96 results on '"Thielen N"'
Search Results
2. Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma:an open-label phase 2 trial
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Groen, K, Stege, CAM, Nasserinejad, K, de Heer, K, van Kampen, RJW, Leys, RBL, Thielen, N, Westerman, M, Wu, KL, Ludwig, I, Issa, DE, Velders, GA, Vekemans, MC, Timmers, GJ, de Boer, F, Tick, LW, Verbrugge, A, Buitenhuis, D, Cunha, SM, van der Spek, E, de Waal, EGM, Sohne, M, Sonneveld, P, Nijhof, IS, Klein, SK, van der Donk, NWCJ, Levin, MD, Ypma, PF, Zweegman, S, Groen, K, Stege, CAM, Nasserinejad, K, de Heer, K, van Kampen, RJW, Leys, RBL, Thielen, N, Westerman, M, Wu, KL, Ludwig, I, Issa, DE, Velders, GA, Vekemans, MC, Timmers, GJ, de Boer, F, Tick, LW, Verbrugge, A, Buitenhuis, D, Cunha, SM, van der Spek, E, de Waal, EGM, Sohne, M, Sonneveld, P, Nijhof, IS, Klein, SK, van der Donk, NWCJ, Levin, MD, Ypma, PF, and Zweegman, S
- Abstract
Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company
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- 2023
3. P906: IXAZOMIB, DARATUMUMAB AND LOW DOSE DEXAMETHASONE IN FRAIL PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM): RESULTS OF THE MAINTENANCE TREATMENT OF THE PHASE II HOVON 143 STUDY
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Groen, K., primary, Seefat, M., additional, Nasserinejad, K., additional, Stege, C. A., additional, van der Spek, E., additional, Bilgin, Y. M., additional, Kentos, A., additional, Sohne, M., additional, van Kampen, R. J., additional, Ludwig, I., additional, Thielen, N., additional, Durdu-Rayman, N., additional, de Graauw, N. C., additional, van de Donk, N. W., additional, de Waal, E. G., additional, Vekemans, M.-C., additional, Timmers, G. J., additional, van der Klift, M., additional, Soechit, S., additional, Geerts, P. A., additional, Silbermann, M. H., additional, Oosterveld, M., additional, Nijhof, I., additional, Sonneveld, P., additional, Klein, S. K., additional, Levin, M.-D., additional, and Zweegman, S., additional
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- 2022
- Full Text
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4. P1065: CONGENITAL ERYTHROCYTOSIS DUE TO HETEROZYGOUS VARIANTS IN THE BISPHOSPHOGLYCERATE MUTASE GENE
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van Dijk, M. J., primary, van Oirschot, B. A., additional, Stam-Slob, M. C., additional, van der Zwaag, B., additional, van Beers, E. J., additional, Jans, J. J., additional, van der Linden, P., additional, Torregrosa Diaz, J. M., additional, Gardie, B., additional, Girodon, F., additional, Schots, R., additional, Thielen, N., additional, and van Wijk, R., additional
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- 2022
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5. Life in the Rocks — Endolithic Algae
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van Thielen, N., Garbary, D. J., and Seckbach, Joseph, editor
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- 1999
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6. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries
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Hoffmann, V S, Baccarani, M, Hasford, J, Lindoerfer, D, Burgstaller, S, Sertic, D, Costeas, P, Mayer, J, Indrak, K, Everaus, H, Koskenvesa, P, Guilhot, J, Schubert-Fritschle, G, Castagnetti, F, Di Raimondo, F, Lejniece, S, Griskevicius, L, Thielen, N, Sacha, T, Hellmann, A, Turkina, A G, Zaritskey, A, Bogdanovic, A, Sninska, Z, Zupan, I, Steegmann, J-L, Simonsson, B, Clark, R E, Covelli, A, Guidi, G, and Hehlmann, R
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- 2015
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7. What determinants of quality of life are important to individual older patients diagnosed with cancer? A qualitative study
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Seghers Nelleke, P.A.L., primary, Kregting, J.A., additional, van Huis, L., additional, Thielen, N., additional, Soubeyran, P., additional, and Hamaker, M.E., additional
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- 2021
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8. Hermansky‐Pudlak syndrome: the importance of molecular subtyping
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THIELEN, N., HUIZING, M., KRABBE, J.G., WHITE, J.G., JANSEN, T.J., MERLE, P.A., GAHL, W.A., and ZWEEGMAN, S.
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- 2010
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9. An Automated Optical Inspection System for PIP Solder Joint Classification Using Convolutional Neural Networks
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Schmidt, K., primary, Rauchensteiner, D., additional, Voigt, C., additional, Thielen, N., additional, Bonig, J., additional, Beitinger, G., additional, and Franke, J., additional
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- 2021
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10. Post-translational modification of the SMAD2/3 linker region: the missing link between osteoarthritis-related inflammation and disturbed transforming growth factor-β signaling
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Thielen, N., primary, van Caam, A., additional, Neefjes, M., additional, Blaney Davidson, E., additional, and van der Kraan, P., additional
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- 2021
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11. Achtergronden bij de richtlijn voor de behandeling van chronische myeloïde leukemie anno 2018 : Diagnostiek, behandeling en bijwerkingenmanagement
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Janssen, J.J.M., Boekhorst, P.A.W., Posthuma, E.F., Klein, S.K., Hoogendoorn, M., Waal, T.T. de, Falkenburg, J.H., Biemond, B.J., Reijden, B.A. van der, Bos, G.M., Petersen, E.J., Blijlevens, N.M., Smit, W.M., Verhoef, G.E., Vellenga, E., Thielen, N., Cornelissen, J.J.L.M, Ossenkoppele, G.J., and Westerweel, P.E.
- Subjects
Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
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- 2018
12. OA-related inflammation inhibits protective transforming growth factor-β signaling via post-translational modification of the SMAD2/3 linker region
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Thielen, N., primary, van Caam, A., additional, Davidson, E. Blaney, additional, and van der Kraan, P., additional
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- 2020
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13. Life in the Rocks — Endolithic Algae
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Thielen, N., primary and Garbary, D. J., additional
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- 1999
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14. Achtergronden bij de richtlijn voor de behandeling van chronische myeloïde leukemie anno 2018 Deel 2: Het belang van responsmijlpalen, monitoring en mutaties en de behandeling van gevorderde CML-fasen
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Janssen, J.J.M., Boekhorst, P.A.W., Posthuma, E.F., Klein, S.K., Hoogendoorn, M., Waal, T.T. de, Falkenburg, J.H., Biemond, B.J., Reijden, B.A. van der, Bos, G.M., Petersen, E.J., Blijlevens, N.M., Smit, W.M., Verhoef, G.E., Vellenga, E., Thielen, N., Cornelissen, J.J., Ossenkoppele, G.J., and Westerweel, P.E.
