop St Louis, APHP, Ctr Invest Clin, Paris, France..
    Rate Of Malignant Transformation In High Risk Et During 5 Years Of Follow-Up Of Cytoreductive Therapy2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 96-96Article in journal (Other academic)
  • 107.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Folkvaljon, Yasin
    Uppsala Univ Hosp, Reg Canc Ctr, Uppsala, Sweden.
    Garmo, Hans
    Uppsala Univ Hosp, Reg Canc Ctr, Uppsala, Sweden.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Fac Life Sci & Med, London, England.
    Besses, C.
    Hosp Mar IMIM, Dept Haematol, Barcelona, Spain.
    Griesshammer, M.
    Johannes Wesling Med Ctr, Hematol & Oncol, Minden, Germany.
    Gugliotta, L.
    St Orsola Malpighi Hosp, Dept Haematol, Bologna, Italy.
    Wu, J.
    Shire Pharmaceut, Global Biometr, Lexington, MA USA.
    Achenbach, H.
    Shire GmBH, Res & Dev, Zug, Switzerland.
    Kiladjian, J. -J
    Harrison, C. N.
    Guys & St Thomas NHS Fdn Trust, Dept Haematol, London, England.
    LEUKEMIC TRANSFORMATION AND SECOND CANCERS IN 3649 HIGH RISK ET PATIENTS IN THE EXELS STUDY2017In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no Suppl. 2, p. 282-282, article id P704Article in journal (Other academic)
  • 108.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Henry, David
    Penn Hosp, Joan Karnell Canc Ctr, Philadelphia, PA 19107 USA..
    Glaspy, John
    Univ Calif Los Angeles, Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90024 USA..
    Chopra, Rakesh
    Indraprastha Apollo Hosp, New Delhi, India..
    Thomsen, Lars L.
    Pharmacosmos AS, Dept Clin & Nonclin Res, Holbaek, Denmark..
    Auerbach, Michael
    Georgetown Univ, Sch Med, Washington, DC USA..
    A Randomized Noninferiority Trial of Intravenous Iron Isomaltoside versus Oral Iron Sulfate in Patients with Nonmyeloid Malignancies and Anemia Receiving Chemotherapy: The PROFOUND Trial2016In: Pharmacotherapy, ISSN 0277-0008, E-ISSN 1875-9114, Vol. 36, no 4, p. 402-414Article in journal (Refereed)
    Abstract [en]

    Study ObjectiveA safe alternative to erythropoiesis-stimulating agents to treat anemia is warranted in patients with cancer and anemia; thus the objective of this trial was to compare the efficacy and safety of intravenous (IV) iron isomaltoside with oral iron in patients with cancer and anemia by testing the noninferiority of IV versus oral iron. DesignPhase III, prospective, open-label, comparative, randomized, noninferiority, multicenter trial. SettingForty-seven hospitals or private cancer clinics in Asia, the United States, and Europe. PatientsA total of 350 patients with cancer and anemia. InterventionPatients were randomized in a 2:1 ratio to either intravenous iron isomaltoside or oral iron sulfate. Patients in the iron isomaltoside group were then randomized into an infusion subgroup (single intravenous infusions of a maximum dose of 1000 mg over 15 min) or a bolus injection subgroup (bolus injections of 500 mg over 2 min). Measurements and Main ResultsThe primary efficacy outcome was change in hemoglobin concentration from baseline to week 4. Changes in other relevant hematology variables, effect on quality of life, and safety outcomes were also assessed. The primary efficacy outcome was tested for noninferiority, whereas the remaining outcomes were tested for superiority. Iron isomaltoside was noninferior to oral iron in change in hemoglobin concentration from baseline to week 4 (difference estimate 0.016, 95% confidence interval -0.26 to 0.29, p<0.001). A faster onset of the hemoglobin response was observed with infusion of iron isomaltoside (superiority test: p=0.03 at week 1), and a sustained effect on hemoglobin level was shown in both the iron isomaltoside and oral iron treatment groups until week 24. A significant mean decrease in fatigue score was observed from baseline to week 12 in the iron isomaltoside group (p<0.001) but not in the oral iron group (p=0.057). A higher proportion of patients treated with oral iron experienced adverse drug reactions (18.8% vs 6.6%, p<0.001) and discontinued the trial due to intolerance (8.0% vs 0.9%, p=0.001). Transient hypophosphatemia (phosphate level less than 2 mg/dl) was reported at similar low frequencies among the groups: 7.1% in the iron isomaltoside infusion subgroup versus 8.5% in the iron isomaltoside bolus injection subgroup versus 5.4% in the oral iron group. ConclusionThis trial demonstrated comparable sustained increases in hemoglobin concentration over time with both iron isomaltoside and oral iron. Iron isomaltoside was better tolerated than oral iron, and fatigue was significantly decreased with iron isomaltoside. Low rates of clinically insignificant hypophosphatemia were reported in patients receiving both treatments.

