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  • 301.
    Grzymala-Lubanski, Bartosz
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Sara
    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.
    Computer aided warfarin dosing in the Swedish national quality registry AuriculA: algorithmic suggestions are performing better than manually changed doses2013In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 131, no 2, p. 130-134Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Warfarin treatment with a high time in therapeutic range (TTR) is correlated to fewer complications. The TTR in Sweden is generally high but varies partly depending on local expertise and traditions. A dosing algorithm could minimize variations and increase treatment quality. Here we evaluate the performance of a computerized dosing algorithm.

    MATERIALS AND METHODS: 53.779 warfarin treated patients from 125 centers using the Swedish national quality registry AuriculA. If certain criteria are met, the algorithm gives one of seven possible dose suggestions, which can be unchanged, decreased or increased weekly dose by 5, 10 or 15%. The outcome evaluated by the resulting INR value was compared between dose suggestions arising from the algorithm that were accepted and those that were manually changed. There were no randomization, and outcomes were retrospectively analyzed.

    RESULTS: Both the algorithm-based and the manually changed doses had worse outcome if only two instead of three previous INR values were available. The algorithm suggestions were superior to manual dosing regarding percent samples within the target range 2-3 (hit-rate) or deviation from INR 2.5 (mean error). Of the seven possible outcomes from the algorithm, six were significantly superior and one equal to the manually changed doses when three previous INR:s were present.

    CONCLUSIONS: The algorithm-based dosing suggestions show better outcome in most cases. This can make dosing of warfarin easier and more efficient. There are however cases where manual dosing fares better. Here the algorithm will be improved to further enhance its dosing performance in the future.

  • 302. Grövdal, Michael
    et al.
    Karimi, Mohsen
    Khan, Rasheed
    Aggerholm, Anni
    Antunovic, Petar
    Astermark, Jan
    Bernell, Per
    Engström, Lena-Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kjeldsen, Lars
    Linder, Olle
    Nilsson, Lars
    Olsson, Anna
    Holm, Mette S
    Tangen, Jon M
    Wallvik, Jonas
    Oberg, Gunnar
    Hokland, Peter
    Jacobsen, Sten E
    Porwit, Anna
    Hellström-Lindberg, Eva
    Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy2010In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 150, no 3, p. 293-302Article in journal (Refereed)
    Abstract [en]

    This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.

  • 303. Gugliotta, L.
    et al.
    Specchia, G.
    Gaidano, G.
    Scalzulli, P. R.
    Tieghi, A.
    Kiladjian, J-J
    Besses, C.
    Griesshammer, M.
    Harrison, C.
    Hamdani, M.
    Achenbach, H.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Treatment Of Essential Thrombocythaemia In Europe: An Observational Study Of 3649 High-Risk Patients In Exels2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 43-43Article in journal (Other academic)
  • 304.
    Gugliotta, L.
    et al.
    St Orsola Malpighi Hosp, Dept Haematol L & A Seragnoli, Bologna, Italy..
    Tortorella, G.
    Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy..
    Besses, C.
    Hosp del Mar IMIM, Dept Haematol, Barcelona, Spain..
    Griesshammer, M.
    Johannes Wesling Med Ctr, Hematol & Oncol, Minden, Germany..
    Harrison, C.
    Guys & St Thomas NHS Fdn Trust, Dept Haematol, London, England..
    Kiladjian, J. J.
    Hop St Louis, APHP, Ctr Invest Clin, Paris, France..
    Wu, J.
    Shire Pharmaceut, Global Biometr, Lexington, MA USA..
    Achenbach, H.
    Shire GmbH, Res & Dev, Zug, Switzerland..
    Marelli, C.
    Shire GmbH, Res & Dev, Zug, Switzerland..
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palpitations And Arrhythmia In 3649 High-Risk Patients With Essential Thrombocythemia: Results From The Prospective Long-Term Observational Exels Study2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 557-557Article in journal (Other academic)
  • 305. Gugliotta, Luigi
    et al.
    Besses, Carlos
    Griesshammer, Martin
    Harrison, Claire
    Kiladjian, Jean-Jacques
    Coll, Ruth
    Smith, Jonathan
    Abhyankar, Brihad
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Combination therapy of hydroxycarbamide with anagrelide in patients with essential thrombocythemia in the evaluation of Xagrid (R) efficacy and long-term safety study2014In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 4, p. 679-687Article in journal (Refereed)
    Abstract [en]

    Available information is limited regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid (R) Efficacy and Long-term Safety study. Of 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167, 54.9%) and anagrelide (n=123, 40.5%). Median weekly doses of hydroxycarbamide and anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581x10(9)/L and 411x10(9)/L before and after starting hydroxycarbamide + anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts less than 400x10(9)/L increased from 33 (21.6%) to 74 (48.4%; P<0.0001), and with platelet counts less than 600x10(9)/L, from 82 (53.6%) to 132 (86.3%; P<0.0001). Hydroxycarbamide + anagrelide was discontinued in 158 patients: 76 (48.1%) stopped hydroxycarbamide, 59 (37.3%) stopped anagrelide, 19 (12.0%) stopped both and 4 (2.5%) had another therapy added. The most frequent reasons for discontinuation were intolerance/side-effects, lack of efficacy, and therapeutic strategy. Combination therapy, usually hydroxycarbamide + anagrelide, is used in approximately 10% of all high-risk patients with essential thrombocythemia and may be a useful approach in treating patients for whom monotherapy is unsatisfactory.

  • 306.
    Guimaraes, Patricia O.
    et al.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Lopes, Renato D.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Alexander, John H.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Thomas, Laine
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Hellkamp, Anne S.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    Hijazi, Ziad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hylek, Elaine M.
    Boston Univ, Med Ctr, Boston, MA USA.
    Gersh, Bernard J.
    Mayo Clin, Coll Med, Dept Cardiovasc Med, Rochester, MN USA.
    Garcia, David A.
    Univ Washington, Sch Med, Med Ctr, Div Hematol,Dept Med, Seattle, WA 98195 USA.
    Verheugt, Freek W. A.
    Hartctr OLVG, Afdeling Cardiol, Amsterdam, Netherlands.
    Hanna, Michael
    Bristol Myers Squibb, Princeton, NJ USA.
    Flaker, Greg
    Univ Missouri, Sch Med, Columbia, MO USA.
    Vinereanu, Dragos
    Univ Med & Pharm Carol Davila, Bucharest, Romania.
    Granger, Christopher B.
    Duke Clin Res Inst, Durham, NC 27705 USA.
    International normalized ratio control and subsequent clinical outcomes in patients with atrial fibrillation using warfarin2019In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 48, no 1, p. 27-34Article in journal (Refereed)
    Abstract [en]

    We explored associations between INR measures and clinical outcomes in patients with AF using warfarin, and whether INR history predicted future INR measurements. We included patients in ARISTOTLE who were randomized to and received warfarin. Among patients who had events, we included those with ≥ 3 INR values in the 180 days prior to the event, with the most recent ≤ 60 days prior to the event, who were on warfarin at the time of event (n = 545). Non-event patients were included in the control group if they had ≥ 180 days of warfarin exposure with ≥ 3 INR measurements (n = 7259). The median (25th, 75th) number of INR values per patient was 29 (21, 38) over a median follow-up of 1.8 years. A total of 87% had at least one INR value < 1.5; 49% had at least one value > 4.0. The last INRs before events (median 14 [24, 7] days) were < 3.0 for at least 75% of patients with major bleeding and > 2.0 for half of patients with ischemic stroke. Historic time in therapeutic range (TTR) was weakly associated with future TTR (R2 = 0.212). Historic TTR ≥ 80% had limited predictive ability to discriminate future TTR ≥ 80% (C index 0.61). In patients with AF receiving warfarin, most bleeding events may not have been preventable despite careful INR control. Our findings suggest that INRs collected through routine management are not sufficiently predictive to provide reassurance about future time in therapeutic range or to prevent subsequent outcomes, and might be over-interpreted in clinical practice.

