84 results on '"Saft, L."'
Search Results
2. The BioLymph study – implementing precision medicine approaches in lymphoma diagnostics, treatment and follow-up: feasibility and first results
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Smedby, K. E., Wästerlid, T., Tham, E., Haider, Z., Joelsson, J., Thorvaldsdottir, B., Krstic, A., Wahlin, B. E., Foroughi-Asl, H., Karlsson, C., Eloranta, S., Saft, L., Palma, M., Kwiecinska, A., Hansson, L., Österborg, A., Wirta, V., Rassidakis, G., Sander, B., Sonnevi, K., and Rosenquist, R.
- Abstract
The BioLymph study – implementing precision medicine approaches in lymphoma diagnostics, treatment and follow-up: feasibility and first results
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- 2023
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3. P543: TARGETING SAMHD1 WITH HYDROXYUREA IN FIRST-LINE CYTARABINE-BASED THERAPY OF NEWLY DIAGNOSED ACUTE MYELOID LEUKAEMIA: RESULTS FROM THE HEAT-AML TRIAL
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Jädersten, M., primary, Lilienthal, I., additional, Tsesmetzis, N., additional, Lourda, M., additional, Bengtzén, S., additional, Bohlin, A., additional, Arnroth, C., additional, Erkers, T., additional, Seashore-Ludlow, B., additional, Giraud, G., additional, Barkhordar, G. S., additional, Tao, S., additional, Fogelstrand, L., additional, Saft, L., additional, Östling, P., additional, Schinazi, R., additional, Kim, B., additional, Schaller, T., additional, Juliusson, G., additional, Deneberg, S., additional, Lehmann, S., additional, Rassidakis, G., additional, Höglund, M., additional, Henter, J.-I., additional, and Herold, N., additional
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- 2022
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4. Patient-specific assays based on whole-genome sequencing data to measure residual disease in children with acute lymphoblastic leukemia – a proof-of- concept study
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Arthur, C, primary, Rezayee, F, additional, Mogensen, N, additional, Saft, L, additional, Rosenquist, R, additional, Nordenskjöld, M, additional, Harila-Saari, A, additional, Tham, E, additional, and Barbany, G, additional
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- 2022
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5. Dendritic Cells in Bone Marrow at Diagnosis and after Chemotherapy in Adult Patients with Acute Myeloid Leukaemia
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Derolf, Å. R., Laane, E., Björklund, E., Saft, L., Björkholm, M., and Porwit, Anna
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- 2014
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6. C014 Expression of p53 or cytoplasmic nucleophosmine associated with increased risk of disease progression in myelodysplastic syndrome with isolated del(5q)
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Jadersten, M., Saft, L., Garelius, H., Hast, R., Nilsson, L., Samuelsson, J., Porwit, A., and Hellström-Lindberg, E.
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- 2009
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7. MULTICENTRE VALIDATION OF A REPRODUCIBLE FLOW CYTOMETRIC SCORE FOR THE DIAGNOSIS OF LOWRISK MYELODYSPLASTIC SYNDROMES: RESULTS OF A EUROPEAN LeukemiaNET STUDY
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Picone, C., Tenore, A., Vanelli, L., LUCA MALCOVATI, Pascutto, C., Ogata, K., Tamura, H., Handa, H., Czader, M., Freeman, S., Vyas, P., Porwit, A., Saft, L., Westers, T. M., Alhan, C., Cali, C., Loosdrecht, A. A., Cazzola, M., and Della Porta, M. G.
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- 2016
8. Reliability of the reported size of removed colorectal polyps
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Rubio, Ca, Grimelius, L., Lindholm, J., Hamberg, H., Porwit, A., Elmberger, G., Hoog, A., Kanter, L., Eriksson, E., Stemme, S., Orrego, A., Saft, L., Petersson, F., La Torre, M., Ekstrom, C., Astrom, K., Rundgren, A., Djokic, M., Chandanos, E., Lenander, C., Machado, M., Per Nilsson, and Mattsson, L.
- Subjects
Observer Variation ,Colonic Diseases ,Rectal Diseases ,Pathology ,Humans ,Intestinal Polyps ,Reproducibility of Results - Abstract
The size of colorectal polyps is important in the clinical management of these lesions.To audit the accuracy in calculating the size of "polyps" by various specialists.Eighteen pathologists and four surgeons measured, with a conventional millimetre ruler, the largest diameter of 12 polyp phantoms. The results of two independent measurements (two weeks apart) were compared with the gold standard-size assessed at The Royal Institute of Technology, Sweden.Thirty-one percent (83/264-trial 1) and 33% (88/264-trial 2) of the measurements underestimated or overestimated the gold standard size by1 mm. Of the 22 experienced participants, 95% (21/22-trial 1) and 91% (20/22-trial 2) misjudged by1 mm the size of one or more polyps. Values given by 13 participants (4.9%) in trial 1 and by 15 participants (5.7%) in trial 2, differed byor = +/-4 mm from the gold standard size. In addition, a big difference between the highest and the lowest values was recorded in some polyps (up to 11.4 mm). Those disparate values were regarded as a human error in reading the scale on the ruler.Using a conventional ruler (the tool of pathologists worldwide) unacceptably high intra-observer and inter-observer variations in assessing the size of polyp-phantoms was found. The volume and the shape of devices, as well as human error in reading the scale of the ruler were confounding factors in size assessment. In praxis, the size is crucial in the management of colorectal polyps. Considering the clinical implications of the results obtained, the possibility of developing a method that will allow assessment of the true size of removed clinical polyps is being explored.
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- 2007
9. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)
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Saft, L., primary, Karimi, M., additional, Ghaderi, M., additional, Matolcsy, A., additional, Mufti, G. J., additional, Kulasekararaj, A., additional, Gohring, G., additional, Giagounidis, A., additional, Selleslag, D., additional, Muus, P., additional, Sanz, G., additional, Mittelman, M., additional, Bowen, D., additional, Porwit, A., additional, Fu, T., additional, Backstrom, J., additional, Fenaux, P., additional, MacBeth, K. J., additional, and Hellstrom-Lindberg, E., additional
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- 2014
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10. Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial
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Tobiasson, M, primary, Dybedahl, I, additional, Holm, M S, additional, Karimi, M, additional, Brandefors, L, additional, Garelius, H, additional, Grövdal, M, additional, Högh-Dufva, I, additional, Grønbæk, K, additional, Jansson, M, additional, Marcher, C, additional, Nilsson, L, additional, Kittang, A O, additional, Porwit, A, additional, Saft, L, additional, Möllgård, L, additional, and Hellström-Lindberg, E, additional
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- 2014
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11. P-098 p53 protein expression predicts outcome and cytogenetic response in patients with low-/INT-1-risk myelodysplastic syndromes treated with lenalidomide
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Saft, L., primary, Karimi, M., additional, Ghaderi, M., additional, Matolscy, A., additional, Fenaux, P., additional, Mufti, G., additional, Giagounidis, A., additional, Selleslag, D., additional, Muus, P., additional, Sanz, G., additional, Mittelman, M., additional, Bowen, D., additional, Porwit, A., additional, Fu, T., additional, Backstrom, J., additional, MacBeth, K., additional, and Hellström-Lindberg, E., additional
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- 2013
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12. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study
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Della Porta, M. G., primary, Picone, C., additional, Pascutto, C., additional, Malcovati, L., additional, Tamura, H., additional, Handa, H., additional, Czader, M., additional, Freeman, S., additional, Vyas, P., additional, Porwit, A., additional, Saft, L., additional, Westers, T. M., additional, Alhan, C., additional, Cali, C., additional, van de Loosdrecht, A. A., additional, and Ogata, K., additional
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- 2012
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13. Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities
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Mollgard, L., primary, Saft, L., additional, Treppendahl, M. B., additional, Dybedal, I., additional, Norgaard, J. M., additional, Astermark, J., additional, Ejerblad, E., additional, Garelius, H., additional, Dufva, I. H., additional, Jansson, M., additional, Jadersten, M., additional, Kjeldsen, L., additional, Linder, O., additional, Nilsson, L., additional, Vestergaard, H., additional, Porwit, A., additional, Gronbaek, K., additional, and Lindberg, E. H., additional
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- 2011
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14. 135 Lower bone marrow myeloid and plasmacytoid dendritic cell counts in high-risk than in low-risk MDS patients and controls
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Saft, L., primary, Björklund, E., additional, Hellström-Lindberg, E., additional, and Porwit, A., additional
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- 2011
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15. Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression
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Jadersten, M., primary, Saft, L., additional, Pellagatti, A., additional, Gohring, G., additional, Wainscoat, J. S., additional, Boultwood, J., additional, Porwit, A., additional, Schlegelberger, B., additional, and Hellstrom-Lindberg, E., additional
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- 2009
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16. Étude Électro-Physiologique Et Histologique De L'Ototoxicité De Certains Antibiotiques.