  • 109.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Samuelsson, Jan
    Univ Hosp Linkoping, Dept Hematol, Linkoping, Sweden.
    Ahlstrand, Erik
    Orebro Univ, Fac Med & Hlth, Dept Med, Orebro, Sweden.
    Ejerblad, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Enevold, Christian
    Copenhagen Univ Hosp, Inst Inflammat Res, Copenhagen, Denmark.
    Ghanima, Waleed
    Ostfold Hosp, Dept Res, Sarpsborg, Norway.
    Hasselbalch, Hans
    Zealand Univ Hosp, Dept Hematol, Roskilde, Denmark.
    Nielsen, Claus H.
    Zealand Univ Hosp, Dept Hematol, Roskilde, Denmark.
    Knutsen, Håvar
    Ulleval Hosp, Dept Hematol, Oslo, Norway.
    Pedersen, Ole B.
    Naestved Hosp, Dept Clin Immunol, Naestved, Denmark.
    Sörensen, Anders
    Copenhagen Univ Hosp, Inst Inflammat Res, Copenhagen, Denmark;Zealand Univ Hosp, Dept Hematol, Roskilde, Denmark.
    Andreasson, Björn
    NU Hosp Grp, Hematol Sect, Specialist Med, Uddevalla, Sweden.
    Inflammatory functional iron deficiency common in myelofibrosis, contributes to anaemia and impairs quality of life. From the Nordic MPN study Group2019In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 102, no 3, p. 235-240Article in journal (Refereed)
    Abstract [en]

    Objectives: The study investigates the hypothesis that inflammation in myelofibrosis (MF) like in myeloma and lymphoma, may disturb iron distribution and contribute to anaemia.

    Methods: A cross-sectional study of 80 MF and 23 ET patients was performed.

    Results: About 35% of anaemic MF patients had functional iron deficiency (FID) with transferrin saturation <20 and normal or elevated S-ferritin (<500 mu g/L). In ET, FID was rare. In MF patients with FID, 70.6% were anaemic, vs 29.4% in patients without FID (P = 0.03). Hepcidin was significantly higher in MF patients with anaemia, including transfusion-dependent patients, 50.6 vs 24.4 mu g/L (P = 0.01). There was a significant negative correlation between Hb and inflammatory markers in all MF patients: IL-2, IL-6 and TNF-alpha, (P < 0.01-0.03), LD (P = 0.004) and hepcidin (P = 0.03). These correlations were also seen in the subgroup of anaemic MF patients (Table ). Tsat correlated negatively with CRP (P < 0.001). Symptom burden was heavier in MF patients with FID, and MPN-SAF quality of life scores correlated with IL-6 and CRP.

    Conclusions: The inflammatory state of MF disturbs iron turnover, FID is common and contributes to anaemia development and impairment of QoL. Anaemic MF patients should be screened for FID.

  • 110.
    Bjerrum, Ole Weis
    et al.
    Rigshosp, Denmark.
    Samuelsson, Jan
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Ghanima, Waleed
    Univ Oslo, Norway; Univ Oslo, Norway.
    Kauppila, Marjut
    Turku Univ Hosp, Finland.
    Andersen, Christen Lykkegaard
    Rigshosp, Denmark; Roskilde Hosp, Denmark.
    Thromboembolism prophylaxis in patients with Philadelphia-negative myeloproliferative neoplasms-Clinical practice among Nordic specialists2018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 5, p. 475-478Article in journal (Refereed)
    Abstract [en]

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

  • 111.
    Bjorck, Fredrik
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Sundsvall, Sweden..
    Sanden, Per
    Umea Univ, Dept Publ Hlth & Clin Med, Sundsvall, Sweden..
    Renlund, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Svensson, Peter J.
    Lund Univ, Dept Coagulat Disorders, Malmo, Sweden..
    Sjalander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, Sundsvall, Sweden..
    Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 2, p. 216-220Article in journal (Refereed)
    Abstract [en]

    Background: Warfarin treatment in Sweden holds a high standard with time in therapeutic range (TTR) over 75%. Internationally, specialized anticoagulation clinics (ACC) have shown higher TTR compared to primary health care centres (PHCC). Objectives: To compare warfarin treatment quality in Sweden for ACC versus PHCC, thereby clarifying whether centralization is for the better. Patients/methods: In total 77.058 patients corresponding to 217.058 treatment years with warfarin in the Swedish national quality register AuriculA from 1. Jan 2006 to 31. Dec 2011. Information regarding TTR was calculated from AuriculA, while patient characteristics and complications were retrieved from the Swedish National Patient Register. Results: Of the 100.554 treatment periods examined, 78.7% were monitored at ACC. Mean TTR for INR 2-3 for all patients irrespective of intended target range was 76.5% with an annual risk of bleeding or thrombotic events of 2.24% and 2.66%, respectively. TTR was significantly higher in PHCC compared to ACC (79.6% vs. 75.7%, p < 0.001), with no significant difference in overall risk of complications. Treatment periods for atrial fibrillation, except intended direct current conversion, showed similar results between ACC and PHCC without significant difference in annual risk of bleeding (2.50% vs. 2.51%) or thrombosis (3.09% vs. 3.16%). After propensity score matching there was still no significant difference in complication risk found. Conclusions: Warfarin treatment quality is consistently high in both ACC and PHCC when monitored through AuriculA in Sweden, both measured as TTR and as risk of complications. In this setting, centralized warfarin monitoring is not likely to improve the results.