  • 307.
    Gunnarsson, N.
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, L.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Wallberg-Jonsson, S.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Sandin, F.
    Reg Canc Ctr, Uppsala, Sweden..
    Björkholm, M.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Dreimane, A.
    Linkoping Univ Hosp, Dept Hematol, Linkoping, Sweden..
    Lambe, M.
    Reg Canc Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Markevarn, B.
    Univ Umea Hosp, Dept Hematol, Umea, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wadenvik, H.
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Själander, A.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Increased prevalence of prior malignancies and autoimmune diseases in patients diagnosed with chronic myeloid leukemia2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 7, p. 1562-1567Article in journal (Refereed)
    Abstract [en]

    We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.

  • 308.
    Gunnarsson, Niklas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Chronic myeloid leukemia and cancer2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Chronic myeloid leukemia (CML) is a relatively rare hematological malignancy with a constant incidence of approximately 90 new cases each year in Sweden (0.9 cases/100 000 inhabitants). The etiology is largely unknown but high doses of ionizing radiation are a known but rare risk factor. The treatment options were for a long time limited to chemotherapies i.e. hydroxyurea and busulfan, interferon’s and allogeneic hematopoietic stem cell transplantation and the median survival were only about four years.

    Since the beginning of the 21st century a new way of treating CML has been introduced, the tyrosine kinase inhibitors (TKI), leading to a rapid decrease in leukemic cells and symptoms. Due to the TKIs, the overall 5-year survival is nowadays approximately 85 % and CML patients have time to develop other diseases, including other malignancies.

    The aims of this thesis was to investigate the present and future prevalence of CML and the prevalence of other malignancies prior and subsequent to the diagnosis of CML, malignancies among first-degree relatives of persons with CML. In addition, the incidence of autoimmune and chronic inflammatory diseases among patients with CML was also investigated.

     

    Methods

    From the Swedish CML register, data over nearly all Swedish CML patients from 2002 and forward were obtained for paper II-IV.

    For paper I, the Swedish cancer register was used to identify all Swedish CML patients since 1970 and the Swedish cause of death register was used to identify an eventual date of death for these patients. With a constant incidence and the relative survival rates for CML patients between 2006 and 2012 as a model, the present and future prevalence was calculated.

    For paper II-IV, data from the Swedish cancer register was used to identify other malignancies than CML. For paper II, information about autoimmune and chronic inflammatory diseases was retrieved from the Swedish national patient register.

    For paper II and IV, five controls matched for year of birth, gender and county of residence were randomly selected from the Swedish register of the total population. To calculate odds ratio (OR), conditional logistic regression was used.

    To calculate the risk of a second malignancy for paper III, Standardized incidence ratio (SIR) was used.

    In paper IV, first-degree relatives (parents, siblings and offsprings) for both cases and controls were retrieved from the Swedish multi-Generation Register, where persons born later than 1932 and registered in Sweden at some time since 1961 are registered.

     

    Results

    Prevalence and survival

    As shown in paper I, the 5-year overall survival for CML patients increased remarkably from 0.18 to 0.82 between 1970 and 2012. The prevalence increased from 3.9 to 11.9 per 100 000 inhabitants in Sweden between 1985 and 2012. By assuming no further improvements in relative survival as compared to the survival rates between 2006 and 2012, the prevalence by 2060 is expected to increase to 22.0 per 100 000 inhabitants. This corresponds to 2 587 CML patients as compared to 1 137 CML patients in 2012.

     

    Malignancies, autoimmune and chronic inflammatory diseases prior to CML

    In study II, more than 45 000 person-years of follow-up were evaluated in 984 CML patients diagnosed between 2002 and 2012. With an OR of 1.47 (95 % CI 1.20–1.82) and 1.55 (95 % CI 1.21–1.98), respectively, the prevalence of prior malignancies and autoimmune diseases were significantly increased as compared to matched controls. On the other hand, no association between CML and chronic inflammatory diseases was shown.

     

    Second malignancies

    In 868 CML patients, diagnosed between 2002 and 2011, 52 malignancies were observed in the Swedish cancer register, as shown in paper III. When compared to expected rates in the background population, a significantly increased risk of second malignancies with a SIR of 1.52 (95 % CI 1.13–1.99) was shown. When looking at specific cancer types, gastrointestinal as well as nose and throat cancer were significantly increased.

     

    Familial aggregation of malignancies

    984 CML patients were identified in paper IV. However, 184 had a birth date prior to 1932, subsequently only 800 patients were analyzed. Among them, 4 287 first-degree relatives were identified, compared to 20 930 first-degree relatives of the matched controls. 611 malignancies were retrieved; no significant increase of malignancies in first-degree relatives of CML patients was shown (OR 1.06; 95 % CI: 0.96–1.16).

     

    Conclusion

    Since CML patients nowadays have a high survival rate, the calculations in this thesis shows that the prevalence of CML will almost double by 2060. CML patients have an increased risk of developing malignancies prior and subsequent to the diagnosis of CML, suggesting a hereditary or acquired predisposition to develop cancer. Since there is no familial aggregation of malignancies in CML patients, a hereditary predisposition to develop cancer is unlikely to be part of the pathogenesis of CML, leaving an acquired predisposition more likely.

  • 309.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Höglund, M.
    Stenke, L.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Sandin, F.
    Björkholm, M.
    Dreimane, A.
    Lambe, M.
    Markevärn, Berit
    Olsson-Strömberg, U.
    Wadenvik, H.
    Richter, J.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Increased prevalence of prior malignancies and autoimmune diseases in patients diagnosed with chronic myeloid leukemia2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 7, p. 1562-1567Article in journal (Refereed)
    Abstract [en]

    We recently reported an increased incidence of second malignancies in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). To elucidate whether this increase may be linked, not to TKI but rather to a hereditary or acquired susceptibility to develop cancer, we estimated the prevalence of malignancies, autoimmune disease (AD) and chronic inflammatory disease (CID) in CML patients prior to their CML diagnosis. Nationwide population-based registers were used to identify patients diagnosed with CML in Sweden 2002-2012 and to estimate the prevalence of other malignancies, AD and CID prior to their CML diagnosis. For each patient with CML, five matched controls were selected from the general population. Conditional logistic regression was used to calculate odds ratios (OR). Nine hundred and eighty-four CML patients were assessed, representing more than 45 000 person-years of follow-up. Compared with matched controls, the prevalence of prior malignancies and AD was elevated in CML patients: OR 1.47 (95% confidence interval (CI) 1.20-1.82) and 1.55 (95% CI 1.21-1.98), respectively. No associations were detected between CML and previous CID. An increased prevalence of other malignancies and AD prior to the diagnosis of CML suggest that a hereditary or acquired predisposition to cancer and/or autoimmunity is involved in the pathogenesis of CML.

  • 310.
    Gunnarsson, Niklas
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Gavle, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, Leif
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Jonsson, Solveig Wallberg
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Sandin, Fredrik
    Reg Canc Ctr, Uppsala, Sweden..
    Bjorkholm, Magnus
    Karolinska Univ Hosp, Div Hematol, Dept Med, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Dreimane, Arta
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Lambe, Mats
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Markevarn, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wadenvik, Hans
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Sjalander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, Sundsvall, Sweden..
    Increased Prevalence of Prior Malignancies and Autoimmune Diseases in Patients Diagnosed with Chronic Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 311.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Höglund, Martin
    Stenke, Leif
    Wållberg Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sandin, Fredrik
    Björkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevärn, Berit
    Olsson-Strömberg, Ulla
    Wadenvik, Hans
    Richter, Johan
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Increased Prevalence of Prior Malignancies and Autoimmune Diseases in Patients Diagnosed with Chronic Myeloid Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 312. Gunnarsson, Niklas
    et al.
    Leif, Stenke
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandin, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Bjorkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevarn, Berit
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Richter, Johan
    Wadenvik, Hans
    Wallvik, Jonas
    Sjalander, Anders
    Second Malignancies Following Treatment of Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 313.
    Gunnarsson, Niklas
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Sandin, Fredrik
    Reg Canc Ctr, Uppsala, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Hosp, Dept Med Sci, Uppsala, Sweden.;Univ Hosp, Div Hematol, Uppsala, Sweden..
    Stenke, Leif
    Karolinska Inst, Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Björkholm, Magnus
    Karolinska Inst, Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Lambe, Mats
    Reg Canc Ctr, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Hosp, Dept Med Sci, Uppsala, Sweden.;Univ Hosp, Div Hematol, Uppsala, Sweden..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Själander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden..
    Population-based assessment of chronic myeloid leukemia in Sweden: striking increase in survival and prevalence2016In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 97, no 4, p. 387-392Article in journal (Refereed)
    Abstract [en]