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Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
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- 2018
15. Achtergronden bij de richtlijn voor de behandeling van chronische myeloïde leukemie anno 2018 Deel 3: Stoppen van de behandeling, beleid bij zwangerschap, studies en therapie-aanbevelingen
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Janssen, J.J.M., Boekhorst, P. Te, Posthuma, E.F., Klein, S.K., Hoogendoorn, M., Waal, T.T. de, Falkenburg, J.H., Biemond, B.J., Reijden, B.A. van der, Bos, G.M., Petersen, E.J., Blijlevens, N.M., Smit, J.M., Verhoef, G.E., Vellenga, E., Thielen, N., Cornelissen, J.J., Ossenkoppele, G.J., and Westerweel, P.E.
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Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Item does not contain fulltext
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- 2018
16. Osteoarhtritis-related inflammatory mediators negate the protective anti-hypertrophic role of transforming growth factor-β in chondrocytes
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Thielen, N., primary, van Caam, A., additional, Moonen, J., additional, Davidson, E. Blaney, additional, and van der Kraan, P., additional
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- 2019
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17. SIOG2021-0094* - What determinants of quality of life are important to individual older patients diagnosed with cancer? A qualitative study
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Seghers Nelleke, P.A.L., Kregting, J.A., van Huis, L., Thielen, N., Soubeyran, P., and Hamaker, M.E.
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- 2021
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18. Impact of hospital experience on the quality of tyrosine kinase inhibitor response monitoring and consequence for chronic myeloid leukemia patient survival
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Geelen, I.G.P. (Inge), Thielen, N. (Noortje), Janssen, J.J.W.M. (Jeroen), Hoogendoorn, M. (Mels), Roosma, T.J.A. (Tanja J. A.), Willemsen, S.P. (Sten), Valk, P.J.M. (Peter), Visser, O.J. (Otto), Cornelissen, J.J. (Jan), Westerweel, P.E. (Peter), Geelen, I.G.P. (Inge), Thielen, N. (Noortje), Janssen, J.J.W.M. (Jeroen), Hoogendoorn, M. (Mels), Roosma, T.J.A. (Tanja J. A.), Willemsen, S.P. (Sten), Valk, P.J.M. (Peter), Visser, O.J. (Otto), Cornelissen, J.J. (Jan), and Westerweel, P.E. (Peter)
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- 2017
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19. Treatment outcome in a population-based, ‘real-world’ cohort of patients with chronic myeloid leukemia
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Geelen, I.G.P. (Inge), Thielen, N. (Noortje), Janssen, J.J.W.M. (Jeroen), Hoogendoorn, M. (Mels), Roosma, T.J.A. (Tanja J. A.), Willemsen, S.P. (Sten), Visser, O.J. (Otto), Cornelissen, J.J. (Jan), Westerweel, P.E. (Peter), Geelen, I.G.P. (Inge), Thielen, N. (Noortje), Janssen, J.J.W.M. (Jeroen), Hoogendoorn, M. (Mels), Roosma, T.J.A. (Tanja J. A.), Willemsen, S.P. (Sten), Visser, O.J. (Otto), Cornelissen, J.J. (Jan), and Westerweel, P.E. (Peter)
- Abstract
Evaluations of the ‘real-world’ efficacy and safety of tyrosine kinase inhibitors in patients with chronic myeloid leukemia are scarce. A nationwide, population-based, chronic myeloid leukemia registry was analyzed to evaluate (deep) response rates to first and subsequent treatment lines and eligibility for a treatment cessation attempt in adults diagnosed between January 2008 and April 2013 in the Netherlands. The registry covered 457 patients; 434 in chronic phase (95%) and 15 (3%) in advanced disease phase. Seventy-five percent of the patients in chronic phase were treated with imatinib and 25% with a second-generation tyrosine kinase inhibitor. At 3 years 44% of patients had discontinued their first-line treatment, mainly due to intolerance (21%) or treatment failure (19%). At 18 months 73% of patients had achieved a complete cytogenetic response and 63% a major molecular response. Deep molecular responses (MR4.0 and MR4.5) were achieved in 69% and 56% of patients, respectively, at 48 months. All response milestones were achieved faster in patients treated upfront with a second-generation tyrosine kinase inhibitor, but ultimately patients initially treated with imatinib also reached similar levels of responses. The 6-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 31%. Our findings show that in a ‘real-world’ setting the long-term outcome of patients treated with tyrosine kinase inhibitors is excellent and the conditions for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients.
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- 2017
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20. Treatment outcome in a population-based, 'real-world' cohort of patients with chronic myeloid leukemia
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Geelen, Inge, Thielen, N, Janssen, J (Jack), Hoogendoorn, M, Roosma, TJA, Willemsen, Sten, Visser, O, Cornelissen, Jan, Westerweel, PE, Geelen, Inge, Thielen, N, Janssen, J (Jack), Hoogendoorn, M, Roosma, TJA, Willemsen, Sten, Visser, O, Cornelissen, Jan, and Westerweel, PE
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- 2017
21. Chronische myeloïde leukemie: evoluerend van fatale stamcelziekte naar genezing
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Thielen, N., Hematology, and CCA - Innovative therapy
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- 2015
22. Chronic Myeloid Leukemia: Evolving from Fatal Stem Cell Disease to Cure
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Thielen, N., Ossenkoppele, Gert, Janssen, Jeroen, Schuurhuis, Gerrit, Hematology, CCA - Innovative therapy, Ossenkoppele, G.J., Janssen, J.J.W.M., and Schuurhuis, G.J.
- Abstract
promotiedatum: 21-5-2015 � prom-id: 12597
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- 2015
23. ANALYSIS OF TREATMENT AND OUTCOME DATA OF 2904 PATIENTS FROM THE EUTOS POPULATION-BASED REGISTRY
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Hoffmann, V. S., Baccarani, M., Hasford, J., Lindoerfer, D., Burgstaller, S., Sertic, D., Costeas, P., Mayer, J., Indrak, K., Everaus, H., Koskenvesa, P., Guilhot, J., Schubert-Fritschle, G., Castagnetti, F., Di Raimondo, F., Lejniece, S., Griskevicius, L., Thielen, N., Sacha, T., Hellmann, A., Turkina, A., Zaritskey, A., Andrija Bogdanovic, Sninska, Z., Zupan, I., Steegmann, J. -L, Simonsson, B., Clark, R., and Hehlmann, R.