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Ardouin, P., Saft, L., and Jobard, P.
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- 1963
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17. Assessment of CD34-positive blasts in bone marrow core biopsy: inter-observer agreement study
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Torlakovic, E. E., Calvo, K. R., George, T. I., Hyjek, E., Lee, S. -H, Mazur, J., Elena Sabattini, Saft, L., Tzankov, A., and Porwit, A.
18. Direct audiometry in audiosurgery. (Abstract)
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Antoli-Candela, Francisco, primary, Antioli-Candela, Fernando, additional, Olaizola, F., additional, and Saft, L., additional
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- 1958
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19. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes: A workshop report with focus on novel entities and a literature review including paediatric cases.
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Saft L, Kvasnicka HM, Boudova L, Gianelli U, Lazzi S, and Rozman M
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- Humans, Child, Bone Marrow pathology, Oncogene Proteins, Fusion genetics, Myeloproliferative Disorders, Eosinophilia genetics, Eosinophilia pathology, Lymphoma pathology, Hematologic Neoplasms pathology
- Abstract
Myeloid/lymphoid neoplasms with eosinophilia (M/LN-eo) and tyrosine kinase (TK) gene fusions are a rare group of haematopoietic neoplasms with a broad range of clinical and morphological presentations. Paediatric cases have increasingly been recognised. Importantly, not all appear as a chronic myeloid neoplasm and eosinophilia is not always present. In addition, standard cytogenetic and molecular methods may not be sufficient to diagnose M/LN-eo due to cytogenetically cryptic aberrations. Therefore, additional evaluation with fluorescence in-situ hybridisation and other molecular genetic techniques (array-based comparative genomic hybridisation, RNA sequencing) are recommended for the identification of specific TK gene fusions. M/LN-eo with JAK2 and FLT3-rearrangements and ETV6::ABL1 fusion were recently added as a formal member to this category in the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In addition, other less common defined genetic alterations involving TK genes have been described. This study is an update on M/LN-eo with TK gene fusions with focus on novel entities, as illustrated by cases submitted to the Bone Marrow Workshop, organised by the European Bone Marrow Working Group (EBMWG) within the frame of the 21st European Association for Haematopathology congress (EAHP-SH) in Florence 2022. A literature review was performed including paediatric cases of M/LN-eo with TK gene fusions., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)
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- 2023
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20. The role of flow cytometry in the classification of myeloid disorders.
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Saft L
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- Humans, Flow Cytometry, Artificial Intelligence, Leukemia, Myeloid, Acute diagnosis, Myeloproliferative Disorders diagnosis, Myelodysplastic Syndromes diagnosis
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The World Health Organization classification (WHO-HAEM5) and the International Consensus Classification (ICC 2022) of myeloid neoplasms are based on the integration of clinical, morphologic, immunophenotypic, and genomic data. Flow cytometric immunophenotyping (FCIP) allows the identification, enumeration, and characterization of hematopoietic cells, and is therefore a powerful tool in the diagnosis, classification, and monitoring of hematological neoplasms. The vast majority of flow cytometry (FCM) studies in chronic myeloid neoplasms focus on its role in myelodysplastic neoplasms (MDS). FCM can also be helpful for the assessment of myeloproliferative neoplasms (MPN) and MDS/MPN, including the early detection of evolving myeloid or lymphoid blast crisis and the characterization of monocytic subsets. The classification of acute myeloid leukemia (AML) is primarily based on cytogenetic and molecular findings; however, FCIP is needed for subclassification of AML, not otherwise specified (NOS; ICC)/AML defined by differentiation (WHO-HAEM5). The main role of FCM in AML remains in making a rapid diagnosis and as a tool for measurable residual disease monitoring. Machine learning and artificial intelligence approaches can be used to analyze and classify FCM data. This article, based on an invited lecture at the 106th Annual Meeting of the German Society of Pathology in 2023, reviews the role of FCM in the classification of myeloid neoplasms, including recent publications on the application of artificial intelligence., (© 2023. The Author(s).)
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- 2023
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21. Case Report: Whole genome sequencing identifies CCDC88C as a novel JAK2 fusion partner in pediatric T-cell acute lymphoblastic leukemia.
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Krstic A, Rezayee F, Saft L, Hammarsjö A, Svenberg P, and Barbany G
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In the present report, we applied whole genome sequencing (WGS) to genetically characterize a case of pediatric T-cell acute lymphoblastic leukemia (ALL) refractory to standard therapy. WGS identified a novel JAK2 fusion, with CCDC88C as a partner. CCDC88C encodes a protein part of the Wnt signaling pathway and has previously been described in hematological malignancies as fusion partner to FLT3 and PDGFRB . The novel CCDC88C :: JAK2 fusion gene results in a fusion transcript, predicted to produce a hybrid protein, which retains the kinase domain of JAK2 and is expected to respond to JAK2 inhibitors. This report illustrates the potential of WGS in the diagnostic setting of ALL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Krstic, Rezayee, Saft, Hammarsjö, Svenberg and Barbany.)
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- 2023
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22. Flow cytometric analysis of myelodysplasia: Pre-analytical and technical issues-Recommendations from the European LeukemiaNet.
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van der Velden VHJ, Preijers F, Johansson U, Westers TM, Dunlop A, Porwit A, Béné MC, Valent P, Te Marvelde J, Wagner-Ballon O, Oelschlaegel U, Saft L, Kordasti S, Ireland R, Cremers E, Alhan C, Duetz C, Hobo W, Chapuis N, Fontenay M, Bettelheim P, Eidenshink-Brodersen L, Font P, Loken MR, Matarraz S, Ogata K, Orfao A, Psarra K, Subirá D, Wells DA, Della Porta MG, Burbury K, Bellos F, Weiß E, Kern W, and van de Loosdrecht A
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- Humans, Flow Cytometry methods, Reference Standards, Biological Assay, Fluorescent Dyes, Myelodysplastic Syndromes diagnosis
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Background: Flow cytometry (FCM) aids the diagnosis and prognostic stratification of patients with suspected or confirmed myelodysplastic syndrome (MDS). Over the past few years, significant progress has been made in the FCM field concerning technical issues (including software and hardware) and pre-analytical procedures., Methods: Recommendations are made based on the data and expert discussions generated from 13 yearly meetings of the European LeukemiaNet international MDS Flow working group., Results: We report here on the experiences and recommendations concerning (1) the optimal methods of sample processing and handling, (2) antibody panels and fluorochromes, and (3) current hardware technologies., Conclusions: These recommendations will support and facilitate the appropriate application of FCM assays in the diagnostic workup of MDS patients. Further standardization and harmonization will be required to integrate FCM in MDS diagnostic evaluations in daily practice., (© 2021 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals LLC on behalf of International Clinical Cytometry Society.)
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- 2023
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23. Multiparameter flow cytometry in the evaluation of myelodysplasia: Analytical issues: Recommendations from the European LeukemiaNet/International Myelodysplastic Syndrome Flow Cytometry Working Group.
