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  • 1. Andersen, Christen Lykkegaard
    et al.
    Bjorn, Mads Emil
    McMullin, Mary Frances
    Harrison, Claire
    Samuelsson, Jan
    Ejerblad, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Zweegman, Sonja
    Fernandes, Savio
    Bareford, David
    Knapper, Steven
    Lofvenberg, Eva
    Linder, Olle
    Andreasson, Bjorn
    Ahlstrand, Erik
    Jensen, Morten Krogh
    Bjerrum, Ole Weis
    Vestergaard, Hanne
    Larsen, Herdis
    Klausen, Tobias Wirenfeldt
    Mourits-Andersen, Torben
    Skov, Vibe
    Thomassen, Mads
    Kruse, Torben
    Gronbaek, Kirsten
    Hasselbalch, Hans Carl
    Circulating YKL-40 in patients with essential thrombocythemia and polycythemia vera treated with the novel histone deacetylase inhibitor vorinostat2014In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 38, no 7, p. 816-821Article in journal (Refereed)
    Abstract [en]

    YKL-40 regulates vascular endothelial growth factors and induces tumor proliferation. We investigated YKL-40 before and after treatment with vorinostat in 31 polycythemia vera (PV) and 16 essential thrombocythemia (ET) patients. Baseline PV patient levels were 2 times higher than in healthy controls (P<0.0001) and 1.7 times higher than in ET (P = 0.02). A significant correlation between YKL-40 at baseline and neutrophils, CRP, LDH, JAK2V617F and platelets in PV patients was observed, as well as a significantly greater reduction of YKL-40 levels in PV patients responding to therapy. YKL-40 might be a novel marker of disease burden and progression in myeloproliferative neoplasms. (C) 2014 Elsevier Ltd. All rights reserved.

  • 2.
    Andersen, Christen Lykkegaard
    et al.
    Dept Hematol, Roskilde Univ Hosp, Roskilde, Denmark..
    Bjorn, Mads Emil
    Dept Hematol, Roskilde Univ Hosp, Roskilde, Denmark..
    McMullin, Mary Frances
    Dept Haematol, Queen Univ Belfast Antrim, Belfast, North Ireland.
    Harrison, Claire
    Dept Haematol, NHS Fdn Trust, London, England.
    Samuelsson, Jan
    Dept Internal Med, Stockholm South Hosp, Stockholm, Sweden..
    Ejerblad, Elisabeth
    Dept Hematol, Univ Uppsala Hosp, Uppsala, Sweden..
    Zweegman, Sonja
    Dept Hematol, Vrije Univ Med Ctr, Amsterdam, Netherlands..
    Fernandes, Savio
    Dept Haematol, Russells Hall Hosp, Dudley, England.
    Bareford, David
    Dept Haematol, Russells Hall Hosp, Dudley, England.
    Knapper, Steven
    Dept Haematol, Cardiff Univ, Cardiff, UK.
    Lofvenberg, Eva
    Hematol Ctr, Karolinska Univ Hosp, Stockholm, Sweden.
    Linder, Olle
    Dept Med, Div Hematol, Örebro Univ Hosp, Örebro, Sweden..
    Andreasson, Bjorn
    Dept Hematol, NU Hosp Org, Uddevalla Hosp, Uddevalla, Sweden.
    Ahlstrand, Erik
    Örebro University Hospital. Dept Med, Div Hematol, Örebro University Hospital, Örebro, Sweden.
    Jensen, Morten Krogh
    Dept Hematol, Herlev Hosp, Herlev, Denmark.
    Bjerrum, Ole Weis
    Dept Hematol, Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark.
    Vestergaard, Hanne
    Dept Hematol, Odense Univ Hosp, Odense, Denmark.
    Larsen, Herdis
    Dept Hematol, Dept Internal Med, Viborg Hosp, Viborg, Denmark.
    Klausen, Tobias Wirenfeldt
    Dept Hematol,Herlev Hosp, Herlev, Denmark.
    Mourits-Andersen, Torben
    Dept Hematol, Esbjerg Cent Hosp, Esbjerg, Denmark.
    Skov, Vibe
    Dept Clin Genet, Odense Univ Hosp, Odense, Denmark.
    Thomassen, Mads
    Dept Clin Genet, Odense Univ Hosp, Odense, Denmark.
    Kruse, Torben
    Dept Clin Genet, Odense Univ Hosp, Odense, Denmark.
    Gronbaek, Kirsten
    Dept Hematol, Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark.
    Hasselbalch, Hans Carl
    Dept Hematol, Roskilde Univ Hosp, Roskilde, Denmark.
    Circulating YKL-40 in patients with essential thrombocythemia and polycythemia vera treated with the novel histone deacetylase inhibitor vorinostat2014In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 38, no 7, p. 816-821Article in journal (Refereed)
    Abstract [en]

    YKL-40 regulates vascular endothelial growth factors and induces tumor proliferation. We investigated YKL-40 before and after treatment with vorinostat in 31 polycythemia vera (PV) and 16 essential thrombocythemia (ET) patients. Baseline PV patient levels were 2 times higher than in healthy controls (P<0.0001) and 1.7 times higher than in ET (P = 0.02). A significant correlation between YKL-40 at baseline and neutrophils, CRP, LDH, JAK2V617F and platelets in PV patients was observed, as well as a significantly greater reduction of YKL-40 levels in PV patients responding to therapy. YKL-40 might be a novel marker of disease burden and progression in myeloproliferative neoplasms.

  • 3. Barbany, Gisela
    et al.
    Andersen, Mette K.
    Autio, Kirsti
    Borgstrom, Georg
    Cavelier Franco, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Golovleva, Irina
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johansson, Bertil
    Johannsson, Johann H.
    Kjeldsen, Eigil
    Nordgren, Ann
    Palmqvist, Lars
    Forestier, Erik
    Additional aberrations of the ETV6 and RUNX1 genes have no prognostic impact in 229 t(12;21)(p13;q22)-positive B-cell precursor acute lymphoblastic leukaemias treated according to the NOPHO-ALL-2000 protocol2012In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 36, no 7, p. 936-938Article in journal (Refereed)
  • 4. Barbany, Gisela
    et al.
    Andersen, Mette K
    Autio, Kirsti
    Borgström, Georg
    Franco, Lucia Cavalier
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johansson, Bertil
    Johannsson, Johann H
    Kjeldsen, Eigil
    Nordgren, Ann
    Palmqvist, Lars
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Additional aberrations of the ETV6 and RUNX1 genes have no prognostic impact in 229 t(12;21)(p13;q22)-positive B-cell precursor acute lymphoblastic leukaemias treated according to the NOPHO-ALL-2000 protocol2012In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 36, no 7, p. 936-938Article in journal (Refereed)
  • 5. Besses, Carlos
    et al.
    Kiladjian, Jean-Jacques
    Griesshammer, Martin
    Gugliotta, Luigi
    Harrison, Claire
    Coll, Ruth
    Smith, Jonathan
    Abhyankar, Brihad
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cytoreductive treatment patterns for essential thrombocythemia in Europe. Analysis of 3643 patients in the EXELS study2013In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 37, no 2, p. 162-168Article in journal (Refereed)
    Abstract [en]

    EXELS is an ongoing phase IV non-interventional study; 3643 high-risk patients with essential thrombocythemia (ET) were recruited across 13 European countries. We report patient characteristics and cytoreductive treatment patterns of ET across Europe. Hydroxycarbamide (HC; 64.3%) and anagrelide (22.0%) were the two main cytoreductive treatments prescribed. The proportions of patients taking either HC or anagrelide varied across countries, as did the number of patients receiving anti-aggregatory therapy in addition to cytoreductive treatment. This real-world evidence demonstrates that, generally, treatment patterns of ET across Europe adhere to expert recommendations, with some notable variations between countries.

