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1. Toxic iron species in lower-risk myelodysplastic syndrome patients: course of disease and effects on outcome

Author

Hoeks, M. Bagguley, T. van Marrewijk, C. Smith, A. Bowen, D. Culligan, D. Kolade, S. Symeonidis, A. Garelius, H. Spanoudakis, M. Langemeijer, S. Roelofs, R. Wiegerinck, E. Tatic, A. Killick, S. Panagiotidis, P. Stanca, O. Hellström-Lindberg, E. Cermak, J. van der Klauw, M. Wouters, H. van Kraaij, M. Blijlevens, N. Swinkels, D.W. de Witte, T. Stauder, R. Walder, A. Pfeilstöcker, M. Schoenmetzler-Makrai, A. Burgstaller, S. Thaler, J. Mandac Rogulj, I. Krejci, M. Voglova, J. Rohon, P. Jonasova, A. Cermak, J. Mikulenkova, D. Hochova, I. Jensen, P.D. Holm, M.S. Kjeldsen, L. Dufva, I.H. Vestergaard, H. Re, D. Slama, B. Fenaux, P. Choufi, B. Cheze, S. Klepping, D. Salles, B. de Renzis, B. Willems, L. De Prost, D. Gutnecht, J. Courby, S. Siguret, V. Tertian, G. Pascal, L. Chaury, M. Wattel, E. Guerci, A. Legros, L. Itzykson, R. Ades, L. Isnard, F. Sanhes, L. Benramdane, R. Stamatoullas, A. Amé, S. Beyne-Rauzy, O. Gyan, E. Platzbecker, U. Badrakan, C. Germing, U. Lübbert, M. Schlenk, R. Kotsianidis, I. Tsatalas, C. Pappa, V. Galanopoulos, A. Michali, E. Panagiotidis, P. Viniou, N. Katsigiannis, A. Roussou, P. Terpos, E. Kostourou, A. Kartasis, Z. Pouli, A. Palla, K. Briasoulis, V. Hatzimichael, E. Vassilopoulos, G. Symeonidis, A. Kourakli, A. Zikos, P. Anagnostopoulos, A. Kotsopoulou, M. Megalakaki, K. Protopapa, M. Vlachaki, E. Konstantinidou, P. Stemer, G. Nemetz, A. Gotwin, U. Cohen, O. Koren, M. Levy, E. Greenbaum, U. Gino-Moor, S. Price, M. Ofran, Y. Winder, A. Goldshmidt, N. Elias, S. Sabag, R. Hellman, I. Ellis, M. Braester, A. Rosenbaum, H. Berdichevsky, S. Itzhaki, G. Wolaj, O. Yeganeh, S. Katz, O. Filanovsky, K. Dali, N. Mittelman, M. Malcovati, L. Fianchi, L. vd Loosdrecht, A. Matthijssen, V. Herbers, A. Pruijt, H. Aboosy, N. de Vries, F. Velders, G. Jacobs, E. Langemeijer, S. MacKenzie, M. Lensen, C. Kuijper, P. Madry, K. Camara, M. Almeida, A. Vulkan, G. Stanca Ciocan, O. Tatic, A. Savic, A. Pedro, C. Xicoy, B. Leiva, P. Munoz, J. Betes, V. Benavente, C. Lozano, M. Martinez, M. Iniesta, P. Bernal, T. Diez Campelo, M. Tormo, D. Andreu Lapiedra, R. Sanz, G. Hesse Sundin, E. Garelius, H. Karlsson, C. Antunovic, P. Jönsson, A. Brandefors, L. Nilsson, L. Kozlowski, P. Hellstrom-Lindberg, E. Grövdal, M. Larsson, K. Wallvik, J. Lorenz, F. Ejerblad, E. Culligan, D. Craddock, C. Kolade, S. Cahalin, P. Killick, S. Ackroyd, S. Wong, C. Warren, A. Drummond, M. Hall, C. Rothwell, K. Green, S. Ali, S. Karakantza, M. Dennis, M. Jones, G. Parker, J. Bowen, A. Radia, R. Das-Gupta, E. Vyas, P. Nga, E. Creagh, D. Ashcroft, J. Mills, J. Bond, L. the EUMDS Registry Participants

