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  • 1. Andersen, Mette K.
    et al.
    Autio, Kirsi
    Barbany, Gisela
    Borgstroem, Georg
    Cavelier, Lucia
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johannsson, Johann H.
    Johansson, Bertil
    Kjeldsen, Eigil
    Nordgren, Ann
    Palmqvist, Lars
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13): clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols2011In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, no 2, p. 235-243Article in journal (Refereed)
    Abstract [en]

    The translocation t(1;19)(q23;p13)/der(19) t(1;19) is a risk stratifying aberration in childhood B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the Nordic countries. We have identified 47 children/adolescents with t(1;19)/der(19) t(1;19)-positive BCP ALL treated on two successive Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols between 1992 and 2007 and have reviewed the clinical and cytogenetic characteristics of these cases, comprising 1.8% of all cases. The translocation was balanced in 15 cases (32%) and unbalanced in 29 cases (62%). The most common additional chromosome abnormalities were del(9p), i(9q), del(6q), and del(13q). The median age was 7 years, the median white blood cell (WBC) count was 16 x 10(9)/l, and the female/male ratio was 1.2. The predicted event-free survival (EFS) at 5 and 10 years was 0.79, whereas the predicted overall survival (OS) at 5 and 10 years was 0.85 and 0.82, respectively. Nine patients had a bone marrow relapse after a median of 23 months; no patient had a central nervous system relapse. Additional cytogenetic abnormalities, age, gender, WBC count or whether the t(1;19) was balanced or unbalanced did not influence EFS or OS. Compared to cases with t(12,21) and high hyperdiploidy, EFS was similar, but overall survival was worse in patients with t(1;19)/der(19) t(1;19) (P = 0.004).

  • 2.
    Andersson, Anne
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enblad, Gunilla
    Department of Oncology, Radiology and Clinical immunology, Section of Oncology, Uppsala University, Uppsala.
    Gustavsson, Anita
    Department of Oncology, Skåne University Hospital, Lund University, Lund .
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hagberg, Hans
    Department of Oncology, Radiology and Clinical immunology, Section of Oncology, Uppsala University, Uppsala .
    Molin, Daniel
    Department of Oncology, Radiology and Clinical immunology, Section of Oncology, Uppsala University, Uppsala .
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Long term risk of infections in Hodgkin lymphoma long-term survivors2011In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 154, no 5, p. 661-663Article in journal (Refereed)
  • 3. Berggren, Daniel Moreno
    et al.
    Folkvaljon, Yasin
    Engvall, Marie
    Sundberg, Johan
    Lambe, Mats
    Antunovic, Petar
    Garelius, Hege
    Lorenz, Fryderyk
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nilsson, Lars
    Rasmussen, Bengt
    Lehmann, Sören
    Hellström-Lindberg, Eva
    Jädersten, Martin
    Ejerblad, Elisabeth
    Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, no 5, p. 614-627Article in journal (Refereed)
    Abstract [en]

    The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2.9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0.05) and for WPSS compared to IPSS (P=0.07). IPSS-R was superior to both IPSS and WPSS for patients aged <= 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.

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

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

  • 5.
    Edling, Charlotte E.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pedersen, Malin
    Experimental Clinical Chemistry, Lund University, Malmö University Hospital, Malmö.
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Rönnstrand, Lars
    Experimental Clinical Chemistry, Lund University, Malmö University Hospital, Malmö.
    Palmer, Ruth H.
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haematopoietic progenitor cells utilise conventional PKC to suppress PKB/Akt activity in response to c-Kit stimulation2007In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 136, no 2, p. 260-268Article in journal (Refereed)
    Abstract [en]