  • 6.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Besses, C.
    Hosp del Mar, IMIM, Dept Haematol, Barcelona, Spain..
    Griesshammer, M.
    Johannes Wesling Med Ctr, Hematol & Oncol, Minden, Germany..
    Gugliotta, L.
    St Orsola Malpighi Hosp, Dept Haematol, L&A Seragnoli, Bologna, Italy..
    Harrison, C.
    Guys & St Thomas NHS Fdn Trust, Dept Haematol, London, England..
    Hamdani, M.
    Shire Pharmaceut, Global Biometr, Wayne, PA USA..
    Achenbach, H.
    Shire AG, Res & Dev, Eysins, Switzerland..
    Kiladjian, J-J
    Hop St Louis, APHP, Ctr Invest Clin, Paris, France..
    Treatment of high risk ET: data from the EXELS study2016In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 44, p. S7-S8Article in journal (Other academic)
  • 7.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Folkvaljon, Folke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Fac Life Sci & Med, London, England.
    Besses, Carlos
    Hosp del Mar, IMIM, Dept Haematol, Barcelona, Spain.
    Griesshammer, Martin
    Johannes Wesling Med Ctr, Hematol & Oncol, Minden, Germany.
    Gugliotta, Luigi
    St Orsola Malpighi Hosp, Dept Haematol L&A Seragnoli, Bologna, Italy.
    Wu, Jingyang
    Shire Pharmaceut, Global Biometr, Lexington, MA USA.
    Achenbach, Heinrich
    Shire GmbH, Res & Dev, Zug, Switzerland.
    Kiladjian, Jean-Jacques
    St Louis Hosp, APHP, Clin Invest Ctr, Paris, France.
    Harrison, Claire N.
    Guys & St Thomas NHS Fdn Trust, Dept Haematol, London, England.
    Leukemic transformation and second cancers in 3649 patients with high-risk essential thrombocythemia in the EXELS study2018In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 74, p. 105-109Article in journal (Refereed)
    Abstract [en]

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

  • 8.
    Creignou, M.
    et al.
    Karolinska Inst Stockholm, Huddinge Ctr Regenerat Med & Hematol, Dept Med, Stockholm, Sweden..
    Ejerblad, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Antunovic, P.
    Linkoping Univ Hosp, Dept Hematol, Linkoping, Sweden..
    Garelius, H.
    Sahlgrens Univ Hosp, Dept Internal Med, Sect Hematol & Coagulat, Gothenburg, Sweden..
    Lorenz, F.
    Norrland Univ Hosp, Dept Med, Umea, Sweden..
    Nilsson, L.
    Lund Univ Hosp, Dept Med, Lund, Sweden..
    Rasmussen, B.
    Orebro Univ Hosp, Dept Med, Orebro, Sweden..
    Walldin, G.
    Karolinska Inst Stockholm, Huddinge Ctr Regenerat Med & Hematol, Dept Med, Stockholm, Sweden..
    Jansson, M.
    Karolinska Inst Stockholm, Huddinge Ctr Regenerat Med & Hematol, Dept Med, Stockholm, Sweden..
    Karimi, M.
    Karolinska Inst Stockholm, Huddinge Ctr Regenerat Med & Hematol, Dept Med, Stockholm, Sweden..
    Hellstrom-Lindberg, E.
    Karolinska Inst Stockholm, Huddinge Ctr Regenerat Med & Hematol, Dept Med, Stockholm, Sweden..
    Jadersten, M.
    Karolinska Inst Stockholm, Huddinge Ctr Regenerat Med & Hematol, Dept Med, Stockholm, Sweden..
    Targeted Sequencing of A Cohort Of 385 Patients With Myelodysplastic Syndromes: A Multicenter, Population-Based Study From Sweden2017In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 55, p. S138-S139Article in journal (Other academic)
  • 9.
    Dickinson, M.
    et al.
    Peter MacCallum Canc Ctr, Haematol Dept, Melbourne, Vic, Australia..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Fenaux, P.
    Univ Paris 13, Hop Avicenne, Assistance Publ Hop Paris, Bobigny, France..
    Mittelman, M.
    Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel..
    Verma, A.
    Albert Einstein Coll Med, Dept Med, Div Med Oncol, New York, NY USA..
    Portella, M. S. O.
    Novartis Pharmaceut, Oncol Clin Dev, E Hanover, NJ USA..
    Burgess, P.
    Novartis Pharma AG, Global Drug Dev, Basel, Switzerland..
    Platzbecker, U.
    Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Internal Med 1, Dresden, Germany..
    Eltrombopag In Combination With Azacitidine For First-Line Treatment Of Mds Patients With Thrombocytopenia: The Randomized, Placebo-Controlled, Phase Iii, Support Study2017In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 55, p. S23-S24Article in journal (Other academic)
  • 10.
    Ekbäck, Maria [Palmetun]
    et al.
    Department of Dermatology, Örebro University Hospital, Örebro, Sweden; Department of Medicine, Örebro University, Örebro, Sweden.
    Uggla, Bertil
    Department of Internal Medicine, Örebro University Hospital, Örebro, Sweden.
    Paraneoplastic pemphigus associated with chronic lymphocytic leukaemia: treatment with alemtuzumab2012In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 36, no 8, p. E190-E191Article in journal (Refereed)
  • 11.
    Eriksson, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Chantzi, Efthymia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gustafsson, Mats G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.2017In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 63, p. 41-46Article in journal (Refereed)
    Abstract [en]

    We previously reported that the anti-malarial drug quinacrine has potential to be repositioned for treatment of acute myeloid leukemia (AML). As a next step towards clinical use, we assessed the efficacy of quinacrine in an AML-PS mouse model and investigated possible synergistic effects when combining quinacrine with nine other antileukemic compounds in two AML cell lines. Furthermore, we explored the in vivo activity of quinacrine in combination with the widely used AML agent cytarabine. The in vivo use of quinacrine (100mg/kg three times per week for two consecutive weeks) significantly suppressed circulating blast cells at days 30/31 and increased the median survival time (MST). The in vitro drug combination analysis yielded promising synergistic interactions when combining quinacrine with cytarabine, azacitidine and geldanamycin. Finally, combining quinacrine with cytarabine in vivo showed a significant decrease in circulating leukemic blast cells and increased MST compared to the effect of either drug used alone, thus supporting the findings from the in vitro combination experiments. Taken together, the repositioning potential of quinacrine for treatment of AML is reinforced by demonstrating significant in vivo activity and promising synergies when quinacrine is combined with different agents, including cytarabine, the hypomethylating agent azacitidine and HSP-90 inhibitor geldanamycin.

  • 12.
    Fergedal, May
    et al.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Åström, Maria
    Department of Internal Medicine, Örebro Medical Center Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Department of Internal Medicine, Örebro Medical Center Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Differences in CD14 and alpha-naphthyl acetate esterase positivity and relation to prognosis in AML1998In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 22, no 1, p. 25-30Article in journal (Refereed)
    Abstract [en]

    Alpha-naphthyl acetate esterase (ANAE) and CD14 expression, used for determination of monocytic cells, were compared and related to prognosis in 65 AML patients. Bone marrow aspiration material from AML patients has been used for the cytochemistry as well as flow cytometry. All non-erythroid cells have been included in the evaluation in both methods. 17/65 cases showed at least 15% difference between the proportion CD14 and ANAE positive cells. Cases with 20% or more CD14 positivity had poorer prognosis. For FAB classes M0-M3, presence of 10% or more CD14 was negative for overall survival (P = 0.01). ANAE did not show significant prognostic influence.

  • 13. Flordal Thelander, Emma
    et al.
    Ichimura, Koichi
    Collins, V. Peter
    Walsh, Sarah H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Barbany, Gisela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hagberg, Anette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Larsson, Catharina
    Lagercrantz, Svetlana
    Detailed assessment of copy number alterations revealing homozygous deletions in 1p and 13q in mantle cell lymphoma2007In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 31, no 9, p. 1219-1230Article in journal (Refereed)
    Abstract [en]

    Mantle cell lymphoma (MCL) is characterized by over-expression of cyclin Dl as a result of the characteristic t(11;14)(q13;q32). However, this translocation alone has proven not to be sufficient for lymphomagenesis, suggesting the involvement of additional alterations. We have characterized 35 cases of MCL by array comparative genomic hybridization with an average resolution of 0.97Mb distributed over the complete human genome. The most common alterations were losses in 1p13.2–p31.1, 6q16.2–q27, 8p21.3, 9p13.2–p24.3, 9q13–q31.3, 11q14.3–q23.3, 13q14.13–q21.31, 13q33.1–q34, and 22q11.23–q13.33 and gains involving 3q21.2–q29, 7p12.1–p22.3, 8q24.13–q24.23, and 18q21.33–q22.3. Four homozygous deletions were identified in totally three patients; two overlapping at 1p32.3, and two adjacent at 13q32.3. The homozygous deletions at 1p32.3 cover the CDKN2C locus (coding for p18), while the region at 13q32.3 does not encompass any known tumor suppressor genes. A gain in 3q was significantly associated with shorter survival (P=0.047).

