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  • 1.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hollander, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mansouri, Larry
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Ednersson, Susanne Bram
    Sahlgrens Univ Hosp, Dept Pathol, Gothenburg, Sweden.
    Andersson, Per-Ola
    Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden;Sodra Alvsborg Hosp Boras, Dept Med, Boras, Sweden.
    Hultdin, Magnus
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Fors, Maja
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Erlanson, Martin
    Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden.
    Degerman, Sofie
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Petersen, Helga Munch
    Copenhagen Univ Hosp, Dept Pathol, Rigshosp, Copenhagen, Denmark.
    Asmar, Fazila
    Copenhagen Univ Hosp, Dept Hematol, Rigshosp, Copenhagen, Denmark.
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Dept Hematol, Rigshosp, Copenhagen, Denmark.
    Enblad, Gunilla
    Uppsala Univ, Expt & Clin Oncol, Dept Immunol Genet & Pathol, Uppsala, Sweden.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma2019In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652Article in journal (Refereed)
    Abstract [en]

    The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.

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  • 2. Andreasson, Ulrika
    et al.
    Edén, Patrik
    Peterson, Carsten
    Högerkorp, Carl-Magnus
    Jerkeman, Mats
    Andersen, Niels
    Berglund, Mattias
    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.
    Borrebaeck, Carl A. K.
    Ek, Sara
    Identification of uniquely expressed transcription factors in highly purified B-cell lymphoma samples2010In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 85, no 6, p. 418-425Article in journal (Refereed)
    Abstract [en]

    Transcription factors (TFs) are critical for B-cell differentiation, affecting gene expression both by repression and transcriptional activation. Still, this information is not used for classification of B-cell lymphomas (BCLs). Traditionally, BCLs are diagnosed based on a phenotypic resemblance to normal B-cells; assessed by immunohistochemistry or flow cytometry, by using a handful of phenotypic markers. In the last decade, diagnostic and prognostic evaluation has been facilitated by global gene expression profiling (GEP), providing a new powerful means for the classification, prediction of survival, and response to treatment of lymphomas. However, most GEP studies have typically been performed on whole tissue samples, containing varying degrees of tumor cell content, which results in uncertainties in data analysis. In this study, global GEP analyses were performed on highly purified, flow-cytometry sorted tumor-cells from eight subgroups of BCLs. This enabled identification of TFs that can be uniquely associated to the tumor cells of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell leukemia (HCL), and mantle cell lymphoma (MCL). The identified transcription factors influence both the global and specific gene expression of the BCLs and have possible implications for diagnosis and treatment.

  • 3. Andréasson, Ulrika
    et al.
    Dictor, Michael
    Jerkeman, Mats
    Berglund, Mattias
    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.
    Linderoth, Johan
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Borrebaeck, Carl A K
    Ek, Sara
    Identification of molecular targets associated with transformed diffuse large B cell lymphoma using highly purified tumor cells2009In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 84, no 12, p. 803-808Article in journal (Refereed)
    Abstract [en]

    Follicular lymphoma (FL) frequently transforms into the more aggressive diffuse large B cell lymphoma (DLBCL-tr), but no protein biomarkers have been identified for predictive or early diagnosis. Gene expression analyses have identified genes changing on transformation but have failed to be reproducible in different studies, reflecting the heterogeneity within the tumor tissue and between tumor samples. Gene expression analyses on Affymetrix Human Genome U133 Plus 2.0 arrays were performed, using flow cytometry sorted tumor cells derived from FL and transformed DLBCL. To identify molecular targets associated with the transformation, subsequent immunohistochemistry (IHC) analyses of the corresponding proteins were performed. Using highly purified cells, this study identified 163 genes, which were significantly deregulated during the transformation in a majority of cases. Among the upregulated transcripts, 13 genes were selected for validation using IHC, based on the availability of commercial antibodies, and galectin-3 and NEK2 proteins specifically identify DLBCL-tr, when compared with FL. We demonstrate that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition. Galectin-3 and NEK2 both identified a subgroup of DLBCL-tr, and the function of these protein markers also suggests a biological role in the transformation process.