    The clinical outcome for patients with chronic myeloid leukemia (CML) has improved dramatically following the introduction of tyrosine kinase inhibitors. An improved survival, combined with a constant incidence, is expected to increase the prevalence of CML. However, data on the prevalence of CML remain scarce. We examined the overall and relative (age and gender matched) survival and assessed the past, present, and projected future prevalence of CML in Sweden. Data on all patients diagnosed with CML between 1970 and 2012 were retrieved from the Swedish Cancer Register and the Swedish Cause of Death Register. The 5-year overall survival increased from 0.18 to 0.82, during the observed time period. Between 2006 and 2012, the 5-year relative survival was close to normal for 40-year-old, but considerably lower for 80-year-old CML patients. The observed prevalence tripled from 1985 to 2012, from 3.9 to 11.9 per 100 000 inhabitants. Assuming no further improvements in relative survival, the prevalence is projected to further increase by 2060 to 22.0 per 100 000 inhabitants (2587 persons in Sweden). The projected dramatic increase in CML prevalence has major medical and health economic implications and needs to be considered in planning how to organize future care of CML patients.

  • 314.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sandin, Fredrik
    Höglund, Martin
    Stenke, Leif
    Björkholm, Magnus
    Lambe, Mats
    Olsson-Strömberg, Ulla
    Richter, Johan
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Population-based assessment of chronic myeloid leukemia in Sweden: striking increase in survival and prevalence2016In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 97, no 4, p. 387-392Article in journal (Refereed)
    Abstract [en]

    The clinical outcome for patients with chronic myeloid leukemia (CML) has improved dramatically following the introduction of tyrosine kinase inhibitors. An improved survival, combined with a constant incidence, is expected to increase the prevalence of CML. However, data on the prevalence of CML remain scarce. We examined the overall and relative (age and gender matched) survival and assessed the past, present, and projected future prevalence of CML in Sweden. Data on all patients diagnosed with CML between 1970 and 2012 were retrieved from the Swedish Cancer Register and the Swedish Cause of Death Register. The 5-year overall survival increased from 0.18 to 0.82, during the observed time period. Between 2006 and 2012, the 5-year relative survival was close to normal for 40-year-old, but considerably lower for 80-year-old CML patients. The observed prevalence tripled from 1985 to 2012, from 3.9 to 11.9 per 100 000 inhabitants. Assuming no further improvements in relative survival, the prevalence is projected to further increase by 2060 to 22.0 per 100 000 inhabitants (2587 persons in Sweden). The projected dramatic increase in CML prevalence has major medical and health economic implications and needs to be considered in planning how to organize future care of CML patients.

  • 315. Gunnarsson, Niklas
    et al.
    Stenke, Leif
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandin, Fredrik
    Bjorkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevarn, Berit
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Richter, Johan
    Wadenvik, Hans
    Wallvik, Jonas
    Sjalander, Anders
    Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era2015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, no 5, p. 683-688Article in journal (Refereed)
    Abstract [en]

    Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. With a median follow-up of 37 (range 0-99)years, 65 (75%) patients developed 75 second malignancies (non-haematological), 52 of which were of the invasive type. Compared to expected rates in the background population, the risk of second malignancies was higher in the CML cohort, with a standardized incidence ratio (SIR) of 152 (95% CI 113-199). The SIR before and after the second year following diagnosis of CML was 158 and 147, respectively. Among specific cancer types, gastrointestinal and nose and throat cancer were significantly increased. Founded on a population-based material, our results indicate that CML patients treated in the TKI era are at an increased risk of developing a second malignancy, with indications that this risk may more likely be linked to CML itself rather than to the TKI treatment.

  • 316.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stenke, Leif
    Höglund, Martin
    Sandin, Fredrik
    Björkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevärn, Berit
    Department of Haematology, University Hospital, Umeå.
    Olsson-Strömberg, Ulla
    Richter, Johan
    Wadenvik, Hans
    Wallvik, Jonas
    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.
    Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era2015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, no 5, p. 683-688Article in journal (Refereed)
    Abstract [en]

    Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. With a median follow-up of 3·7 (range 0-9·9) years, 65 (7·5%) patients developed 75 second malignancies (non-haematological), 52 of which were of the invasive type. Compared to expected rates in the background population, the risk of second malignancies was higher in the CML cohort, with a standardized incidence ratio (SIR) of 1·52 (95% CI 1·13-1·99). The SIR before and after the second year following diagnosis of CML was 1·58 and 1·47, respectively. Among specific cancer types, gastrointestinal and nose and throat cancer were significantly increased. Founded on a population-based material, our results indicate that CML patients treated in the TKI era are at an increased risk of developing a second malignancy, with indications that this risk may more likely be linked to CML itself rather than to the TKI treatment.

  • 317. Gunnarsson, R.
    et al.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mansouri, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Göransson, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jansson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rasmussen, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Staaf, J.
    Lundin, J.
    Norin, S.
    Buhl, A. M.
    Smedby, K. E.
    Hjalgrim, H.
    Karlsson, K.
    Jurlander, J.
    Juliusson, G.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Large but not small copy-number alterations correlate to high-risk genomic aberrations and survival in chronic lymphocytic leukemia: a high-resolution genomic screening of newly diagnosed patients2010In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 24, no 1, p. 211-215Article in journal (Refereed)
  • 318. Gurbel, Paul A.
    et al.
    Bergmeijer, Thomas O.
    Tantry, Udaya S.
    ten Berg, Jurrien M.
    Angiolillo, Dominick J.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Tomas L.
    Svensson, Peter
    Jakubowski, Joseph A.
    Brown, Patricia B.
    Duvvuru, Suman
    Sundseth, Scott
    Walker, Joseph R.
    Small, David
    Moser, Brian A.
    Winters, Kenneth J.
    Erlinge, David
    The effect of CYP2C19 gene polymorphisms on the pharmacokinetics and pharmacodynamics of prasugrel 5-mg, prasugrel 10-mg and clopidogrel 75-mg in patients with coronary artery disease2014In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 112, no 3, p. 589-597Article in journal (Refereed)
    Abstract [en]

    CYP2C19 genotype has been shown to impact response to clopidogrel 75-mg but not prasugrel 10-mg. Here, we assessed effects of CYP2C19 metaboliser status on pharmacokinetics (PK) and pharmacodynamic (PD) responses to prasugrel 5-mg and 10-mg and clopidogrel 75-mg using data from two PK/PD studies in stable coronary artery disease (CAD) patients (GENERATIONS and FEATHER). Active metabolite concentrations (area under the curve, AUC([0-tlast])), maximum platelet aggregation (MPA) measured by light transmission aggregometry, vasodilator-stimulated phosphoprotein platelet reactivity index, and VerifyNow P2Y12-platelet reaction units (VN-PRU) were analysed by CYP2C19-predicted phenotype (extensive metaboliser [EM; N=154], *2-*8 non-carriers, vs reduced metaboliser [RM; N=41],*2-*8 carriers/*17 non-carriers). AUC((0-tlast)) was unaffected by metaboliser status for prasugrel 5-mg and 10-mg (geometric mean EM/RM ratios 1.00, 95% confidence interval [Cl]: 0.86,1.17, p>0.99; and 0.97, 95% CI:0.85,1.12, p=0.71, respectively), but was lower among RMs receiving clopidogrel 75-mg (1.37, 95% CI:1.14,1.65, p<0.001). Platelet reactivity was not significantly affected by CYP2C19 metaboliser status for prasugrel 5-mg, or for prasugrel 10-mg by MPA and VN-PRU, but for clopidogrel 75-mg was significantly higher in reduced metabolisers (all measures p<0.01). Prasugrel 10-mg showed greater antiplatelet effects vs clopidogrel 75-mg (all comparisons p<0.001). Prasugrel 5-mg showed greater antiplatelet effects vs clopidogrel 75-mg in RMs (all p<0.001), and comparable effects in EMs (all p >= 0.37). In contrast to clopidogrel, prasugrel active metabolite PK was not influenced by CYP2C19 genotype. Antiplatelet effect for prasugrel 10-mg was greater irrespective of metaboliser status and for prasugrel 5-mg was greater for RMs and comparable for EMs as compared to clopidogrel 75-mg.