  • 14. Gruber, A
    et al.
    Björkholm, M
    Brinch, L
    Evensen, S
    Gustavsson, B
    Hedenus, M
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Hematology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Lofvenberg, E
    Nesthus, I
    Simonsson, B
    Sjö, M
    Stenke, L
    Tangen, JM
    Tidefelt, U
    Uden, AM
    Paul, C
    Liliemark, J
    A phase I/II study of the MDR modulator Valspodar (PSC 833) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia2003In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 27, no 4, p. 323-328Article in journal (Refereed)
    Abstract [en]

    The cyclosporine analog Valspodar (PSC 833, Novartis Pharma) is a strong inhibitor of the mdr1 gene product p-glycoprotein (pgp). A phase I/II study was conducted in order to evaluate if addition of Valspodar to treatment with daunorubicin and cytarabine, given to patients with primary refractory or relapsed acute myeloid leukemia, could increase the complete remission rate. Fifty-three patients were treated in cohorts of three to six patients. Twelve patients reached a complete remission in bone marrow, five of whom also normalized their peripheral blood values. Three patients experienced treatment-related deaths from pneumonia, liver failure and cerebral hemorrhage, respectively. It is concluded that Valspodar 10mg/kg per 24h in combination with daunorubicin 45mg/m2 for 3 days and cytarabine 1g/m2 twice daily for 4 days is tolerable in this heavily pre-treated group of patients. Due to the moderate treatment results, the phase II part of the study was ended prematurely. The modulation of only pgp did not give an obvious improvement of the treatment results in this group of patients. ⌐ 2002 Elsevier Science Ltd. All rights reserved.

  • 15.
    Hagberg, Anette
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wickenberg-Bolin, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barbany, Gisela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gene expression analysis identifies a genetic signature potentially associated with response to alpha-IFN in chronic phase CML patients2007In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 31, no 7, p. 931-938Article in journal (Refereed)
    Abstract [en]

    Microarray-based gene expression analysis was performed on diagnostic chronic phase CML patient samples prior to interferon treatment. Fifteen patient samples corresponding to six cytogenetic responders and nine non-responders were included. Genes differentially expressed between responder and non-responder patients were listed and a subsequent leave-one-out cross validation (LOOV) procedure showed that the top 20 genes allowed the highest prediction accuracy. The relevant genes were quantified by real-time PCR that supported the microarray results. We conclude that it might be possible to use gene expression analysis to predict future response to interferon in CML diagnostic samples.

  • 16.
    Jansson, Johan
    et al.
    Linnaeus University, Faculty of Science and Engineering, School of Natural Sciences. University of Rochester, USA.
    Hsu, Yu-Chiao
    University of Rochester, USA.
    Kuzin, Igor I.
    University of Rochester, USA.
    Campbell, Andrew
    University of Rochester, USA.
    Mullen, Craig A.
    University of Rochester, USA.
    Acute lymphoblastic leukemia cells that survive combination chemotherapy in vivo remain sensitive to allogeneic immune effects2011In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 6, p. 800-807Article in journal (Refereed)
    Abstract [en]

    Allogeneic hematopoietic stem cell transplantation is often performed for patients with acute lymphoblastic leukemia (ALL) whose disease has relapsed after chemotherapy treatment. However, graft versus leukemia (GVL) effects in ALL are generally weak and the mechanisms of this weakness are unknown. These studies tested the hypothesis that ALL cells that have survived conventional chemotherapy in vivo acquire relative resistance to the allogeneic GVL effect. C57BL/6 mice were injected with murine pre-B ALL lines driven by human mutations and then were treated with combination chemotherapy. ALL cells surviving therapy were analysed in vitro and in vivo for acquisition of resistance to chemotherapy, radiation, cytolytic T cells, NK cells, LAK cells and cytokines. In vivo drug treatment did lead to leukemia population with more rapid proliferation and also decreased sensitivity to vincristine, doxorubicin and radiation. However, drug treatment did not produce ALL populations that were less sensitive to GVL effects in vitro or in vivo.

  • 17.
    Kaderi, Mohd Arifin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Mansouri, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Zainuddin, Norafiza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Gunnarsson, Rebeqa
    Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden.
    Jansson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Kimby, Eva
    Department of Hematology, Karolinska Institutet, Stockholm, Sweden.
    Åleskog, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lundin, Jeannette
    Departments of Hematology/Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Melbye, Mads
    Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden.
    Jurlander, Jesper
    Department of Hematology, The Leukemia Laboratory, Rigshospitalet, Copenhagen, Denmark.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia2010In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 34, no 3, p. 335-339Article in journal (Refereed)
    Abstract [en]

    The 309T>G polymorphism in the promoter region of the MDM2gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment. Furthermore, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status and recurrent genomic aberrations. In summary, this study argues against the use of the MDM2 SNP309 as a prognostic marker in CLL.

  • 18.
    Kaderi, Mohd Arifin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jansson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Merup, Mats
    Karlsson, Karin
    Roos, Göran
    Åleskog, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tobin, Gerard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia2008In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 32, no 6, p. 984-987Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease with no known single predisposing genetic factor shown in all cases. Recently, a single nucleotide polymorphism (SNP) T393C in the GNAS1 gene has been reported to have a clinical impact on CLL progression and overall survival. In order to further investigate the T393C SNP in CLL, we have genotyped 279 CLL cases and correlated the genotypes to clinical outcome and other known prognostic factors such as the immunoglobulin heavy chain variable (IGHV) gene mutation status and CD38 expression. In the present study, no difference in overall survival or time to treatment was observed in the CLL patients with the different genotypes in contrast to the previous report. Furthermore, no correlation was observed with the T393C genotypes and IGHV mutational status, Binet stage or CD38 in this cohort. In summary, our data does not support the use of the T393C GNAS SNP as a clinical prognostic factor in CLL.

  • 19.
    Knaust, Eva
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Porwit-MacDonald, Anna
    Department of Pathology, Division of Hematology, Karolinska Hospital and Institutet, Stockholm, Sweden.
    Gruber, Astrid
    Departments of Medicine, Division of Hematology, Karolinska Hospital and Institutet, Stockholm, Sweden.
    Xu, Dawei
    Departments of Medicine, Division of Hematology, Karolinska Hospital and Institutet, Stockholm, Sweden.
    Peterson, Curt
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Different effects of metabolic inhibitors and cyclosporin A on daunorubicin transport in leukemia cells from patients with AML2003In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 27, no 2, p. 183-191Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to determine the role of transport proteins in daunorubicin (Dnr) accumulation and efflux in leukemia cells from 36 patients with acute myeloid leukemia (AML). Mononuclear cells were isolated and incubated with 1 μM Dnr with/without addition of 3 μM cyclosporin A (CyA) or metabolic inhibitors (MI). Cellular Dnr concentration in leukemia blast cells was measured with flow cytometry. After washing and reincubation of the cells in drug-free medium, Dnr efflux was followed with/without addition of CyA or MI. Levels of mRNA expression for mdr1, multidrug resistance associated protein (mrp) and lung resistance protein (lrp) were determined with reverse transcriptase-polymerase chain reaction (RT-PCR). MI enhanced cellular Dnr accumulation to a higher extent than CyA whereas CyA reduced Dnr efflux more efficiently than MI (P<0.001). There was a significant difference in Dnr accumulation between samples with low and high mdr1 mRNA levels but only in the presence of MI or CyA. Our results imply that other factors than P-glycoprotein (Pgp) are of major importance for in vitro Dnr accumulation in AML blasts and that the role of Pgp as a drug efflux pump is not conclusive.