  • 4.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Iskas, Michalis
    Gardiner, Anne
    Davis, Zadie
    Plevova, Karla
    Nguyen-Khac, Florence
    Malcikova, Jitka
    Anagnostopoulos, Achilles
    Glide, Sharron
    Mould, Sarah
    Stepanovska, Kristina
    Brejcha, Martin
    Belessi, Chrysoula
    Davi, Frederic
    Pospisilova, Sarka
    Athanasiadou, Anastasia
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Oscier, David
    Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: A systematic reappraisal of classic cytogenetic data2014In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 89, no 3, p. 249-255Article in journal (Refereed)
    Abstract [en]

    The significance of chromosomal translocations (CTRAs) and karyotype complexity (KC) in chronic lymphocytic leukemia (CLL) remains uncertain. To gain insight into these issues, we evaluated a series of 1001 CLL cases with reliable classic cytogenetic data obtained within 6 months from diagnosis before any treatment. Overall, 320 cases were found to carry 1 CTRAs. The most frequent chromosome breakpoints were 13q, followed by 14q, 18q, 17q, and 17p; notably, CTRAs involving chromosome 13q showed a wide spectrum of translocation partners. KC (3 aberrations) was detected in 157 cases and significantly (P<0.005) associated with unmutated IGHV genes and aberrations of chromosome 17p. Furthermore, it was identified as an independent prognostic factor for shorter time-to-first-treatment. CTRAs were assigned to two categories (i) CTRAs present in the context of KC, often with involvement of chromosome 17p aberrations, occurring mostly in CLL with unmutated IGHV genes; in such cases, we found that KC rather than the presence of CTRAs per se negatively impacts on survival; (ii) CTRAs in cases without KC, having limited if any impact on survival. On this evidence, we propose that all CTRAs in CLL are not equivalent but rather develop by different processes and are associated with distinct clonal behavior. Am. J. Hematol. 89:249-255, 2014. (c) 2013 Wiley Periodicals, Inc.

  • 5.
    Ekberg, Sara
    et al.
    Karolinska Inst, Div Clin Epidemiol, Dept Medicin Solna, Stockholm, Sweden.
    Jerkeman, Mats
    Lund Univ, Inst Clin Sci, Dept Pathol & Oncol, Lund, Sweden.
    Andersson, Per-Ola
    Gothenburg Univ, Boras & Sahlgrenska Acad, South Alvsborg Hosp, Dept Hematol, Gothenburg, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wahlin, Bjoern E.
    Karolinska Inst, Div Hematol, Deparment Med Huddinge, Stockholm, Sweden.
    Hasselblom, Sverker
    Deparment Res Dev & Educ, Halmstad, Sweden.
    Andersson, Therese M.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Eloranta, Sandra
    Karolinska Inst, Div Clin Epidemiol, Dept Medicin Solna, Stockholm, Sweden.
    Smedby, Karin E.
    Karolinska Univ Hosp, Ctr Hematol, Solna, Sweden;Karolinska Inst, Div Clin Epidemiol, Dept Medicin Solna, Stockholm, Sweden.
    Long-term survival and loss in expectancy of life in a population-based cohort of 7114 patients with diffuse large B-cell lymphoma2018In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 93, no 8, p. 1020-1028Article in journal (Refereed)
    Abstract [en]

    Survival has improved among patients with diffuse large B-cell lymphoma (DLBCL) with the addition of anti-CD20 antibody therapy. We aimed to quantify trends and remaining loss in expectation of life (LEL) due to DLBCL at a national population-based level. Patients diagnosed with DLBCL 2000-2013 (N=7114) were identified through the Swedish Lymphoma Registry and classified according to the age-adjusted International Prognostic Index (aaIPI). The novel measure LEL is the difference between remaining life years among patients and the general population and was predicted using flexible parametric models from diagnosis and among 2-year survivors, by age and sex. Median age at DLBCL-diagnosis was 70 (18-105) years and 54.8% presented with stage III-IV disease. On average, LEL due to DLBCL decreased from 8.0 (95% CI: 7.7-8.3) to 4.6 (95% CI: 4.5-4.6) years over the study period. By risk group, LEL was most reduced among patients with aaIPI >= 2 aged 50-60 years. However, these patients were still estimated to lose >8 years in 2013 (eg, LELmales50years 8.6 years (95% CI: 5.0-12.3)). Among 2-year survivors, LEL was reduced from 6.1 years (95% CI: 5.6-6.5) (aaIPI >= 2) and 3.8 years (95% CI: 3.6-4.1) (aaIPI<2) to 1.1 (95% CI: 1.1-1.2) and 1.0 year (95% CI: 0.8-1.1), respectively. The reduction was observed across all ages. Results for females were similar. By using LEL we illustrate the improvement of DLBCL survival over time. Despite adequate immunochemotherapy, substantial LEL among patients with IPI >= 2 points to remaining unmet medical needs. We speculate that observed reduced losses among 2-year survivors indicate a reduction of late relapses.