  • 319. Guruprasad, Puneeth
    et al.
    Mannino, Robert G.
    Caruso, Christina
    Zhang, Hanqing
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Josephson, Cassandra D.
    Roback, John D.
    Lam, Wilbur A.
    Integrated automated particle tracking microfluidic enables high-throughput cell deformability cytometry for red cell disorders2019In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 94, no 2, p. 189-199Article in journal (Refereed)
    Abstract [en]

    Investigating individual red blood cells (RBCs) is critical to understanding hematologic diseases, as pathology often originates at the single-cell level. Many RBC disorders manifest in altered biophysical properties, such as deformability of RBCs. Due to limitations in current biophysical assays, there exists a need for high-throughput analysis of RBC deformability with single-cell resolution. To that end, we present a method that pairs a simple in vitro artificial microvasculature network system with an innovative MATLAB-based automated particle tracking program, allowing for high-throughput, single-cell deformability index (sDI) measurements of entire RBC populations. We apply our technology to quantify the sDI of RBCs from healthy volunteers, Sickle cell disease (SCD) patients, a transfusion-dependent beta thalassemia major patient, and in stored packed RBCs (pRBCs) that undergo storage lesion over 4 weeks. Moreover, our system can also measure cell size for each RBC, thereby enabling 2D analysis of cell deformability vs cell size with single cell resolution akin to flow cytometry. Our results demonstrate the clear existence of distinct biophysical RBC subpopulations with high interpatient variability in SCD as indicated by large magnitude skewness and kurtosis values of distribution, the "shifting" of sDI vs RBC size curves over transfusion cycles in beta thalassemia, and the appearance of low sDI RBC subpopulations within 4 days of pRBC storage. Overall, our system offers an inexpensive, convenient, and high-throughput method to gauge single RBC deformability and size for any RBC population and has the potential to aid in disease monitoring and transfusion guidelines for various RBC disorders.

  • 320. Gustaf, Edgren
    et al.
    Bjorkholm, Magnus
    Bernell, Per
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dickman, Paul W.
    Survival from Acute Lymphoblastic Leukemia (ALL) in Adult Patients in the United States and Sweden: Evidence of Recent Improvement2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 321.
    Gustafsson, Britt M.
    et al.
    Karolinska Inst, CLINTEC, Dept Clin Sci Intervent & Technol, SE-14186 Stockholm, Sweden.
    Mattsson, Kristin
    Karolinska Inst, CLINTEC, Dept Clin Sci Intervent & Technol, SE-14186 Stockholm, Sweden.
    Bogdanovic, Gordana
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.
    Leijonhufvud, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Honkaniemi, Emma
    Karolinska Inst, CLINTEC, Dept Clin Sci Intervent & Technol, SE-14186 Stockholm, Sweden;Karolinska Univ Hosp, Liljeholmen Child & Adolescent Med Facil, Dept Paediat, Stockholm, Sweden.
    Ramme, Kim
    Karolinska Inst, CLINTEC, Dept Clin Sci Intervent & Technol, SE-14186 Stockholm, Sweden;Karolinska Univ Hosp, Astrid Lindgrens Children s Hosp, Dept Pediat Hematol Immunol & Stem Cell Transplan, Stockholm, Sweden.
    Ford, Anthony M.
    Inst Canc Res, Div Mol Pathol, Ctr Evolut & Canc, London, England.
    Origins of STIL-TAL1 fusion genes in children who later developed paediatric T-cell acute lymphoblastic leukaemia: An investigation of neonatal blood spots2018In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 65, no 11, article id e27310Article in journal (Refereed)
    Abstract [en]

    SCL/TAL1 interrupting locus (STIL)-T-cell acute leukaemia (TAL1) fusion genes are present in approximately 11-27% of children with paediatric T-cell acute lymphoblastic leukaemia (T-ALL), but the developmental timing of the rearrangement is still unknown. To investigate whether the fusion gene can be detected in neonatal blood spots (NBSs) from paediatric patients diagnosed with T-cell ALL, we analysed DNA from 38 paediatric patients with T-ALL by nested polymerase chain reaction and electrophoresis. The STIL-TAL1 fusion gene was not detected in NBSs from any of the 38 patients with T-ALL, suggesting that STIL-TAL1 fusion genes are most probably postnatal events in paediatric T-ALL.

  • 322. Gülen, T
    et al.
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dahlén, B
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 279, no 3, p. 211-228Article, review/survey (Refereed)
    Abstract [en]

    Mastocytosis is a complex disorder characterized by the accumulation of abnormal mast cells (MC) in the skin, bone marrow and/or other visceral organs. The clinical manifestations result from MC-derived mediators and, less frequently, from destructive infiltration of MCs. Patients suffer from a variety of symptoms including pruritus, flushing and life-threatening anaphylaxis. Whilst mastocytosis is likely to be suspected in a patient with typical skin lesions [i.e. urticaria pigmentosa (UP)], the absence of cutaneous signs does not rule out the diagnosis of this disease. Mastocytosis should be suspected in cases of recurrent, unexplained or severe insect-induced anaphylaxis or symptoms of MC degranulation without true allergy. In rare cases, unexplained osteoporosis or unexplained haematological abnormalities can be underlying feature of mastocytosis, particularly when these conditions are associated with elevated baseline serum tryptase levels. The diagnosis is based on the World Health Organization criteria, in which the tryptase level, histopathological and immunophenotypic evaluation of MCs and molecular analysis are crucial. A somatic KIT mutation, the most common of which is D816V, is usually detectable in MCs and their progenitors. Once a diagnosis of systemic mastocytosis (SM) is made, it is mandatory to assess the burden of the disease, its activity, subtype and prognosis, and the appropriate therapy. Mastocytosis comprises seven different categories that range from indolent forms, such as cutaneous and indolent SM, to progressive forms, such as aggressive SM and MC leukaemia. Although prognosis is good in patients with indolent forms of the disease, patients with advanced categories have a poor prognosis.

  • 323. Gülen, T
    et al.
    Sander, B
    Nilsson, G
    Palmblad, J
    Sotlar, K
    Horny, H-P
    Hägglund, Hans
    Department of Hematology, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Systemic mastocytosis: progressive evolution of an occult disease into fatal mast cell leukemia2012In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 29, no 5, p. 3540-3546Article in journal (Refereed)
    Abstract [en]

    Systemic mastocytosis (SM) may be associated with a clonal hematopoietic non-mast cell-lineage disease (AHNMD). SM and AHNMD even may be clonally related. This report contributes to a better understanding of the different morphological aspects of SM by demonstrating that various AHNMDs can be detected in one patient during the course of disease. Routinely processed biopsy specimens of bone marrow and spleen removed from a 63-year-old man were investigated including a broad panel of immunohistochemical stainings. KIT codon 816 mutation analysis was carried out by melting point analysis of nested PCR products amplified from DNA of pooled microdissected mast cells. The histomorphological features of the initial bone marrow showed diffuse infiltration by hairy cell leukemia (HCL). Occult SM was only detected retrospectively by demonstration of a slight diffuse increase in loosely scattered, spindle-shaped mast cells carrying the activating point mutation KIT ( D816V ). In the second bone marrow, core biopsy removed about two years later HCL had been completely eradicated, while a diagnosis of SM-AHNMD with multifocal compact mast cell infiltrates associated with a myeloproliferative neoplasm (MPN) and significant increase in eosinophilic granulocytes was established. The third and last bone marrow biopsy specimen lacked the features of both MPN and HCL but showed progression into a secondary mast cell leukemia (MCL) with a focal sarcomatous component. To the best of the authors' knowledge, this is the first description of a case of SM-AHNMD with coexisting hematological neoplasms of lymphatic and myeloid origin initially presenting as occult disease and terminating as secondary MCL.