  • 112. Bjorklund, Andreas T.
    et al.
    Carlsten, Mattias
    Schaffer, Marie
    Liu, Lisa
    Cooley, Sarah A.
    Miller, Jeffrey S.
    Watz, Emma
    Palma, Marzia
    Hansson, Lotta
    Wahlin, Bjorn E.
    Mollgard, Lars
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Blomberg, Pontus
    Ljungman, Per T.
    Hellstrom-Lindberg, Eva
    Ljunggren, Hans-Gustaf
    Malmberg, Karl-Johan
    Early and Transient Microchimerism Associated with Complete Remission after Adoptively Transferred Haploidentical NK Cells Against High Risk Myelodysplastic Syndrome and Refractory Acute Myeloid Leukemia2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 113.
    Björck, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Warfarin treatment quality in stroke prevention2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

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

    Methods

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

    Results

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

    Conclusions

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

  • 114.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ek, Agnes
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Warfarin persistence among atrial fibrillation patients – why is treatment ended?2016In: Cardiovascular Therapeutics, ISSN 1755-5914, Vol. 34, no 6, p. 468-474Article in journal (Refereed)
    Abstract [en]

    Background and Aim

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

    Methods

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

    Results

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

    Conclusions

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

  • 115.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Kadhim, Hayder
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Predictors for INR-control in a well-managed warfarin treatment setting2019In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 47, no 2, p. 227-232Article in journal (Refereed)
    Abstract [en]

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

  • 116.
    Björck, Fredrik
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Renlund, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Svensson, Peter J.
    Lund Univ, Dept Coagulat Disorders, Malmö, Sweden..
    Själander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Warfarin persistence among stroke patients with atrial fibrillation2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 4, p. 744-748Article in journal (Refereed)
    Abstract [en]

    Introduction: Warfarin treatment discontinuation is significant among patients with atrial fibrillation (AF). For AF patients with stroke a warfarin persistence rate of 0.45 after 2 years has previously been reported. No consistent predictors for discontinuation have been established. Aims: Evaluation of warfarin persistence and variables associated with discontinuation, in a large Swedish cohort with unselected stroke/TIA patients with AF treated with warfarin. Materials and methods: 4 583 patients with stroke/TIA and AF in the Swedish National Patient Register (NPR), from 1. Jan 2006 to 31. Dec 2011, were matched with the Swedish national quality register AuriculA. They were followed until treatment cessation, death or end of study. Baseline characteristics and CHA(2)DS(2)VASc score were retrieved from NPR. Treatment-time was retrieved from AuriculA. Results: Overall proportion of warfarin persistence was 0.78 (95% confidence interval (CI) 0.76 to 0.80) after one year, 0.69 (95% CI 0.67 to 0.71) after 2 years and 0.47 (95% CI 0.43 to 0.51) after 5 years. Variables clearly associated with higher discontinuation were dementia (hazard ratio (HR) 2.22, CI 1.51-3.27) and alcohol abuse (HR 1.66, CI 1.19-2.33). Chronic obstructive pulmonary disease (COPD), cancer and chronic heart failure (CHF) were each associated with over 20% increased risk of treatment discontinuation. Higher CHA(2)DS(2)VASc score and start-age lead to lower persistence (p < 0.001). Conclusions: Persistence to warfarin in unselected stroke/TIA patients with AF is in Sweden greater than previously reported. Lower persistence is found among patients with high treatment start-age, incidence of dementia, alcohol abuse, cancer, CHF, COPD and/or high CHA(2)DS(2)VASc score.

  • 117.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renlund, Henrik
    Svensson, Peter J
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Warfarin persistence among stroke patients with atrial fibrillation2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 4, p. 744-748Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 118.
    Björck, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sandén, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renlund, Henrik
    Svensson, Peter J
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Warfarin treatment quality is consistently high in both anticoagulation clinics and primary care setting in Sweden2015In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 136, no 2, p. 216-220Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 119.
    Björkholm, Magnus
    et al.
    Karolinska Univ Hosp, Dept Med, Div Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Bower, Hannah
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Dickman, Paul W.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lambert, Paul C.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Andersson, Therese M-L
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Temporal Trends in Chronic Myeloid Leukemia Outcome Using the Loss in Expectation of Life: A Swedish Population-Based Study2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 120.
    Björkholm, Magnus
    et al.
    Karolinska Univ Hosp Solna, Dept Med, Div Hematol, Stockholm, Sweden;Karolinska Inst, Stockholm, Sweden.
    Weibull, Caroline E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Eloranta, Sandra
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden;Karolinska Univ Hosp Solna, Stockholm, Sweden.
    Smedby, Karin E.
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden;Karolinska Univ Hosp Solna, Stockholm, Sweden.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden;Karolinska Univ Hosp Solna, Stockholm, Sweden.
    Dickman, Paul W.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Greater attention should be paid to developing therapies for elderly patients with Hodgkin lymphoma: A population-based study from Sweden2018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 101, no 1, p. 106-114Article in journal (Refereed)
    Abstract [en]

    Objective: Forty percent of Hodgkin lymphoma (HL) patients are older than 50years at diagnosis, a fact which is not commonly recognized. Older patients do significantly worse than younger patients and are rarely included in clinical trials.