  • 6. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjorn
    Nahi, Hareth
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5 '-nucleotidase2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 12, p. 1001-1006Article in journal (Refereed)
    Abstract [en]

    De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A> C rs2072671 and 2451C> T rs532545), 50-nucleotidase (cN-II 7A> G rs10883841), and deoxycytidine kinase (DCK 30UTR 948T> C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and 2451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P< 0.001 and 5 vs. 23 months, P50.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P50.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML. Am. J. Hematol. 88: 1001-1006, 2013.

  • 7.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ekberg, Sara
    Jerkeman, Mats
    Chang, Ellen T
    Björkholm, Magnus
    Andersson, Therese M L
    Smedby, Karin E
    Eloranta, Sandra
    Long-term survival in young and middle-aged Hodgkin lymphoma patients in Sweden 1992-2009-trends in cure proportions by clinical characteristics2015In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 90, no 12, p. 1128-1134Article in journal (Refereed)
    Abstract [en]

    Trends in Hodgkin lymphoma (HL) survival among patients treated outside of clinical trials provide real-world benchmark estimates of prognosis and help identify patient subgroups for targeted trials. In a Swedish population-based cohort of 1947 HL patients diagnosed in 1992-2009 at ages 18-59 years, we estimated relative survival (RS), cure proportions (CP), and median survival times using flexible parametric cure models. Overall, the CP was 89% (95% CI: 0.87-0.91) and median survival of the uncured was 4.6 years (95% CI: 3.0-6.3). For patients aged 18-50 years diagnosed after the year 2000, CP was high and stable, whereas for patients of 50-59 years, cure was not reached. The survival of relapse-free patients was similar to that of the general population (RS5-year : 0.99; 95% CI: 0.98-0.99, RS15-year : 0.95; 95% CI: 0.92-0.97). The excess mortality of relapsing patients was 19 times (95% CI: 12-31) that of relapse-free patients. Despite modern treatments, patients with adverse prognostic factors (e.g., advanced stage) still had markedly worse outcomes [CP stage: IIIB 0.82 (95% CI: 0.73-0.89); CP stage: IVB 0.72, (95% CI: 0.60-0.81)] and patients with international prognostic score (IPS) ≥3 had 2.7 times higher excess mortality (95% CI: 1.0-7.0, p = 0.04) than patients with IPS <3. High-risk patients selected for 6-8 courses of BEACOPP (bleomycin, etoposide, doxorubicin, cyclofosphamide, vincristine, procarbazine, prednisone)-chemotherapy had a 15-year relative survival of 87%, (95% CI: 0.80-0.92), whereas the corresponding estimate for patients selected for 6-8 courses of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) was 93% (95% CI: 0.88-0.97). These population-based results indicate limited fatal side-effects in the 15-year perspective with contemporary treatments, while the unmet need of effective relapse treatment remains of concern. BEACOPP-chemotherapy was still not sufficient in high-risk HL patients. Am. J. Hematol., 2015.