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Porwit A, Béné MC, Duetz C, Matarraz S, Oelschlaegel U, Westers TM, Wagner-Ballon O, Kordasti S, Valent P, Preijers F, Alhan C, Bellos F, Bettelheim P, Burbury K, Chapuis N, Cremers E, Della Porta MG, Dunlop A, Eidenschink-Brodersen L, Font P, Fontenay M, Hobo W, Ireland R, Johansson U, Loken MR, Ogata K, Orfao A, Psarra K, Saft L, Subira D, Te Marvelde J, Wells DA, van der Velden VHJ, Kern W, and van de Loosdrecht AA
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- Humans, Flow Cytometry methods, Antigens, CD34, Granulocytes pathology, Monocytes pathology, Immunophenotyping, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes pathology
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Multiparameter flow cytometry (MFC) is one of the essential ancillary methods in bone marrow (BM) investigation of patients with cytopenia and suspected myelodysplastic syndrome (MDS). MFC can also be applied in the follow-up of MDS patients undergoing treatment. This document summarizes recommendations from the International/European Leukemia Net Working Group for Flow Cytometry in Myelodysplastic Syndromes (ELN iMDS Flow) on the analytical issues in MFC for the diagnostic work-up of MDS. Recommendations for the analysis of several BM cell subsets such as myeloid precursors, maturing granulocytic and monocytic components and erythropoiesis are given. A core set of 17 markers identified as independently related to a cytomorphologic diagnosis of myelodysplasia is suggested as mandatory for MFC evaluation of BM in a patient with cytopenia. A myeloid precursor cell (CD34
+ CD19- ) count >3% should be considered immunophenotypically indicative of myelodysplasia. However, MFC results should always be evaluated as part of an integrated hematopathology work-up. Looking forward, several machine-learning-based analytical tools of interest should be applied in parallel to conventional analytical methods to investigate their usefulness in integrated diagnostics, risk stratification, and potentially even in the evaluation of response to therapy, based on MFC data. In addition, compiling large uniform datasets is desirable, as most of the machine-learning-based methods tend to perform better with larger numbers of investigated samples, especially in such a heterogeneous disease as MDS., (© 2022 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals LLC on behalf of International Clinical Cytometry Society.)- Published
- 2023
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24. A series of case studies illustrating the role of flow cytometry in the diagnostic work-up of myelodysplastic syndromes.
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Westers TM, Saft L, van der Velden VHJ, Te Marvelde JG, Dunlop A, Ireland R, Valent P, Porwit A, Béné MC, and van de Loosdrecht AA
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- Humans, Flow Cytometry methods, Bone Marrow, Bone Marrow Cells, Immunophenotyping, Myelodysplastic Syndromes diagnosis
- Abstract
Current guidelines recommend flow cytometric analysis as part of the diagnostic assessment of patients with cytopenia suspected for myelodysplastic syndrome. Herein we describe the complete work-up of six cases using multimodal integrated diagnostics. Flow cytometry assessments are illustrated by plots from conventional and more recent analysis tools. The cases demonstrate the added value of flow cytometry in case of hypocellular, poor quality, or ambiguous bone marrow cytomorphology. Moreover, they demonstrate how immunophenotyping results support clinical decision-making in inconclusive and clinically 'difficult' cases., (© 2022 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals LLC on behalf of International Clinical Cytometry Society.)
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- 2023
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25. Multicenter prospective evaluation of diagnostic potential of flow cytometric aberrancies in myelodysplastic syndromes by the ELN iMDS flow working group.
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Kern W, Westers TM, Bellos F, Bene MC, Bettelheim P, Brodersen LE, Burbury K, Chu SC, Cullen M, Porta MD, Dunlop AS, Johansson U, Matarraz S, Oelschlaegel U, Ogata K, Porwit A, Preijers F, Psarra K, Saft L, Subirá D, Weiß E, van der Velden VHJ, and van de Loosdrecht A
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- Humans, Flow Cytometry methods, Leukocytes, Immunophenotyping, Myelodysplastic Syndromes diagnosis, Leukemia, Myelomonocytic, Chronic diagnosis
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Background: Myelodysplastic syndromes (MDS) represent a diagnostic challenge. This prospective multicenter study was conducted to evaluate pre-defined flow cytometric markers in the diagnostic work-up of MDS and chronic myelomonocytic leukemia (CMML)., Methods: Thousand six hundred and eighty-two patients with suspected MDS/CMML were analyzed by both cytomorphology according to WHO 2016 criteria and flow cytometry according to ELN recommendations. Flow cytometric readout was categorized 'non-MDS' (i.e. no signs of MDS/CMML and limited signs of MDS/CMML) and 'in agreement with MDS' (i.e., in agreement with MDS/CMML)., Results: Flow cytometric readout categorized 60% of patients in agreement with MDS, 28% showed limited signs of MDS and 12% had no signs of MDS. In 81% of cases flow cytometric readouts and cytomorphologic diagnosis correlated. For high-risk MDS, the level of concordance was 92%. A total of 17 immunophenotypic aberrancies were found independently related to MDS/CMML in ≥1 of the subgroups of low-risk MDS, high-risk MDS, CMML. A cut-off of ≥3 of these aberrancies resulted in 80% agreement with cytomorphology (20% cases concordantly negative, 60% positive). Moreover, >3% myeloid progenitor cells were significantly associated with MDS (286/293 such cases, 98%)., Conclusion: Data from this prospective multicenter study led to recognition of 17 immunophenotypic markers allowing to identify cases 'in agreement with MDS'. Moreover, data emphasizes the clinical utility of immunophenotyping in MDS diagnostics, given the high concordance between cytomorphology and the flow cytometric readout. Results from the current study challenge the application of the cytomorphologically defined cut-off of 5% blasts for flow cytometry and rather suggest a 3% cut-off for the latter., (© 2022 International Clinical Cytometry Society.)
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- 2023
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26. Clinical application of flow cytometry in patients with unexplained cytopenia and suspected myelodysplastic syndrome: A report of the European LeukemiaNet International MDS-Flow Cytometry Working Group.
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van de Loosdrecht AA, Kern W, Porwit A, Valent P, Kordasti S, Cremers E, Alhan C, Duetz C, Dunlop A, Hobo W, Preijers F, Wagner-Ballon O, Chapuis N, Fontenay M, Bettelheim P, Eidenschink-Brodersen L, Font P, Johansson U, Loken MR, Te Marvelde JG, Matarraz S, Ogata K, Oelschlaegel U, Orfao A, Psarra K, Subirá D, Wells DA, Béné MC, Della Porta MG, Burbury K, Bellos F, van der Velden VHJ, Westers TM, Saft L, and Ireland R
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- Humans, Flow Cytometry, Myelodysplastic Syndromes diagnosis
- Abstract
This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes (MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow-up of MDS patients., (© 2021 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals LLC on behalf of International Clinical Cytometry Society.)
- Published
- 2023
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27. Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial.
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Jädersten M, Lilienthal I, Tsesmetzis N, Lourda M, Bengtzén S, Bohlin A, Arnroth C, Erkers T, Seashore-Ludlow B, Giraud G, Barkhordar GS, Tao S, Fogelstrand L, Saft L, Östling P, Schinazi RF, Kim B, Schaller T, Juliusson G, Deneberg S, Lehmann S, Rassidakis GZ, Höglund M, Henter JI, and Herold N
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- Humans, Hydroxyurea therapeutic use, Arabinofuranosylcytosine Triphosphate therapeutic use, SAM Domain and HD Domain-Containing Protein 1, Hot Temperature, Antineoplastic Combined Chemotherapy Protocols, Neoplasm Recurrence, Local, Daunorubicin therapeutic use, Cytarabine therapeutic use, Cytarabine pharmacology, Leukemia, Myeloid, Acute drug therapy
- Abstract
Background: Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1., Objectives: In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients., Methods: Nine patients were enrolled and received at least two courses of ara-C (1 g/m
2 /2 h b.i.d. d1-5, i.e., a total of 10 g/m2 per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m2 d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed., Results: The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 × 109 /L and to platelet recovery >50 × 109 /L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (allo-HSCT). With a median follow-up of 18.0 (range 14.9-20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in second complete remission., Conclusion: Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)- Published
- 2022
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28. Patient-Specific Assays Based on Whole-Genome Sequencing Data to Measure Residual Disease in Children With Acute Lymphoblastic Leukemia: A Proof of Concept Study.