    Receptor tyrosine kinase (RTK) c-Kit signalling is crucial for the proliferation, survival and differentiation of haematopoietic stem cells (HSCs). To further understand the mechanisms underlying these events we explored how the downstream mediators interact. The present study investigated the function of conventional protein kinase Cs (c-PKC) in c-Kit mediated signalling pathways in HSC-like cell lines. This analysis supported earlier findings, that steel factor (SF) activates c-PKC, extracellular signal-regulated kinase (Erk) and protein kinase B (PKB). The present results were consistent with an important role of c-PKC in the positive activation of Erk and for proliferation. Further, it was observed that c-PKC negatively regulated PKB activity upon SF stimulation, indicating that c-PKC acts as a suppressor of c-Kit signalling. Finally, these observations were extended to show that c-PKC mediated the phosphorylation of the endogenous c-Kit receptor on serine 746, resulting in decreased overall tyrosine phosphorylation of c-Kit upon SF stimulation. This report showed that this specific feedback mechanism of c-PKC mediated phosphorylation of the c-Kit receptor has consequences for both proliferation and survival of HSC-like cell lines.

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

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

  • 7.
    Gunnarsson, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stenke, Leif
    Höglund, Martin
    Sandin, Fredrik
    Björkholm, Magnus
    Dreimane, Arta
    Lambe, Mats
    Markevärn, Berit
    Department of Haematology, University Hospital, Umeå.
    Olsson-Strömberg, Ulla
    Richter, Johan
    Wadenvik, Hans
    Wallvik, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era2015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 169, no 5, p. 683-688Article in journal (Refereed)
    Abstract [en]

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

  • 8.
    Hedenus, Michael
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences.
    Adriansson, Magnus
    Watson, David
    Matcham, James
    Rossi, Gregory
    Littlewood, Timothy J
    San Miguel, Jesus
    Kramer, Mark H H
    Schipperus, Martin R
    Juvonen, Eeva
    Taylor, Kerry
    Belch, Andrew
    Altés, Albert
    Martinelli, Giovanni
    Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study2003In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 122, no 3, p. 394-403Article in journal (Refereed)
  • 9.
    Hedenus, Michael
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences.
    Hansen, Sören
    Taylor, Kerry
    Arthur, Chris
    Emmerich, Berthold
    Dewey, Claire
    Watson, David
    Rossi, Gregory
    Österborg, Anders
    Randomized dose-finding study of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies2002In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 119, no 1, p. 79-86Article in journal (Refereed)
  • 10. Karlsson, Lene
    et al.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hasle, Henrik
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Nyström, Ulrika Noren
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Palle, Josefine
    Tierens, Anne
    Zeller, Bernward
    Abrahamsson, Jonas
    Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia2017In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, no 4, p. 592-602Article in journal (Refereed)
    Abstract [en]

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

  • 11. Karrman, Kristina
    et al.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Andersen, Mette K
    Autio, Kirsi
    Borgström, Georg
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Kerndrup, Gitte
    Johansson, Bertil
    High incidence of the ETV6/RUNX1 fusion gene in paediatric precursor B-cell acute lymphoblastic leukaemias with trisomy 21 as the sole cytogenetic change: a Nordic series of cases diagnosed 1989-2005.2006In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 135, no 3, p. 352-4Article in journal (Refereed)
    Abstract [en]

    Trisomy 21 is common in ETV6/RUNX1-positive acute lymphoblastic leukaemia (ALL); both these aberrations are associated with a favourable outcome. The prognostic impact of +21 as a sole cytogenetic change could be due to a cryptic t(12;21)(p13;q22). The occurrence of ETV6/RUNX1 was determined in 66 childhood ALLs with an acquired +21 and a chromosome number <51. ETV6/RUNX1 was found in 45% of cases and in the majority (10/18; 56%) of ALLs with sole +21. Event-free survival did not differ between the t(12;21)-positive and -negative cases. Thus, the prognostic impact of +21 is not attributable to cryptic ETV6/RUNX1.