    Methods: Using data from Swedish Cancer and Lymphoma Registries, we estimated relative survival ratios (RSRs) for 7997 HL patients (diagnosed 1973-2013; 45% 50years).

    Results: The 1-year RSRs (95% confidence interval; CI) for males aged 45-59, 60-69, 70-80, and 81years and over, diagnosed in 2013, were 0.95 (0.91-0.97), 0.88 (0.81-0.92), 0.74 (0.63-0.81), and 0.52 (0.35-0.67), respectively. The corresponding 1-year RSRs for females were 0.97 (0.94-0.98), 0.91 (0.85-0.95), 0.82 (0.73-0.88), and 0.66 (0.50-0.77). No improvements in 1-year of 5-year relative survival from 2000 to 2013 were observed for patients aged 45-59 or 60-69 but there were modest improvements for patients aged 70years and older. Importantly, we saw no changes in the distribution of disease or patient characteristics between 2000 and 2013.

    Conclusions: Elderly patients constitute a large group with clearly unmet medical needs. Our findings motivate a more active approach to including elderly patients in clinical trials. Our study provides a baseline for outcome comparison after the broader introduction of targeted drugs.

  • 121.
    Björnsson, Jon Mar
    et al.
    Lund University, Department of Molecular Medicine.
    Larsson, Nina
    Lund University, Department of Molecular Medicine.
    Brun, Ann C. M.
    Lund University, Department of Molecular Medicine.
    Andersson, Elisabet
    Lund University, Department of Molecular Medicine.
    Lundström, Patrik
    Lund University, Department of Molecular Medicine.
    Larsson, Jonas
    Lund University, Department of Molecular Medicine.
    Repetowska, Ewa
    Lund University, Department of Molecular Medicine.
    Ehinger, Mats
    Lund University, Department of Molecular Medicine.
    Humphries, R. Keith
    University of British Columbia, Department of Medicine.
    Karlsson, Stefan
    Lund University, Department of Molecular Medicine.
    Reduced proliferative capacity of hematopoietic stem cells deficient in hoxb3 and hoxb42003In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 23, no 11, p. 3872-3883Article in journal (Refereed)
    Abstract [en]

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

  • 122.
    Blanco, G.
    et al.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Puiggros, A.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Athanasiadou, A.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Garcia-Malo, M. D.
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Collado, R.
    Consorcio Hosp Gen Univ, Serv Hematol, Valencia, Spain..
    Xochelli, A.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Rodriguez-Rivera, M.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Ortega, M.
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Calasanz, M. J.
    Univ Navarra, Dept Genet, Serv Citogenet, Pamplona, Spain..
    Luno, E.
    Hosp Univ Cent Asturias, Serv Hematol, Oviedo, Spain..
    Vargas, M. T.
    Hosp Univ Virgen de la Macarena, Seville, Spain..
    Grau, J.
    Univ Autonoma Barcelona, Inst Recerca Leucemia Josep Carreras IJC, ICO Hosp Germans Trias & Pujol, Serv Lab Hematol, Badalona, Spain..
    Martinez-Laperche, C.
    Hosp GU Gregorio Maranon, Serv Hematol, Lab Genet Hematol, Madrid, Spain.;Inst Invest Sanitaria Gregorio Maranon, Madrid, Spain..
    Valiente, A.
    Complejo Hospitalario Navarra, Serv Genet, Pamplona, Spain.;Complejo Hospitalario Navarra, Serv Hematol, Pamplona, Spain..
    Papaioannou, G.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Cervera, J.
    Hosp Univ La Fe, Unidad Genet, Valencia, Spain..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Pinan, M. A.
    Hosp Cruces, Serv Hematol, Bilbao, Spain..
    Stalika, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Hernandez-Rivas, J. M.
    Univ Salamanca, Hosp Univ Salamanca, Ctr Invest Canc, IBSAL,IBMCC,CSIC,Serv Hematol, Salamanca, Spain..
    Batlle, A.
    Hosp Univ Marques de Valdecilla, Serv Hematol, Santander, Spain..
    Salido, M.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Ortuno, F.
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Melero, C.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Robles, D.
    Hosp Txagorritxu, Serv Hematol, Vitoria, Spain..
    Ferrer, A.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Ivars, D.
    Consorcio Hosp Gen Univ, Serv Hematol, Valencia, Spain..
    Rodriguez, A.
    Hosp Univ Virgen de la Macarena, Seville, Spain..
    Gonzalez, M.
    Univ Salamanca, Hosp Univ Salamanca, Ctr Invest Canc, IBSAL,IBMCC,CSIC,Serv Hematol, Salamanca, Spain..
    Bosch, F.
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Abrisqueta, P.
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Stamatopoulos, K.
    G Papanicolaou Hosp, Inst Appl Biosci, CERTH, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, Inst Appl Biosci, CERTH, HCT Unit, Thessaloniki, Greece..
    Espinet, B.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Chromosome 8 Abnormalities Are Associated With An Even Worse Outcome And Karyotype Complexity In Patients With Chronic Lymphocytic Leukemia And Tp53 Aberrations2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 229-230Article in journal (Other academic)
  • 123. Blimark, Cecilie Hveding
    et al.
    Turesson, Ingemar
    Genell, Anna
    Ahlberg, Lucia
    Björkstrand, Bo
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Forsberg, Karin
    Juliusson, Gunnar
    Linder, Olle
    Mellqvist, Ulf-Henrik
    Nahi, Hareth
    Kristinsson, Sigurdur Y
    Outcome and survival of myeloma patients diagnosed 2008-2015. Real world data on 4904 patients from the Swedish Myeloma Registry (SMR)2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 3, p. 506-513Article in journal (Refereed)
    Abstract [en]