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Arthur C, Rezayee F, Mogensen N, Saft L, Rosenquist R, Nordenskjöld M, Harila-Saari A, Tham E, and Barbany G
- Abstract
Risk-adapted treatment in acute lymphoblastic leukemia (ALL) relies on genetic information and measurable residual disease (MRD) monitoring. In this proof of concept study, DNA from diagnostic bone marrow (BM) of six children with ALL, without stratifying genetics or central nervous system (CNS) involvement, underwent whole-genome sequencing (WGS) to identify structural variants (SVs) in the leukemic blasts. Unique sequences generated by SVs were targeted with patient-specific droplet digital PCR (ddPCR) assays. Genomic DNA (gDNA) from BM and cell-free DNA (cfDNA) from plasma and cerebrospinal fluid (CSF) were analyzed longitudinally. WGS with 30× coverage enabled target identification in all cases. Limit of quantifiability (LoQ) and limit of detection (LoD) for the ddPCR assays (n = 15) were up to 10
-5 and 10-6 , respectively. All targets were readily detectable in a multiplexed ddPCR with minimal DNA input (1 ng of gDNA) at a 10-1 dilution, and targets for half of the patients were also detectable at a 10-2 dilution. The level of MRD in BM at end of induction and end of consolidation block 1 was in a comparable range between ddPCR and clinical routine methods for samples with detectable residual disease, although our approach consistently detected higher MRD values for patients with B-cell precursor ALL. Additionally, several samples with undetectable MRD by flow cytometry were MRD-positive by ddPCR. In plasma, the level of leukemic targets decreased in cfDNA over time following the MRD level detected in BM. cfDNA was successfully extracted from all diagnostic CSF samples (n = 6), and leukemic targets were detected in half of these. The results suggest that our approach to design molecular assays, together with ddPCR quantification, is a technically feasible option for accurate MRD quantification and that cfDNA may contribute valuable information regarding MRD and low-grade CNS involvement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arthur, Rezayee, Mogensen, Saft, Rosenquist, Nordenskjöld, Harila-Saari, Tham and Barbany.)- Published
- 2022
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29. Outcome in PCNSL patients and its association with PD-L1+ leukocytes in the tumor microenvironment.
- Author
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Abdulla M, Hollander P, Lindskog C, Sundström C, Enblad G, Saft L, and Amini RM
- Subjects
- B7-H1 Antigen, Biomarkers, Tumor, Humans, Lymphocytes, Tumor-Infiltrating pathology, Tumor Microenvironment, Central Nervous System Neoplasms pathology, Lymphoma, Non-Hodgkin
- Published
- 2022
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30. "Randomized phase II study of azacitidine ± lenalidomide in higher-risk myelodysplastic syndromes and acute myeloid leukemia with a karyotype including Del(5q)".
- Author
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Rasmussen B, Göhring G, Bernard E, Nilsson L, Tobiasson M, Jädersten M, Garelius H, Dybedal I, Grønbaek K, Ejerblad E, Lorenz F, Flogegård M, Marcher CW, Öster Fernström A, Cavelier L, Papaemmanuil E, Ebeling F, Kittang AO, Nørgaard JM, Saft L, Möllgård L, and Hellström-Lindberg E
- Subjects
- Azacitidine, Chromosome Deletion, Chromosomes, Human, Pair 5 genetics, Humans, Karyotype, Lenalidomide therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics
- Published
- 2022
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31. Intracerebral manifestation of iatrogenic, immunodeficiency-associated polymorphic B-LPD with morphology mimicking Hodgkin lymphoma: a case report and literature review.
- Author
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Saft L, Perdiki-Grigoriadi M, and Rassidakis G
- Abstract
Iatrogenic immunodeficiency-associated lymphoproliferative disorders (IA-LPD) may arise in patients treated with immunosuppressive drugs for autoimmune disease or other conditions. Polymorphic EBV-positive B-lymphoproliferations often have features mimicking Hodgkin lymphoma and typically a self-limited, indolent course. We present an unusual case with isolated, intracerebral manifestation of polymorphic B-LPD with features of classic Hodgkin-lymphoma in an immunosuppressed patient treated with methotrexate and infliximab, including clinical-radiological features and a detailed description of morphological findings, together with a literature review on reported cases of primary CNS manifestation of cHL and IA-LPD with Hodgkin-like morphology. The patient achieved complete remission following neurosurgery with gross total tumor resection and drug withdrawal without any additional treatment. Post-operative staging revealed no evidence for focal relapse or systemic disease during the 18 months follow-up period. Among the previously reported 24 cases of primary, isolated Hodgkin lymphoma in the central nervous system, three similar cases of iatrogenic, IA-LPDs were identified and are discussed here. Polymorphic B-LPD are destructive lesions with a range of morphologic features and disease manifestations. It is clinically important to recognize the spectrum of proliferations with features of classic Hodgkin lymphoma in immunodeficiency, iatrogenic settings, because they are likely to impact the choice of treatment strategies., Supplementary Information: The online version contains supplementary material available at 10.1007/s12308-021-00478-0., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2022.)
- Published
- 2022
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32. Eosinophilia/Hypereosinophilia in the Setting of Reactive and Idiopathic Causes, Well-Defined Myeloid or Lymphoid Leukemias, or Germline Disorders.
- Author
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Kelemen K, Saft L, Craig FE, Orazi A, Nakashima M, Wertheim GB, George TI, Horny HP, King RL, Quintanilla-Martinez L, Wang SA, Rimsza LM, and Reichard KK
- Subjects
- Diagnosis, Differential, Female, Fusion Proteins, bcr-abl metabolism, Genetic Predisposition to Disease, Germ Cells pathology, Histological Techniques, Humans, Leukemia diagnosis, Leukemia pathology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myeloid, Accelerated Phase diagnosis, Leukemia, Myeloid, Accelerated Phase pathology, Male, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes pathology, Pathology, Molecular, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Eosinophilia diagnosis, Eosinophilia etiology, Eosinophilia pathology, Hematologic Neoplasms diagnosis, Hematologic Neoplasms pathology, Hypereosinophilic Syndrome diagnosis, Hypereosinophilic Syndrome pathology, Leukemia, Lymphoid diagnosis, Leukemia, Lymphoid pathology
- Abstract
Objectives: To report the findings of the 2019 Society for Hematopathology/European Association for Haematopathology Workshop within the categories of reactive eosinophilia, hypereosinophilic syndrome (HES), germline disorders with eosinophilia (GDE), and myeloid and lymphoid neoplasms associated with eosinophilia (excluding entities covered by other studies in this series)., Methods: The workshop panel reviewed 109 cases, assigned consensus diagnosis, and created diagnosis-specific sessions., Results: The most frequent diagnosis was reactive eosinophilia (35), followed by acute leukemia (24). Myeloproliferative neoplasms (MPNs) received 17 submissions, including chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). Myelodysplastic syndrome (MDS), MDS/MPN, and therapy-related myeloid neoplasms received 11, while GDE and HES received 12 and 11 submissions, respectively., Conclusions: Hypereosinophilia and HES are defined by specific clinical and laboratory criteria. Eosinophilia is commonly reactive. An acute leukemic onset with eosinophilia may suggest core-binding factor acute myeloid leukemia, blast phase of chronic myeloid leukemia, BCR-ABL1-positive leukemia, or t(5;14) B-lymphoblastic leukemia. Eosinophilia is rare in MDS but common in MDS/MPN. CEL, NOS is a clinically aggressive MPN with eosinophilia as the dominant feature. Bone marrow morphology and cytogenetic and/or molecular clonality may distinguish CEL from HES. Molecular testing helps to better subclassify myeloid neoplasms with eosinophilia and to identify patients for targeted treatments., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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33. The diagnostic and prognostic role of flow cytometry in idiopathic and clonal cytopenia of undetermined significance (ICUS/CCUS): A single-center analysis of 79 patients.