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- 2015
24. Chronische myeloïde leukemie en therapietrouw
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Thielen, N., Boons, C.C.L.M., Hugtenburg, J.G., Ossenkoppele, G.J., Janssen, J.J.W.M., Hematology, Clinical pharmacology and pharmacy, and CCA - Innovative therapy
- Published
- 2014
25. Hoge dosis imatinib versus hoge dosis imatinib in combinatie met intermediaire dosis cytarabine bij patiënten met nieuw gediagnosticeerde chronische myeloïde leukemie: een gerandomiseerde fase III-studie van de Stichting HematoOncologie voor Volwassenen Nederland (HOVON)
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Thielen, N., van der Holt, B., Verhoef, G.E.G., Ammerlaan, R.A.H.M., Sonneveld, P., Janssen, J.J.W.M., Deenik, W., Falkenburg, J.H.F., Kersten, M.J., Sinnige, H.A.M., Schipperus, M., Schattenberg, A., van Marwijk Kooy, R., Smit, W.M., Chu, I.W.T., Valk, P.J.M., Ossenkoppele, G.J., Cornelissen, J.J., Hematology, and CCA - Innovative therapy
- Published
- 2014
26. Silicon integrated RC snubbers for applications up to 900V with reduced mechanical stress and high manufacturability
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Krach, F., primary, Thielen, N., additional, Heckel, T., additional, Bauer, A. J., additional, Erlbacher, T., additional, and Frey, L., additional
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- 2016
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27. Simulating wafer bow for integrated capacitors using a multiscale approach
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Wright, A., primary, Krach, F., additional, Thielen, N., additional, Grunler, S., additional, Erlbacher, T., additional, and Pichler, P., additional
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- 2016
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28. The EUTOS population-based registry : incidence and clinical characteristics of 2904 CML patients in 20 European Countries
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Hoffmann, V. S., Baccarani, M., Hasford, J., Lindoerfer, D., Burgstaller, S., Sertic, D., Costeas, P., Mayer, J., Indrak, K., Everaus, H., Koskenvesa, P., Guilhot, J., Schubert-Fritschle, G., Castagnetti, F., Di Raimondo, F., Lejniece, S., Griskevicius, L., Thielen, N., Sacha, T., Hellmann, A., Turkina, A. G., Zaritskey, A., Bogdanovic, A., Sninska, Z., Zupan, I., Steegmann, J-L, Simonsson, Bengt, Clark, R. E., Covelli, A., Guidi, G., Hehlmann, R., Hoffmann, V. S., Baccarani, M., Hasford, J., Lindoerfer, D., Burgstaller, S., Sertic, D., Costeas, P., Mayer, J., Indrak, K., Everaus, H., Koskenvesa, P., Guilhot, J., Schubert-Fritschle, G., Castagnetti, F., Di Raimondo, F., Lejniece, S., Griskevicius, L., Thielen, N., Sacha, T., Hellmann, A., Turkina, A. G., Zaritskey, A., Bogdanovic, A., Sninska, Z., Zupan, I., Steegmann, J-L, Simonsson, Bengt, Clark, R. E., Covelli, A., Guidi, G., and Hehlmann, R.
- Abstract
This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100 000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.
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- 2015
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29. New insights into the pathogenesis of chronic myeloid leukaemia: towards a path to cure
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Thielen, N., Ossenkoppele, G.J., Schuurhuis, G.J., Janssen, J.J.W.M., Hematology, Hematology laboratory, and CCA - Innovative therapy
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- 2011
30. [Adult-onset Still's disease and haemophagocytic syndrome]
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Cornet, A.D., Thielen, N., Kramer, M.H.H., Nanayakkara, P.W.B., Kooter, A.J., Internal medicine, and ICaR - Ischemia and repair
- Abstract
A 49-year-old woman with a history of adult-onset Still's disease (AOSD) presented with fever, general malaise and a rash. Laboratory blood testing revealed an extremely high level of serum ferritin, essentially restricting the differential diagnosis to either haemophagocytic syndrome as a complication of AOSD, or a flare-up of the latter. Haemophagocytosis as a complication of AOSD was diagnosed in our patient. After treatment with prednisone, she fully recovered and the serum ferritin returned to a normal level. Haemophagocytic syndrome is a rare but potentially life-threatening complication of lymphoproliferative and autoimmune diseases, as well as of viral infections. It is characterised by high fever, hepatosplenomegaly, cytopenia and extremely high levels of serum ferritin. Activation of macrophages and histiocytes induces phagocytosis of erythrocytes in the bone marrow and other parts of the reticuloendothelial system. The fact that haemophagocytic syndrome and AOSD are often described together, and coincide with extremely elevated serum ferritin levels characteristic to both entities, suggests a related pathogenesis.
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- 2010
31. The Eutos Population-Based Registry : Evaluation of Baseline Characteristics and First Treatment Choices Of 2983 Newly Diagnosed Chronic Myeloid Leukemia (Cml) Patients from 20 European Countries
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Lindoerfer, D., Hoffmann, V. S., Rosti, G., Castagnetti, F., Saussele, S., Guilhot, J., Simonsson, Bengt, Steegmann, J. L., Mayer, J., Indrak, K., Turkina, A. G., Zaritskey, A., Labar, B., Zupan, I. P., Thielen, N., Clark, R. E., Thaler, J., Melanthiou, F., Everaus, H., Porkka, K., Bogdanovic, A. D., Schubert-Fritschle, G., Panagiotidis, P., Masszi, T., Lejniece, S., Griskevicius, L., Hellmann, A., Prejzner, W., Sacha, T., Almeida, A., Dyagil, I., Colita, A., Mihaylov, G., Hehlmann, R., Hasford, J., Baccarani, M., Lindoerfer, D., Hoffmann, V. S., Rosti, G., Castagnetti, F., Saussele, S., Guilhot, J., Simonsson, Bengt, Steegmann, J. L., Mayer, J., Indrak, K., Turkina, A. G., Zaritskey, A., Labar, B., Zupan, I. P., Thielen, N., Clark, R. E., Thaler, J., Melanthiou, F., Everaus, H., Porkka, K., Bogdanovic, A. D., Schubert-Fritschle, G., Panagiotidis, P., Masszi, T., Lejniece, S., Griskevicius, L., Hellmann, A., Prejzner, W., Sacha, T., Almeida, A., Dyagil, I., Colita, A., Mihaylov, G., Hehlmann, R., Hasford, J., and Baccarani, M.
- Published
- 2014
32. The Eutos Population Based Registry - Incidences of CML Across Europe
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Hoffmann, V., Lindoerfer, D., Thaler, J., Labar, B., Melanthiou, F., Mayer, J., Everaus, H., Porkka, K., Guillhot, J., Schubert-Fritschle, G., Castagnetti, F., Lejniece, S., Griskevicius, L., Thielen, N., Hellmann, A., Turkina, A., Zaritskey, A., Bogdanovic, A. D., Indrak, K., Zupan, I. P., Casado, L. F., Simonsson, Bengt, Clark, R. E., Hehlmann, R., Hasford, J., Baccarani, M., Hoffmann, V., Lindoerfer, D., Thaler, J., Labar, B., Melanthiou, F., Mayer, J., Everaus, H., Porkka, K., Guillhot, J., Schubert-Fritschle, G., Castagnetti, F., Lejniece, S., Griskevicius, L., Thielen, N., Hellmann, A., Turkina, A., Zaritskey, A., Bogdanovic, A. D., Indrak, K., Zupan, I. P., Casado, L. F., Simonsson, Bengt, Clark, R. E., Hehlmann, R., Hasford, J., and Baccarani, M.
- Published
- 2014
33. High-dose imatinib versus high-dose imatinib in combination with intermediate-dose cytarabine in patients with first chronic phase myeloid leukemia: a randomized phase III trial of the Dutch-Belgian HOVON study group.