Published
2021

4. Toxic iron species in lower-risk myelodysplastic syndrome patients : course of disease and effects on outcome

Author

Hoeks, Marlijn, Bagguley, Tim, van Marrewijk, Corine, Smith, Alex, Bowen, David, Culligan, Dominic, Kolade, Seye, Symeonidis, Argiris, Garelius, Hege, Spanoudakis, Michail, Langemeijer, Saskia, Roelofs, Rian, Wiegerinck, Erwin, Tatic, Aurelia, Killick, Sally, Panagiotidis, Panagiotis, Stanca, Oana, Hellström-Lindberg, Eva, Cermak, Jaroslav, van der Klauw, Melanie, Wouters, Hanneke, van Kraaij, Marian, Blijlevens, Nicole, Swinkels, Dorine W., de Witte, Theo, Stauder, R., Walder, A., Pfeilstöcker, M., Schoenmetzler-Makrai, A., Burgstaller, S., Thaler, J., Mandac Rogulj, I., Krejci, M., Voglova, J., Rohon, P., Jonasova, A., Cermak, J., Mikulenkova, D., Hochova, I., Jensen, P. D., Holm, M. S., Kjeldsen, L., Dufva, I. H., Vestergaard, H., Re, D., Slama, B., Fenaux, P., Choufi, B., Cheze, S., Klepping, D., Salles, B., de Renzis, B., Willems, L., De Prost, D., Gutnecht, J., Courby, S., Siguret, V., Tertian, G., Pascal, L., Chaury, M., Wattel, E., Guerci, A., Legros, L., Itzykson, R., Ades, L., Isnard, F., Sanhes, L., Benramdane, R., Stamatoullas, A., Amé, S., Beyne-Rauzy, O., Gyan, E., Platzbecker, U., Badrakan, C., Germing, U., Lübbert, M., Schlenk, R., Kotsianidis, I., Tsatalas, C., Pappa, V., Galanopoulos, A., Michali, E., Panagiotidis, P., Viniou, N., Katsigiannis, A., Roussou, P., Terpos, E., Kostourou, A., Kartasis, Z., Pouli, A., Palla, K., Briasoulis, V., Hatzimichael, E., Vassilopoulos, G., Symeonidis, A., Kourakli, A., Zikos, P., Anagnostopoulos, A., Kotsopoulou, M., Megalakaki, K., Protopapa, M., Vlachaki, E., Konstantinidou, P., Stemer, G., Nemetz, A., Gotwin, U., Cohen, O., Koren, M., Levy, E., Greenbaum, U., Gino-Moor, S., Price, M., Ofran, Y., Winder, A., Goldshmidt, N., Elias, S., Sabag, R., Hellman, I., Ellis, M., Braester, A., Rosenbaum, H., Berdichevsky, S., Itzhaki, G., Wolaj, O., Yeganeh, S., Katz, O., Filanovsky, K., Dali, N., Mittelman, M., Malcovati, L., Fianchi, L., vd Loosdrecht, A., Matthijssen, V., Herbers, A., Pruijt, H., Aboosy, N., de Vries, F., Velders, G., Jacobs, E., Langemeijer, S., MacKenzie, M., Lensen, C., Kuijper, P., Madry, K., Camara, M., Almeida, A., Vulkan, G., Stanca Ciocan, O., Tatic, A., Savic, A., Pedro, C., Xicoy, B., Leiva, P., Munoz, J., Betes, V., Benavente, C., Lozano, M., Martinez, M., Iniesta, P., Bernal, T., Diez Campelo, M., Tormo, D., Andreu Lapiedra, R., Sanz, G., Hesse Sundin, E., Garelius, H., Karlsson, C., Antunovic, P., Jönsson, A., Brandefors, L., Nilsson, L., Kozlowski, P., Hellstrom-Lindberg, E., Grövdal, M., Larsson, K., Wallvik, J., Lorenz, F., Ejerblad, E., Culligan, D., Craddock, C., Kolade, S., Cahalin, P., Killick, S., Ackroyd, S., Wong, C., Warren, A., Drummond, M., Hall, C., Rothwell, K., Green, S., Ali, S., Bowen, D., Karakantza, M., Dennis, M., Jones, G., Parker, J., Bowen, A., Radia, R., Das-Gupta, E., Vyas, P., Nga, E., Creagh, D., Ashcroft, J., Mills, J., Bond, L., Life Course Epidemiology (LCE), and VU University medical center