    Epidemiology and outcome of myeloma is mainly reported from large university centers and collaborative groups and do not represent real world patients. The Swedish Myeloma Registry is a prospective population-based registry documenting characteristics, treatments and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose to improve the management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first line treatment up to 2014, with a follow-up until December 2016. We present age-adjusted incidence, patient characteristics at baseline, treatment, response, and survival. Baseline data was available with a 97% coverage in 4,904 patients (median age 71 years, males 70 years, females 73 years, 72% were 65 years or older), and one-year follow-up of 3,558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100 000 inhabitants and year. Among initially symptomatic patients (n=3,988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients up to 66 years, and to 22% of patients 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first line treatment, rising from 31% in 2008 to 81% 2014. In MM, the median relative survival of patients 65 years or younger was 7.7 years, and 3.4 years in 66 years and older. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (p<0.05), and with a significant higher overall survival with a HR of 0.84 (95% CI 0.77-0.92; p< 0.05). There was small, but significant survival benefit in patients treated in university hospitals (HR 0.93; 95% CI 0.87-0.99, p<0.05). Analysis of progression-free survival has to await collection of additional follow-up data. We here report on a near complete real world population of myeloma patients during an 8-year period, when newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden compare to other large registry studies and responses and survival improved during the study period.

  • 124.
    Blimark, Cecilie Hveding
    et al.
    Univ Gothenburg, Sweden; Skane Univ Hosp, Sweden.
    Turesson, Ingemar
    Skåne University Hospital, Lund-Malmö, Sweden.
    Genell, Anna
    Western Sweden Hlth Care Reg, Sweden.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Björkstrand, Bo
    Karolinska Inst, Sweden.
    Carlson, Kristina
    Uppsala Univ Hosp, Sweden.
    Forsberg, Karin
    Umeå Univ Hosp, Sweden.
    Juliusson, Gunnar
    Lund Univ, Sweden.
    Linder, Olle
    Örebro Univ Hosp, Sweden.
    Mellqvist, Ulf-Henrik
    Univ Gothenburg, Sweden; Skane Univ Hosp, Sweden; Boras Hosp, Sweden.
    Nahi, Hareth
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Kristinsson, Sigurdur Y.
    Karolinska Inst, Sweden; Univ Iceland, Iceland; Karolinska Univ Hosp, Sweden.
    Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish Myeloma Registry2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 3, p. 506-513Article in journal (Refereed)
    Abstract [en]

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

  • 125.
    Bochennek, K.
    et al.
    Univ Hosp Frankfurt, Pediat Hematol & Oncol, Frankfurt, Germany..
    Dantonello, T.
    Olgahosp Klinikum Stuttgart, Cooperat Weichteilsarkom Studie CWS Study Ctr, Stuttgart, Germany..
    Borkhardt, A.
    Univ Hosp Duesseldorf, Pediat Hematol & Oncol, Dusseldorf, Germany..
    Dirksen, U.
    Univ Hosp Muenster, Pediat Oncol & Hematol, Munster, Germany..
    Eggert, A.
    Charite, Pediat Hematol & Oncol, D-13353 Berlin, Germany..
    Greiner, J.
    Ostschweizer Sauglings & Kinderspital, Ctr Pediat Hematol & Oncol, CH-9007 St Gallen, Switzerland..
    Handgretinger, R.
    Univ Hosp, Tubingen, Germany.;Fac Med Tuebingen, Genereal Pediat Hematol & Oncol, Tubingen, Germany..
    Kazanowska, B.
    Univ Hosp Wroclaw, Dept Pediat Bone Marrow Transplantat Oncol & Hema, Wroclaw, Poland..
    Kratz, C.
    Hannover Med Sch, Pediat Hematol & Oncol, Hannover, Germany..
    Ladenstein, R.
    St Anna Childrens Hosp, CCRI, Vienna, Austria..
    Ljungman, Gustaf
    Childrens Univ Hosp Uppsala, Dept Pediat Hematol & Oncol, Uppsala, Sweden..
    Hallmen, E.
    Olgahosp Klinikum Stuttgart, Cooperat Weichteilsarkom Studie CWS Study Ctr, Stuttgart, Germany..
    Koscielniak, E.
    Olgahosp Klinikum Stuttgart, Cooperat Weichteilsarkom Studie CWS Study Ctr, Stuttgart, Germany..
    Klingebiel, T.
    Univ Hosp Frankfurt, Pediat Hematol & Oncol, Frankfurt, Germany..
    Better Outcome With Maintenance Therapy: Pediatric Patients With Stage Iv Soft Tissue Sarcoma Benefit From Long Term Therapy Compared To Sct Or No Further Therapy2015In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 62, p. S152-S152Article in journal (Other academic)
  • 126.
    Boknäs, N.
    et al.
    Linköping University, Linköping, Sweden.
    Faxälv, L.
    Linköping University, Linköping, Sweden.
    Ramström, Sofia
    LLinköping University, Linköping, Sweden.
    Lindahl, T.
    Linköping University, Linköping, Sweden.
    Thrombin generation in plasma measured with a commercial reagent for the detection of microparticle-derived tissue factor is heavily influenced by contact activation2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no S1, p. 401-402Article in journal (Refereed)
  • 127.
    Boknäs, Niklas
    et al.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Faxälv, Lars
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Sanchez Cenellas, Daniel
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Wallstedt, Maria
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Grenegård, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Lindahl, Tomas L.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Thrombin-induced platelet activation via PAR4: pivotal role for exosite II2014In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, no 3, p. 558-565Article in journal (Refereed)
    Abstract [en]