  • 20.
    Li, Aihong
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rosenquist, R
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindh, Jack
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Detailed clonality analysis of relapsing precursor B acute lymphoblastic leukemia: implications for minimal residual disease detection.2001In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 25, no 12, p. 1033-45Article in journal (Refereed)
    Abstract [en]

    Genetic instability has important implications for detection of minimal residual disease (MRD) when the target is a clonal genetic marker revealed at diagnosis. A successful MRD detection approach requires a stable marker and for lymphoid leukemias clonal rearrangements of immunoglobulin (Ig) and T cell receptor (TCR) genes are commonly used. In the present study, Ig heavy chain (IgH) and TCR (gamma and delta) genes were studied in 18 consecutive, relapsing precursor-B ALL patients. At least one clonal rearrangement was found in all cases at presentation (IgH 94%, TCRgamma 39% and TCRdelta 28%). An altered rearrangement pattern between diagnosis and relapse was demonstrated in 14 patients (78%). At least one stable molecular target was found in 13 out of 18 cases (72%). Clonal differences between diagnostic and relapse samples were explained by: (1) loss of original rearrangements; (2) V(H) to DJ(H) joining; (3) V(H) gene replacement; (4) appearance of new rearrangements. In two cases with apparently new IgH gene rearrangements at relapse extended sequencing of the diagnostic samples revealed minor clonal rearrangements identical to the relapse clones. Interestingly, one patient displayed instability on both the IgH and TCR gene loci, whereas a stable Igkappa rearrangement was found at presentation and relapse. These data show that clonal diversity is common in precursor-B ALL and strongly suggest that MRD detection should include multiple gene targets to minimize false-negative samples. Even so, five of our 18 relapse cases (28%) lacked stable clonal markers and should have been unsuitable for MRD detection.

  • 21.
    Lönnerholm, Gudmar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Thörn, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Heldrup, Jesper
    Jacobsson, Stefan
    Li, Aihong
    Olofsson, Tor
    Porwit, Anna
    Söderhäll, Stefan
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Forestier, Erik
    In vitro cellular drug sensitivity at diagnosis is correlated to minimal residual disease at end of induction therapy in childhood acute lymphoblastic leukemia2009In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 33, no 1, p. 46-53Article in journal (Refereed)
    Abstract [en]

    Leukemic cells from 85 children with newly diagnosed precursor B-lineage ALL were tested for in vitro drug sensitivity to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. There was a significant correlation between MRD day 29 and in vitro sensitivity to prednisolone (p<0.001) and doxorubicin (p=0.017), drugs administered during induction therapy. In patients with t(12;21) (n=20), in vitro sensitivity to doxorubicin was an independent factor for MRD <0.1% (p=0.031;  R2=0.66). Thus, data show that in vitro drug sensitivity at diagnosis is correlated to cell kill during induction therapy as measured by MRD day 29.

  • 22.
    Lönnerholm, Gudmar
    et al.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Thörn, Ingrid
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Sundström, Christer
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Frost, Britt-Marie
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Abrahamsson, Jonas
    Qween Silvias Children's Hospital, Gothenburg, Sweden.
    Behrendtz, Mikael
    Department of Pediatrics, University Hospital, Linköping, Sweden.
    Heldrup, Jesper
    Department of Pediatrics, Lund University Hospital, Lund, Sweden.
    Jacobsson, Stefan
    Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Li, Aihong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Olofsson, Tor
    Division of Hematology & Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Porwit, Anna
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Söderhäll, Stefan
    Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Rolf
    Department of Medical Sciences, Section of Pharmacology, University Hospital, Uppsala, Sweden.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    In vitro cellular drug sensitivity at diagnosis is correlated to minimal residual disease at end of induction therapy in childhood acute lymphoblastic leukemia2009In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 33, no 1, p. 46-53Article in journal (Refereed)
    Abstract [en]

    Leukemic cells from 85 children with newly diagnosed precursor B-lineage ALL were tested for in vitro drug sensitivity to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. There was a significant correlation between MRD day 29 and in vitro sensitivity to prednisolone (p<0.001) and doxorubicin (p=0.017), drugs administered during induction therapy. In patients with t(12;21) (n=20), in vitro sensitivity to doxorubicin was an independent factor for MRD <0.1% (p=0.031; R(2)=0.66). Thus, data show that in vitro drug sensitivity at diagnosis is correlated to cell kill during induction therapy as measured by MRD day 29.

  • 23.
    Lönnerholm, Gudmar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Thörn, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Frost, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Flaegstad, Trond
    Departmnt of Pediatrics, University and University Hospital, Tromsoe, Norway.
    Heyman, Mats
    Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Jonsson, Olafur Gisli
    Department of Pediatrics, Landspitalinn, Reykjavik, Iceland.
    Harila-Saari, Arja
    Department of Pediatrics and Adolescence, Oulu University Hospital, Oulu, Finland.
    Madsen, Hans O
    Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark.
    Porwit, Anna
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Schmiegelow, Kjeld
    Pediatric Clinic II, Rigshospitalet, Copenhagen, Denmark.
    Söderhäll, Stefan
    Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Wesenberg, Finn
    Department of Pediatrics, National Hospital, Oslo, Norway.
    Vettenranta, Kim
    Department of Pediatrics, University of Tampere, Finland.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Forestier, Erik
    Department of Clinical Sciences, Paediatrics, University of Umeå, Sweden.
    In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia2011In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 4, p. 472-478Article in journal (Refereed)
    Abstract [en]

    Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD <0.1% day 29. The risk of any relapse was correlated to vincristine and doxorubicin resistance, with a relative risk of 3.7 (95% CI 1.3-10.5; p=0.016) for patients resistant to both drugs. There was a significant correlation also for the subgroup with extra-medullary relapses. Our findings indicate that analysis of drug resistance can add prognostic information to other known risk-factors including MRD.

  • 24.
    Lönnerholm, Gudmar
    et al.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Thörn, Ingrid
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Sundström, Christer
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Frost, Britt-Marie
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Flaegstad, Trond
    Departmnt of Pediatrics, University and University Hospital, Tromsoe, Norway.
    Heyman, Mats
    Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Jonsson, Olafur Gisli
    Department of Pediatrics, Landspitalinn, Reykjavik, Iceland.
    Harila-Saari, Arja
    Department of Pediatrics and Adolescence, Oulu University Hospital, Oulu, Finland.
    Madsen, Hans O
    Department of Clinical Immunology, Rigshospitalet, Copenhagen, Denmark.
    Porwit, Anna
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Schmiegelow, Kjeld
    Pediatric Clinic II, Rigshospitalet, Copenhagen, Denmark.
    Söderhäll, Stefan
    Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Wesenberg, Finn
    Department of Pediatrics, National Hospital, Oslo, Norway.
    Vettenranta, Kim
    Department of Pediatrics, University of Tampere, Finland.
    Larsson, Rolf
    Department of Medical Sciences, Section of Pharmacology, University Hospital, Uppsala, Sweden.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia2011In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 4, p. 472-478Article in journal (Refereed)
    Abstract [en]

    Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD <0.1% day 29. The risk of any relapse was correlated to vincristine and doxorubicin resistance, with a relative risk of 3.7 (95% CI 1.3-10.5; p=0.016) for patients resistant to both drugs. There was a significant correlation also for the subgroup with extra-medullary relapses. Our findings indicate that analysis of drug resistance can add prognostic information to other known risk-factors including MRD.

  • 25.
    Mansouri, Mahmoud
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sevov, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Fahlgren, Emma
    Tobin, Gerard
    Jondal, Mikael
    Osorio, Lyda
    Roos, Göran
    Olivecrona, Gunilla
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lipoprotein lipase is differentially expressed in prognostic subsets of chronic lymphocytic leukemia but displays invariably low catalytical activity2010In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 34, no 3, p. 301-306Article in journal (Refereed)
    Abstract [en]

    Lipoprotein lipase (LPL) expression has been shown to correlate with IGHV mutational status and to predict outcome in chronic lymphocytic leukemia (CLL). We here investigated the prognostic impact of LPL expression in relation to other prognostic markers including IGHV3-21 usage in 140 CLL patients. Additionally, we studied the catalytic activity of LPL in CLL cells. A significant difference in LPL mRNA expression was detected in IGHV unmutated compared to mutated CLL patients (p<0.001). However, the poor-prognostic mutated/stereotyped IGHV3-21 patients did not differ from other mutated CLL cases. Clinical outcome was significantly different in CLL cases with high versus low LPL expression (p<0.001), and LPL expression exceeded mutation status/IGHV3-21 usage as an independent prognostic marker. Finally, LPL protein expression correlated significantly with mRNA expression and was higher in IGHV unmutated versus mutated CLL (p=0.018), although the majority of synthesized protein was catalytically inactive indicating a non-catalytical function in CLL.