  • 8.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Eloranta, Sandra
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Ekberg, Sara
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Chang, Ellen T.
    Ctr Epidemiol & Computat Biol Hlth Sci Practice E, Menlo Pk, CA 92697 USA.;Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA..
    Neovius, Martin
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden.;Karolinska Univ Hosp, Div Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Increased healthcare use up to 10 years among relapse-free Hodgkin lymphoma survivors in the era of intensified chemotherapy and limited radiotherapy2017In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 92, no 3, p. 251-258Article in journal (Refereed)
    Abstract [en]

    With today's excellent cure rates for Hodgkin lymphoma (HL), the number of long-term survivors is increasing. This study aims to provide a global assessment of late adverse effects for workingage HL survivors treated with contemporary protocols (combination chemotherapy and limited radiotherapy). From Swedish nationwide registers we identified 1017 HL survivors diagnosed in 2000-2009, aged 18-60 years (median 32) and surviving at least one year post-diagnosis, and 4031 age-,sex-, and calendar-year-matched population comparators. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) for outpatient visits and inpatient bed-days after the first year up to 14 years post-diagnosis (through 2013) were estimated across treatment subgroups, considering relapse-free time and using negative binomial regression. Scheduled outpatient visits for HL were excluded. The rate of outpatient visits was nearly double (IRR = 1.8, 95% CI: 1.6-2.0) that among comparators and higher rates persisted up to 10 years post-diagnosis. The rate of inpatient bed-days among relapse-free survivors was more than three-fold (IRR = 3.6, 95% CI: 2.74.7) that of comparators and the increase persisted up to four years post-diagnosis. Patients requiring 6-8 chemotherapy courses had higher rates of outpatient visits (IRR = 1.4, 95% CI: 1.11.7) and bed-days (IRR-4.7, 95% CI: 2.9-7.8) than patients treated with 2-4 courses+radiotherapy. Previously seldom reported reasons for the excess healthcare use included chest pain, keratitis, asthma, diabetes mellitus, and depression. Contemporary treatment, chemotherapy in particular, was associated with excess healthcare use among HL survivors during the first decade postdiagnosis. The reasons for healthcare visits reflected a wide range of disorders, indicating the need of broad individualized care in addition to specific screening programs.

  • 9.
    Goldberg, Stuart L.
    et al.
    Hackensack Univ, Med Ctr, John Theurer Canc Ctr, 92 Second St, Hackensack, NJ 07601 USA..
    Cortes, Jorge E.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Gambacorti-Passerini, Carlo
    Univ Milano Bicocca, San Gerardo Hosp, Monza, Italy..
    Hehlmann, Ruediger
    Heidelberg Univ, Mannheim, Germany..
    Khoury, H. Jean
    Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA..
    Michallet, Mauricette
    Ctr Hosp Lyon Sud, Pierre Benite, France..
    Paquette, Ron L.
    Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA..
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala Univ, Uppsala, Sweden..
    Zyczynski, Teresa
    Bristol Myers Squibb Co, Princeton, NJ USA..
    Foreman, Aimee
    ICON Plc, San Francisco, CA USA..
    Abruzzese, Elisabetta
    S Eugenio Hosp, Rome, Italy..
    Andorsky, David
    Rocky Mt Canc Ctr, Boulder, CO USA..
    Beeker, Aart
    Spaarne Hosp, Hoofddorp, Netherlands..
    Cony-Makhoul, Pascale
    Ctr Hosp Annecy Genevois, Pringy, France..
    Hansen, Richard
    Inst Med, IDGGQ, Kaiserslautern, Germany..
    Lomaia, Elza
    Federal Almazov North West Med Res Ctr, St Petersburg, Russia..
    Olavarria, Eduardo
    Imperial Coll London, Hammersmith Hosp, London, England..
    Mauro, Michael J.
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    First-line treatment selection and early monitoring patterns in chronic phase-chronic myeloid leukemia in routine clinical practice: SIMPLICITY2017In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 92, no 11, p. 1214-1223Article in journal (Refereed)
    Abstract [en]