  • 324. Hadimeri, Ursula
    et al.
    Warme, Anna
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A single treatment, using Far Infrared light improves blood flow conditions in arteriovenous fistula2017In: Clinical hemorheology and microcirculation, ISSN 1386-0291, E-ISSN 1875-8622, Vol. 66, no 3, p. 211-217Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A native arteriovenous fistula (AVF) is recommended for angio access in patients on chronic hemodialysis (HD). Fistula patency has been improved by exposure to Far Infrared light (FIR).

    OBJECTIVE: To investigate whether a single FIR treatment could alter blood velocity, AVF diameter or inflammatory markers. METHODS: Thirty patients with a native AVF in the forearm were included. Each patient was his/her own control. Ultrasound (US) examinations were performed before and after a single FIR treatment.

    RESULTS: A single FIR treatment resulted in a significant increase in blood velocity over the AV fistula from a mean of 2.1 +/- 1.0 m/s to 2.3 +/- 1.0 m/s (p = 0.02). The diameter of the arterialized vein became wider; 0,72 cm +/- 0.02 to 0,80 cm +/- 0.02, (p = 0.006). The increase in fistula blood velocity correlated positively with base line serum-urate p = 0.004) and the increase in venous diameter with the base line plasma orosomucoid concentration (p = 0.005).

    CONCLUSIONS: This study shows that a single FIR treatment significantly increased AVF blood velocity and vein diameter. Thus, one FIR treatment can help maturation of AVF in the early postoperative course.

  • 325.
    Hagberg, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hogberg, K.
    Jensen, B. A.
    Leppa, S.
    Munksgaard, L.
    Szatkowski, D.
    Retrospective Analysis of Primary Chemoimmunotherapy with Bendamustine in Combination with Rituximab in Patients with Indolent and Mantle-Cell Lymphomas2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no S1, p. 692-692Article in journal (Other academic)
  • 326. Hagglund, H.
    et al.
    Askmark, H.
    Stromberg, U.
    Axelsson, H.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Isaksson, C.
    Wahlin, A.
    Andersen, O.
    Johansson, J.
    Press, R.
    Autologous haematopoietic stem cell transplantation: a viable treatment option for chronic inflammatory demyelinating polyneuropathy2013In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 48, p. S336-S336Article in journal (Other academic)
  • 327.
    Hagren, Birger
    et al.
    Ersta Sköndal University College, Department of Health Care Sciences.
    Pettersen, Inga-Märta
    Severinsson, Elisabeth
    Lützén, Kim
    Ersta Sköndal University College, Department of Health Care Sciences.
    Clyne, Naomi
    Maintenance haemodialysis: patients’ experiences of their life situation2005In: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 14, no 3, p. 294-300Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to examine how patients suffering from CKD on maintenance haemodialysis experience their life situation. The focus was on how treatment encroaches on time and space and how patients experience care. The rationale was that this knowledge is necessary to provide professional support that takes into consideration a person's whole life situation.The experiences of patients with chronic kidney disease (CKD) undergoing maintenance haemodialysis have been studied in many quantitative studies, which translate patients’ subjective experiences into objectively quantifiable data. However, there are few qualitative studies examining the experiences of these patients’ life situation and expressing their experiences within the context of a nursing and caregiver's perspective.Data were collected by interviews with 41 patients between the ages of 29 and 86 years who participated in the study. A content analysis was used to identify common themes that describe the patients’ experiences of their life situation.Three main themes were identified,‘not finding space for living’,‘feelings evoked in the care situation’ and,‘attempting to manage restricted life’. The first theme‘not finding space for living’ consisted of two sub-themes:‘struggling with time-consuming care’ and‘feeling that life is restricted’. The second theme‘feelings evoked in the care situation’ consisted of two sub-themes:‘sense of emotional distance’ and‘feeling vulnerable’.The patients in this study indirectly expressed an existential struggle, indicating that encroachment of time and space were important existential dimensions of CKD. The findings indicated that caregivers were not always aware of this inducing a sense of emotional distance and a sense of vulnerability in the patients.Caregivers in dialysis units have to consider haemodialysis patients’ experience of a sense of emotional distance in their relationship to caregivers. Nurses and doctors need to create routines within nursing practice to overcome this.

  • 328.
    Hagren, Birger
    et al.
    Karolinska institutet.
    Pettersen, Inga-Märta
    Severinsson, Elisabeth
    Lützén, Kim
    Clyne, Naomi
    The haemodialysis machine as a lifeline: experiences of suffering from end-stage renal disease2001In: Journal of Advanced Nursing, ISSN 0309-2402, E-ISSN 1365-2648, Vol. 34, no 2, p. 196-202Article in journal (Refereed)
  • 329.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    DNA methylation signatures in precursor lymphoid neoplasms: with focus on clinical implications &  the biology behind2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Precursor lymphoid neoplasms, namely acute lymphoblastic leukemias (ALL) and lymphoblastic lymphomas (LBL), are characterized by an aggressive proliferation of malignant progenitor B- or T-cells. To improve risk classification at diagnosis, better prognostic and treatment stratifying biomarkers are needed. Altered DNA methylation pattern is a hallmark of neoplastic transformation, and has been employed as a molecular prognostic and predictive marker in various cancers, including hematological malignancies. Our research group previously identified a CpG island methylator phenotype (CIMP) panel that classified pediatric T-ALL patients into prognostic subgroups.

    The aim of this thesis was to evaluate distinct DNA methylation signatures in precursor lymphoid neoplasms, and to validate the prognostic value of CIMP classification in separate patient cohorts. Additionally, the biological mechanisms underlying the distinct CIMP methylation signatures in these malignancies were investigated.

    The prognostic relevance of CIMP classification was validated in an independent Nordic cohort of pediatric T-ALL patients. Combination of CIMP status with minimal residual disease (MRD) status, could further dissect the high-risk MRD positive T-ALL patients into two CIMP subgroups with significantly distinct outcomes. Furthermore, CIMP classification at diagnosis was shown to predict overall survival in relapsed BCP-ALL patients. CIMP methylation signatures were also identified in T-LBL patients, indicating a broader relevance of CIMP based classification in lymphoid malignancies. Investigating the biology behind CIMP methylation signatures showed the association of CIMP status with the proliferative history of the leukemic cells. A differential transcriptomic analysis revealed a correlation of CIMP subgroups with known T-ALL drivers, as well as with novel genes in T-ALL biology. Finally, we identified distinct DNA methylation patterns and genetic aberrations in T-ALL and T-LBL that might contribute to the different clinical presentation of these two diseases. In conclusion, we validated the prognostic significance of CIMP methylation signature in precursor lymphoid malignancies and identified transcriptomic profiles that associated with the subgroups. DNA methylation is a strong candidate for further risk classification in lymphoid neoplasms and our findings can contribute to the identification of new potential targets for treatment.

  • 330.
    Haider, Zahra
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Noren-Nyström, Ulrika
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Epigenetic and genetic distinctions between T-cell acute lymphoblastic leukemia and lymphomaManuscript (preprint) (Other academic)
  • 331.
    Haider, Zahra
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Köhn, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Schmiegelow, Kjeld
    Flaegstad, Trond
    Kanerva, Jukka
    Heyman, Mats
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression2019In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, no 1, p. 311-324Article in journal (Refereed)
    Abstract [en]

    Classification of pediatric T‐cell acute lymphoblastic leukemia (T‐ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T‐ALL patients were characterized by genome‐wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2‐1, and novel genes in T‐ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP− subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL‐TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP−), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T‐ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies.