  • 26.
    Masquelier, Michéle
    et al.
    Karolinska, Stockholm.
    Lundgren, Bo
    Finland.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Vitols, Sigurd
    Karolinska, Stockholm.
    Cytotoxic effect of a lipophilic alkylating agent after incorporation into low density lipoprotein or emulsions: Studies in human leukemic cells2006In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 30, no 2, p. 136-144Article in journal (Refereed)
    Abstract [en]

    The use of low density lipoprotein (LDL) as drug carrier in acute myeloblastic leukemia chemotherapy is attractive due to high LDL uptake by leukemic cells. Lipid-based formulations, such as liposomes or microemulsions are promising alternatives. In the current study, we incorporated N-trifluoroacetyl-adriamycin-14-valerate (AD32), a lipophilic derivative of daunorubicin (DNR), and WB4291, a lipophilic alkylating agent, into LDL or lipid microemulsions and evaluated their cytotoxic activities towards leukemic cell lines using as references DNR and melphalan. The incorporation of AD32 into LDL or emulsion resulted in complexes with poor cytotoxicity. WB4291-LDL and WB4291-emulsion exerted, on the other hand, promising cytotoxic effects towards parental and resistant K562 and HL60 cell lines. © 2005 Elsevier Ltd. All rights reserved.

  • 27. Miftakhova, Regina
    et al.
    Sandberg, Tove
    Malmö högskola, Faculty of Health and Society (HS).
    Longno, Sharon
    Björk, Peter
    Björnsson, Sven
    Lazarevic, Vladimir L J
    Persson, Jenny
    Bredberg, Anders
    Exploring novel therapeutic options in T-LGL, including epigenetic modulation: a case report2010In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 34, no 7, p. e145-e149Article in journal (Refereed)
    Abstract [en]

    T cell large granular lymphocyte leukemia (T-LGL) is a chronic disease covering a wide spectrum of clinical presentations in the border-land between reactive autoimmunity and overt leukemia [1-2]. Most T-LGL patients follow an indolent course, and display a fairly uniform immunophenotype: TCR alfa/beta+, CD3+, CD4-, CD8+, CD56-, CD57+. This disease often causes significant morbidity mediated by anemia and granulocytopenia, considered to occur by mechanism of T cell cytokines. There is no consensus for optimal therapy of T-LGL, but beneficial effects have been reported for a number of agents including cyclosporin, methotrexate, cyclophosphamide and nucleoside analogs [1-2]. However, to the best of our knowledge, there is no experience with some modalities currently in use for closely related disorders. The purpose of the experiments reported in this case report was to evaluate the need for clinical studies on such therapies, including epigenetic modulation and extracorporeal photopheresis.

  • 28.
    Norin, Stefan
    et al.
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Bjorkstrand, Bo
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Rommel, Franz
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Timberg, Lars
    Kristianstad Central Hospital, Sweden.
    Andersson, Per-Ola
    Sahlgrens University Hospital, Sweden.
    Haggstrom, Johan
    Kalmar Hospital, Sweden.
    Aldrin, Anders
    Visby Hospital, Sweden.
    Hansson, Lotta
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Severe infusion-related reactions are uncommon in rituximab-treated CLL patients in clinical practice: Results from a Swedish national observational study2015In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 39, no 1, p. 33-37Article in journal (Refereed)
    Abstract [en]

    There have been concerns about serious infusion-related adverse drug reactions (ADR) with rituximabin chronic lymphocytic leukemia (CLL). We therefore conducted an observational trial in which CLL patients planned for rituximab-containing therapy were eligible. Ninety-six patients from 19 centers were enrolled. The most common regimen was rituximab, fludarabine and cyclophosphamide. Fifty-six patients experienced ADR during rituximab infusion. Reactions greater than= grade 3 occurred in five patients and no cases of tumor lysis syndrome were recorded. Despite a high number of circulating tumor cells few severe ADR were noted. Thus, rituximab containing regimens can be considered safe for CLL patients in general practice.

  • 29. Pauly, Frida
    et al.
    Smedby, Karin E.
    Jerkeman, Mats
    Hjalgrim, Henrik
    Ohlsson, Mattias
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Borrebaeck, Carl A. K.
    Wingren, Christer
    Identification of B-cell lymphoma subsets by plasma protein profiling using recombinant antibody microarrays2014In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 38, no 6, p. 682-690Article in journal (Refereed)
    Abstract [en]

    B-cell lymphoma (BCL) heterogeneity represents a key issue, often making the classification and clinical management of these patients challenging. In this pilot study, we outlined the first resolved view of BCL disease heterogeneity on the protein level by deciphering disease-associated plasma biomarkers, specific for chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, using recombinant antibody microarrays targeting mainly immunoregulatory proteins. The results showed the BCLs to be heterogeneous, and revealed potential novel subgroups of each BCL. In the case of diffuse large B-cell lymphoma, we also indicated a link between the novel subgroups and survival.