    Thrombin-induced platelet activation via PAR1 and PAR4 is an important event in haemostasis. Although the underlying mechanisms responsible for ensuring efficient PAR1 activation by thrombin have been extensively studied, the potential involvement of recognitions sites outside the active site of the protease in thrombin-induced PAR4 activation is largely unknown. In this study, we developed a new assay to assess the importance of exosite I and II for PAR4 activation with alpha- and gamma-thrombin. Surprisingly, we found that exosite II is critical for activation of PAR4. We also show that this dependency on exosite II likely represents a new mechanism, as it is unaffected by blockage of the previously known interaction between thrombin and glycoprotein Ib alpha.

  • 128.
    Boknäs, Niklas
    et al.
    Linköping University, Linköping, Sweden .
    Faxälv, Lars
    Linköping University, Linköping, Sweden .
    Ström, Jakob O.
    Linköping University, Linköping, Sweden .
    Tengvall, Pentti
    University of Gothenburg, Gothenburg, Sweden.
    Theodorsson, Elvar
    Linköping University, Linköping, Sweden .
    Ramström, Sofia
    Linköping University, Linköping, Sweden .
    Lindahl, Tomas L.
    Linköping University, Linköping, Sweden .
    Platelets do not generate activated factor XII: how inappropriate experimental models have led to misleading conclusions2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 10, p. 1692-1694Article in journal (Refereed)
  • 129.
    Boknäs, Niklas
    et al.
    Department of Haematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
    Macwan, Ankit S.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Södergren, Anna L.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Cardiovascular Research Centre, Örebro University, School of Medical Sciences, Örebro, Sweden.
    Platelet function testing at low platelet counts: When can you trust your analysis?2019In: Research and Practice in Thrombosis and Haemostasis, E-ISSN 2475-0379, Vol. 3, no 2, p. 285-290Article in journal (Refereed)
    Abstract [en]

    Background: Although flow cytometry is often brought forward as a preferable method in the setting of thrombocytopenia, the relative effects of low sample counts on results from flow cytometry-based platelet function testing (FC-PFT) in comparison with light transmission aggregometry (LTA) and multiple electrode aggregometry (MEA) has not been reported.

    Objectives: To compare the effects of different sample platelet counts (10, 50, 100, and 200x10(9)L(-1)) on platelet activation measured with FC-PFT, LTA, and MEA using the same anticoagulant and agonist concentrations as for the commercial MEA test.

    Methods: Platelets were stimulated with two commonly used platelet agonists (ADP [6.5 mu molL(-1)] and PAR1-AP [TRAP, 32 mu molL(-1)]). The specified sample platelet counts were obtained by combining platelet-rich and platelet poor hirudinized plasma in different proportions with or without red blood cells.

    Results: For FC, P-selectin exposure and PAC-1 binding was reduced at 10x10(9)L(-1) after stimulation with PAR1-AP (by approximately 20% and 50%, respectively), but remained relatively unchanged when ADP was used as agonist (n=9). The platelet count-dependent effects observed with PAR1-AP were eliminated when samples were pre-incubated with apyrase, implying that reduced purinergic signaling was the main underlying factor (n=5). Both aggregometry-based PFTs showed a 50% reduction at 50x10(9)L(-1) and more than 80% reduction at 10x10(9)L(-1), irrespective of agonist used (n=7).

    Conclusions: Although FC-PFT is generally preferable to aggregometry-based PFTs in situations with low sample platelet counts, a careful optimization of experimental parameters is still required in order to eliminate platelet count-related effects.