  • 332.
    Halcox, Julian P.
    et al.
    Swansea University College of Medicine, UK.
    Tubach, Florence
    INSERM, France ; Paris Diderot University, France.
    Lopez-Garcia, Esther
    Universidad Autónoma de Madrid, Spain ; CIBERESP, Spain.
    De Backer, Guy
    University of Ghent, Belgium.
    Borghi, Claudio
    University of Bologna, Italy.
    Dallongeville, Jean
    Université Lille-Nord de France, France.
    Guallar, Eliseo
    Johns Hopkins Bloomberg School of Public Health, USA ; National Center for Cardiovascular Research, Spain.
    Medina, Jesús
    AstraZeneca Farmacéutica Spain, Spain.
    Perk, Joep
    Linnaeus University, Faculty of Health and Life Sciences, Department of Health and Caring Sciences.
    Sazova, Oguen
    AstraZeneca Global Medical Affairs, UK.
    Sweet, Stephen
    Oxford PharmaGenesis Ltd, UK.
    Roy, Carine
    INSERM, France ; Hôpital Bichat-Claude Bernard, France.
    Banegas, José R.
    Universidad Autónoma de Madrid, Spain ; CIBERESP, Spain.
    Rodriguez-Artalejo, Fernando
    Universidad Autónoma de Madrid, Spain ; CIBERESP, Spain.
    Low Rates of Both Lipid-Lowering Therapy Use and Achievement of Low-Density Lipoprotein Cholesterol Targets in Individuals at High-Risk for Cardiovascular Disease across Europe2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 2, article id e0115270Article in journal (Refereed)
    Abstract [en]

    Aims To analyse the treatment and control of dyslipidaemia in patients at high and very high cardiovascular risk being treated for the primary prevention of cardiovascular disease (CVD) in Europe. Methods and Results Data were assessed from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA, ClinicalTrials.gov identifier: NCT00882336), which included a randomly sampled population of primary CVD prevention patients from 12 European countries (n = 7641). Patients' 10-year risk of CVD-related mortality was calculated using the Systematic Coronary Risk Evaluation (SCORE) algorithm, identifying 5019 patients at high cardiovascular risk (SCORE >= 5% and/or receiving lipid-lowering therapy), and 2970 patients at very high cardiovascular risk (SCORE >= 10% or with diabetes mellitus). Among high-risk individuals, 65.3% were receiving lipid-lowering therapy, and 61.3% of treated patients had uncontrolled low-density lipoprotein cholesterol (LDL-C) levels (>= 2.5 mmol/L). For very-high-risk patients (uncontrolled LDL-C levels defined as >= 1.8 mmol/L) these figures were 49.5% and 82.9%, respectively. Excess 10-year risk of CVD-related mortality (according to SCORE) attributable to lack of control of dyslipidaemia was estimated to be 0.72% and 1.61% among high-risk and very-high-risk patients, respectively. Among high-risk individuals with uncontrolled LDL-C levels, only 8.7% were receiving a high-intensity statin (atorvastatin >= 40 mg/day or rosuvastatin >= 20 mg/day). Among very-high-risk patients, this figure was 8.4%. Conclusions There is a considerable opportunity for improvement in rates of lipid-lowering therapy use and achievement of lipid-level targets in high-risk and very-high-risk patients being treated for primary CVD prevention in Europe.

  • 333.
    Hall, Trent
    et al.
    St Jude Childrens Res Hosp, Memphis, TN USA.;Univ Tennessee, Hlth Sci Ctr, Knoxville, TN 37996 USA..
    Walker, Megan
    St Jude Childrens Res Hosp, Arlington, VA USA..
    Ganuza, Miguel
    St Jude Childrens Res Hosp, Arlington, VA USA..
    Bordas, Marie
    Univ Paris 07, Paris, France..
    Holmfeldt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    McKinney-Freeman, Shannon
    St Jude Childrens Res Hosp, Arlington, VA USA..
    Nuclear Factor I/X Protects Murine Hematopoeitic Stem And Progenitor Cells From Stress-Induced Apoptosis In Ex Vivo Culture2016In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 44, no 9, p. S78-S78Article in journal (Other academic)
  • 334. Hallböök, H
    et al.
    Hägglund, H
    Stockelberg, D
    Nilsson, P-G
    Karlsson, K
    Björkholm, M
    Linderholm, M
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Linder, O
    Smedmyr, B
    Autologous and allogeneic stem cell transplantation in adult ALL: the Swedish Adult ALL Group experience2005In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 35, no 12, p. 1141-1148Article in journal (Refereed)
    Abstract [en]

    Adult patients with acute lymphoblastic leukaemia (ALL) have been treated according to national protocols in Sweden since 1986. Stem cell transplantation (SCT) has been recommended in first remission for patients with risk factors for relapse, and for standard risk patients only after relapse. In this retrospective study, the results of autologous and allogeneic SCT in these populations were evaluated. In total, 187 patients with a median age of 34 years (17-66 years) underwent SCT. The 5-year disease-free survival (DFS), for all patients, was 26% (Confidence intervals (CI) 20-32%). The 5-year DFS was higher for patients transplanted in first remission 32% (CI 24-40%) compared to 14% (CI 5-23%; P<0.0001) in patients transplanted beyond first remission. No significant differences in DFS (P=0.06) were determined between autologous, related donor and unrelated donor SCT in the whole cohort. A lower relapse rate was counterbalanced by higher treatment-related mortality in patients undergoing allogeneic SCT. In Philadelphia-positive ALL, allogeneic SCT was superior to autologous SCT, with a 5-year DFS of 30% (CI 12-47%) vs 0% (P=0.04). Limited chronic graft-versus-host-disease (GVHD) was associated with an improved DFS of 53% (CI 38-69%) compared to no chronic GVHD of 22% (CI 10-36%; P=0.0008), indicating a clinically important graft-versus-leukaemia effect.

  • 335.
    Halldorsdottir, Anna Margret
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Marincevic, Millaray
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stamatopoulos, Kostas
    Sander, Birgitta
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mantle cell lymphoma displays a homogenous methylation profile: A comparative analysis with chronic lymphocytic leukemia2012In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 87, no 4, p. 361-367Article in journal (Refereed)
    Abstract [en]

    Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.

  • 336.
    Halldén, Christer
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Mårtensson, A.
    Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund University, Malmö.
    Nilsson, Daniel
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, T.
    Department of Biology, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Lidén, Annika C.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Ljung, R.
    Department of Paediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Lund University, Malmö.
    Origin of Swedish hemophilia B mutations2013In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 11, no 11, p. 2001-2008Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: More than 1100 mutations that cause hemophilia B (HB) have been identified. At the same time, specific F9 mutations are present at high frequencies in certain populations, which raise questions about the origin of HB mutations.

    OBJECTIVES: To describe the mutation spectrum of all HB families in Sweden and investigate if mutations appearing in several families are due to independent recurrent mutations (RMs) or to a common mutation event (i.e. are identical by descent (IBD)).

    PATIENTS/METHODS: The registered Swedish HB population consists of patients from 86 families. Mutations were identified by resequencing and identical haplotypes were defined using 74 markers and a control population of 285 individuals. The ages of IBD mutations were estimated using ESTIAGE.

    RESULTS: Out of 77 presumably unrelated patients with substitution mutations, 47 patients (61%) had mutations in common with other patients. Haplotyping of the 47 patients showed that 24 patients had IBD mutations (51%) with estimated ages of between two and 23 generations. A majority of these patients had mild disease. Eight of the 15 mutations observed in more than one family were C>T transitions in CpG sites and all eight were RMs.

    CONCLUSIONS: The association of IBD mutations with a mild phenotype is similar to what has been previously observed in hemophilia A. Noteworthy features of the mutations that are common to more than one family are the equal proportions of patients with RM and IBD mutations and the correlation between the occurrence of RMs and C>T transitions at CpG sites.