  • 12.
    Kuchinskaya, Ekaterina
    et al.
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Heyman, Mats
    Astrid Lindgren’s Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Nordgren, Ann
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Söderhäll, Stefan
    Astrid Lindgren’s Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Wehner, Peder
    Paediatric Oncology Department, University Hospital, Odense, Denmark.
    Vettenranta, Kim
    Paediatric Oncology Department, University Hospital, Tampere, Finland.
    Jonsson, Olafur
    Childrens Hospital, Hringsins, Landspitali, Hringbraut, Reykjavik, Iceland.
    Wesenberg, Finn
    Barneklinikken, Rikshospitalet, Oslo, Norway.
    Sahlén, Sigrid
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Nordenskjöld, Magnus
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Blennow, Elisabeth
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Interphase fluorescent in situ hybridization deletion analysis of the 9p21 region and prognosis in childhood acute lymphoblastic leukaemia (ALL): results from a prospective analysis of 519 Nordic patients treated according to the NOPHO-ALL 2000 protocol2011In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 152, no 5, p. 615-622Article in journal (Refereed)
    Abstract [en]

    Interphase fluorescent in situ hybridization (FISH) was applied on diagnostic BM smears from 519 children with acute lymphoblastic leukaemia (ALL) in order to establish the frequency and prognostic importance of 9p21 deletion in children enrolled in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) - 2000 treatment protocol. Among the patients, 452 were diagnosed with B-cell precursor (BCP)-ALL and 66 with T-ALL. A higher incidence of 9p21 deletions was found in T-ALL (38%) compared to BCP-ALL (15·7%). Homozygous deletions were found in 19·7% of T-ALL and 4·0% of BCP-ALL; hemizygous deletions were found in 18·2% and 11·7% respectively. In our series, 9p21 deletions were detected in all age groups with a steady rise in the frequency with age. There was no significant difference in outcome between cases with or without 9p21 deletion or between cases with hemi- or homozygous deletions of 9p21. In conclusion, in this large series of childhood ALL deletion of 9p21 was not associated with worse prognosis. However, interphase FISH deletion analysis of 9p21 could be used as a first step to detect unfavourable subtle cytogenetic aberrations such as the dic(9;20) rearrangement.

  • 13.
    Li, Aihong
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Goldwasser, Meredith A
    Zhou, Jianbiao
    Armstrong, Scott A
    Wang, Hongjun
    Dalton, Virginia
    Fletcher, Jonathan A
    Sallan, Stephen E
    Silverman, Lewis B
    Gribben, John G
    Distinctive IGH gene segment usage and minimal residual disease detection in infant acute lymphoblastic leukaemias.2005In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 131, no 2, p. 185-92Article in journal (Refereed)
    Abstract [en]

    Infant acute lymphoblastic leukaemia (ALL) represents a rare but unique subset with poor prognosis. We analysed mixed-lineage leukaemia (MLL) gene rearrangements and the sequences of complete and incomplete immunoglobulin heavy chain gene rearrangements (IGH) in 14 infants (age < or = 12 months at diagnosis) enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. The dynamics of the leukaemic clone were followed during the course of the disease by quantitative real-time polymerase chain reaction of IGH rearrangements. Sixteen sequences were obtained from 13 (93%) of these infants. There was marked over usage of the V(H)6.1 gene segment (64%) in infants compared with older children with ALL (8%), (P < 0.001) and overusage of D(H)6 (P = 0.004) and J(H)1 (P = 0.004). Poor outcome was associated with MLL gene rearrangements rather than any specific V(H)D(H)J(H) gene usage patterns. Levels of minimal residual disease (MRD) at the end of induction appeared to be high in infants with ALL compared with older children, and although the number of infant cases studied was small, there were no differences in MRD levels after induction therapy in infant ALL with or without MLL gene rearrangements (P = 0.41) and quantitative MRD assessment at the early time points may not be predictive of outcome. Novel treatment strategies are required to improve the outcome in this poor prognosis subset of children with ALL.

  • 14. Linderoth, Johan
    et al.
    Edén, Patrik
    Ehinger, Mats
    Valcich, Jeanette
    Jerkeman, Mats
    Bendahl, Pär-Ola
    Berglund, Mattias
    Enblad, Gunilla
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cavallin-Ståhl, Eva
    Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma2008In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 141, no 4, p. 423-432Article in journal (Refereed)
    Abstract [en]