    Achieving successful outcomes in chronic phase-chronic myeloid leukemia (CP-CML) requires careful monitoring of cytogenetic/molecular responses (CyR/MR). SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor use and management patterns in patients with CP-CML receiving first-line imatinib (n = 416), dasatinib (n = 418) or nilotinib (n = 408) in the US and 6 European countries in routine clinical practice. Twelve-month follow-up data of 1242 prospective patients (enrolled October 01 2010-September 02 2015) are reported. 81% of patients had baseline comorbidities. Treatment selection was based on perceived efficacy over patient comorbidity profile. There was a predominance of imatinib-treated patients enrolled earlier in the study, with subsequent shift toward dasatinib- and nilotinib-treated patients by 2013/2014. Monitoring for either CyR/MR improved over time and was documented for 36%, 82%, and 95% of patients by 3, 6, and 12 months, respectively; 5% had no documentation of CyR/MR monitoring during the first year of therapy. Documentation of MR/CyR testing was higher in Europe than the US (P < .001) and at academic versus community practices (P = .001). Age <65 years, patients being followed at sites within Europe, those followed at academic centers and patients no longer on first-line therapy were more likely to be monitored by 12 months. SIMPLICITY demonstrates that the NCCN and ELN recommendations on response monitoring have not been consistently translated into routine clinical practice. In the absence of appropriate monitoring practices, clinical response to TKI therapy cannot be established, any needed changes to treatment strategy will thus not be implemented, and long-term patient outcomes are likely to be impacted.

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  • 10.
    Halldorsdottir, Anna Margret
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Marincevic, Millaray
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stamatopoulos, Kostas
    Sander, Birgitta
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mantle cell lymphoma displays a homogenous methylation profile: A comparative analysis with chronic lymphocytic leukemia2012In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 87, no 4, p. 361-367Article in journal (Refereed)
    Abstract [en]

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

  • 11. Hasselbalch, H.
    et al.
    Junker, P.
    Lisse, I.
    Lindqvist, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Engström Laurent, A.
    Circulating hyaluronan in the myelofibrosis/osteomyelosclerosis syndrome and other myeloproliferative disorders1991In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 36, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    The serum concentration of hyaluronan (HYA) was determined in 59 patients with various myeloproliferative disorders, including 33 patients with idiopathic myelofibrosis. In 18 patients the serum concentration of the aminoterminal propeptide of type III procollagen (PIIINP) was measured concomitantly. Raised serum HYA levels were seen in patients with active disease compared with age-matched healthy subjects, whereas no significant difference in serum HYA was seen between patients with stable disease and age-matched controls. Serum HYA concentrations correlated significantly with the leukocyte count (rho = 0.38; P less than 0.02) and with the serum concentration of PIIINP (rho = 0.50; P less than 0.001). During cytotoxic treatment, the serum HYA and PIIINP concentrations decreased in concert with declining leukocyte counts. These findings suggest that clonal expansion is accompanied by a bone marrow stromal reaction similar to the repair processes following injury to soft connective tissues. The relatively modest changes in serum HYA with frequent overlaps between patient categories and healthy subjects imply that the clinical utility of single determinations of serum HYA in the present disease groups is restrained. On the other hand, sequential measurements of HYA may provide a reflection of the myeloproliferative process in individual patients.

  • 12.
    Hehlmann, Ruediger
    et al.
    Heidelberg Univ, Weinheim, Germany;ELN Fdn, Weinheim, Germany.
    Cortes, Jorge E.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Zyczynski, Teresa
    Bristol Myers Squibb Co, Princeton, NJ USA.
    Gambacorti-Passerini, Carlo
    Univ Milano Bicocca, San Gerardo Hosp, Monza, Italy.
    Goldberg, Stuart L.
    Hackensack Univ Med Ctr, John Theurer Canc Ctr, Hackensack, NJ USA.
    Mauro, Michael J.
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA.
    Michallet, Mauricette
    Ctr Hosp Lyon Sud, Pierre Benite, France.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Williams, Loretta A.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Gajavelli, Srikanth
    Bristol Myers Squibb Co, Princeton, NJ USA.
    DeGutis, Irene
    Bristol Myers Squibb Co, Princeton, NJ USA.
    Sen, Ginny P.
    ICON Clin Res LLC, San Francisco, CA USA.
    Paquette, Ron L.
    UCLA Med Ctr, Los Angeles, CA USA.
    Tyrosine kinase inhibitor interruptions, discontinuations and switching in patients with chronic-phase chronic myeloid leukemia in routine clinical practice: SIMPLICITY2019In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 94, no 1, p. 46-54Article in journal (Refereed)
    Abstract [en]