  • 30.
    Radivoyevitch, Tomas
    et al.
    Cleveland Clin Fdn, Dept Quantitat Hlth Sci, 9500 Euclid Ave, Cleveland, OH 44195 USA;Cleveland Clin Fdn, Dept Hematol & Oncol Res, 9500 Euclid Ave, Cleveland, OH 44195 USA.
    Dean, Robert M.
    Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA;Royal Melbourne Hosp City Campus, Melbourne, Vic, Australia.
    Shaw, Bronwen E.
    Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA.
    Brazauskas, Ruta
    Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA;Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA.
    Tecca, Heather R.
    Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA.
    Molenaar, Remco J.
    Cleveland Clin Fdn, Dept Quantitat Hlth Sci, 9500 Euclid Ave, Cleveland, OH 44195 USA;Cleveland Clin Fdn, Dept Hematol & Oncol Res, 9500 Euclid Ave, Cleveland, OH 44195 USA;Acad Med Ctr, Dept Med Oncol, Amsterdam, Netherlands.
    Battiwalla, Minoo
    NHLBI, Hematol Branch, Bethesda, MD 20892 USA.
    Savani, Bipin N.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Flowers, Mary E. D.
    Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA.
    Cooke, Kenneth R.
    Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Pediat Blood & Marrow Transplantat Program, Baltimore, MD USA.
    Hamilton, Betty K.
    Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA;Royal Melbourne Hosp City Campus, Melbourne, Vic, Australia.
    Kalaycio, Matt
    Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA;Royal Melbourne Hosp City Campus, Melbourne, Vic, Australia.
    Maciejewski, Jaroslaw P.
    Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA;Royal Melbourne Hosp City Campus, Melbourne, Vic, Australia.
    Ahmed, Ibrahim
    Childrens Mercy Hosp & Clin, Dept Hematol Oncol & Bone Marrow Transplantat, Kansas City, MO USA.
    Akpek, Gorgun
    Rush Univ, Med Ctr, Stem Cell Transplantat & Cell Therapy, Chicago, IL 60612 USA.
    Bajel, Ashish
    Buchbinder, David
    Childrens Hosp Orange Cty, Div Pediat Hematol, Orange, CA 92668 USA.
    Cahn, Jean-Yves
    CHU Grenoble Alpes, Dept Hematol, Grenoble, France.
    D'Souza, Anita
    Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA.
    Daly, Andrew
    Tom Baker Canc Clin, Calgary, AB, Canada.
    DeFilipp, Zachariah
    Massachusetts Gen Hosp, Blood & Marrow Transplant Program, Boston, MA 02114 USA.
    Ganguly, Siddhartha
    Univ Kansas, Med Ctr, Blood & Marrow Transplantat, Kansas City, KS 66103 USA.
    Hamadani, Mehdi
    Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA.
    Hayashi, Robert J.
    Washington Univ, Dept Pediat, Sch Med St Louis, St Louis, MO 63130 USA.
    Hematti, Peiman
    Univ Wisconsin Hosp & Clin, Dept Med, Madison, WI 53792 USA.
    Inamoto, Yoshihiro
    Natl Canc Ctr, Div Hematopoiet Stem Cell Transplantat, Tokyo, Japan.
    Khera, Nandita
    Mayo Clin, Dept Hematol Oncol, Phoenix, AZ USA.
    Kindwall-Keller, Tamila
    Univ Virginia Hlth Syst, Div Hematol Oncol, Charlottesville, VA USA.
    Landau, Heather
    Mem Sloan Kettering Canc Ctr, Div Hematol, Bone Marrow Transplant Serv, 1275 York Ave, New York, NY 10021 USA.
    Lazarus, Hillard
    Case Western Reserve Univ, Seidman Canc Ctr, Cleveland, OH 44106 USA.
    Majhail, Navneet S.
    Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA;Royal Melbourne Hosp City Campus, Melbourne, Vic, Australia.
    Marks, David I.
    Univ Hosp Bristol NHS Trust, Adult Bone Marrow Transplant, Bristol, Avon, England.
    Olsson, Richard F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Seo, Sachiko
    Natl Canc Res Ctr East, Dept Hematol & Oncol, Chiba, Japan.
    Steinberg, Amir
    Mt Sinai Hosp, Dept Hematol Oncol, New York, NY 10029 USA.
    William, Basem M.
    Ohio State Med Ctr, Columbus, OH USA.
    Wirk, Baldeep
    Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA.
    Yared, Jean A.
    Univ Maryland, Dept Med, Baltimore, MD 21201 USA.
    Aljurf, Mahmoud
    King Faisal Specialist Hosp & Res Ctr, Dept Oncol, Riyadh, Saudi Arabia.
    Abidi, Muneer H.
    Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI USA.
    Allewelt, Heather
    Duke Univ, Med Ctr, Durham, NC USA.
    Beitinjaneh, Amer
    Univ Miami, Miami, FL USA.
    Cook, Rachel
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA.
    Cornell, Robert F.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Fay, Joseph W.
    Baylor Univ, Med Ctr, Dallas, TX USA.
    Hale, Gregory
    Johns Hopkins All Childrens Hosp, Dept Hematol Oncol, St Petersburg, FL USA.
    Chakrabarty, Jennifer Holter
    Univ Oklahoma, Dept Hematol Oncol, Oklahoma City, OK USA.
    Jodele, Sonata
    Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA.
    Kasow, Kimberly A.
    Univ N Carolina, Chapel Hill, NC 27515 USA.
    Mahindra, Anuj
    Scripps Blood & Marrow Transplant Program, La Jolla, CA USA.
    Malone, Adriana K.
    Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA.
    Popat, Uday
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Rizzo, J. Douglas
    Natl Canc Res Ctr East, Dept Hematol & Oncol, Chiba, Japan.
    Schouten, Harry C.
    Acad Ziekenhuis, Dept Hematol, Maastricht, Netherlands.
    Warwick, Anne B.
    Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA.
    Wood, William A.
    Univ N Carolina, Chapel Hill, NC 27515 USA.
    Sekeres, Mikkael A.
    Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA;Royal Melbourne Hosp City Campus, Melbourne, Vic, Australia.
    Litzow, Mark R.
    Mayo Clin, Dept Med, Rochester, MN USA.
    Gale, Robert P.
    Imperial Coll London, Dept Med, London, England.
    Hashmi, Shahrukh K.
    King Faisal Specialist Hosp & Res Ctr, Dept Oncol, Riyadh, Saudi Arabia.
    Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma2018In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 74, p. 130-136Article in journal (Refereed)
    Abstract [en]

    Background: Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

    Methods: 9028 recipients of hematopoietic cell autotransplants (1995-2010) for Hodgkin lymphoma (HL; n=916), non-Hodgkin lymphoma (NHL; n=3546) and plasma cell myeloma (PCM; n=4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS.

    Results: 335 MDS/ AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR=4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR=2.5 [1.1, 2.5]); (2) >= 3 versus 1 line of chemotherapy for NHL (HR=1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005-2010 versus 1995-1999 (HR=2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/ MDS in HL, NHL and PCM to be 5-10 times the background rate. In contrast, relative risks were 10-50 for AML and approximately 100 for MDS in the autotransplant cohort.

    Conclusions: There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

  • 31. Scotch, Allison H
    et al.
    Kosiorek, Heidi
    Scherber, Robyn
    Dueck, Amylou C
    Slot, Stefanie
    Zweegman, Sonja
    Boekhorst, Peter A W Te
    Commandeur, Suzan
    Schouten, Harry
    Sackmann, Federico
    Fuentes, Ana Kerguelen
    Hernández-Maraver, Dolores
    Pahl, Heike L
    Griesshammer, Martin
    Stegelmann, Frank
    Döhner, Konstanze
    Lehmann, Thomas
    Bonatz, Karin
    Reiter, Andreas
    Boyer, Francoise
    Etienne, Gabriel
    Ianotto, Jean-Christophe
    Ranta, Dana
    Roy, Lydia
    Cahn, Jean-Yves
    Harrison, Claire N
    Radia, Deepti
    Muxi, Pablo
    Maldonado, Norman
    Besses, Carlos
    Cervantes, Francisco
    Johansson, Peter L
    Barbui, Tiziano
    Barosi, Giovanni
    Vannucchi, Alessandro M
    Paoli, Chiara
    Passamonti, Francesco
    Andreasson, Bjorn
    Ferrari, Maria L
    Rambaldi, Alessandro
    Samuelsson, Jan
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Xiao, Zhijian
    Xu, Zefeng
    Zhang, Yue
    Sun, Xiujuan
    Xu, Junqing
    Kiladjian, Jean-Jacques
    Zhang, Peihong
    Gale, Robert Peter
    Mesa, Ruben A
    Geyer, Holly L
    Symptom burden profile in myelofibrosis patients with thrombocytopenia: Lessons and unmet needs2017In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 63, p. 34-40Article in journal (Refereed)
    Abstract [en]

    Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n = 89) and without (n = 329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count < 100 x10(9)/L (moderate 51-100 x 10(9)/L; severe <= 50 x10(9)/L), was associated with anemia (76% vs. 45%, p < 0.001), leukopenia (29% vs. 11%, p < 0.001), and need for red blood cell transfusion (35% vs. 19%, p = 0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p < 0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p = 0.04), leukopenia (40% vs. 20%, p = 0.04), and transfusion requirements (51% vs. 20%, p = 0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies.

  • 32.
    Siegbahn, Agneta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rosén, A.
    Venge, Per
    Aman, P.
    Nilsson, K.
    Production of chemokinetic inhibitory factor (CIF) by normal blood and spleen B lymphocytes1986In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 10, no 2, p. 179-186Article in journal (Other academic)
    Abstract [en]

    We have recently reported the partial purification and characterization of of a new lymphokine, the heat-labile chemokinetic inhibitory factor (CIF) which inhibits neutrophil movement. We have also shown that this lymphokine is produced and secreted by cultured B-chronic lymphocytic leukaemia (CLL) cells in vitro. The present study shows that highly purified resting normal B lymphocytes from blood and spleen have the capacity to produce CIF spontaneously. After activation with anti-IgM or EBV-infection the lymphocytes produced a number of other factors, heat-stable chemokinetic inhibitory factors and heat-labile chemokinetic enhancing factors. Supernatants from a collection of human B-cell lines representing different stages of B-cell differentiation were also investigated. None of these cell lines produced CIF. The present results show that the production of CIF is not restricted to the malignant B-CLL cell but is also produced by a subset of normal blood and spleen B cells.

  • 33.
    Söderlund, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Uppsala Hosp, Sect Hematol, Entrance 50, S-75185 Uppsala, Sweden.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Persson, Inger
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway; Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway.
    Richter, Johan
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland; Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland; Univ Helsinki, Dept Clin Chem, Helsinki, Finland.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli2016In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 50, p. 95-103Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: The simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation.

    METHODS: Samples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib). Samples were analyzed by Mesoscale Discovery, Myriad RBM MAP technology and Olink Proseek.

    RESULTS: Multiple plasma proteins were differentially expressed before and after initiation of TKI therapy. Protein patterns demonstrated a possible shift towards Th1-immunity and reduced angiogenic stimuli. Further, some plasma proteins were identified that can be of potential interest to study further for biologic, prognostic or therapeutic significance such as E-selectin, uPAR, growth hormone and carbonic anhydrase IX.