  • 337.
    Halldén, Christer
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Nilsson, Daniel
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Säll, Torbjorn
    Department of Biology, Lund University.
    Lind-Halldén, Christina
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Lidén, Annika C.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Forskningsmiljön Biomedicin.
    Ljung, R.
    Department of Pediatrics and Malmö Center for Thrombosis and Hemostasis, Lund University.
    Origin of Swedish hemophilia A mutations2012In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 10, no 12, p. 2503-2511Article in journal (Refereed)
    Abstract [en]

     Background: Hemophilia A (HA) has a high level of variation within the disease class, with more than 1000 mutations being listed in the HAMSTeRS database. At the same time a number of F8 mutations are present in specific populations at high frequencies. Objectives: The simultaneous presence of large numbers of rare mutations and a small number of high-frequency mutations raises questions about the origins of HA mutations. The present study was aimed at describing the origins of HA mutations in the complete Swedish population. The primary issue was to determine what proportion of identical mutations are identical by descent (IBD) and what proportion are attributable to recurrent mutation events. The age of IBD mutations was also determined. Patients/Methods: In Sweden, the care of HA is centralized, and the Swedish HA population consists of ∼ 750 patients from > 300 families (35% severe, 15% moderate, and 50% mild). Identical haplotypes were defined by single-nucleotide polymorphism and microsatellite haplotyping, and the ages of the mutations were estimated with estiage. Results: Among 212 presumably unrelated patients with substitution mutations, 97 (46%) had mutations in common with other patients. Haplotyping of the 97 patients showed that 47 had IBD mutations (22%) with estimated ages of between two and 35 generations. The frequency of mild disease increased with an increasing number of patients sharing the mutations. Conclusions: A majority of the IBD mutations are mild and have age estimates of a few hundred years, but some could date back to the Middle Ages.

  • 338.
    Halldórsdóttir, Anna Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Genetic and Epigenetic Profiling of Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) both belong to the group of mature B-cell malignancies. However, MCL is typically clinically aggressive while the clinical course of CLL varies. CLL can be divided into prognostic subgroups based on IGHV mutational status and into multiple subsets based on closely homologous (stereotyped) B-cell receptors. In paper I we investigated 31 MCL cases using high-density 250K single-nucleotide polymorphism arrays and gene expression arrays. Although most copy-number aberrations (CNAs) were previously reported in MCL, a novel deletion was identified at 20q (16%) containing the candidate tumor suppressor gene ZFP64. A high proliferation gene expression signature was associated with poor prognosis, large CNAs, 7p gains and 9q losses. Losses at 1p/8p/13q/17p were associated with increased genomic complexity. In paper II we sequenced exons 4 to 8 of the TP53 gene in 119 MCL cases. 17p copy-number status was known from previous studies or determined by real-time quantitative polymerase chain reaction. TP53 mutations were detected in 14% of cases and were strongly associated with poor survival while 17p deletions were more common (32%) but did not predict survival. In papers III and IV we applied high-resolution genomic 27K methylation arrays to 20 MCL and 39 CLL samples. In paper III MCL displayed a homogenous methylation profile without correlation with the proliferation signature whereas MCL was clearly separated from CLL. Gene ontology analysis revealed enrichment of developmental genes, in particular homeobox transcription factor genes, among targets methylated in MCL. In paper IV we compared three different stereotyped CLL subsets: #1 (IGHV unmutated), #2 (IGHV3-21) and #4 (IGHV mutated). Many genes were differentially methylated between each two subsets and immune response genes (e.g. CD80 and CD86) were enriched among genes methylated in subset #1 but not in subsets #2/#4.

    In summary, CNAs were frequent and not random in MCL. Specific CNAs correlated with a high proliferation gene expression signature or genomic complexity. TP53 mutations predicted short survival whereas 17p deletions did not. A high proliferation signature was not associated with differential DNA methylation in MCL, which demonstrated a homogeneous methylation pattern. In contrast, genomic methylation patterns differed between MCL and CLL and between stereotyped CLL subsets.

  • 339.
    Hamad, Osama A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mitroulis, Ioannis
    Tech Univ Dresden, Dept Clin Pathobiochem, D-01062 Dresden, Germany.;Tech Univ Dresden, Inst Clin Chem & Lab Med, D-01062 Dresden, Germany..
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kozarcanin, Huda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Chavakis, Triantafyllos
    Tech Univ Dresden, Dept Clin Pathobiochem, D-01062 Dresden, Germany.;Tech Univ Dresden, Inst Clin Chem & Lab Med, D-01062 Dresden, Germany..
    Ricklin, Daniel
    Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA..
    Lambris, John D.
    Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA..
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Linnaeus Univ, Linnaeus Ctr Biomat Chem, Kalmar, Sweden..
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD182015In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 114, no 6, p. 1207-1217Article in journal (Refereed)
    Abstract [en]

    Complement component C3 has a potential role in thrombotic pathologies. It is transformed, without proteolytic cleavage, into C3(H2O) upon binding to the surface of activated platelets. We hypothesise that C3(H2O) bound to activated platelets and to platelet-derived microparticles (PMPs) contributes to platelet-PMN complex (PPC) formation and to the binding of PMPs to PMNs. PAR-1 activation of platelets in human whole blood from normal individuals induced the formation of CD16(+)/CD42a(+) PPC. The complement inhibitor compstatin and a C5a receptor antagonist inhibited PPC formation by 50 %, while monoclonal antibodies to C3(H2O) or anti-CD11b inhibited PPC formation by 75-100 %. Using plasma protein-depleted blood and blood from a C3-deficient patient, we corroborated the dependence on C3, obtaining similar results after reconstitution with purified C3. By analogy with platelets, PMPs isolated from human serum were found to expose C3(H2O) and bind to PMNs. This interaction was also blocked by the anti-C3(H2O) and anti-CD11b monoclonal antibodies, indicating that C3(H2O) and CD11b are involved in tethering PMPs to PMNs. We confirmed the direct interaction between C3(H2O) and CD11b by quartz crystal microbalance analysis using purified native C3 and recombinant CD11b/CD18 and by flow cytometry using PMP and recombinant CD11b. Transfectants expressing CD11b/CD18 were also shown to specifically adhere to surface-bound C3(H2O). We have identified contact-activated C3(H2O) as a novel ligand for CD11b/CD18 that mediates PPC formation and the binding of PMPs to PMNs. Given the various roles of C3 in thrombotic reactions, this finding is likely to have important pathophysiological implications.

  • 340. Hamadani, Mehdi
    et al.
    Hari, Parameswaran N.
    Zhang, Ying
    Carreras, Jeanette
    Akpek, Goerguen
    Aljurf, Mahmoud D.
    Ayala, Ernesto
    Bachanova, Veronika
    Chen, Andy I.
    Chen, Yi-Bin
    Costa, Luciano J.
    Fenske, Timothy S.
    Freytes, Cesar O.
    Ganguly, Siddhartha
    Hertzberg, Mark S.
    Holmberg, Leona A.
    Inwards, David J.
    Kamble, Rammurti T.
    Kanfer, Edward J.
    Lazarus, Hillard M.
    Marks, David I.
    Nishihori, Taiga
    Olsson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Reddy, Nishitha M.
    Rizzieri, David A.
    Savani, Bipin N.
    Solh, Melhem
    Vose, Julie M.
    Wirk, Baldeep
    Maloney, David G.
    Smith, Sonali M.
    Montoto, Silvia
    Saber, Wael
    Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell Transplantation2014In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 20, no 11, p. 1729-1736Article in journal (Refereed)
    Abstract [en]

    The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P < .001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.