    In order to identify genes associated with primary chemotherapy-resistance, gene expression profiles (GEP) in tumour tissue from 37 patients with de novo diffuse large B-cell lymphoma (DLBCL), stage II-IV, either in continuous complete remission (n = 24) or with progressive disease during primary treatment (n = 13), were examined using spotted 55K oligonucleotide arrays. Immunohistochemistry was used for confirmation at the protein level. The top 86 genes that best discriminated between the two cohorts were chosen for further analysis. Only seven of 86 genes were overexpressed in the refractory cohort, e.g. RABGGTB and POLE, both potential targets for drug intervention. Seventy-nine of 86 genes were overexpressed in the cured cohort and mainly coded for proteins expressed in the tumour microenvironment, many of them involved in proteolytic activity and remodelling of extra cellular matrix. Furthermore, major histocompatibility complex class I molecules, CD3D and ICAM1 were overexpressed, indicating an enhanced immunological reaction. Immunohistochemistry confirmed the GEP results. The frequency of tumour infiltrating lymphocytes, macrophages, and reactive cells expressing ICAM-1, lysozyme, cathepsin D, urokinase plasminogen activator receptor, signal transducer and activator of transcription 1, and galectin-3 was higher in the cured cohort. These findings indicate that a reactive microenvironment has an impact on the outcome of chemotherapy in DLBCL.

  • 15. Liwing, Johan
    et al.
    Uttervall, Katarina
    Lund, Johan
    Aldrin, Anders
    Blimark, Cecilie
    Carlson, Kristina
    Enestig, Jon
    Flogegård, Max
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gruber, Astrid
    Kviele, Helene Haglöf
    Johansson, Peter
    Lauri, Birgitta
    Mellqvist, Ulf-Henrik
    Swedin, Agneta
    Svensson, Magnus
    Näsman, Per
    Alici, Evren
    Gahrton, Gösta
    Aschan, Johan
    Nahi, Hareth
    Improved survival in myeloma patients: starting to close in on the gap between elderly patients and a matched normal population2014In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 164, no 5, p. 684-693Article in journal (Refereed)
    Abstract [en]

    The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2.8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4.9 years) compared to conventional treatment (2.3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6.9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.

  • 16.
    Mauerer, Katja
    et al.
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Zahrieh, David
    Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Gorgun, Gullu
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Li, Aihong
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Zhou, Jianbiao
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Ansén, Sascha
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Rassenti, Laura Z
    CLL Research Consortium, University of California San Diego, CA, USA.
    Gribben, John G
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
    Immunoglobulin gene segment usage, location and immunogenicity in mutated and unmutated chronic lymphocytic leukaemia2005In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 129, no 4, p. 499-510Article in journal (Refereed)
    Abstract [en]

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

  • 17. Merup, Mats
    et al.
    Lazarevic, Vladimir
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Nahi, Hareth
    Andreasson, Björn
    Malm, Claes
    Nilsson, Lars
    Brune, Mats
    LeBlanc, Katarina
    Kutti, Jack
    Birgegård, Gunnar
    Different outcome of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens.2006In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 135, no 3, p. 367-373Article in journal (Refereed)
  • 18.
    Norén-Nyström, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Heyman, Mats
    Frisk, Per
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sundström, Christer
    Porwit, Anna
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Vascular density in childhood acute lymphoblastic leukaemia correlates to biological factors and outcome.2009In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 146, no 5, p. 521-530Article in journal (Refereed)
    Abstract [en]

    The issue of angiogenesis and its clinical relevance in childhood acute lymphoblastic leukaemia (ALL) is controversial. In the present study, microvessel density (MVD), analysed in 185 diagnostic bone marrow biopsies, was higher in T-cell ALL compared to B-cell precursor (BCP)-ALL (P = 0.013). In the BCP group, cases with t(12;21) were characterized by a low MVD while patients with high-hyperdiploid leukaemia (HeH, 51-61 chromosomes) showed a high MVD compared to other BCP patients (P = 0.001 and 0.002 respectively). There was a correlation between MVD and white blood cell (WBC) count in high-risk BCP patients (P = 0.021). In addition, BCP patients with a high marrow reticulin fibre density and high MVD had an unfavourable outcome compared to the other BCP patients (P = 0.002). The fraction of vessels in which lumina were filled with blasts (blast congested vessel fraction) correlated strongly with WBC count (P < 0.001). These findings indicate that the angiogenic process interacts with other stroma-factors, such as reticulin fibre density, in its effect on outcome, and is coupled to both the ALL genotype and phenotype. One possible implication is that different subtypes of childhood ALL may respond differently to anti-angiogenic drugs as a supplement in first-line treatment.