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Thielen, N., Holt, B. van der, Verhoef, G.E., Ammerlaan, R.A., Sonneveld, P., Janssen, J.J.W.M., Deenik, W., Falkenburg, J.H.F., Kersten, M.J., Sinnige, H.A.M., Schipperus, M., Schattenberg, A.V., Marwijk Kooy, R. van, Smit, W.M., Chu, I.W., Valk, P.J., Ossenkoppele, G.J., Cornelissen, J.J., Thielen, N., Holt, B. van der, Verhoef, G.E., Ammerlaan, R.A., Sonneveld, P., Janssen, J.J.W.M., Deenik, W., Falkenburg, J.H.F., Kersten, M.J., Sinnige, H.A.M., Schipperus, M., Schattenberg, A.V., Marwijk Kooy, R. van, Smit, W.M., Chu, I.W., Valk, P.J., Ossenkoppele, G.J., and Cornelissen, J.J.
- Abstract
1 augustus 2013, Item does not contain fulltext, Despite the revolutionary change in the prognosis of chronic myeloid leukemia (CML) patients with the introduction of imatinib, patients with resistant disease still pose a considerable problem. In this multicenter, randomized phase III trial, we investigate whether the combination of high-dose imatinib and intermediate-dose cytarabine compared to high-dose imatinib alone, improves the rate of major molecular response (MMR) in newly diagnosed CML patients. This study was closed prematurely because of declining inclusion due to the introduction of second generation tyrosine kinase inhibitors and only one third of the initially required patients were accrued. One hundred nine patients aged 18-65 years were randomly assigned to either imatinib 800 mg (n = 55) or to imatinib 800 mg in combination with two successive cycles of cytarabine 200 mg/m(2) for 7 days (n = 54). After a median follow-up of 41 months, 67 % of patients were still on protocol treatment. The MMR rate at 12 months was 56 % in the imatinib arm and 48 % in the combination arm (p = 0.39). Progression-free survival was 96 % after 1 year and 89 % after 4 years. Four-year overall survival was 97 %. Adverse events grades 3 and 4 were more common in the combination arm. The addition of intermediate-dose of cytarabine to imatinib did not improve the MMR rate at 12 months. However, the underpowering of the study precludes any definitive conclusions. This trial is registered at www.trialregister.nl (NTR674).
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- 2013
34. The EUTOS population-based registry : incidence and clinical characteristics of 2904 CML patients in 20 European Countries
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G. Guidi, Michele Baccarani, F. Di Raimondo, Gabriele Schubert-Fritschle, Fausto Castagnetti, J-L Steegmann, Bengt Simonsson, A. Covelli, Tomasz Sacha, Irena Preloznik Zupan, Joelle Guilhot, Andrija Bogdanovic, Verena S. Hoffmann, Karel Indrak, Sandra Lejniece, Dubravka Sertić, Ruediger Hehlmann, Sonja Burgstaller, Richard E. Clark, Noortje Thielen, Perttu Koskenvesa, Joerg Hasford, Andrey Zaritskey, Zuzana Sninská, Laimonas Griskevicius, Hele Everaus, Paul Costeas, Anna G. Turkina, Jiří Mayer, Doris Lindoerfer, Andrzej Hellmann, Hematology, CCA - Innovative therapy, Hoffmann, V.S, Baccarani, M., Hasford, J., Lindoerfer, D., Burgstaller, S., Sertic, D., Costeas, P., Mayer, J., Indrak, K., Everaus, H., Koskenvesa, P., Guilhot, J., Schubert-Fritschle, G., Castagnetti, F., Di Raimondo, F., Lejniece, S., Griskevicius, L., Thielen, N., Sacha, T., Hellmann, A., Turkina, A.G., Zaritskey, A., Bogdanovic, A., Sninska, Z., Zupan, I., Steegmann, J.-L., Simonsson, B., Clark, R.E., Covelli, A., Guidi, G., and Hehlmann, R.
- Subjects
Adult ,Male ,Registrie ,medicine.medical_specialty ,Pediatrics ,Cancer Research ,Prognosi ,Population ,Alpha interferon ,Follow-Up Studie ,Cohort Studies ,Young Adult ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Epidemiology ,Medicine ,Humans ,Registries ,Young adult ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,business.industry ,Incidence (epidemiology) ,Incidence ,Medicine (all) ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,3. Good health ,Europe ,Anesthesiology and Pain Medicine ,Oncology ,Observational study ,Female ,Cohort Studie ,business ,Cohort study ,Chronic myelogenous leukemia ,Follow-Up Studies ,Human - Abstract
This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.
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- 2015
35. Impact of comorbidity on health-related quality of life in newly diagnosed patients with lymphoma or multiple myeloma: results from the PROFILES-registry.
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Ekels A, van de Poll-Franse LV, Issa DE, Hoogendoorn M, Nijziel MR, Koster A, de Jong CN, Achouiti A, Thielen N, Tick LW, Te Boome LCJ, Bohmer LH, Tiren-Verbeet NL, Veldhuis GJ, de Boer F, van der Klift M, Posthuma EFM, and Oerlemans S
- Abstract
With the increasing prevalence of comorbidity in an ageing population, it is crucial to better understand the impact of comorbidity on health-related quality of life (HRQoL) after lymphoma or multiple myeloma (MM) diagnosis. We included 261 newly diagnosed patients (67% response rate) diagnosed with lymphoma or MM between October 2020 and March 2023 in a longitudinal survey. The European Organisation for Research and Treatment of Cancer (EORTC) questionnaires were used to measure generic and disease-specific HRQoL. Evidence-based guidelines for interpretation of the EORTC questionnaires were used to identify clinical importance. Patients were classified as having 'no comorbidity', 'mild comorbidity' (e.g. arthrosis or rheumatism), or 'moderate-severe comorbidity' (e.g. heart or lung disease), using the adapted self-administered comorbidity questionnaire. At diagnosis, the mean age was 64 years, 63% were male and 38% reported no comorbidity, 33% mild comorbidity, and 29% moderate-severe comorbidity. Patients with mild or moderate-severe comorbidity reported clinically relevant worse HRQoL at diagnosis than patients without comorbidity. One year post-diagnosis most outcomes showed clinically relevant improvement, irrespective of comorbidity. However, outcomes of physical functioning (β=-7.9, p < 0.05), global health status (β=-7.6, p < 0.05), bone pain (β = 8.1 to 9.1, p < 0.05), muscle/joint pain (β = 14.5 to 18.8, p < 0.01) and muscle weakness (β = 10.4 to 15.6, p < 0.05) improved less among those with comorbidity, and clinically relevant differences between comorbidity groups persisted over time. With clinically relevant worse HRQoL at diagnosis and less recovery of HRQoL during the first year after diagnosis in patients with comorbidity, consideration of both prognosis and HRQoL is important when making treatment decisions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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36. The course of self-perceived cognitive functioning among patients with lymphoma and the co-occurrence with fatigue and psychological distress.