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Iron Overload, Iron, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Ferroportin, Lower risk, Gastroenterology, Article, Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], 03 medical and health sciences, 0302 clinical medicine, Hepcidin, Internal medicine, Humans, Medicine, Blood Transfusion, Prospective Studies, Aged, Soluble transferrin receptor, biology, business.industry, Transferrin saturation, Hematology, Middle Aged, Erythroferrone, Prognosis, 3. Good health, Survival Rate, Ferritin, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Oncology, Myelodysplastic Syndromes, 030220 oncology & carcinogenesis, biology.protein, Erythropoiesis, Female, business, Myelodysplastic syndrome, Follow-Up Studies, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Red blood cell transfusions (RBCT) remain the cornerstone of supportive care in lower-risk myelodysplastic syndrome (LRMDS) [1]. Transfusion dependency in LRMDS patients is associated with inferior outcomes, mainly attributed to severe bone marrow failure [2]. However, iron toxicity, due to frequent RBCT or ineffective erythropoiesis, may be an additional negative prognostic factor [3,4,5,6]. Recently, much progress has been made in unraveling the iron metabolism. The peptide hormone hepcidin is the key regulator by inhibiting iron uptake through degradation of ferroportin, a cellular iron exporter [7]. Erythroferrone and GDF15, produced by erythroblasts, inhibit hepcidin production, which leads to increased uptake and cellular release of iron for the purpose of erythropoiesis [8]. The pathophysiology of iron metabolism in MDS is still not completely understood. Exceedingly high reactive oxygen species (ROS) levels are associated with iron toxicity, disease development, and progression in MDS patients [9,10,11,12]. Malondialdehyde (MDA), resulting from lipid peroxidation of polyunsaturated fatty acids, is a biomarker of oxidative stress [10, 12]. Currently, little is known about the prognostic impact of ROS in MDS patients. The aim of this study is twofold: (1) describe iron and oxidative stress parameters over time in LRMDS patients and (2) to assess their effect on overall and progression-free survival. The EUMDS registry prospectively collects observational data on newly diagnosed LRMDS patients from 148 centers in 16 countries in Europe and Israel as of January 2008. All patients provided informed consent. Clinical data were collected at baseline and at each six-monthly follow-up visit. Serum samples were collected prospectively at each visit from 256 patients included in six participating countries. Conventional iron parameters were measured with routine assays. We additionally analyzed hepcidin, growth differentiation factor 15 (GDF15), soluble transferrin receptor (sTfR), non-transferrin bound iron (NTBI), labile plasma iron (LPI), and MDA. Subjects were prospectively followed until death, loss to follow-up, or withdrawal of consent. All iron parameters were measured centrally at the department of Laboratory Medicine of the Radboudumc, Nijmegen, The Netherlands. Serum samples were collected just prior to transfusion in transfusion-dependent patients and stored at −80 °C. Details on the assays and reference ranges of hepcidin, GDF15, sTfR, NTBI, LPI, and MDA are provided in the supplement. The Spearman rank test was used to evaluate correlations between iron parameters. We stratified the results by transfusion dependency per visit and the presence of ring sideroblasts. When evaluating temporal changes in iron parameters, with linear quantile mixed models, we excluded patients from the timepoint they received iron chelation therapy. Overall survival (OS) was defined as the time from MDS diagnosis to death or, in case of progression-free survival, to date of progression or death; patients still alive at the end of follow-up were censored. Time-dependent Kaplan–Meier curves and cox proportional hazards models were used. In total, 256 consecutive patients, were included in this study. Over five six-monthly visits, 1040 samples were collected. Table 1 describes the patient characteristics. Most patients without ring sideroblasts were transfusion-independent at diagnosis (nonRS-TI; 55.9%), 18.8% with ring sideroblasts were transfusion-independent (RS-TI), 18.4% without ring sideroblasts were transfusion-dependent (nonRS-TD), and 7% with ring sideroblasts were transfusion-dependent patients (RS-TD). The median follow-up time was 6.6 years (95% CI 5.9–7.0). LPI was positively correlated with transferrin saturation (TSAT) (r = 0.15, p < 0.001, Fig. S1). LPI values increased exponentially at TSAT values above 80%. This effect was most pronounced in the transfusion-dependent groups, but also observed in the RS-TI group. MDA was weakly correlated with NTBI (r = 0.09, p = 0.069) and negatively correlated with hemoglobin level (r = −0.1, p = 0.033). GDF15 and hepcidin were negatively correlated in the RS-TI and nonRS-TD group and significantly negatively correlated in the RS-TD group (r = −0.34, p = 0.007, Fig. S2). Serum ferritin levels were elevated in all subgroups with a mean value of 858 µg/L at visit 5. The highest serum ferritin levels were observed in the RS-TD group (mean value at visit 5: 2092 µg/L, Table S1). Serum ferritin increased significantly per visit in the RS-TD group (beta 454.46 µg/L; 95% CI 334.65–574.27), but not in the other groups (Table S2). All subgroups, except for the nonRS-TI, had elevated TSAT levels. TSAT levels were most markedly increased in the RS-TD group with a mean TSAT of 88% at visit 5 (Table S1). In both transfusion-dependent groups the median increase per visit was significant (Table S2). LPI was elevated in the RS-TD group exclusively with a mean value of 0.59 µmol/L at visit 5 (Table S1). NTBI was elevated in all subgroups, with the highest values in the RS-TD group (Table S1). The increase in median NTBI level was significant in both transfusion-dependent groups (Table S2). Hepcidin levels were markedly elevated in the nonRS-TD group. Interestingly, hepcidin levels were lower in the RS-TD group, probably reflecting ineffective erythropoiesis, likewise supported by lower hepcidin/ferritin ratios in RS groups (Table S1). Median hepcidin levels increased over time in the transfusion-dependent subgroups only (Table S2). GDF15 levels, analyzed in the light of its potential role in hepcidin suppression, were increased in all subgroups (Table S1). The RS subgroups had higher GDF15 levels compared to the nonRS groups, reflecting increased erythropoiesis. Mean sTfR levels were within the reference range in all subgroups except for the RS-TI group, which showed elevated levels, reflecting...