  • 19. Olsson, Linda
    et al.
    Oefverholm, Ingegerd Ivanov
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Zachariadis, Vasilios
    Nordlund, Jessica
    Sjoegren, Helene
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Nordgren, Ann
    Paulsson, Kajsa
    Heyman, Mats
    Barbany, Gisela
    Johansson, Bertil
    The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 20132015In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 170, no 6, p. 847-858Article in journal (Refereed)
    Abstract [en]

    Paediatric B-cell precursor acute lymphoblastic leukaemias (BCP ALL) with IKZF1 deletions (IKZF1) are associated with a poor outcome. However, there are conflicting data as to whether IKZF1 is an independent risk factor if minimal residual disease (MRD) and other copy number alterations also are taken into account. We investigated 334 paediatric BCP ALL, diagnosed 1992-2013 and treated according to Nordic Society for Paediatric Haematology and Oncology ALL protocols, with known IKZF1 status based on either single nucleotide polymorphism array (N=218) or multiplex ligation-dependent probe amplification (N=116) analyses. IKZF1, found in 15%, was associated with inferior 10-year probabilities of event-free (60% vs. 83%; P<0001) and overall survival (pOS; 73% vs. 89%; P=0001). Adjusting for known risk factors, including white blood cell (WBC) count and MRD, IKZF1 was the strongest independent factor for relapse and death. IKZF1 was present in 27% of cases with non-informative cytogenetics (BCP-other') and a poor 10-year pOS was particularly pronounced in this group (58% vs. 90%; P<0001). Importantly, neither MRD nor WBC count predicted events in the IKZF1-positive cases. Co-occurrence of pseudoautosomal region 1 (PAR1) deletions in Xp22.33/Yp11.32 (P2RY8-CRLF2) and IKZF1 increased the risk of relapse (75% vs. 30% for cases with only IKZF1; P=0045), indicating that BCP-other ALL with both P2RY8-CRLF2 and IKZF1 constitutes a particularly high-risk group.

  • 20. Olsson, Linda
    et al.
    Zettermark, Sofia
    Biloglav, Andrea
    Castor, Anders
    Behrendtz, Mikael
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Paulsson, Kajsa
    Johansson, Bertil
    The genetic landscape of paediatric de novo acute myeloid leukaemia as defined by single nucleotide polymorphism array and exon sequencing of 100 candidate genes2016In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, no 2, p. 292-301Article in journal (Refereed)
    Abstract [en]

    Cytogenetic analyses of a consecutive series of 67 paediatric (median age 8 years; range 0-17) de novo acute myeloid leukaemia (AML) patients revealed aberrations in 55 (82%) cases. The most common subgroups were KMT2A rearrangement (29%), normal karyotype (15%), RUNX1-RUNX1T1 (10%), deletions of 5q, 7q and/or 17p (9%), myeloid leukaemia associated with Down syndrome (7%), PML-RARA (7%) and CBFBMYH11 (5%). Single nucleotide polymorphism array (SNP-A) analysis and exon sequencing of 100 genes, performed in 52 and 40 cases, respectively (39 overlapping), revealed >= 1 aberration in 89%; when adding cytogenetic data, this frequency increased to 98%. Uniparental isodisomies (UPIDs) were detected in 13% and copy number aberrations (CNAs) in 63% (median 2/case); three UPIDs and 22 CNAs were recurrent. Twenty-two genes were targeted by focal CNAs, including AEBP2 and PHF6 deletions and genes involved in AML-associated gene fusions. Deep sequencing identified mutations in 65% of cases (median 1/case). In total, 60 mutations were found in 30 genes, primarily those encoding signalling proteins (47%), transcription factors (25%), or epigenetic modifiers (13%). Twelve genes (BCOR, CEBPA, FLT3, GATA1, KIT, KRAS, NOTCH1, NPM1, NRAS, PTPN11, SMC3 and TP53) were recurrently mutated. We conclude that SNP-A and deep sequencing analyses complement the cytogenetic diagnosis of paediatric AML.