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Ekels A, Oerlemans S, Schagen SB, Issa DE, Thielen N, Nijziel MR, van der Poel MWM, Arts LPJ, Posthuma EFM, and van de Poll-Franse LV
- Abstract
Purpose: To investigate the proportion of patients with lymphoma with persistent clinically relevant cognitive impairment, and its relation to treatment, fatigue, and psychological distress., Methods: Patients with diffuse-large-B-cell-lymphoma (DLBCL), follicular-lymphoma (FL), and chronic-lymphocytic-leukemia (CLL)/small-lymphocytic-lymphoma (SLL), diagnosed between 2004-2010 or 2015-2019, were followed up to 8 years post-diagnosis. Sociodemographic and clinical data were obtained from the Netherlands Cancer Registry and the Population-based HAematological Registry for Observational Studies. The EORTC QLQ-C30 was used to assess cognitive functioning and fatigue, and the HADS to assess psychological distress. Individual growth curve models were performed. Results were compared with an age- and sex-matched normative population., Results: A total of 924 patients were included (70% response rate). Persistent cognitive impairment was twice as high in patients (30%) compared to the normative population (15%). Additionally, 74% of patients reported co-occurring symptoms of persistent fatigue and/or psychological distress. Patients with FL (- 23 points, p < 0.001) and CLL/SLL (- 10 points, p < 0.05) reported clinically relevant deterioration of cognitive functioning, as did the normative population (FLnorm - 5 points, DLBCLnorm - 4 points, both p < 0.05). Younger age, higher fatigue, and/or psychological distress at inclusion were associated with worse cognitive functioning (all p's < 0.01). Treatment appeared less relevant., Conclusion: Almost one-third of patients with lymphoma report persistent cognitive impairment, remaining present up to 8 years post-diagnosis. Early onset and co-occurrence of symptoms highlight the need for clinicians to discuss symptoms with patients early., Implications for Cancer Survivors: Early recognition of cognitive impairment could increase timely referral to suitable supportive care (i.e., lifestyle interventions) and reduce (long-term) symptom burden., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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37. Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma: an open-label phase 2 trial.
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Groen K, Stege CAM, Nasserinejad K, de Heer K, van Kampen RJW, Leys RBL, Thielen N, Westerman M, Wu KL, Ludwig I, Issa DE, Velders GA, Vekemans MC, Timmers GJ, de Boer F, Tick LW, Verbrugge A, Buitenhuis D, Cunha SM, van der Spek E, de Waal EGM, Sohne M, Sonneveld P, Nijhof IS, Klein SK, van de Donk NWCJ, Levin MD, Ypma PF, and Zweegman S
- Abstract
Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients., Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297., Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment., Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients., Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited., Competing Interests: Claudia Stege. Speaker's Bureau: Sanofi, Celgene/Bristol Myers Squibb, Takeda. Consulting or Advisory Role: Sanofi, Janssen. Marie-Christiane Vekemans. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Janssen, Takeda, Bristol Myers Squibb/Celgene. Consulting or Advisory Role: Amgen, Celgene-Bristol Myers Squibb, Janssen, Takeda, Sanofi, Pfizer, GlaxoSmithKline, Menarini. Ka-Lung Wu. Consulting or Advisory Role: Pfizer, Janssen, Bristol Myers Squibb. Niels W. C. J. van de Donk. Consulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, Bayer, Roche, Pfizer, Abbvie, Adaptive. Research Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis. Gert Jan Timmers. Participation on an Advisory Board: Novartis. Travel, Accommodations, Expenses: Novartis, Janssen. Ellen van der Spek. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen. Pieter Sonneveld. Participation on a Data Safety Monitoring Board or Advisory Board: Celgene, Janssen, Amgen, Bristol Myers Squibb, Karyopharm Therapeutics, Pfizer. Research Funding: Janssen, Amgen, Bristol Myeres Squibb/Celgene, Karyopharm Therapeutics, Pfizer. Inger S. Nijhof. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen, Celgene/Bristol Myers Squibb, Sanofi. Mark-David Levin. Support for attending meetings and/or travel: Janssen, Takeda. Paula F. Ypma. Payment or honoraria for presentations: Janssen. Support for attending meetings and/or travel: Janssen. Sonja Zweegman. Consulting or Advisory Role: Janssen-Cilag, Takeda, Celgene/Bristol Myers Squibb, Sanofi, Oncopeptides (no personal funding). Research Funding: Janssen, Takeda. No other potential conflicts of interest were reported., (© 2023 The Author(s).)
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- 2023
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38. Evaluation of the procoagulant state in chronic immune thrombocytopenia before and after eltrombopag treatment-a prospective cohort study.
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van Dijk WEM, Poolen GC, Huisman A, Koene HR, Fijnheer R, Thielen N, van Bladel ER, van Galen KPM, Schutgens REG, and Urbanus RT
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- Adult, Humans, Prospective Studies, Factor VIII, Thrombin, von Willebrand Factor, Hydrazines adverse effects, Purpura, Thrombocytopenic, Idiopathic diagnosis, Purpura, Thrombocytopenic, Idiopathic drug therapy, Purpura, Thrombocytopenic, Idiopathic chemically induced, Thrombocytopenia, Thrombophilia chemically induced
- Abstract
Background: Thrombopoietin receptor agonists are frequently used in treating immune thrombocytopenia (ITP) owing to high response rates and good tolerability. ITP is associated with an increased risk of thrombosis. Whether treatment with eltrombopag further increases this risk is controversial. The mechanisms behind the thrombotic risk in ITP are unclear., Objectives: To assess platelet function and hypercoagulability in patients with ITP and the effect of eltrombopag thereon., Methods: This prospective multicenter study assessed adult primary patients with ITP who were starting eltrombopag treatment. Platelet (re)activity and hypercoagulability were measured in whole blood or plasma before start and after 2 to 3 weeks of eltrombopag treatment and compared with those of controls. Change over time was assessed by mixed-effects models, and the results were corrected for multiple testing., Results: We included 16 patients and 33 controls. At baseline, patients with ITP exhibited lower expression of glycoprotein VI, more activated platelets, and lower reactivity toward agonists compared with controls. β-Thromboglobulin levels reduced and thrombin generation peak height increased compared with those of controls. In line with this finding, patients with ITP showed high factor VIII (median, 217%; IQR, 174%-272%) and von Willebrand factor levels (median, 167%; IQR, 109%-198%). Eltrombopag treatment increased thrombin generation potential: lag time decreased and peak height and endogeneous thrombin potential increased. The latter changes were not significant after correction for multiple testing., Conclusion: Patients with ITP in this study were in a hypercoagulable state, with preactivated platelets, increased thrombin generation potential, and increased levels of factor VIII and von Willebrand factor. Eltrombopag treatment further increased plasma thrombin generation potential but no other hemostatic parameters., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2023
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39. Heterozygosity for bisphosphoglycerate mutase deficiency expressing clinically as congenital erythrocytosis: A case series and literature review.