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

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  • 13. Hulegårdh, Erik
    et al.
    Nilsson, Christer
    Lazarevic, Vladimir
    Garelius, Hege
    Antunovic, Petar
    Derolf, Asa Rangert
    Möllgård, Lars
    Uggla, Bertil
    Wennström, Lovisa
    Wahlin, Anders
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Juliusson, Gunnar
    Stockelberg, Dick
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Characterization and prognostic features of secondary acute myeloid leukemia (AML) in a population-based setting: A report from the Swedish Acute Leukemia Registry2015In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 90, no 3, p. 208-214Article in journal (Refereed)
    Abstract [en]

    Patients with secondary AML often escape inclusion in clinical trials and thus, population-based studies are crucial for its accurate characterization. In this first large population-based study on secondary AML, we studied AML with an antecedent hematological disease (AHD-AML) or therapy-related AML (t-AML) in the population-based Swedish Acute Leukemia Registry. The study included 3363 adult patients of which 2474 (73.6%) had de novo AML, 630 (18.7%) AHD-AML and 259 (7.7%) t-AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26-1.79) and t-AML (1.72; 1.38-2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and t-AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population-based setting has a striking impact on survival in younger AML patients whereas it lacks prognostic value among the elderly patients.

  • 14. Jardin, Fabrice
    et al.
    Pujals, Anais
    Pelletier, Laura
    Bohers, Elodie
    Camus, Vincent
    Mareschal, Sylvain
    Dubois, Sydney
    Sola, Brigitte
    Ochmann, Marlène
    Lemonnier, François
    Viailly, Pierre-Julien
    Bertrand, Philippe
    Maingonnat, Catherine
    Traverse-Glehen, Alexandra
    Gaulard, Philippe
    Damotte, Diane
    Delarue, Richard
    Haioun, Corinne
    Argueta, Christian
    Landesman, Yosef
    Salles, Gilles
    Jais, Jean-Philippe
    Figeac, Martin
    Copie-Bergman, Christiane
    Molina, Thierry Jo
    Picquenot, Jean Michel
    Cornic, Marie
    Fest, Thierry
    Milpied, Noel
    Lemasle, Emilie
    Stamatoullas, Aspasia
    Moeller, Peter
    Dyer, Martin J S
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bastard, Christian
    Tilly, Hervé
    Leroy, Karen
    Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma.2016In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 91, no 9, p. 923-30Article in journal (Refereed)
    Abstract [en]

    Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein. Am. J. Hematol. 91:923-930, 2016. © 2016 Wiley Periodicals, Inc.

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  • 15.
    Lauseker, Michael
    et al.
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Bachl, Katharina
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Turkina, Anna
    Natl Res Ctr Hematol, Moscow, Russia.
    Faber, Edgar
    Palacky Univ, Univ Hosp, Dept Hematol Oncol, Olomouc, Czech Republic.
    Prejzner, Witold
    Med Univ Gdansk, Dept Hematol, Gdansk, Poland.
    Strömberg, Ulla Ohlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Baccarani, Michele
    Univ Bologna, Dept Hematol & Oncol L&A, Bologna, Italy.
    Lomaia, Elza
    Almazov Med Res Ctr, Clin Oncol Res Dept Oncol & Hematol, St Petersburg, Russia.
    Zackova, Daniela
    Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic;Masaryk Univ, Brno, Czech Republic.
    Ossenkoppele, Gert
    Vrije Univ Amsterdam Med Ctr, Amsterdam Univ Med Ctr, Dept Hematol, Amsterdam, Netherlands.
    Griskevicius, Laimonas
    Vilnius Univ, Vilnius Univ Hosp Santaros Klin, Vilnius, Lithuania;Vilnius Univ, Inst Clin Med, Vilnius, Lithuania.
    Schubert-Fritschle, Gabriele
    Ludwig Maximilians Univ Munchen, Munich Canc Registry, Munich, Germany.
    Sacha, Tomasz
    Jagiellonian Univ Hosp, Chair & Dept Hematol, Krakow, Poland.
    Heibl, Sonja
    Klinikum Wels Grieskirchen, Dept Internal Med 4, Wels, Austria.
    Koskenvesa, Perttu
    Helsinki Univ Hosp, Ctr Canc, Helsinki, Finland;Univ Helsinki, Hematol Res Unit, Helsinki, Finland.
    Bogdanovic, Andrija
    Univ Belgrade, Clin Hematol CCS, Belgrade, Serbia;Univ Belgrade, Fac Med, Belgrade, Serbia.
    Clark, Richard E.
    Univ Liverpool, Inst Translat Med, Liverpool, Merseyside, England.
    Guilhot, Joelle
    CHU Poitiers, Clin Invest Ctr, INSERM, CIC 1402, Poitiers, France.
    Hoffmann, Verena S.
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Hasford, Joerg
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Hochhaus, Andreas
    Univ Klinikum Jena, Klin Innere Med 2, Abt Hamatol Onkol, Jena, Germany.
    Pfirrmann, Markus
    Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany.
    Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin2019In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 94, no 11, p. 1236-1243Article in journal (Refereed)
    Abstract [en]

    Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate.

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  • 16. Lazarevic, Vladimir Lj
    et al.
    Remberger, Mats
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Juliusson, Gunnar
    Kimby, Eva
    Malm, Claes
    Wahlin, Anders
    Omar, Hamdy
    Johansson, Jan-Erik
    Myeloablative allogeneic stem cell transplantation for lymphoblastic lymphoma in Sweden: a retrospective study2011In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 86, no 8, p. 709-710Article in journal (Refereed)
  • 17.
    Lazarevic, Vladimir
    et al.
    Skane Univ Hosp, Dept Hematol & Vasc Dis, SE-22185 Lund, Sweden.;Lund Univ, Stem Cell Ctr, Lund, Sweden..
    Rosso, Aldana
    Skane Univ Hosp, Epidemiol & Registry Ctr South Sweden, SE-22185 Lund, Sweden..
    Juliusson, Gunnar
    Skane Univ Hosp, Dept Hematol & Vasc Dis, SE-22185 Lund, Sweden.;Lund Univ, Stem Cell Ctr, Lund, Sweden..
    Antunovic, Petar
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Rangert-Derolf, Asa
    Karolinska Univ Hosp, Div Hematol Stockholm & Huddinge, Dept Med, Karolinska, Sweden..
    Lehmann, Soren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Div Hematol Stockholm & Huddinge, Dept Med, Karolinska, Sweden..
    Mollgard, Lars
    Sahlgrens Univ Hosp, Dept Med, S-41345 Gothenburg, Sweden..
    Uggla, Bertil
    Orebro Univ Hosp, Sch Hlth & Med Sci, Dept Med, Orebro, Sweden..
    Wennstrom, Lovisa
    Sahlgrens Univ Hosp, Dept Med, S-41345 Gothenburg, Sweden..
    Wahlin, Anders
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Johansson, Bertil
    Univ & Reg Labs Reg Skane, Dept Clin Genet, Lund, Sweden.;Lund Univ, Div Clin Genet, Dept Lab Med, Lund, Sweden..
    Prognostic significance of high hyperdiploid and triploid/tetraploid adult acute myeloid leukemia2015In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 90, no 9, p. 800-805Article in journal (Refereed)
    Abstract [en]

    To ascertain the clinical implications of high hyperdiploid (HH; 49-65 chromosomes) and triploid/tetraploid (TT; >65 chromosomes) adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Of the 3,654 cytogenetically informative cases diagnosed between January 1997 and May 2014, 68 (1.9%) were HH (n=50)/TT (n=18). Patients with HH/TT were older than those with intermediate risk (IR) AML (median 71 years vs. 67 years; P=0.042) and less often had de novo AML (63% vs. 79%; P=0.004); no such differences were observed between HH/TT and complex karyotype (CK) AML. The overall survival (OS) was similar between patients with HH/TT and CK AML (median 0.9 years vs. 0.6 years; P=0.082), whereas OS was significantly longer (median 1.6 years; P=0.028) for IR AML. The OS was shorter for cases with HH than with TT (median 0.6 years vs. 1.4 years; P=0.032) and for HH/TT AMLs with adverse abnormalities (median 0.8 years vs. 1.1 years; P=0.044). In conclusion, HH/TT AML is associated with a poor outcome, but chromosome numbers >65 and absence of adverse aberrations seem to translate into a more favorable prognosis. Thus, HH/TT AMLs are clinically heterogeneous and should not automatically be grouped as high risk.Am. J. Hematol. 90:800-805, 2015.