- Author
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Dimopoulos K, Hansen OK, Sjö LD, Saft L, Schjødt IM, Werner Hansen J, and Grønbaek K
- Subjects
- Adult, Aged, Aged, 80 and over, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Myelodysplastic Syndromes pathology, Myeloproliferative Disorders pathology, Prognosis, Clonal Hematopoiesis, Flow Cytometry, Myelodysplastic Syndromes diagnosis, Myeloproliferative Disorders diagnosis
- Abstract
Objective: The aim of this study was to evaluate the diagnostic and prognostic role of multiparameter flow cytometry (FC) in patients with idiopathic cytopenia of undetermined significance (ICUS) and clonal cytopenia of undetermined significance (CCUS)., Methods: We performed FC using a standardized panel and two different diagnostic algorithms (Ogata, Wells) in a well-characterized cohort of 79 patients with ICUS/CCUS and compared it with a retrospective blinded morphological evaluation and data from targeted next-generation DNA sequencing of 20 myelodysplastic syndrome (MDS)-related genes., Results: Our data show that FC has low sensitivity in distinguishing CCUS from ICUS patients (40.5% for Ogata score and 59.5% for Wells score). The Wells score was suggestive of dysplasia in ICUS/CCUS patients with concurrent morphological signs of dysplasia in the bone marrow (following re-evaluation by two hematopathologists) and in CCUS patients with a higher mutational burden. Eight patients with ICUS/CCUS from our cohort progressed to another myeloid malignancy (MDS, acute myeloid leukemia, or chronic myelomonocytic leukemia), all showing flow cytometric signs of dysplasia., Conclusion: FC performs poorly in diagnosing CCUS versus ICUS. However, it can potentially provide prognostic information in cytopenic patients by identifying a subgroup of patients with a higher grade of dysplasia, higher mutational burden, and higher risk of progression and, together with mutational screening, also identify a group of patients who might require morphological reassessment of dysplastic changes in their bone marrow., (© 2019 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.)
- Published
- 2020
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34. Overexpression of chromatin remodeling and tyrosine kinase genes in iAMP21-positive acute lymphoblastic leukemia.
- Author
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Ivanov Öfverholm I, Zachariadis V, Taylan F, Marincevic-Zuniga Y, Tran AN, Saft L, Nilsson D, Syvänen AC, Lönnerholm G, Harila-Saari A, Nordenskjöld M, Heyman M, Nordgren A, Nordlund J, and Barbany G
- Subjects
- Child, Chromatin Assembly Factor-1, Chromatin Assembly and Disassembly genetics, Chromosome Aberrations, Cytogenetics, Humans, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Protein-Tyrosine Kinases genetics
- Abstract
Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). The biology behind the high relapse risk is unknown and the aim of this study was to further characterize the genomic and transcriptional landscape of iAMP21. Using DNA arrays and sequencing, we could identify rearrangements and aberrations characteristic for iAMP21. RNA sequencing revealed that only half of the genes in the minimal region of amplification (20/45) were differentially expressed in iAMP21. Among them were the top overexpressed genes ( p < 0.001) in iAMP21 vs. BCP ALL without iAMP21 and three candidate genes could be identified, the tyrosine kinase gene DYRK1A and chromatin remodeling genes CHAF1B and SON. While overexpression of DYRK1A and CHAF1B is associated with poor prognosis in malignant diseases including myeloid leukemia, this is the first study to show significant correlation with iAMP21-positive ALL.
- Published
- 2020
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35. Challenges in Diagnosing Myelodysplastic Syndromes in the Era of Genetic Testing: Proceedings of the 13th Workshop of the European Bone Marrow Working Group.
- Author
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Hebeda KM, Tzankov A, Boudova L, Saft L, Hasserjian RP, de Boer M, Fend F, Orazi A, and Leguit R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Bone Marrow pathology, Education, Female, Genetic Testing, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Myelodysplastic Syndromes classification, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology, Sequence Analysis, DNA, Chromosome Aberrations, Myelodysplastic Syndromes diagnosis
- Abstract
The 13th workshop of the European Bone Marrow Working Group in Utrecht, The Netherlands, was devoted to studying myelodysplastic syndromes (MDS) and their boundaries. The panel received 44 cases submitted to the 3 invited categories, which included: reactive cytopenias with dysplasia, idiopathic cytopenia of undetermined significance, clonal haematopoiesis of indeterminate potential, idiopathic dysplasia of uncertain significance and overt MDS. For this summary, we have selected 17 cases that highlight difficulties in separating true MDS from other causes of cytopenia and the intricate relationship between clonal haematopoiesis and true MDS. In addition, cases of overt MDS with challenging features were also selected. All cases were stained for p53 expression. Using instructive submitted cases we discuss the following: (1) cytopenia with clonal haematopoiesis not fulfilling MDS criteria, (2) cytopenia and/or dysplasia with germline mutations and/or familial history suggesting an underlying gene defect, (3) MDS based on a recurrent chromosomal abnormality and (4) overt MDS with diagnostic difficulties due to concurrent treatment or disease. The lively discussion in the open forum of the workshop illustrated the need for better integrative understanding of the evolution of acquired genetic abnormalities in haematopoiesis, and the challenge of diagnosing true MDS in cytopenic patients with genetic abnormalities, either germline or acquired., (© 2018 S. Karger AG, Basel.)
- Published
- 2019
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36. Revising flow cytometric mini-panel for diagnosing low-grade myelodysplastic syndromes: Introducing a parameter quantifying CD33 expression on CD34+ cells.
- Author
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Ogata K, Sei K, Saft L, Kawahara N, Porta MGD, Chapuis N, and Yamamoto Y
- Subjects
- Adult, Aged, Aged, 80 and over, Antigens, CD34, Biomarkers analysis, Female, Granulocytes pathology, Humans, Male, Middle Aged, Sensitivity and Specificity, Bone Marrow Cells pathology, Flow Cytometry methods, Immunophenotyping methods, Myelodysplastic Syndromes diagnosis, Sialic Acid Binding Ig-like Lectin 3 analysis
- Abstract
Diagnosis of myelodysplastic syndromes (MDS) is not straightforward when objective data, such as blast excess and abnormal cytogenetics, are lacking. Expert laboratories use flow cytometry (FCM) to help diagnose MDS. However, most of FCM protocols for MDS are complex, requiring a high level of expertise and high cost. We have reported a FCM mini-panel consisting of four FCM parameters (so-called Ogata score), which is simple to conduct and inexpensive. In this paper, to refine this mini-panel, we have introduced a new FCM parameter, which quantifies CD33 expression on CD34+ cells (called Granulocyte/CD34 cell CD33 ratio). Bone marrow cells from MDS without blast excess (low-grade MDS) and controls were stained with CD34, CD45, and CD33 and analyzed for five parameters ("Granulocyte/CD34 cell CD33 ratio" plus four parameters in the Ogata score). By a multivariate logistic regression model, only three parameters, including "Granulocyte/CD34 cell CD33 ratio" had statistically significant power for diagnosing low-grade MDS. Based on the results, we constructed a new scoring system, which showed approximately 50% sensitivity and more than 95% specificity in diagnosing low-grade MDS. Our revised mini-panel is suitable for screening samples suspected for MDS and provides a basis for further improvement in diagnostic FCM protocols for MDS., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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37. CD274 (PD-L1)/PDCD1 (PD-1) expression in de novo and transformed diffuse large B-cell lymphoma.
- Author
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Kwiecinska A, Tsesmetzis N, Ghaderi M, Kis L, Saft L, and Rassidakis GZ
- Subjects
- Adult, B7-H1 Antigen, Child, Humans, Programmed Cell Death 1 Receptor, Rituximab, Tumor Microenvironment, Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse
- Published
- 2018
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38. Megakaryocytes harbour the del(5q) abnormality despite complete clinical and cytogenetic remission induced by lenalidomide treatment.