Published
2021
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5. Toxic iron species in lower-risk myelodysplastic syndrome patients: course of disease and effects on outcome

Author

Hoeks, M.P.A., Bagguley, T., Marrewijk, C.J. van, Smith, A, Bowen, D., Culligan, D., Kolade, S., Symeonidis, A., Garelius, H, Spanoudakis, M., Langemeijer, S.M., Roelofs, R.W., Wiegerinck, E.T.G., Tatic, A., Killick, S., Panagiotidis, P., Stanca, O., Hellström-Lindberg, E., Cermak, J., Klauw, M. van der, Wouters, H, Kraaij, M.G.J. van, Blijlevens, N.M.A., Swinkels, D.W., Witte, T.J. de, Hoeks, M.P.A., Bagguley, T., Marrewijk, C.J. van, Smith, A, Bowen, D., Culligan, D., Kolade, S., Symeonidis, A., Garelius, H, Spanoudakis, M., Langemeijer, S.M., Roelofs, R.W., Wiegerinck, E.T.G., Tatic, A., Killick, S., Panagiotidis, P., Stanca, O., Hellström-Lindberg, E., Cermak, J., Klauw, M. van der, Wouters, H, Kraaij, M.G.J. van, Blijlevens, N.M.A., Swinkels, D.W., and Witte, T.J. de

Abstract

Item does not contain fulltext

Published
2021

17. Early specialist palliative care on quality of life for malignant pleural mesothelioma: A randomised controlled trial

Author

Brims, Fraser, Gunatilake, S., Lawrie, I., Marshall, L., Fogg, C., Qi, C., Creech, L., Holtom, N., Killick, S., Yung, B., Cooper, D., Stadon, L., Cook, P., Fuller, E., Walther, J., Plunkett, C., Bates, A., Mackinlay, C., Tandon, A., Maskell, N., Forbes, K., Rahman, N., Gerry, S., Chauhan, A., Brims, Fraser, Gunatilake, S., Lawrie, I., Marshall, L., Fogg, C., Qi, C., Creech, L., Holtom, N., Killick, S., Yung, B., Cooper, D., Stadon, L., Cook, P., Fuller, E., Walther, J., Plunkett, C., Bates, A., Mackinlay, C., Tandon, A., Maskell, N., Forbes, K., Rahman, N., Gerry, S., and Chauhan, A.