  • 21. Palle, J
    et al.
    Frost, B M
    Forestier, E
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Gustafsson, G
    Nygren, P
    Hellebostad, M
    Jonsson, O G
    Kanerva, J
    Schmiegelow, K
    Larsson, R
    Lönnerholm, G
    Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage.2005In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 129, no 2, p. 189-98Article in journal (Refereed)
    Abstract [en]

    Rearrangements in the 11q23 region, the site of the mixed lineage leukaemia (MLL) gene, are found in both childhood acute myeloid (AML) and lymphoblastic (ALL) leukaemia. We studied the in vitro drug resistance by the fluorometric microculture cytotoxicity assay (FMCA) in 132 children with AML and 178 children with ALL (aged 0-17 years). In AML, children with t(9;11) (n = 10) were significantly more sensitive to cytarabine (P < 0.001) and doxorubicin (P = 0.005) than non-11q23 rearranged patients (n = 108). Children with other 11q23 rearrangements (n = 14) differed less from non-rearranged children. The 'AML-profile' common to all three groups included relative resistance to glucocorticoids and vincristine. In ALL, children with 11q23 rearrangement (n = 22) were significantly more sensitive to cytarabine (P = 0.026) than children without 11q23 rearrangement (n = 156), also after stratification for white blood cell count. In conclusion, the findings indicate that the cellular drug resistance is correlated to both the cell lineage and the type of 11q23 rearrangement. High cellular sensitivity to cytarabine and doxorubicin might explain the excellent treatment results in children with AML and t(9;11). The present study supports the strategy of contemporary protocols to include high-dose cytarabine in the treatment of 11q23-positive patients both in AML and ALL.

  • 22.
    Sandström, Herbert
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Wahlin, A
    Eriksson, M
    Bergström, I
    Serum thymidine kinase in congenital dyserythropoietic anaemia type III.1994In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 87, no 3, p. 653-4Article in journal (Refereed)
    Abstract [en]

    Serum thymidine kinase (TK) was determined in a family with congenital dyserythropoietic anaemia type III (CDA, type III). 20 patients and 10 of their healthy siblings were investigated. Elevated TK was found in all 20 patients (median 56.2 U) but their healthy siblings had normal values (median 2.65 U). We suggest that determination of TK should be used for discrimination between healthy siblings and individuals affected by CDA type III when bone marrow examination is not suitable.

  • 23.
    Sandström, Herbert
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Wahlin, A
    Eriksson, M
    Holmgren, G
    Lind, L
    Sandgren, O
    Angioid streaks are part of a familial syndrome of dyserythropoietic anaemia (CDA III).1997In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 98, no 4, p. 845-9Article in journal (Refereed)
    Abstract [en]

    Congenital dyserythropoietic anaemia type III (CDA III) is a rare disease inherited in an autosomal dominant way and characterized by mild to moderate haemolytic anaemia. Most patients are adapted to their disease and have no or few complaints. Bone marrow examination shows a characteristic picture with erythroid hyperplasia and multinucleate erythroblasts. 20% of patients in a Swedish family affected with the CDA III condition have monoclonal gammopathy or multiple myeloma. By linkage and recombination analysis in the same family, the gene linked to the CDA III condition (CDAN3) has been located to chromosome 15q22. In this paper we report the observation of visual disturbances with macular degeneration and angioid streaks in six patients with CDA III and discuss the apparent association between CDA III, angioid streaks and monoclonal gammopathy. We suggest that this triad forms a previously unreported syndrome.