- Author
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Scharenberg C, Jansson M, Saft L, and Hellström-Lindberg E
- Subjects
- Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Bone Marrow pathology, Clonal Evolution, Cytogenetic Analysis, Hematologic Neoplasms diagnosis, Humans, Immunophenotyping, In Situ Hybridization, Fluorescence, Lenalidomide, Megakaryocyte-Erythroid Progenitor Cells metabolism, Megakaryocyte-Erythroid Progenitor Cells pathology, Megakaryocytes pathology, Remission Induction, Thalidomide administration & dosage, Thalidomide adverse effects, Thalidomide therapeutic use, Treatment Outcome, Antineoplastic Agents therapeutic use, Chromosome Deletion, Chromosomes, Human, Pair 5, Hematologic Neoplasms drug therapy, Hematologic Neoplasms genetics, Megakaryocytes metabolism, Thalidomide analogs & derivatives
- Abstract
The mechanisms underlying lenalidomide-resistance of del(5q) MDS stem cells remain to be elucidated and may include cell-intrinsic as well as microenvironmental causes. Abnormal hypolobated megakaryocytes constitute one of the hallmarks of del(5q) MDS. We hypothesized that these cells have potential implications for the regulation of haematopoietic stem cells (HSC) similarly to what has recently been described for megakaryocytes in the murine system. Therefore, we conducted a study to determine the response of abnormal hypolobated megakaryocytes to lenalidomide therapy. We studied lenalidomide-treated patients in the MDS-004 trial as well as a cohort seen at our institution. Morphological evaluation at time of complete cytogenetic remission (CCyR) demonstrated the persistence of hypolobated megakaryocytes in all evaluable patients (n = 9). Furthermore, we provide evidence that the abnormal hypolobated morphology is restricted to del(5q) megakaryocytes, both at diagnosis and during CCyR. Using fluorescence in situ hybridisation analysis on flow-sorted stem- and progenitor populations, we observed a similar degree of clonal involvement in megakaryocyte-erythroid-progenitors as in HSC. Taken together, our findings suggest that megakaryocyte morphology might aid in the evaluation of patients where discontinuation of lenalidomide is considered and offers interesting hypotheses for further investigation of lenalidomide resistance., (© 2018 John Wiley & Sons Ltd.)
- Published
- 2018
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39. SF3B1 -initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells.
- Author
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Mortera-Blanco T, Dimitriou M, Woll PS, Karimi M, Elvarsdottir E, Conte S, Tobiasson M, Jansson M, Douagi I, Moarii M, Saft L, Papaemmanuil E, Jacobsen SEW, and Hellström-Lindberg E
- Subjects
- Aged, Aged, 80 and over, Animals, Cell Differentiation, Female, Humans, Male, Mice, Middle Aged, Spliceosomes metabolism, Hematopoietic Stem Cells metabolism, Lymphocytes metabolism, Mutation genetics, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology, Myeloid Cells metabolism, Phosphoproteins genetics, RNA Splicing Factors genetics
- Abstract
Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal ( SF3B1 mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for SF3B1 mutations targeting lymphomyeloid HSCs and compatible with mutated SF3B1 negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the SF3B1 mutated clone. Upon transplantation into immune-deficient mice, SF3B1 mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of SF3B1 mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring SF3B1 mutated MDS-RS., (© 2017 by The American Society of Hematology.)
- Published
- 2017
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40. Cytomorphology review of 100 newly diagnosed lower-risk MDS patients in the European LeukemiaNet MDS (EUMDS) registry reveals a high inter-observer concordance.
- Author
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de Swart L, Smith A, MacKenzie M, Symeonidis A, Neukirchen J, Mikulenková D, Vallespí T, Zini G, Paszkowska-Kowalewska M, Kruger A, Saft L, Fenaux P, Bowen D, Hellström-Lindberg E, Čermák J, Stauder R, Tatic A, Holm MS, Malcovati L, Mądry K, Droste J, Blijlevens N, de Witte T, and Germing U
- Subjects
- Adult, Aged, Aged, 80 and over, Bone Marrow Examination methods, Bone Marrow Examination standards, Cytodiagnosis standards, Female, Humans, Male, Middle Aged, Myelodysplastic Syndromes blood, Reproducibility of Results, Sensitivity and Specificity, Young Adult, Cytodiagnosis methods, Myelodysplastic Syndromes diagnosis, Observer Variation, Registries statistics & numerical data
- Abstract
The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS) patients belonging to the IPSS low or intermediate-1 category, newly diagnosed by local cytologists. The diagnosis of MDS can be challenging, and some data report inter-observer variability with regard to the assessment of the MDS subtype. In order to ensure that correct diagnoses were made by the participating centres, blood and bone marrow slides of 10% of the first 1000 patients were reviewed by an 11-person panel of cytomorphologists. All slides were rated by at least 3 panel members (median 8 panel members; range 3-9). Marrow slides from 98 out of 105 patients were of good quality and therefore could be rated properly according to the WHO 2001 classification, including assessment of dysplastic lineages. The agreement between the reviewers whether the diagnosis was MDS or non-MDS was strong with an intra-class correlation coefficient (ICC) of 0.85. Six cases were detected not to fit the entry criteria of the registry, because they were diagnosed uniformly as CMML or AML by the panel members. The agreement by WHO 2001 classification was strong as well (ICC = 0.83). The concordance of the assessment of dysplastic lineages was substantial for megakaryopoiesis and myelopoiesis and moderate for erythropoiesis. Our data show that in general, the inter-observer agreement was high and a very low percentage of misdiagnosed cases had been entered into the EUMDS registry. Further studies including histomorphology are warranted.
- Published
- 2017
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41. Progression in patients with low- and intermediate-1-risk del(5q) myelodysplastic syndromes is predicted by a limited subset of mutations.
- Author
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Scharenberg C, Giai V, Pellagatti A, Saft L, Dimitriou M, Jansson M, Jädersten M, Grandien A, Douagi I, Neuberg DS, LeBlanc K, Boultwood J, Karimi M, Jacobsen SE, Woll PS, and Hellström-Lindberg E
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Computational Biology methods, Disease Progression, Female, Gene Expression, Gene Expression Profiling, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Humans, Lenalidomide, Male, Mesenchymal Stem Cells metabolism, Middle Aged, Myelodysplastic Syndromes therapy, Prognosis, Stem Cell Niche, Thalidomide analogs & derivatives, Thalidomide therapeutic use, Treatment Outcome, Chromosome Deletion, Chromosomes, Human, Pair 5, Mutation, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics
- Abstract
A high proportion of patients with lower-risk del(5q) myelodysplastic syndromes will respond to treatment with lenalidomide. The median duration of transfusion-independence is 2 years with some long-lasting responses, but almost 40% of patients progress to acute leukemia by 5 years after starting treatment. The mechanisms underlying disease progression other than the well-established finding of small TP53 -mutated subclones at diagnosis remain unclear. We studied a longitudinal cohort of 35 low- and intermediate-1-risk del(5q) patients treated with lenalidomide (n=22) or not (n=13) by flow cytometric surveillance of hematopoietic stem and progenitor cell subsets, targeted sequencing of mutational patterns, and changes in the bone marrow microenvironment. All 13 patients with disease progression were identified by a limited number of mutations in TP53 , RUNX1 , and TET2 , respectively, with PTPN11 and SF3B1 occurring in one patient each. TP53 mutations were found in seven of nine patients who developed acute leukemia, and were documented to be present in the earliest sample (n=1) and acquired during lenalidomide treatment (n=6). By contrast, analysis of the microenvironment, and of hematopoietic stem and progenitor cells by flow cytometry was of limited prognostic value. Based on our data, we advocate conducting a prospective study aimed at investigating, in a larger number of cases of del(5q) myelodysplastic syndromes, whether the detection of such mutations before and after lenalidomide treatment can guide clinical decision-making., (Copyright© Ferrata Storti Foundation.)
- Published
- 2017
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42. Immunophenotypic analysis of erythroid dysplasia in myelodysplastic syndromes. A report from the IMDSFlow working group.