  • 130.
    Boknäs, Niklas
    et al.
    Department of Hematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Faxälv, Lars
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Lindahl, Tomas L.
    Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Flow cytometry-based platelet function testing is predictive of symptom burden in a cohort of bleeders2018In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, no 5, p. 512-519Article in journal (Refereed)
    Abstract [en]

    Platelet function disorders (PFDs) are common in patients with mild bleeding disorders (MBDs), yet the significance of laboratory findings suggestive of a PFD remain unclear due to the lack of evidence for a clinical correlation between the test results and the patient phenotype. Herein, we present the results from a study evaluating the potential utility of platelet function testing using whole-blood flow cytometry in a cohort of 105 patients undergoing investigation for MBD. Subjects were evaluated with a test panel comprising two different activation markers (fibrinogen binding and P-selectin exposure) and four physiologically relevant platelet agonists (ADP, PAR1-AP, PAR4-AP, and CRP-XL). Abnormal test results were identified by comparison with reference ranges constructed from 24 healthy controls or with the fifth percentile of the entire patient cohort. We found that the abnormal test results are predictive of bleeding symptom severity, and that the greatest predictive strength was achieved using a subset of the panel, comparing measurements of fibrinogen binding after activation with all four agonists with the fifth percentile of the patient cohort (p = 0.00008, hazard ratio 8.7; 95% CI 2.5-40). Our results suggest that whole-blood flow cytometry-based platelet function testing could become a feasible alternative for the investigation of MBDs. We also show that platelet function testing using whole-blood flow cytometry could provide a clinically relevant quantitative assessment of platelet-related hemostasis.

  • 131.
    Borssen, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Cullman, Inger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sundstrom, Christer
    Porwit, Anna
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup2011In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, no 12, p. 1144-1151Article in journal (Refereed)
    Abstract [en]

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

  • 132.
    Borssen, Magnus
    et al.
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Haider, Zahra
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Landfors, Mattias
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Larsson, Pär
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Kanerva, Jukka
    Univ Helsinki, Cent Hosp, Childrens Hosp, Helsinki, Finland..
    Schmiegelow, Kjeld
    Univ Copenhagen, Rigshosp, Dept Paediat & Adolescent Med, Copenhagen, Denmark.;Univ Copenhagen, Inst Clin Med, Copenhagen, Denmark..
    Flaegstad, Trond
    Univ Tromso, Dept Pediat, Tromso, Norway.;Univ Hosp North Norway, Tromso, Norway..
    Jonsson, Olafur Gisli
    Landspitali Univ Hosp, Childrens Hosp, Pediat Hematol Oncol, Reykjavik, Iceland..
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Forestier, Erik
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Heyman, Mats
    Karolinska Univ Hosp, Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
    Hultdin, Magnus
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Degerman, Sofie
    Umea Univ, Dept Med Biosci, Blg 6M,2nd Floor, SE-90185 Umea, Sweden..
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia2018In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 31Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 133.
    Borssén, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schmiegelow, Kjeld
    Åsberg, Ann E.
    Kanerva, Jukka
    Madsen, Hans O.
    Marquart, Hanne
    Heyman, Mats
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Paediatrics, University Hospital of Trondheim, Norway.
    DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, p. 1185-1192Article in journal (Refereed)
    Abstract [en]

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

  • 134.
    Borssén, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nordlund, Jessica
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Flaegstad, Trond
    Jónsson, Ólafur Gísli
    Frost, Britt-Marie
    Palle, Josefine
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Heyman, Mats
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lönnerholm, Gudmar
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia2018In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 31Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 135. Bower, Hannah
    et al.
    Björkholm, Magnus
    Dickman, Paul W
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lambert, Paul C
    Andersson, Therese M-L
    Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population2016In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 24, p. 2851-2858Article in journal (Refereed)
    Abstract [en]

    PURPOSE: A dramatic improvement in the survival of patients with chronic myeloid leukemia (CML) occurred after the introduction of imatinib mesylate, the first tyrosine kinase inhibitor (TKI). We assessed how these changes affected the life expectancy of patients with CML and life-years lost as a result of CML between 1973 and 2013 in Sweden.

    MATERIALS AND METHODS: Patients recorded as having CML in the Swedish Cancer Registry from 1973 to 2013 were included in the study and followed until death, censorship, or end of follow-up. The life expectancy and loss in expectation of life were predicted from a flexible parametric relative survival model.

    RESULTS: A total of 2,662 patients with CML were diagnosed between 1973 and 2013. Vast improvements in the life expectancy of these patients were seen over the study period; larger improvements were seen in the youngest ages. The great improvements in life expectancy translated into great reductions in the loss in expectation of life. Patients of all ages diagnosed in 2013 will, on average, lose < 3 life-years as a result of CML.

    CONCLUSION: Imatinib mesylate and new TKIs along with allogeneic stem cell transplantation and other factors have contributed to the life expectancy in patients with CML approaching that of the general population today. This will be an important message to convey to patients to understand the impact of a CML diagnosis on their life. In addition, the increasing prevalence of patients with CML will have a great effect on future health care costs as long as continuous TKI treatment is required.

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

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

  • 137.
    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.