    CONCLUSIONS: Plasma proteomics seems feasible and useful in CML patients, both for studying patterns of protein expression and for identifying single proteins differentially expressed before and after treatment. Plasma proteomics may be useful to map disease activity and biological processes. Hence, plasma proteomics can be used to understand drug mechanisms and treatment responses in CML.

  • 34.
    Söderlund, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Persson, Inger
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Ilanderd, Mette
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland;Univ Helsinki, Dept Clin Chem & Hematol, Helsinki, Finland.
    Guilhot, Joelle
    CHU Poitiers, INSERM, Poitiers, France.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.
    Koskenvesa, Perttu
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland.
    Richter, Johan
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.
    Saussele, Susanne
    Heidelberg Univ, Univ Med Mannheim, Mediz Klin 3, Mannheim, Germany.
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland;Univ Helsinki, Dept Clin Chem & Hematol, Helsinki, Finland.
    Strömberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Plasma proteomics of biomarkers for inflammation or cancer cannot predict relapse in chronic myeloid leukaemia patients stopping tyrosine kinase inhibitor therapy2020In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 90, article id 106310Article in journal (Refereed)
    Abstract [en]

    Several studies have now shown that chronic myeloid leukaemia (CML) patients in deep molecular remission may discontinue tyrosine kinase inhibitor (TKI) treatment with a treatment free remission (TFR) rate of approximately 40-60 %. Some factors influencing the possibility of TFR have been described but better tools are needed for individual prediction of long-term TFR. Herein, two multiplex panels were utilised to analyse a total of 162 different plasma proteins from 56 patients included in the TKI stopping trial EURO-SKI (Saussele a al., 2018). The purpose was to identify possible plasma protein markers for prediction of successful TKI discontinuation and to evaluate effects of TKI discontinuation on plasma protein profiles. No protein biomarkers sampled before TKI discontinuation could separate relapse cases from non-relapse cases but some plasma proteins differed between patients who relapsed and those who remained in TFR when followed over time after TKI cessation. In conclusion, the plasma protein markers in this study could not predict relapse after TKI discontinuation but may be of use to understand the mechanisms involved in maintenance of TFR.

  • 35.
    Thorsélius, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Walsh, Sarah H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Heterogeneous somatic hypermutation status confounds the cell of origin in hairy cell leukemia2005In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 29, no 2, p. 153-158Article in journal (Refereed)
    Abstract [en]

    Hairy cell leukemia (HCL) is thought to arise from a post-germinal center (GC) B-cell, however the exact normal counterpart remains unclear. We performed VH gene analysis of 32 HCL cases, revealing somatically mutated VH genes (<98% homology) in 27 cases and unmutated VH genes in five cases, four of which displayed germline VH genes. Intraclonal heterogeneity was evident in the majority of eight mutated HCLs investigated, although at a lower level compared to GC-derived lymphomas. A novel finding of preferential VH3-30 gene usage was detected (19% of HCLs). Our data confounds the postulated post-GC origin in HCL considering (1) the finding of unmutated HCLs, generally correlating with a pre-GC origin, and (2) the presence of intraclonal variation in mutated HCLs. The latter suggests that the transformed B-cell was frozen when it still had an active mutation process, implying a closer relation to the GC than previously assumed. Furthermore, restricted VH3-30 usage indicates that antigen selection could be a promoting factor in HCL development.

  • 36.
    Thörn, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Hermansson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Barbany, Gisela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Monitoring minimal residual disease with flow cytometry, antigen-receptor gene rearrangements and fusion transcript quantification in Philadelphia-positive childhood acute lymphoblastic leukemia2009In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 33, no 8, p. 1047-1054Article in journal (Refereed)
    Abstract [en]

    In this study, we followed minimal residual disease (MRD) in eight children with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) using (i) flow cytometry (FCM), (ii) real-time quantitative PCR of IG/TCR gene rearrangements and (iii) RT-PCR detecting fusion gene transcripts. In six of the eight cases the kinetics of MRD clearance was comparable. One of the two discordant cases could be explained by presence of an alternative fusion transcript. The other discordant case showed high BCR-ABL1 RNA level while the other methods did not detect any MRD. In our limited material quantitative RT-PCR of fusion gene transcripts seemed particularly useful to measure MRD in Ph+ ALL. However, BCR-ABL1 expression may not reflect the percentage of leukemic cells as FCM and IG/TCR rearrangement quantification do, and these methods are thus complementary.

  • 37.
    Uggla, Bertil
    et al.
    Department of Medicine, Örebro Medical Center Hospital, Örebro, Sweden.
    Möllgård, Lars
    Department of Hematology, Huddinge Uniersity Hospital, Huddinge, Sweden.
    Ståhl, Elisabeth
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Mossberg, Lise-Lott Mossberg
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Paul, Christer
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden; Karolinska Institute, Stockholm, Sweden.
    Tidefelt, Ulf
    Department of Medicine, Örebro Medical Center Hospital, Örebro, Sweden; Karolinska Institute, Stockholm, Sweden.
    Expression of topoisomerase IIalpha in the G0/G1 cell cycle phase of fresh leukemic cells2001In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 25, no 11, p. 961-966Article in journal (Refereed)
    Abstract [en]

    Topoisomerase IIalpha (topoII alpha) is the target enzyme for several antineoplastic drugs. Correlation between low expression of topo IIalpha and drug resistance has been shown in vitro, but there is limited evidence of a correlation to initial response to treatment or to overall prognosis. Normal cells express topo IIalpha in S/G2/M phase of the cell cycle but not in G0/G1 phase. However, some data suggest that topo IIalpha could be expressed in G0/G1 phase in malignant cells. We have investigated the expression of topo IIalpha in leukemic cells from 25 patients with acute leukemia by flow cytometry, separating cells of different cell cycle phases. We demonstrated that 9/25 samples showed >50% positive cells in G0/G1, and another five samples showed >20%. This finding could possibly provide an explanation to previous difficulties in correlating topo IIalpha expression with clinical outcome. Six of eight patients, where >20% of the cells in G0/G1 were positive for topo IIalpha, entered CR, compared to one of five patients with <20% topo IIalpha positive cells in G0/G1. We suggest that topo IIalpha expression in G0/G1 in leukemic cells may be of predictive value for clinical response to cytostatic drugs.

  • 38.
    Uggla, Bertil
    et al.
    Department of Medicine, Örebro University Hospital, Örebro; Karolinska Institute, Stockholm.
    Ståhl, Elisabet
    Clinical Research Centre, Örebro University Hospital, Örebro.
    Wågsäter, Dick
    Örebro University, Department of Nursing and Caring Sciences.
    Paul, Christer
    Department of Haematology, Huddinge University Hospital, Stockholm; Karolinska Institute, Stockholm.
    Karlsson, Mats G.
    Department of Pathology, Örebro University Hospital, Örebro.
    Sirsjö, Allan
    Örebro University, Department of Nursing and Caring Sciences.
    Tidefelt, Ulf
    Örebro University, Department of Clinical Medicine. Department of Medicine, Örebro University Hospital, Örebro.
    BCRP mRNA expression v. clinical outcome in 40 adult AML patients2005In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 29, no 2, p. 141-146Article in journal (Refereed)
    Abstract [en]

    Efflux pumps are considered being mechanisms behind drug resistance in acute myeloid leukaemia (AML). A recently described efflux pump, breast cancer resistance protein (BCRP), can be expressed in AML, but its clinical importance is uncertain. In this study BCRP mRNA expression was determined in samples from 40 AML patients by real-time RT-PCR. The expression varied from negative to 76 times that of control cells. There was no difference in BCRP mRNA expression between patients responding to induction treatment and non-responders. However, in the group of responders, the 14 patients with the highest expression had significantly shorter overall survival (mean 38 months, SEM 15 months) than the 14 patients with the lowest (74 months, SEM 16 months) (P = 0.047). This suggests a possible role of BCRP in drug resistance in AML.