- Author
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Westers TM, Cremers EM, Oelschlaegel U, Johansson U, Bettelheim P, Matarraz S, Orfao A, Moshaver B, Brodersen LE, Loken MR, Wells DA, Subirá D, Cullen M, Te Marvelde JG, van der Velden VH, Preijers FW, Chu SC, Feuillard J, Guérin E, Psarra K, Porwit A, Saft L, Ireland R, Milne T, Béné MC, Witte BI, Della Porta MG, Kern W, and van de Loosdrecht AA
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Biomarkers, Bone Marrow Cells metabolism, Case-Control Studies, Female, Flow Cytometry, Humans, Immunophenotyping, Male, Middle Aged, Young Adult, Erythroid Cells metabolism, Erythroid Cells pathology, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology
- Abstract
Current recommendations for diagnosing myelodysplastic syndromes endorse flow cytometry as an informative tool. Most flow cytometry protocols focus on the analysis of progenitor cells and the evaluation of the maturing myelomonocytic lineage. However, one of the most frequently observed features of myelodysplastic syndromes is anemia, which may be associated with dyserythropoiesis. Therefore, analysis of changes in flow cytometry features of nucleated erythroid cells may complement current flow cytometry tools. The multicenter study within the IMDSFlow Working Group, reported herein, focused on defining flow cytometry parameters that enable discrimination of dyserythropoiesis associated with myelodysplastic syndromes from non-clonal cytopenias. Data from a learning cohort were compared between myelodysplasia and controls, and results were validated in a separate cohort. The learning cohort comprised 245 myelodysplasia cases, 290 pathological, and 142 normal controls; the validation cohort comprised 129 myelodysplasia cases, 153 pathological, and 49 normal controls. Multivariate logistic regression analysis performed in the learning cohort revealed that analysis of expression of CD36 and CD71 (expressed as coefficient of variation), in combination with CD71 fluorescence intensity and the percentage of CD117
+ erythroid progenitors provided the best discrimination between myelodysplastic syndromes and non-clonal cytopenias (specificity 90%; 95% confidence interval: 84-94%). The high specificity of this marker set was confirmed in the validation cohort (92%; 95% confidence interval: 86-97%). This erythroid flow cytometry marker combination may improve the evaluation of cytopenic cases with suspected myelodysplasia, particularly when combined with flow cytometry assessment of the myelomonocytic lineage., (Copyright© Ferrata Storti Foundation.)- Published
- 2017
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43. Mutations in idiopathic cytopenia of undetermined significance assist diagnostics and correlate to dysplastic changes.
- Author
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Hansen JW, Westman MK, Sjö LD, Saft L, Kristensen LS, Ørskov AD, Treppendahl M, Andersen MK, and Grønbaek K
- Subjects
- Adult, Aged, Aged, 80 and over, Bone Marrow Examination, DNA (Cytosine-5-)-Methyltransferases genetics, DNA Methyltransferase 3A, DNA-Binding Proteins genetics, Dioxygenases, Female, Humans, Male, Middle Aged, Myelodysplastic Syndromes diagnosis, Pancytopenia etiology, Proto-Oncogene Proteins genetics, Repressor Proteins genetics, Sequence Analysis, DNA, Serine-Arginine Splicing Factors genetics, Disease Progression, Mutation, Myelodysplastic Syndromes genetics, Pancytopenia genetics
- Abstract
Cytopenia is common in the elderly population and etiology may be difficult to assess. Here, we investigated the occurrence of mutations in patients with idiopathic cytopenia of undetermined significance and the usefulness in improving diagnostics. We included 60 patients with persistent cytopenia > 6 months without definite diagnosis of hematological neoplasm after routine assessment. Bone marrow material underwent a blinded morphology review and DNA was sequenced with a targeted 20 gene panel representing the most commonly mutated genes in myelodysplastic syndrome. Thirty seven (62%) patients carried at least one mutation at inclusion, and of these 95% carried a mutation in TET2, ASXL1, SRSF2, or DNMT3A. The most commonly mutated gene was TET2 observed in 43% of all patients. During one to eight years follow-up seven patients progressed to a myeloid neoplasm and six of these had a detectable mutation at study entry. Median time to progression was 53 months (range 10-78), and at time of progression each patient had at least two mutations detected. Mutations in TP53 and NRAS were not present in patients at inclusion, but identified as secondary hits triggering progression. The morphology review was concordant in 68% of all cases, and 93% of the cases reclassified into the group "highly suspicious for MDS" had a mutation. All patients who had a concordant review "highly suspicious for MDS" had at least two mutations detected. Overall, we show that morphology examination is challenging in this heterogeneous group and targeted sequencing helps identify patients at risk of progression. Am. J. Hematol. 91:1234-1238, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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44. TERT rs2736100 genotypes are associated with differential risk of myeloproliferative neoplasms in Swedish and Chinese male patient populations.
- Author
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Dahlström J, Liu T, Yuan X, Saft L, Ghaderi M, Wei YB, Lavebratt C, Li P, Zheng C, Björkholm M, and Xu D
- Subjects
- Aged, Alleles, Case-Control Studies, China, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Myeloproliferative Disorders ethnology, Risk, Sweden, Telomere Homeostasis, Asian People genetics, Myeloproliferative Disorders genetics, Polymorphism, Single Nucleotide, Telomerase genetics, White People genetics
- Abstract
The telomerase reverse transcriptase (TERT) gene rs2736100_C allele has recently been shown to be associated with an increased risk for myeloproliferative neoplasms (MPNs) among Caucasians. However, it is unknown if this association is present in other ethnical populations and whether rs2736100 allele frequencies mirror the incidence of MPNs in a population. Here we genotyped TERT rs2736100 variants in 126 Swedish and 101 Chinese MPN patients and their age-, sex-, and ethnically-matched healthy controls. Healthy Chinese adults had a higher frequency of the A allele and lower frequencies of the C allele compared to Swedish counterparts (57.4 vs 47.0 % for A, 42.6 vs 53.0 % for C, P = 0.006). Both Swedish and Chinese patients harbored significantly higher C allele frequency than their controls (62.7 vs 53.0 % and 57.4 vs 42.6 % for Swedish and Chinese, respectively, P = 0.004). Swedes and Chinese bearing the CC genotype had a significantly increased risk of MPN compared to AA carriers (OR = 2.47; 95 % CI: 1.33-4.57, P = 0.003, for Swedes, and OR = 3.45; 95 % CI: 1.52-7.85, P = 0.005, for Chinese). Further analyses showed that rs2736100_CC was associated with robustly enhanced risk in males only (CC vs AA, OR = 5.11; 95 % CI: 2.19-11.92, P < 0.0001). The CC-carrying MPN patients exhibited significantly higher TERT expression than patients with the AC genotype. Collectively, the rs2736100_C is a risk allele for MPNs in Swedish and Chinese males, and the lower incidence of MPNs in the Chinese population is correlated with a lower rs2736100_C risk allele frequency., Competing Interests: Compliance with ethical standards The study was approved by the Shandong University Second Hospital Ethics Committee and Stockholm Regional Ethics Review Board, and informed consent was obtained from all the participants. Conflict of interest The authors declare that they have no conflict of interest.
- Published
- 2016
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45. Detection of central nervous system involvement in childhood acute lymphoblastic leukemia by cytomorphology and flow cytometry of the cerebrospinal fluid.
- Author
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Ranta S, Nilsson F, Harila-Saari A, Saft L, Tani E, Söderhäll S, Porwit A, Hultdin M, Noren-Nyström U, and Heyman M
- Subjects
- Adolescent, Brain Neoplasms diagnosis, Child, Child, Preschool, Female, Humans, Immunophenotyping, Infant, Male, Recurrence, Brain Neoplasms cerebrospinal fluid, Cerebrospinal Fluid cytology, Flow Cytometry methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma cerebrospinal fluid
- Abstract
Background: Therapy directed at the central nervous system (CNS) is an essential part of the treatment for childhood acute lymphoblastic leukemia (ALL). The current evaluation of CNS involvement based on cytomorphological examination of the cerebrospinal fluid (CSF) alone is not as sensitive with low cell counts as flow cytometric immunophenotyping (FCI) of the CSF. However, the importance of low CSF blasts counts at diagnosis is uncertain. We sought to determine the significance of FCI in relation to conventional morphological examination., Procedure: We retrospectively compared FCI of the CSF with cytomorphology at diagnosis or relapse of childhood ALL. All patients were diagnosed 2000-2012 in Stockholm or Umeå, Sweden. Clinical data were collected from medical records and the Nordic leukemia registry. Treatment assignment was based on morphological examination only., Results: The cohort was comprised of 214 patients with ALL. CSF involvement was detected by both methods in 20 patients, in 17 by FCI alone, and in one patient by cytomorphology alone. The relapse rate was higher for patients with negative cytology but positive FCI compared to those without CNS involvement using both methods. The difference was especially marked in the current protocol. However, none of the patients with negative CSF cytology but positive FCI had a CNS relapse., Conclusions: FCI of the CSF increased the detection rate of CNS involvement of ALL approximately two times compared to cytomorphology. Patients with low-level CNS involvement may benefit from additional intensified systemic or CNS-directed therapy, but larger studies are needed., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2015
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46. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine.