  • 24. Thörn, Ingrid
    et al.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Botling, Johan
    Thuresson, Britt
    Wasslavik, Carina
    Björklund, Elisabet
    Li, Aihong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lindström-Eriksson, Eleonor
    Malec, Maria
    Grönlund, Elisabeth
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Torikka, Kerstin
    Heldrup, Jesper
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Söderhäll, Stefan
    Jacobsson, Stefan
    Olofsson, Tor
    Porwit, Anna
    Lönnerholm, Gudmar
    Rosenquist, Richard
    Sundström, Christer
    Minimal residual disease assessment in childhood acute lymphoblastic leukaemia: a Swedish multi-centre study comparing real-time polymerase chain reaction and multicolour flow cytometry2011In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 152, no 6, p. 743-53Article in journal (Refereed)
    Abstract [en]

    Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the risk of relapse in childhood acute lymphoblastic leukaemia (ALL). In this Swedish multi-centre study of childhood ALL diagnosed between 2002 and 2006, the MRD levels were analysed in 726 follow-up samples in 228 children using real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes and multicolour flow cytometry (FCM). Using an MRD threshold of 0·1%, which was the sensitivity level reached in all analyses, the concordance between RQ-PCR and FCM MRD values at day 29 was 84%. In B-cell precursor ALL, an MRD level of ≥0·1% at day 29 predicted a higher risk of bone marrow relapse (BMR) with both methods, although FCM was a better discriminator. However, considering the higher median MRD values achieved with RQ-PCR, a higher MRD cut-off (≥0·2%) improved the predictive capacity of RQ-PCR. In T-ALL, RQ-PCR was notably superior to FCM in predicting risk of BMR. That notwithstanding, MRD levels of ≥0·1%, detected by either method at day 29, could not predict isolated extramedullary relapse. In conclusion, the concordance between RQ-PCR and FCM was high and hence both methods are valuable clinical tools for identifying childhood ALL cases with increased risk of BMR.

  • 25. Tierens, Anne
    et al.
    Bjørklund, Elizabeth
    Siitonen, Sanna
    Marquart, Hanne Vibeke
    Wulff-Juergensen, Gitte
    Pelliniemi, Tarja-Terttu
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hasle, Henrik
    Jahnukainen, Kirsi
    Lausen, Birgitte
    Jonsson, Olafur G.
    Palle, Josefine
    Zeller, Bem
    Fogelstrand, Linda
    Abrahamsson, Jonas
    Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study2016In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, no 4, p. 600-609Article in journal (Refereed)
    Abstract [en]

    Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society of Paediatric Haemato-Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event-free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0.1% RD cut-off level. RD-negative and -positive patients after first induction showed a 5-year EFS of 65.7% and 22.7%, respectively (P < 0.001) and an OS of 77.6% (P = 0.025) and 51.8%. RD-negative and -positive patients at start of consolidation therapy had a 5-year EFS of 57.7% and 11.7%, respectively (P < 0001) and an OS of 786% and 2811%) (P < 0001). In multivariate analysis only RD was significantly correlated with survival. RD before consolidation therapy was the strongest independent prognostic factor for EFS [hazard ratio (HR): 5.0; 95% confidence interval (CI): 1.9-133] and OS (HR: 7.0; 95% CI: 20-245). In conclusion, RD before consolidation therapy identifies patients at high risk of relapse in need of intensified treatment. In addition, RD detection can be performed in a multicentre setting and can be implemented in future trials.

  • 26.
    Wahlin, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Markevärn, Berit
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Golovleva, I
    Nilsson, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia.2001In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 115, no 1, p. 25-33Article in journal (Refereed)
    Abstract [en]

    Prognostic factors were studied in a series of 211 acute myeloid leukaemia (AML) patients over 60 years of age, treated at a single centre. The patients were allocated into three risk groups based on cytogenetics, occurrence of antecedent haematological disorder and leucocyte count. Only 3% had low-risk features, 39% had intermediate- and 58% had adverse-risk features. Complete remission (CR) was achieved in 43% of all patients. In multivariate analyses, the number of cycles needed to achieve CR and the risk group were significantly associated with the duration of CR. Median survival time for the entire cohort of patients was only 107 d. Advanced age, low induction treatment intensity, treatment during earlier years and adverse-risk group were associated with shorter overall survival times. Risk group classification may help selection of elderly patients with a good chance of benefiting from intensive treatment to actually receive such treatment, while sparing others with a low probability of survival benefit from toxic treatment. Low intensity induction treatment reduces the chance of obtaining complete remission, produces inferior survival times and should consequently be avoided when the aim is to obtain complete remission. In elderly AML patients, introducing age and re-evaluation of intermediate and good prognosis patients regarding response to induction treatment may improve the risk group classification.