  • 138.
    Brekkan, Ari
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Degerman, Johanna
    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.
    Model-based evaluation of low dose factor VIII prophylaxis in haemophilia A2019In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 25, no 3, p. 408-415Article in journal (Refereed)
    Abstract [en]

    Introduction The optimal treatment modality for haemophilia A is lifelong prophylaxis which is expensive and may not be implementable everywhere where factor VIII (FVIII) availability is limited. A less costly alternative to prophylaxis is low-dose prophylaxis (LDP) which was compared to conventional prophylaxis in this model-based simulation study. Aim To explore whether LDP is motivated where standard prophylaxis is not implementable, including evaluating LDP efficacy compared to high-dose prophylaxis and investigating the potential economic benefit of individualized dosing. Methods For a virtual adult haemophilia A population, FVIII activity levels were simulated following alternative treatment regimens, based on a published population PK model. The regimens included very LDP, LDP and conventional prophylaxis twice and thrice weekly. The annual probability of bleeding was predicted based on the weekly time spent below 1 IU/dL, using a previously published relationship. Additionally, PK-based dose individualization was evaluated to determine FVIII savings using Bayesian forecasting. Results A treatment regimen of 10 IU/kg administered thrice weekly cost 75% less than a standard high-dose regimen and was predicted to have a 5% higher median probability of annual bleeds. PK-based dose individualization may result in further cost-savings, but implementation needs benefit versus feasibility consideration. Conclusion Based on simulations, a promising LDP regimen was identified that decreased treatment costs compared with standard high-dose prophylaxis at a small increase in bleeding risk. The results indicate that LDP is advocated where the standard-of-care is on-demand treatment; however, the results should be considered in the context of any limitations of the applied models.

  • 139.
    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.

  • 140. Brunstein, Claudio G
    et al.
    Pasquini, Marcelo C
    Kim, Soyoung
    Fei, Mingwei
    Adekola, Kehinde
    Ahmed, Ibrahim
    Aljurf, Mahmoud
    Agrawal, Vaibhav
    Auletta, Jeffrey J
    Battiwalla, Minoo
    Bejanyan, Nelli
    Bubalo, Joseph
    Cerny, Jan
    Chee, Lynette
    Ciurea, Stefan O
    Freytes, Cesar
    Gadalla, Shahinaz M
    Gale, Robert Peter
    Ganguly, Siddhartha
    Hashmi, Shahrukh K
    Hematti, Peiman
    Hildebrandt, Gerhard
    Holmberg, Leona A
    Lahoud, Oscar B
    Landau, Heather
    Lazarus, Hillard M
    de Lima, Marcos
    Mathews, Vikram
    Maziarz, Richard
    Nishihori, Taiga
    Norkin, Maxim
    Olsson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Reshef, Ran
    Rotz, Seth
    Savani, Bipin
    Schouten, Harry C
    Seo, Sachiko
    Wirk, Baldeep M
    Yared, Jean
    Mineishi, Shin
    Rogosheske, John
    Perales, Miguel-Angel
    Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Hematopoietic Cell Transplantation2019In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 25, no 3, p. 480-487Article in journal (Refereed)
    Abstract [en]

    Data are limited on whether to adjust high-dose chemotherapy before autologous hematopoietic cell transplant (autoHCT) in obese patients. This study explores the effects of dose adjustment on the outcomes of obese patients, defined as body mass index (BMI) ≥ 30 kg/m2. Dose adjustment was defined as a reduction in standard dosing ≥ 20%, based on ideal, reported dosing and actual weights. We included 2 groups of US patients who had received autoHCT between 2008 and 2014. Specifically, we included patients with multiple myeloma (MM, n = 1696) treated with high-dose melphalan and patients with Hodgkin or non-Hodgkin lymphomas (n = 781) who received carmustine, etoposide, cytarabine, and melphalan conditioning. Chemotherapy dose was adjusted in 1324 patients (78%) with MM and 608 patients (78%) with lymphoma. Age, sex, BMI, race, performance score, comorbidity index, and disease features (stage at diagnosis, disease status, and time to transplant) were similar between dose groups. In multivariate analyses for MM, adjusting for melphalan dose and for center effect had no impact on overall survival (P = .894) and treatment-related mortality (TRM) (P = .62), progression (P = .12), and progression-free survival (PFS; P = .178). In multivariate analyses for lymphoma, adjusting chemotherapy doses did not affect survival (P = .176), TRM (P = .802), relapse (P = .633), or PFS (P = .812). No center effect was observed in lymphoma. This study demonstrates that adjusting chemotherapy dose before autoHCT in obese patients with MM and lymphoma does not influence mortality. These results do not support adjusting chemotherapy dose in this population.

  • 141. 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.

  • 142. 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.

  • 143. 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.

  • 144. 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.

  • 145. 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.

  • 146. 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.

  • 147. 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)
  • 148.
    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.

  • 149.
    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.

  • 150. Buus, Terkild Brink
    et al.
    Willerslev-Olsen, Andreas
    Fredholm, Simon
    Blumel, Edda
    Nastasi, Claudia
    Gluud, Maria
    Hu, Tengpeng
    Lindahl, Lise M.
    Iversen, Lars
    Fogh, Hanne
    Gniadecki, Robert
    Litvinov, Ivan V.
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Clinical Research Center, Lund University, Malmö, Sweden.
    Bonefeld, Charlotte Menne
    Geisler, Carsten
    Christensen, Jan Praysgaard
    Krejsgaard, Thorbjorn
    Litman, Thomas
    Woetmann, Anders
    Odum, Niels
    Single-cell heterogeneity in Sézary syndrome2018In: Blood Advances, ISSN 2473-9529, Vol. 2, no 16, p. 2115-2126Article in journal (Refereed)
    Abstract [en]

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

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