  • 39.
    Uggla, Bertil
    et al.
    Örebro University Hospital, Sweden .
    Ståhl, Elisabeth
    Örebro University Hospital, Sweden.
    Wågsäter, Dick
    Örebro University, Sweden.
    Paul, Christer
    Huddinge University Hospital, Stockholm, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital, Sweden.
    Sirsjö, Allan
    Örebro University, Sweden.
    Tidefelt, Ulf
    Örebro University Hospital, Sweden .
    BCRP mRNA expression v. clinical outcome in 40 adult AML patients2005In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 29, no 2, p. 141-146Article in journal (Refereed)
    Abstract [en]

    Efflux pumps are considered being mechanisms behind drug resistance in acute myeloid leukaemia (AML). A recently described efflux pump, breast cancer resistance protein (BCRP), can be expressed in AML, but its clinical importance is uncertain, In this study BCRP mRNA expression was determined in samples from 40 AML patients by real-time RT-PCR. The expression varied from negative to 76 times that of control cells. There was no difference in BCRP mRNA expression between patients responding to induction treatment and non-responders. However, in the group of responders, the 14 patients with the highest expression had significantly shorter overall Survival (mean 38 months, SEM 15 months) than the 14 patients with the lowest (74 months, SEM 16 months) (P = 0.047). This suggests a possible role of BCRP in drug resistance in AML.

  • 40. Vallera, D. A.
    et al.
    Felices, M.
    Sarhan, D.
    Brandt, L.
    KTH.
    Guldevall, K.
    KTH.
    Warlick, E. D.
    Cooley, S.
    Weisdorf, D. J.
    Onfelt, B.
    Miller, J. S.
    USING GENETIC ENGINEERING TO IMPROVE THE BISPECIFIC ANTIBODY PLATFORM FOR MDS THERAPY2017In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 55, p. S126-S126Article in journal (Refereed)
  • 41.
    Walsh, Sarah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Sundström, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Roos, Göran
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia derives from an extensively hypermutated B cell that lacks ongoing somatic hypermutation2005In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 29, no 7, p. 729-734Article in journal (Refereed)
    Abstract [en]

    Lymphoplasmacytic lymphoma (LPL) is a rare lymphoma thought to originate from a B cell stimulated to differentiate to a plasma cell, and which is usually accompanied by clonal IgM secretion, defining the diagnosis of Waldenström's macroglobulinemia (WM). However, the immunoglobulin variable heavy chain (VH) gene usage and the somatic hypermutation status have not been widely investigated in LPL. LPL biopsies (CD19+/CD20+/CD22+/CD5/CD10/CD23/κ+) from 14 patients were included most of whom had a serum IgM component of variable magnitude (two cases with IgG). Highly mutated VH genes (mean mutation rate 8%) were revealed in 13 of 14 LPLs, whereas one case displayed a germline VH gene configuration. Cloning of the VH gene rearrangements in nine cases showed homogeneous sequences without intraclonal heterogeneity. Furthermore, no bias in the VH gene usage was shown, with VH3, VH4, and VH1 gene family members represented. These data confirm that the LPL precursor cell has been exposed to the germinal centre environment, as indicated by extensive hypermutation, but also that the transformation event occurred after affinity maturation, since there was a lack of intraclonal variation. Additionally, the VH gene repertoire was not skewed in LPL/WM as has been demonstrated in other B cell malignancies.

  • 42.
    Zainuddin, Norafiza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Ren, Zhi-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Lindell, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Roos, Göran
    Department of Medical Biosciences, Pathology, Umeå University, Umeå.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype2009In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 33, no 1, p. 60-66Article in journal (Refereed)
    Abstract [en]

    Presence of TP53 mutations has been associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), although this has remained controversial. The TP53 codon 72 polymorphism has shown negative impact on cancer survival, but this has not been analyzed in DLBCL. Furthermore, the MDM2 SNP309 has been associated with earlier age of onset in DLBCL. Here, we investigated the clinical impact of TP53 mutations, MDM2 SNP309 and TP53 codon 72 polymorphisms on survival in DLBCL of germinal center (GC) and non-GC subtypes. Thirteen of the 102 (12.7%) patients displayed TP53 mutations. Overall, TP53 mutations had a significant effect on lymphoma-specific survival (LSS, P=0.009) and progression-free survival (PFS, P=0.028). In particular, inferior survival was observed in TP53-mutated DLBCLs of GC subtype (LSS, P=0.002 and PFS, P=0.006). Neither MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. Altogether, our data suggests that TP53 mutations are associated with poor outcome in GC-DLBCL patients.

  • 43.
    Zainuddin, Norafiza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lindell, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Roos, Göran
    Department of Medical Biosciences, Pathology, Umeå University, Umeå.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Quantitative evaluation of p16INK4a promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma2011In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 4, p. 438-443Article in journal (Refereed)
    Abstract [en]

    The p16INK4a tumor suppressor gene can be inactivated by a variety of events including promoter hypermethylation. In diffuse large B-cell lymphoma (DLBCL), p16INK4a methylation has been associated with advanced disease stage and higher IPI. The prognostic impact of p16INK4a methylation in DLBCL remains unclear; however, it has been suggested to correlate with inferior outcome. To further investigate the clinical impact of p16INK4a methylation in DLBCL, promoter methylation of this gene was assessed quantitatively by pyrosequencing. Forty-two of 113 (37%) DLBCL patients with methylation level above 5% were categorized as methylated and subsequently divided into low, intermediate and high methylation categories. Overall, no association was shown between the extent of p16INK4a methylation and patients’ clinical characteristics, except disease stage (P=0.049). Moreover, we could not reveal any impact of p16INK4a methylation on lymphoma-specific survival. Although >25% of p16INK4a methylation correlated with a better progression-free survival (P=0.048), the significance of this finding, if any, needs to be further investigated. In conclusion, our finding questions the role of p16INK4a promoter methylation as a negative prognostic factor in DLBCL.

  • 44. Zainuddin, Norafiza
    et al.
    Kanduri, Meena
    Berglund, Mattias
    Lindell, Monica
    Amini, Rose-Marie
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sundström, Christer
    Enblad, Gunilla
    Rosenquist, Richard
    Quantitative evaluation of p16(INK4a) promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma2011In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 4, p. 438-443Article in journal (Refereed)
    Abstract [en]

    The p16INK4a tumor suppressor gene can be inactivated by a variety of events including promoter hypermethylation. In diffuse large B-cell lymphoma (DLBCL), p16INK4a methylation has been associated with advanced disease stage and higher IPI. The prognostic impact of p16INK4a methylation in DLBCL remains unclear; however, it has been suggested to correlate with inferior outcome. To further investigate the clinical impact of p16INK4a methylation in DLBCL, promoter methylation of this gene was assessed quantitatively by pyrosequencing. Forty-two of 113 (37%) DLBCL patients with methylation level above 5% were categorized as methylated and subsequently divided into low, intermediate and high methylation categories. Overall, no association was shown between the extent of p16INK4a methylation and patients' clinical characteristics, except disease stage (P=0.049). Moreover, we could not reveal any impact of p16INK4a methylation on lymphoma-specific survival. Although >25% of p16INK4a methylation correlated with a better progression-free survival (P=0.048) in patients <65 years old, the significance of this finding, if any, needs to be further investigated. In conclusion, our finding questions the role of p16INK4a promoter methylation as a negative prognostic factor in DLBCL.

  • 45.
    Zainuddin, Norafiza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Murray, Fiona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Gunnarsson, Rebeqa
    Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund.
    Smedby, Karin Ekström
    Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Jurlander, Jesper
    Department of Hematology, Leukemia Laboratory, Rigshospitalet, Copenhagen, Denmark.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia2011In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 35, no 2, p. 272-274Article in journal (Refereed)
    Abstract [en]

    TP53 mutations in the absence of 17p-deletion correlate with rapid disease progression and poor survival in chronic lymphocytic leukemia (CLL). Herein, we determined the TP53 mutation frequency in 268 newly diagnosed CLL patients from a population-based material. Overall, we detected TP53 mutations in 3.7% of patients (n= 10), where 7/10 cases showed a concomitant 17p-deletion, confirming the high prevalence of TP53 mutation in 17p-deleted patients. Only 3 (1.1%) of the newly diagnosed patients in our cohort thereby carried TP53 mutations without 17p-deletion, a frequency that is much lower than previous reports on referral cohorts (3-6%). Our findings imply that TP53 mutations are rare at CLL onset and instead may arise during disease progression.

1 - 45 of 45
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