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Chronic Lymphocytic Leukemia in Norway 1953-2012

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Chronic Lymphocytic Leukemia in Norway 1953-2012 Chronic lymphocytic leukemia in Norway 1953-2012 Doctoral thesis by Andrea Lenartova Cand.med. Department of Hematology Institute of Clinical Medicine University of Oslo Oslo University Hospital Norway 2020 © Andrea Lenartova, 2020 Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8377-726-0 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Print production: Reprosentralen, University of Oslo. Contents Acknowledgements ........................................................................................................................... 4 Abbreviations ...................................................................................................................................... 6 Thesis summary ................................................................................................................................. 7 Articles in the thesis ........................................................................................................................ 10 Introduction ........................................................................................................................................ 11 Zooming in ..................................................................................................................................... 11 CLL pathogenesis ....................................................................................................................... 11 CLL cells are mature B-lymphocytes ....................................................................................... 12 B-cell receptors role and clinical usage ................................................................................... 13 B-cell receptor maturation ......................................................................................................... 14 DNA rearrangement, formation of unique antigen-binding site ........................................... 14 Somatic hypermutation .............................................................................................................. 15 Immunglobuline heavy chain variable region mutated vs. unmutated ............................... 15 How the cancerous transformation begins? ........................................................................... 16 DNA mutations ............................................................................................................................ 16 Monoclonal B- cell lymphocytosis ............................................................................................ 17 High count monoclonal B-cell lymphocytosis is a precursor for CLL .................................. 17 What makes the B-cell clone to proliferate? ........................................................................... 17 Zooming out ................................................................................................................................... 18 How can epidemiological studies add to knowledge in pathogenesis? ............................. 18 The Cancer Registry of Norway ............................................................................................... 18 History of CLL diagnosis ............................................................................................................ 19 History of CLL registration in Norway ...................................................................................... 20 Incidental diagnosis and clinical symptoms ............................................................................ 21 Trends in CLL incidence in Scandinavia and World .............................................................. 21 Trends in survival ........................................................................................................................ 21 CLL treatment principles during the study period (1953-2012) ........................................... 22 Second hematologic malignancy in CLL ............................................................................... 23 Richter syndrome ............................................................................................................................ 23 Hodgkin variant of Richter syndrome ...................................................................................... 28 Second myeloid malignancy ......................................................................................................... 30 Thesis aims ........................................................................................................................................ 32 Materials and methods .................................................................................................................... 33 Study population ............................................................................................................................. 33 Data sources ................................................................................................................................... 33 2 Study design .................................................................................................................................... 34 Statistical analyses ......................................................................................................................... 34 Follow up time ............................................................................................................................. 34 Incidence rates ............................................................................................................................ 34 Observed survival, Kaplan-Meier survival analysis ............................................................... 35 Expected survival ........................................................................................................................ 35 Relative survival and net cancer survival ................................................................................ 35 Results/summary of the papers ................................................................................................... 37 Quality of registration and validity .......................................................................................... 37 Summary paper I ........................................................................................................................... 38 Results published in Paper I ..................................................................................................... 38 Updated results of trends in incidence and survival of CLL patients diagnosed 1953- 2012 in Norway (Paper I updated) ........................................................................................... 38 Incidence of CLL ......................................................................................................................... 41 Basis for diagnosis ..................................................................................................................... 41 Survival ......................................................................................................................................... 41 Differences between 1993-2002 and 2003-2012, summarized. ......................................... 48 Summary Paper II, Richter syndrome in CLL patients in Norway 1953-2017 ............... 50 Summary Paper III, Second hematologic malignancy in CLL patients diagnosed 2003-2012 ........................................................................................................................................ 55 Discussion .......................................................................................................................................... 57 Methodological considerations ................................................................................................ 57 Information bias........................................................................................................................... 57 Selection bias .............................................................................................................................. 59 Confounding bias ........................................................................................................................ 59 Completeness of follow up ........................................................................................................ 59 Incidence rates stratification ..................................................................................................... 59 Bias in survival estimates .......................................................................................................... 60 Relative cancer survival vs. net cancer survival .............................................................. 61 General discussion ...................................................................................................................... 62 Paper I .......................................................................................................................................... 62 Paper II ........................................................................................................................................ 66 Paper III ....................................................................................................................................... 69 Ethical considerations
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