  • 27. Zachariadis, Vasilios
    et al.
    Schoumans, Jacqueline
    Barbany, Gisela
    Heyman, Mats
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Johansson, Bertil
    Nordenskjöld, Magnus
    Nordgren, Ann
    Homozygous deletions of CDKN2A are present in all dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukaemias and may be important for leukaemic transformation2012In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 159, no 4, p. 488-491Article in journal (Refereed)
  • 28. Zdebska, E
    et al.
    Gołaszewska, E
    Fabijańska-Mitek, J
    Schachter, H
    Shalev, H
    Tamary, H
    Sandström, Herbert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Wahlin, A
    Kościelak, J
    Glycoconjugate abnormalities in patients with congenital dyserythropoietic anaemia type I, II and III.2001In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 114, no 4, p. 907-13Article in journal (Refereed)
    Abstract [en]

    Congenital dyserythropoietic anaemia type II (CDA II) is well known for glycosylation abnormalities affecting erythrocyte membrane glycoconjugates that encompass hypoglycosylation of band 3 glycoprotein and accumulation of glycosphingolipids: lactotriaosylceramides, neolactotriaosylceramide and polyglycosylceramides. These abnormalities were not observed in erythrocytes from patients with CDA of either type I or III. Recently, however, we have described a CDA type I patient in Poland with identical, though less pronounced, glycoconjugate abnormalities to those observed in patients with CDA type II. The abnormalities included partial unglycosylation of O-linked glycosylation sites in glycophorin A. These abnormalities are now reported in three Bedouin patients from Israel with CDA type I. In addition, the erythrocyte membranes of these patients exhibited highly increased globotetraosylceramide content. Glycoconjugate abnormalities were also present in erythrocyte membranes from three patients from Northern Sweden with CDA type III but they almost exclusively affected glycosphingolipids. In erythrocytes of all patients examined including one with CDA type II, polyglycosylceramides were significantly hypoglycosylated although, on a molar basis, their contents in erythrocyte membranes were increased. Thus, glycoconjugate abnormalities of varying intensity occur in erythrocyte membranes from all patients with CDA that were investigated.

  • 29. Zeller, Bernward
    et al.
    Glosli, Heidi
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ha, Shau-Yin
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Hasle, Henrik
    Abrahamsson, Jonas
    Hyperleucocytosis in paediatric acute myeloid leukaemia - the challenge of white blood cell counts above 200 x 10(9)/l. The NOPHO experience 1984-20142017In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, no 3, p. 448-456Article in journal (Refereed)
    Abstract [en]

    Hyperleucocytosis in paediatric acute myeloid leukaemia (AML) is associated with increased morbidity and mortality. We studied hyperleucocytosis in 890 patients with AML aged 0-18 years registered in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) registry, with special focus on very high white blood cell counts (WBC > 200 x 10/l). Eighty-six patients (10%) had WBC 100-199 x 10(9)/l and 57 (6%) had WBC >= 200 x 10(9)/l. Patients with WBC >= 200 x 10(9)/l had a high frequency of t(9;11) and a paucity of trisomy 8. Due to the high frequency of deaths within the first 2 weeks (30% vs. 1% for all others), overall survival in this group was inferior to patients with WBC <200 x 10(9)/l (39% vs. 61%). Main cause of early death was intracranial haemorrhage and leucostasis. Twenty-six per cent of these patients never started antileukaemic protocol therapy. Leukapheresis or exchange transfusion was used in 24% of patients with hyperleucocytosis without impact on survival. Patients with hyperleucocytosis surviving the first week had identical survival as patients with lower WBC. We conclude that death within the first days after diagnosis is the major challenge in patients with high WBC and advocate rapid initiation of intensive chemotherapy.

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