- Author
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Svensson T, Chowdhury O, Garelius H, Lorenz F, Saft L, Jacobsen SE, Hellström-Lindberg E, and Cherif H
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Azacitidine adverse effects, Benzoates adverse effects, Blood Platelets drug effects, Blood Platelets pathology, Cell Cycle drug effects, Drug Synergism, Drug Therapy, Combination, Female, Hematopoietic Stem Cells drug effects, Humans, Hydrazines adverse effects, Ischemic Attack, Transient etiology, Ischemic Attack, Transient pathology, Male, Middle Aged, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology, Pilot Projects, Platelet Count, Pyrazoles adverse effects, Receptors, Thrombopoietin agonists, Receptors, Thrombopoietin metabolism, Remission Induction, Thrombocytopenia complications, Thrombocytopenia metabolism, Thrombocytopenia pathology, Treatment Outcome, Venous Thrombosis etiology, Venous Thrombosis pathology, Antineoplastic Agents administration & dosage, Azacitidine administration & dosage, Benzoates administration & dosage, Hydrazines administration & dosage, Myelodysplastic Syndromes drug therapy, Pyrazoles administration & dosage, Thrombocytopenia drug therapy
- Abstract
Objectives: Thrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients., Patients and Methods: Previously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 10(9) /L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine., Results: Twelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs., Conclusion: The combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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47. Perturbations of the endocannabinoid system in mantle cell lymphoma: correlations to clinical and pathological features.
- Author
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Wasik AM, Nygren L, Almestrand S, Zong F, Flygare J, Wennerholm SB, Saft L, Andersson P, Kimby E, Wahlin BE, Christensson B, and Sander B
- Abstract
The cannabinoid receptors are upregulated in many types of cancers, including mantle cell lymphoma (MCL) and have been suggested to constitute novel therapeutic targets. The expression pattern of the key members of the endocannabinoid system was analyzed in a well-characterized MCL patient cohort and correlated to biological features. 107 tumor tissues were analyzed for the mRNA levels of cannabinoid receptors 1 and 2 (CNR1 and CNR2) and the two main enzymes regulating the endocannabinoid anandamide levels in tissue: NAPEPLD and FAAH (participating in synthesis and degradation, respectively). NAPEPLD, CNR1 and CNR2 were overexpressed while FAAH expression was reduced in MCL compared to non-malignant B-cells. Both low CNR1 and high FAAH levels correlated with lymphocytosis (p=0.016 and p=0.022, respectively) and with leukocytosis (p=0.0018 and p=0.047). Weak to moderate CNR1 levels were a feature of SOX11 negative MCL (p=0.006). Both high CNR2 and high FAAH levels correlated to anemia (p=0.0006 and p=0.038, respectively). In conclusion, the relative expression of the anandamide synthesizing and metabolizing enzymes in MCL is heavily perturbed. This finding, together with high expression of cannabinoid receptors, could favor enhanced anandamide signaling and suggest that targeting the endocannabinoid system might be considered as part of lymphoma therapy.
- Published
- 2014
- Full Text
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48. Bone marrow dendritic cells are reduced in patients with high-risk myelodysplastic syndromes.
- Author
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Saft L, Björklund E, Berg E, Hellström-Lindberg E, and Porwit A
- Subjects
- Adolescent, Adult, Aged, Case-Control Studies, Cell Count, Child, Child, Preschool, Down-Regulation, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Myelodysplastic Syndromes immunology, Risk, Severity of Illness Index, Young Adult, Bone Marrow Cells pathology, Dendritic Cells pathology, Myelodysplastic Syndromes pathology
- Abstract
Dendritic cells (DC) are antigen-presenting cells that play a pivotal role in coordinating functions of the immune system. Previous studies suggest that bone marrow (BM) failure in myelodysplastic syndromes (MDS) may be in part immune-mediated, and that the high propensity for relapse may reflect decreased immune surveillance. This study aimed to assess the frequency of DC in BM samples from well-annotated untreated MDS patients by using 4-colour flow cytometry. DC levels were markedly reduced in all subtypes of MDS. The clinical impact of this finding on therapy response and relapse after, e.g. allogeneic stem cell transplantation warrants further investigation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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49. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.
- Author
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Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, Hedlund A, Hast R, Schlegelberger B, Porwit A, Hellström-Lindberg E, and Mufti GJ
- Subjects
- Adult, Aged, Aged, 80 and over, Disease Progression, Female, Humans, Leukemia, Myeloid, Acute complications, Male, Middle Aged, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes mortality, Peptide Fragments metabolism, Prognosis, Risk, Tumor Suppressor Protein p53 metabolism, Chromosome Deletion, Chromosomes, Human, Pair 5, Genes, p53, Myelodysplastic Syndromes genetics
- Abstract
Purpose: To determine the frequency of TP53 mutations and the level of p53 protein expression by immunohistochemistry (IHC) in low-risk myelodysplastic syndromes (MDS) with del(5q) and to assess their impact on disease progression., Patients and Methods: Pre- and postprogression bone marrow (BM) samples from 55 consecutive patients with International Prognostic Scoring System low risk (n = 32) or intermediate-1 risk (n = 23) were studied by next-generation sequencing of TP53. IHC for p53 was performed on 148 sequential BM samples., Results: TP53 mutations with a median clone size of 11% (range, 1% to 54%) were detected in 10 patients (18%) already at an early phase of the disease. Mutations were equally common in low-risk and intermediate-1-risk patients and were associated with evolution to acute myeloid leukemia (5 of 10 v 7 of 45; P = .045). Nine of 10 patients carrying mutations showed more than 2% BM progenitors with strong p53 staining. The probability of a complete cytogenetic response to lenalidomide was lower in mutated patients (0 of 7 v 12 of 24; P = .024)., Conclusion: By using sensitive deep-sequencing technology, we demonstrated that TP53 mutated populations may occur at an early disease stage in almost a fifth of low-risk MDS patients with del(5q). Importantly, mutations were present years before disease progression and were associated with an increased risk of leukemic evolution. TP53 mutations could not be predicted by common clinical features but were associated with p53 overexpression. Our findings indicate a previously unrecognized heterogeneity of the disease which may significantly affect clinical decision making.
- Published
- 2011
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50. Reliability of the reported size of removed colorectal polyps.
- Author
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Rubio CA, Grimelius L, Lindholm J, Hamberg H, Porwit A, Elmberger G, Höög A, Kanter L, Eriksson E, Stemme S, Orrego A, Saft L, Petersson F, De La Torre M, Ekström C, Astrom K, Rundgren A, Djokic M, Chandanos E, Lenander C, Machado M, Nilsson P, and Mattsson L
- Subjects
- Humans, Observer Variation, Pathology methods, Pathology standards, Reproducibility of Results, Colonic Diseases pathology, Intestinal Polyps pathology, Rectal Diseases pathology
- Abstract
Background: The size of colorectal polyps is important in the clinical management of these lesions., Aim: To audit the accuracy in calculating the size of "polyps" by various specialists., Materials and Methods: Eighteen pathologists and four surgeons measured, with a conventional millimetre ruler, the largest diameter of 12 polyp phantoms. The results of two independent measurements (two weeks apart) were compared with the gold standard-size assessed at The Royal Institute of Technology, Sweden., Results: Thirty-one percent (83/264-trial 1) and 33% (88/264-trial 2) of the measurements underestimated or overestimated the gold standard size by >1 mm. Of the 22 experienced participants, 95% (21/22-trial 1) and 91% (20/22-trial 2) misjudged by >1 mm the size of one or more polyps. Values given by 13 participants (4.9%) in trial 1 and by 15 participants (5.7%) in trial 2, differed by > or = +/-4 mm from the gold standard size. In addition, a big difference between the highest and the lowest values was recorded in some polyps (up to 11.4 mm). Those disparate values were regarded as a human error in reading the scale on the ruler., Conclusion: Using a conventional ruler (the tool of pathologists worldwide) unacceptably high intra-observer and inter-observer variations in assessing the size of polyp-phantoms was found. The volume and the shape of devices, as well as human error in reading the scale of the ruler were confounding factors in size assessment. In praxis, the size is crucial in the management of colorectal polyps. Considering the clinical implications of the results obtained, the possibility of developing a method that will allow assessment of the true size of removed clinical polyps is being explored.
- Published
- 2006
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