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van Dijk MJ, van Oirschot BA, Stam-Slob MC, Waanders E, van der Zwaag B, van Beers EJ, Jans JJM, van der Linden PW, Torregrosa Diaz JM, Gardie B, Girodon F, Schots R, Thielen N, and van Wijk R
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- Adult, Humans, Bisphosphoglycerate Mutase genetics, Heterozygote, Hemoglobins, Oxygen, Polycythemia congenital, Anemia, Hemolytic, Metabolism, Inborn Errors
- Abstract
Erythrocytosis is associated with increased red blood cell mass and can be either congenital or acquired. Congenital secondary causes are rare and include germline variants increasing haemoglobin (Hb)-oxygen affinity (e.g., Hb or bisphosphoglycerate mutase (BPGM) variants) or affecting oxygen-sensing pathway proteins. Here, we describe five adults from three kindreds with erythrocytosis associated with heterozygosity for BPGM variants, including one novel. Functional analyses showed partial BPGM deficiency, reduced 2,3-bisphosphoglycerate levels and/or increased Hb-oxygen affinity. We also review currently known BPGM variants. This study contributes to raising awareness of BPGM variants, and in particular that heterozygosity for BPGM deficiency may already manifest clinically., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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40. Ixazomib, Daratumumab, and Low-Dose Dexamethasone in Frail Patients With Newly Diagnosed Multiple Myeloma: The Hovon 143 Study.
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Stege CAM, Nasserinejad K, van der Spek E, Bilgin YM, Kentos A, Sohne M, van Kampen RJW, Ludwig I, Thielen N, Durdu-Rayman N, de Graauw NCHP, van de Donk NWCJ, de Waal EGM, Vekemans MC, Timmers GJ, van der Klift M, Soechit S, Geerts PAF, Silbermann MH, Oosterveld M, Nijhof IS, Sonneveld P, Klein SK, Levin MD, and Zweegman S
- Subjects
- Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Boron Compounds administration & dosage, Dexamethasone administration & dosage, Female, Follow-Up Studies, Glycine administration & dosage, Glycine analogs & derivatives, Humans, Male, Multiple Myeloma pathology, Prognosis, Prospective Studies, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Frail Elderly statistics & numerical data, Multiple Myeloma drug therapy, Quality of Life
- Abstract
Purpose: Frail patients with newly diagnosed multiple myeloma have an inferior outcome, mainly because of a high discontinuation rate due to toxicity. We designed a phase II trial specifically for frail patients, evaluating the efficacy and tolerability of ixazomib-daratumumab-low-dose-dexamethasone (Ixa-Dara-dex)., Methods: Sixty-five patients, who were frail according to the International Myeloma Working Group frailty index, were treated with nine induction cycles Ixa-Dara-dex followed by maintenance with Ixa-Dara for a maximum of 2 years., Results: The overall response rate on induction therapy was 78%. After a median follow-up of 22.9 months, median progression-free survival (PFS) was 13.8 months and 12-month overall survival (OS) was 78%. Median PFS and 12-month OS were 21.6 months and 92% in patients who were frail based on age > 80 years alone, versus 13.8 months and 78%, and 10.1 months and 70% in patients who were frail based on additional frailty parameters either ≤ 80 or > 80 years of age, respectively. In 51% of patients, induction therapy had to be discontinued prematurely, of which 6% because of noncompliance to study treatment, 9% because of toxicity, and 9% because of death (8% within 2 months, of which 80% because of toxicity). Quality of life improved during induction treatment, being clinically meaningful already after three induction cycles., Conclusion: Ixa-Dara-dex lead to a high response rate and improved quality of life. However, treatment discontinuation because of toxicity and early mortality, negatively influencing PFS and OS, remains a concern in frail patients. The outcome was heterogeneous across frail subpopulations. This should be taken into account in the design and interpretation of future studies in frail patients, to pave the way for more precise treatment guidance., Competing Interests: Ellen van der SpekOther Relationship: Amgen Alain KentosConsulting or Advisory Role: Amgen, Sanofi, Janssen-Cilag Niels W. C. J. van de DonkConsulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, BayerSpeakers' Bureau: Janssen Research & Development, Celgene, Amgen, Bristol Myers SquibbResearch Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis Esther G. M. de WaalSpeakers' Bureau: CelgeneTravel, Accommodations, Expenses: Roche Marie-Christiane VekemansConsulting or Advisory Role: Amgen, Celgene, Bristol Myers Squibb, Janssen, TakedaTravel, Accommodations, Expenses: Amgen, Bristol Myers Squibb, Teva, Janssen Gert Jan TimmersConsulting or Advisory Role: Daiichi Sankyo Ned, Janssen-CilagSpeakers' Bureau: Novartis, ServierTravel, Accommodations, Expenses: Gilead Sciences Paul A. F. GeertsHonoraria: SanofiConsulting or Advisory Role: Janssen-Cilag Inger S. NijhofConsulting or Advisory Role: Janssen, Celgene/Bristol Myers Squibb Pieter SonneveldConsulting or Advisory Role: Celgene, Janssen, Amgen, Karyopharm Therapeutics, CARsgen TherapeuticsResearch Funding: Janssen, Amgen, Skyline Diagnostics Mark-David LevinHonoraria: AbbVie, Celgene, Janssen, TakedaTravel, Accommodations, Expenses: Takeda, Janssen Sonja ZweegmanConsulting or Advisory Role: Janssen-Cilag, Takeda, Celgene, Sanofi, OncopeptidesResearch Funding: Janssen-Cilag, Takeda, CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Takeda, CelgeneNo other potential conflicts of interest were reported.
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- 2021
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41. Osteoarthritis-Related Inflammation Blocks TGF-β's Protective Effect on Chondrocyte Hypertrophy via (de)Phosphorylation of the SMAD2/3 Linker Region.
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Thielen N, Neefjes M, Wiegertjes R, van den Akker G, Vitters E, van Beuningen H, Blaney Davidson E, Koenders M, van Lent P, van de Loo F, van Caam A, and van der Kraan P
- Subjects
- Adult, Animals, Cattle, Cell Line, Tumor, Humans, Hypertrophy metabolism, Inflammation metabolism, Interleukin-1beta pharmacology, Osteoarthritis genetics, Osteoarthritis pathology, Phosphorylation drug effects, Phosphorylation genetics, Protein Domains drug effects, Recombinant Proteins pharmacology, Signal Transduction drug effects, Smad2 Protein genetics, Smad3 Protein genetics, Synovial Membrane metabolism, Transfection, Transforming Growth Factor beta1 genetics, Transforming Growth Factor beta1 pharmacology, Chondrocytes metabolism, Chondrocytes pathology, Osteoarthritis metabolism, Signal Transduction genetics, Smad2 Protein chemistry, Smad2 Protein metabolism, Smad3 Protein chemistry, Smad3 Protein metabolism, Transforming Growth Factor beta1 metabolism
- Abstract
Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-β signaling via SMAD2/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1β and OA-synovium conditioned medium negated SMAD2/3 transcriptional activity in chondrocytes. This inhibition of TGF-β signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1β was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA.
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- 2021
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42. Increased IL-6 receptor expression and signaling in ageing cartilage can be explained by loss of TGF-β-mediated IL-6 receptor suppression.