  • 341. Hammer, Anne Sofie Borg
    et al.
    Juul-Dam, Kristian
    Sandahl, Julie Damgaard
    Abrahamsson, Jonas
    Balwierz, Walentyna
    Guilmatre, Audrey
    Haltrich, Iren
    Jahnukainen, Kirsi
    Kolb, E. Anders
    Kovacs, Gabor
    Leverger, Guy
    Locatelli, Franco
    Masetti, Riccardo
    Norén-Nyström, Ulrika
    Umeå University.
    Raimondi, Susana C.
    Rasche, Mareike
    Reinhardt, Dirk
    Taki, Tomohiko
    Tomizawa, Daisuke
    Zeller, Bernward
    Hasle, Henrik
    Kjeldsen, Eigil
    Hypodiploidy in Childhood Acute Myeloid Leukemia: A Retrospective Cohort Study within the International Berlin-Frankfurt-Munster Study Group2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Article in journal (Other academic)
  • 342.
    Hansson, Lotta
    et al.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Winqvist, Maria
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Asklid, Anna
    Karolinska Inst, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden..
    Andersson, P-O
    Boras Hosp, Dept Hematol, Boras, Sweden..
    Karlsson, Karin
    Univ Lund Hosp, Dept Hematol, S-22185 Lund, Sweden..
    Karlsson, Claes
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Lauri, Birgitta
    Sunderbyn Hosp, Dept Hematol, Sunderbyn Lulea, Sweden..
    Lundin, Jeanette
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden..
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Norin, Stefan
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Sandstedt, Anna
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Osterborg, Anders
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden..
    Real-World Results on Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Data from 97 Swedish Patients Treated in a Compassionate Use Program2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 343. Harrison, C.
    et al.
    Tiplady, C.
    Fernandes, S.
    Knechtli, C.
    Sadullah, S.
    Besses, C.
    Greisshammer, M.
    Gugliotta, L.
    Kiladjian, J. J.
    Hamdani, M.
    Achenbach, H.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Treatment of essential thrombocythaemia in Europe: an observational study of 3649 high-risk patients in EXELS2015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, no S1, p. 7-7Article in journal (Other academic)
  • 344.
    Harrysson, Sara
    et al.
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Hematol, Solna, Sweden.
    Eloranta, Sandra
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden.
    Ekberg, Sara
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jerkeman, Mats
    Lund Univ, Inst Clin Sci, Dept Oncol & Pathol, Lund, Sweden.
    Hasselblom, Sverker
    Reg Halland, Dept Res Dev & Educ, Halmstad, Sweden.
    Wahlin, Björn E.
    Karolinska Univ Hosp, Dept Hematol, Solna, Sweden;Karolinska Inst, Div Hematol, Dept Med Huddinge, Stockholm, Sweden.
    Andersson, Per-Ola
    South Alvsborg Hosp, Dept Hematol, Boras, Sweden;Gothenburg Univ, Sahlgrenska Acad, Gothenburg, Sweden.
    Smedby, Karin E.
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Hematol, Solna, Sweden.
    Incidence and Outcome of Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) in a Population-Based Cohort of 3165 Patients in Sweden2018In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Article in journal (Other academic)
  • 345. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    De Bont, Evelina S.
    de Haas, Valerie
    De Moerloose, Barbara
    Forestier, Erik
    Ha, Shau Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Reedijk, Ardine
    Saks, Kadri
    Zeller, Bernward
    Anthracycline Type during Induction Associated with Outcome in Pediatric t(8;21) and Inv(16) AML2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 346. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur Gisli
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 20042012In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, no 5, p. 978-984Article in journal (Refereed)
    Abstract [en]

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

  • 347.
    Hasni, Muhammad Sharif
    et al.
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Berglund, Mattias
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Yakimchuk, Konstantin
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Guan, Jiyu
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Linderoth, Johan
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Okret, Sam
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Estrogen receptor beta 1 in diffuse large B-cell lymphoma growth and as a prognostic biomarker2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 2, p. 418-427Article in journal (Refereed)
    Abstract [en]

    Diffuse large B-cell lymphoma (DLBCL) shows a higher incidence in males versus females. Epidemiological studies have shown that female gender is a favorable prognostic factor, which may be explained by estrogens. Here we show that when grafting human DLBCL cells to immunocompromised mice, tumor growth in males is faster. When treating mice grafted with either germinal center or activated B-cell like DLBCL cells with the selective estrogen receptor beta (ER beta) agonist diarylpropionitrile, tumor growth was significantly inhibited. Furthermore, nuclear ER beta 1 expression analysis in primary DLBCL's by immunohistochemistry revealed expression in 89% of the cases. Nuclear ERb1 expression was in a univariate and multivariate analysis, an independent prognostic factor for adverse progression-free survival in Rituximab-chemotherapy treated DLBCL (p = 0.02 and p = 0.04, respectively). These results suggest that estrogen signaling through ERb1 is an interesting future therapeutic target for treatment of DLBCL, and that ERb1 expression can be used as a prognostic marker.

  • 348.
    Hedbrant, Johan
    et al.
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering.
    Bjorne, Assar
    Specialisttandvården, Lasarettet Ystad.
    Ny mätmetod för käkmuskulaturen kan finna orsaken till tinnitus: Slutrapport Nutek 92-119041997Report (Other academic)
    Abstract [sv]

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

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

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

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

  • 349. Hehlmann, R.
    et al.
    Cortes, J.
    Gambacorti-Passerini, C.
    Goldberg, S. L.
    Khoury, H. J.
    Mauro, M.
    Michallet, M.
    Mohamed, H.
    Powell, T.
    Paquette, R.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Subar, M.
    Zyczynski, T.
    TYROSINE KINASE INHIBITOR (TKI) SWITCHING: EXPERIENCE FROM SIMPLICITY, A PROSPECTIVE OBSERVATIONAL STUDY OF CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA (CP-CML) PATIENTS IN CLINICAL PRACTICE2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no S1, p. 328-329Article in journal (Other academic)
  • 350.
    Hehlmann, Ruediger
    et al.
    Heidelberg Univ, Weinheim, Germany;ELN Fdn, Weinheim, Germany.
    Cortes, Jorge E.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Zyczynski, Teresa
    Bristol Myers Squibb Co, Princeton, NJ USA.
    Gambacorti-Passerini, Carlo
    Univ Milano Bicocca, San Gerardo Hosp, Monza, Italy.
    Goldberg, Stuart L.
    Hackensack Univ Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA.
    Mauro, Michael J.
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA.
    Michallet, Mauricette
    Ctr Hosp Lyon Sud, Pierre Benite, France.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Williams, Loretta A.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Gajavelli, Srikanth
    Bristol Myers Squibb Co, Princeton, NJ USA.
    DeGutis, Irene
    Bristol Myers Squibb Co, Princeton, NJ USA.
    Sen, Ginny P.
    ICON Clin Res LLC, San Francisco, CA USA.
    Paquette, Ron L.
    UCLA Med Ctr, Los Angeles, CA USA.
    Tyrosine kinase inhibitor interruptions, discontinuations and switching in patients with chronic-phase chronic myeloid leukemia in routine clinical practice: SIMPLICITY2019In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 94, no 1, p. 46-54Article in journal (Refereed)
    Abstract [en]

    SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor (TKI) use and management patterns in patients with chronic phase-chronic myeloid leukemia in the US and Europe in routine clinical practice. Herein we describe interruptions, discontinuations and switching of TKI therapy during the initial 2 years of treatment among 1121 patients prospectively enrolled between October 1, 2010 and March 7, 2017. Patient characteristics were broadly similar between the imatinib (n = 370), dasatinib (n = 376), and nilotinib (n = 375) cohorts. Treatment interruptions occurred in 16.4% (year 1) and 4.0% (year 2) of patients, mainly attributed to hematologic intolerances. Treatment discontinuations occurred in 21.8% (year 1) and 10.2% (year 2) of patients, with the highest rate within the first 3 months for intolerance. Switching of TKI was seen in 17.8% (year 1) and 9.5% (year 2) of patients. Significant associations were found between TKI switching and female gender (year 1), age >= 65 years at diagnosis (year 2) and treatment with imatinib (year 2). Intolerance was the most common reason given for patients discontinuing and for switching TKI therapy; however resistance was also cited. Lack of response monitoring in routine clinical practice may have resulted in lower identification of resistance in this dataset. Data from SIMPLICITY suggest that, in routine clinical practice, intolerance and resistance to TKIs influence decisions to change treatment. Changes in TKI therapy are frequent, with nearly a third of patients discontinuing their first-line TKI.

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