  • 18.
    Llorens, Jose
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Metzendorf, Christoph
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology. Heidelberg Univ, Biochem Ctr, Neuenheimer Feld 328, D-69120 Heidelberg, Germany..
    Missirlis, Fanis
    Ctr Invest & Estudios Avanzados, Dept Fisiol Biofis & Neurociencias, Mexico City, DF, Mexico..
    Lind, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Mitoferrin Deficiency Provokes An Ecdysone Synthesis Impairment And An Immune System Overreaction2016In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 91, no 3, p. E199-E199Article in journal (Other academic)
  • 19.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Grabowski, Pawel
    Degerman, Sofie
    Svenson, Ulrika
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cahill, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Smedby, Karin Ekstrom
    Geisler, Christian
    Juliusson, Gunnar
    Roos, Goran
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 8, p. 647-651Article in journal (Refereed)
    Abstract [en]

    Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n=265) and in relation to other prognostic markers. Short telomeres were particularly associated with high-risk genetic markers, such as NOTCH1, SF3B1, or TP53 aberrations, and predicted a short time to treatment (TTT) and overall survival (OS) (both P<0.0001). TL was an independent prognostic factor and subdivided patients with otherwise good-prognostic features (e.g., mutated IGHV genes, favorable cytogenetics) into subgroups with different outcome. Furthermore, in follow-up samples (n=119) taken 5-8 years after diagnosis, TL correlated well with TL at diagnosis and remained unaffected by treatment. Altogether, these novel data indicate that short TL already at diagnosis is associated with poor outcome in CLL and that TL can be measured at later stages of the disease. 

  • 20.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hooper, Sean D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Juliusson, Gunnar
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Next generation RNA-sequencing in prognostic subsets of chronic lymphocytic leukemia2012In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 87, no 7, p. 737-740Article in journal (Refereed)
    Abstract [en]

    Advances in next-generation RNA-sequencing have revealed the complexity of transcriptomes by allowing both coding and noncoding (nc) RNAs to be analyzed. However, limited data exist regarding the whole transcriptional landscape of chronic lymphocytic leukemia (CLL). In this pilot-study, we evaluated RNA-sequencing in CLL by comparing two subsets which carry almost identical or `` stereotyped'' B-cell receptors with distinct clinical outcome, that is the poor-prognostic subset # 1 (n = 4) and the more favorable-prognostic subset # 4 (n = 4). Our analysis revealed that 156 genes (e.g. LPL, WNT9A) and 76 ncRNAs, (e. g. SNORD48, SNORD115) were differentially expressed between the subsets. This technology also enabled us to identify numerous subset-specific splice variants (n = 406), which were predominantly expressed in subset # 1, including a splice-isoform of MSI2 with a novel start exon. A further important application of RNA-sequencing was for mutation detection and revealed 16-30 missense mutations per sample; notably many of these changes were found in genes with a strong potential for involvement in CLL pathogenesis, e. g., ATM and NOTCH2. This study not only demonstrates the effectiveness of RNA-sequencing for identifying mutations, quantifying gene expression and detecting splicing events, but also highlights the potential such global approaches have to significantly advance our understanding of the molecular mechanisms behind CLL development. 

  • 21.
    Mattsson, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sandin, Fredrik
    Kimby, Eva
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Increasing prevalence of chronic lymphocytic leukemia with an estimated future rise: a nationwide population-based study2020In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 95, no 2, p. E36-E38Article in journal (Other academic)
  • 22. Metzendorf, Christoph
    et al.
    Lind, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Comparative Physiology.
    Mitoferrin is Essential for Normal Development in Drosophila2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 5, p. E76-E77Article in journal (Other academic)
1 - 22 of 22
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