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Wiegertjes R, Thielen NGM, van Caam APM, van Laar M, van Beuningen HM, Koenders MI, van Lent PLEM, van der Kraan PM, van de Loo FAJ, and Blaney Davidson EN
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- Animals, Cattle, Matrix Metalloproteinase 3 metabolism, Phosphorylation, STAT3 Transcription Factor metabolism, Suppressor of Cytokine Signaling 3 Protein metabolism, Aging physiology, Cartilage, Articular metabolism, Receptors, Interleukin-6 metabolism, Signal Transduction, Transforming Growth Factor beta physiology
- Abstract
Objective: Osteoarthritis (OA) development is strongly associated with ageing, possibly due to age-related changes in transforming growth factor-β (TGF-β) signaling in cartilage. Recently, we showed that TGF-β suppresses interleukin (IL)-6 receptor (IL-6R) expression in chondrocytes. As IL-6 is involved in cartilage degeneration, we hypothesized that age-related loss of TGF-β signaling results in increased IL-6R expression and signaling in ageing cartilage., Design: Bovine articular cartilage was collected and immediately processed to study age-related changes in IL-6R expression using qPCR and IHC (age-range: 0.5-14 years). Moreover, cartilage from young and aged cows was stimulated with rhIL-6 and/or rhTGF-β1 to measure IL-6-induced p-STAT3 using Western blot. Expression of STAT3-responsive genes was analyzed using qPCR., Results: Expression of IL-6 receptor (bIL-6R) significantly increased in cartilage upon ageing (slope: 0.32, 95%CI: 0.20-0.45), while expression of glycoprotein 130 (bGP130) was unaffected. Cartilage stimulation with IL-6 showed increased induction of p-STAT3 upon ageing (slope: 0.14, 95%CI: 0.08-0.20). Furthermore, IL-6-mediated induction of STAT3-responsive genes like bSOCS3 and bMMP3 was increased in aged compared to young cartilage. Interestingly, the ability of TGF-β to suppress bIL6R expression in young cartilage was lost upon ageing (slope: 0.21, 95%CI: 0.13-0.30). Concurrently, an age-related loss in TGF-β-mediated suppression of IL-6-induced p-STAT3 and bSOCS3 expression was observed., Conclusions: Ageing results in enhanced IL-6R expression and subsequent IL-6-induced p-STAT3 signaling in articular cartilage. This is likely caused by age-related loss of protective TGF-β signaling, resulting in loss of TGF-β-mediated IL-6R suppression. Because of the detrimental role of IL-6 in cartilage, this mechanism may be involved in age-related OA development., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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43. Nutritional status and interventions for patients with cancer - A systematic review.
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Hamaker ME, Oosterlaan F, van Huis LH, Thielen N, Vondeling A, and van den Bos F
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- Aged, Humans, Nutritional Status, Nutritional Support, Quality of Life, Malnutrition epidemiology, Malnutrition etiology, Neoplasms therapy
- Abstract
Background: Malnourishment is commonly seen in ageing, cancer and many chronic conditions, and is associated with poorer prognosis., Aim: We set out to collect all currently available evidence on the association between nutritional status assessed with a validated screening tool and prognosis or course of treatment in older patients with cancer, and on the benefit of nutritional interventions in improving these outcomes., Methods: A systematic search in MEDLINE and EMBASE., Results: We included 71 studies on the association between nutritional status and outcome in (older) patients with cancer and 17 studies on the benefit of nutritional interventions in improving outcomes in this patient population. There is a significant association between nutritional status and increased intermediate- and long-term mortality (hazard ratio 1.87 (95% confidence interval 1.62-2.17). Those with poorer nutritional status were less likely to complete oncologic treatment according to plan and had higher health care consumption. Benefit of dietary interventions was limited although dietary counselling may lead to improved quality of life while nutritional support may lead to a decrease in post-operative complication rates., Conclusion: Nutritional status is associated with poorer survival, decreased treatment completion and higher health care consumption and nutritional interventions are only able to negate these negatives outcome to a very limited degree., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2021
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44. Characterizing Antibiotic Use in Hospitalized Patients With a Documented Penicillin Allergy.
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Bleeker A, Brown M, Kooima T, Thielen N, Nazir J, and Laible B
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- Cephalosporins, Humans, Penicillins adverse effects, Retrospective Studies, Anti-Bacterial Agents adverse effects, Drug Hypersensitivity epidemiology
- Abstract
Introduction: Patients with self-reported penicillin allergies frequently receive unnecessary broad-spectrum antibiotics, which are associated with poor outcomes for patients and healthcare systems. The objective of this study was to determine the significance of broad-spectrum antibiotic prescription among patients with a documented penicillin allergy., Methods: Retrospective chart review identified a cohort of penicillin allergic patients admitted to the primary medical-surgical floors at Avera McKennan that received intravenous or oral antibiotics. We recorded the allergy manifestation and severity, and all antibiotics administered within 24 hours of admission. The cohort was further divided into various subgroups and analyzed using Chi-Square or a Fischer's exact test., Results: 190 patients with documented penicillin allergies received antibiotics between Dec. 1, 2018, and March 31, 2019. A severe penicillin allergy was documented in 86.3 percent of cases. Cephalosporins, vancomycin, and fluoroquinolones represented 34.1 percent, 18.2 percent, and 12.7 percent of initial antibiotics, respectively. No significance was noted in the comparison of antibiotic choice between patients with a specified versus an unspecified penicillin allergy. The number of cephalosporin prescriptions was significantly lower in a surgical prophylaxis subgroup of patients compared to a non-surgical prophylaxis subgroup., Conclusion: Our study supports literature suggesting patients with documented penicillin allergies are at risk of unwarranted broad-spectrum antibiotic use. We noted an alarming number of unverified penicillin allergies. Prescription patterns did not appear to be altered based on verification or type of recorded allergic reaction. Surgical patients may be at greater risk. Our findings call for heightened antibiotic stewardship especially regarding patients with a documented penicillin allergy., (Copyright© South Dakota State Medical Association.)
- Published
- 2020
45. Geriatric assessment in older patients with a hematologic malignancy: a systematic review.
- Author
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Scheepers ERM, Vondeling AM, Thielen N, van der Griend R, Stauder R, and Hamaker ME
- Subjects
- Activities of Daily Living, Aged, Aged, 80 and over, Geriatric Assessment, Humans, Middle Aged, Nutritional Status, Frailty diagnosis, Frailty epidemiology, Hematologic Neoplasms diagnosis, Hematologic Neoplasms epidemiology, Hematologic Neoplasms therapy
- Abstract
The aim of this systematic review is to give an update of all currently available evidence on the relevance of a geriatric assessment in the treatment of older patients with hematologic malignancies. A systematic search in MEDLINE and EMBASE was performed to find studies in which a geriatric assessment was used to detect impaired geriatric domains or to address the association between geriatric assessment and survival or clinical outcome measures. The literature search included 4,629 reports, of which 54 publications from 44 studies were included. Seventy-three percent of the studies were published in the last 5 years. The median age of the patients was 73 years (range, 58-86) and 71% had a good World Health Organization (WHO) performance status. The median prevalence of geriatric impairments varied between 17% and 68%, even in patients with a good WHO performance status. Polypharmacy, nutritional status and instrumental activities of daily living were most frequently impaired. Whereas several geriatric impairments and frailty (based on a frailty screening tool or summarized geriatric assessment score) were predictive for a shorter overall survival, WHO performance status lost its predictive value in most studies. The association between geriatric impairments and treatment-related toxicity varied, with a trend towards a higher risk of (non-)hematologic toxicity in frail patients. During the follow-up, frailty seemed to be associated with treatment non-completion, especially when patients were malnourished. Patients with a good physical capacity had a shorter stay in hospital and a lower rate of hospitalization. Geriatric assessment, even in patients with a good performance status, can detect impaired geriatric domains and these impairments may be predictive of mortality. Moreover, geriatric impairments suggest a higher risk of treatment-related toxicity, treatment non-completion and use of healthcare services. A geriatric assessment should be considered before starting treatment in older patients with hematologic malignancies., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
- Full Text
- View/download PDF
46. Chemotherapy in the oldest old: Choices and outcomes.
- Author
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van Walree IC, van Breukelen ELG, Thielen N, van Rens MTM, van Huis-Tanja LH, and Hamaker ME
- Subjects
- Activities of Daily Living, Aged, 80 and over, Analysis of Variance, Feasibility Studies, Female, Humans, Male, Netherlands, Patient Care Planning standards, Practice Guidelines as Topic, Retrospective Studies, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasms drug therapy
- Abstract
Treatment decision-making in older patients with cancer is difficult due to a paucity of data evaluating chemotherapy tolerability in this population. We investigated the feasibility of chemotherapy in the oldest old and performed a singl-centre retrospective analysis of patients aged ≥80 years initiating chemotherapy for one of five common solid malignancies or non-Hodgkin lymphoma between 2010 and 2016. Treatment plan and course were extracted from medical files. Primary outcome was whether chemotherapy was completed according to plan, defined as a calculated relative dose intensity (RDI) ≥85%. A total of 104 patients receiving 129 chemotherapy lines were included. Median age at diagnosis was 82 years (range 80-94 years). Most patients (64%) received palliative intent chemotherapy. Primary and secondary chemotherapy adaptations were implemented in 63% and 65% of the cases, and hospitalisation occurred in a quarter. 52% of all cases completed chemotherapy according to plan. Almost half of the chemotherapy regimens started in the oldest old were not completed according to plan, despite frequently implemented upfront adaptations. The decision to start chemotherapy in these patients should be carefully considered. To improve decision-making in current practice, there is a need for the implementation of validated tools assessing chemotherapy feasibility in these patients., (© 2019 John Wiley & Sons Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
47. [A man with backache and a genital skin lesion].
- Author
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Scheepers ERM, Flinterman AE, and Thielen N
- Subjects
- Aged, Back Pain etiology, Biopsy, Genital Neoplasms, Male pathology, Humans, Male, Paget Disease, Extramammary pathology, Skin pathology, Skin Neoplasms pathology, Genital Neoplasms, Male diagnosis, Paget Disease, Extramammary diagnosis, Skin Neoplasms diagnosis
- Abstract
A 72-year-old man was admitted to hospital because of backache. Physical examination also revealed a genital skin lesion with inguinal lymphadenopathy. Skin biopsy showed an infiltrating adenoma, arising from extramammary Paget disease. MRI of the vertebral column revealed multiple osteolytic lesions, likely metastases. The patient was diagnosed with metastatic extramammary Paget disease, which has a poor prognosis.
- Published
- 2019
48. Validation of the EUTOS long-term survival score in a recent independent cohort of "real world" CML patients.
- Author
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Geelen IGP, Sandin F, Thielen N, Janssen JJWM, Hoogendoorn M, Visser O, Cornelissen JJ, Hoglund M, and Westerweel PE
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Imatinib Mesylate therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Male, Middle Aged, Young Adult, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality
- Published
- 2018
- Full Text
- View/download PDF
49. The effect of a geriatric evaluation on treatment decisions and outcome for older cancer patients - A systematic review.
- Author
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Hamaker ME, Te Molder M, Thielen N, van Munster BC, Schiphorst AH, and van Huis LH
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Medical Oncology methods, Neoplasms psychology, Treatment Adherence and Compliance psychology, Treatment Outcome, Decision Making, Geriatric Assessment methods, Neoplasms therapy
- Abstract
Aim: The aim of this systematic review is to summarise all available data on the effect of a geriatric evaluation on the multidisciplinary treatment of older cancer patients, focussing on oncologic treatment decisions, the implementation of non-oncologic interventions and the impact on treatment outcome., Methods: A systematic search in MEDLINE and EMBASE for studies on the effect of a geriatric evaluation on oncologic and non-oncologic treatment decisions and outcome for older cancer patients., Results: 36 publications from 35 studies were included. After a geriatric evaluation, the oncologic treatment plan was altered in a median of 28% of patients (range 8-54%), primarily to a less intensive treatment option. Non-oncologic interventions were recommended in a median of 72% of patients (range 26-100%), most commonly involving social issues (39%), nutritional status (32%) and polypharmacy (31%). Effect on treatment outcome was varying, with a trend towards a positive effect on treatment completion (positive effect in 75% of studies) and treatment-related toxicity/ complications (55% of studies)., Conclusion: A geriatric evaluation affects oncologic and non-oncologic treatment and appears to improve treatment tolerance and completion for older cancer patients. Fine-tuning the decision-making process for this growing patient population will require more specific and robust data on the effect of a geriatric evaluation on relevant oncologic and non-oncologic outcomes such as survival and quality of life., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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50. Omitting cytogenetic assessment from routine treatment response monitoring in chronic myeloid leukemia is safe.
- Author
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Geelen IGP, Thielen N, Janssen JJWM, Hoogendoorn M, Roosma TJA, Valk PJM, Visser O, Cornelissen JJ, and Westerweel PE
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytogenetic Analysis, Disease Management, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Male, Netherlands epidemiology, Population Surveillance, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors therapeutic use, Registries, Treatment Outcome, Leukemia, Myelogenous, Chronic, BCR-ABL Positive epidemiology
- Abstract
Objectives: The monitoring of response in chronic myeloid leukemia (CML) is of great importance to identify patients failing their treatment in order to adjust TKI choice and thereby prevent progression to advanced stage disease. Cytogenetic monitoring has a lower sensitivity, is expensive, and requires invasive bone marrow sampling. Nevertheless, chronic myeloid leukemia guidelines continue to recommend performing routine cytogenetic response assessments, even when adequate molecular diagnostics are available., Methods: In a population-based registry of newly diagnosed CML patients in the Netherlands, all simultaneous cytogenetic and molecular assessments performed at 3, 6, and 12 months were identified and response of these matched assessments was classified according to European Leukemia Net (ELN) recommendations. The impact of discrepant cytogenetic and molecular response classifications and course of patients with additional chromosomal abnormalities were evaluated., Results: The overall agreement of 200 matched assessments was 78%. In case of discordant responses, response at 24 months was consistently better predicted by the molecular outcome. Cytogenetic response assessments provided relevant additional clinical information only in some cases of molecular "warning." The development of additional cytogenetic abnormalities was always accompanied with molecular failure., Conclusion: We conclude that it is safe to omit routine cytogenetics for response assessment during treatment and to only use molecular monitoring, in order to prevent ambiguous classifications, reduce costs, and reduce the need for invasive bone marrow sampling. Cytogenetic re-assessment should still be performed when molecular response is suboptimal., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
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