Abstract

Purpose: Malignant pleural mesothelioma (MPM) has a high symptom burden and poor survival. Evidence from other cancer types suggests some benefit in health-related quality of life (HRQoL) with early specialist palliative care (SPC) integrated with oncological services, but the certainty of evidence is low. Methods: We performed a multicentre, randomised, parallel group controlled trial comparing early referral to SPC versus standard care across 19 hospital sites in the UK and one large site in Western Australia. Participants had newly diagnosed MPM; main carers were additionally recruited. Intervention: review by SPC within 3 weeks of allocation and every 4 weeks throughout the study. HRQoL was assessed at baseline and every 4 weeks with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30. Primary outcome: change in EORTC C30 Global Health Status 12 weeks after randomisation. Results: Between April 2014 and October 2016, 174 participants were randomised. There was no significant between group difference in HRQoL score at 12 weeks (mean difference 1.8 (95% CI -4.9 to 8.5; p=0.59)). HRQoL did not differ at 24 weeks (mean difference -2.0 (95% CI -8.6 to 4.6; p=0.54)). There was no difference in depression/anxiety scores at 12 weeks or 24 weeks. In carers, there was no difference in HRQoL or mood at 12 weeks or 24 weeks, although there was a consistent preference for care, favouring the intervention arm. Conclusion: There is no role for routine referral to SPC soon after diagnosis of MPM for patients who are cared for in centres with good access to SPC when required. Trial registration number: ISRCTN18955704.

Published
2019

28. S838 TRANSFUSION DEPENDENCY IS ASSOCIATED WITH PRESENCE OF TOXIC IRON SPECIES AND INFERIOR SURVIVAL IN PATIENTS WITH LOWER-RISK MYELODYSPLASTIC SYNDROMES

Author

Hoeks, M., primary, Bagguley, T., additional, Roelofs, R., additional, de Swart, L., additional, Bowen, D., additional, Symeonidis, A., additional, van Marrewijk, C., additional, Hellstrom-Lindberg, E., additional, Tatic, A., additional, Langemeijer, S., additional, Culligan, D., additional, Macheta, M., additional, Garelius, H., additional, Spanoudakis, M., additional, Killick, S., additional, Panagiotidis, P., additional, Stanca Ciocan, O., additional, Mills, J., additional, Pottinger, B., additional, Ackroyd, S., additional, Hall, C., additional, Droste, J., additional, Smith, A., additional, Swinkels, D., additional, and de Witte, T., additional

Published
2019
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37. 2016 National audit of red cell use in adult haematology patients

Author

Karakantza, M, Birchall, J, Killick, S, Kallmayer, C, McSporran, W, Addison, J, Wood, M, Stanworth, S, and Estcourt, L

Abstract

Current data show that patients with haematological malignancies receive 15–20% of the total red blood cells (RBC) transfused annually. The increasing life expectancy and improved treatment and supportive options are changing the demographics of haematology patients receiving transfusions from those that are on chemotherapy to those that require a regular transfusion programme for chronic bone marrow failure, especially myelodysplastic syndromes (MDS).

Published
2017
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39. Targeted resequencing analysis of 31 genes commonly mutated in myeloid disorders in serial samples from myelodysplastic syndrome patients showing disease progression

Author

Pellagatti, A, Roy, S, Di Genua, C, Burns, A, McGraw, K, Valletta, S, Larrayoz, M J, Fernandez-Mercado, M, Mason, J, Killick, S, Mecucci, C, Calasanz, M J, List, A, Schuh, A, and Boultwood, J

Subjects
LANDSCAPE, MUTATIONS, High-Throughput Nucleotide Sequencing, Membrane Proteins, Nuclear Proteins, CLONAL HEMATOPOIESIS, Genes, p53, GTP Phosphohydrolases, Repressor Proteins, Ribonucleoproteins, Myelodysplastic Syndromes, Core Binding Factor Alpha 2 Subunit, Mutation, Disease Progression, Humans, Letter to the Editor
Published
2015

41. Human Gonadotrophin Preparations

Author

Doré, P. C., Rice, C., Killick, S., Vine, Steven, Chui, David, Rumington, Michael, Gregory, Linda, Wells, Catherine, and Walker, Sheila

Published
1994

45. Identification of Aberrant Splicing Events in Myelodysplastic Syndrome Patients with Splicing Factor Gene Mutations

Author

Pellagatti, A., primary, Steeples, V., additional, Sharma, E., additional, Repapi, E., additional, Yip, B.H., additional, Armstrong, R.N., additional, Dolatshad, H., additional, Lockstone, H., additional, Taylor, S., additional, Giagounidis, A., additional, Vyas, P., additional, Papaemmanuil, E., additional, Woll, P., additional, Killick, S., additional, Malcovati, L., additional, Hellström-Lindberg, E., additional, Cazzola, M., additional, Smith, C.W.J., additional, and Boultwood, J., additional

Published
2017
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47. Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes

Author

Dolatshad, H, primary, Pellagatti, A, additional, Liberante, F G, additional, Llorian, M, additional, Repapi, E, additional, Steeples, V, additional, Roy, S, additional, Scifo, L, additional, Armstrong, R N, additional, Shaw, J, additional, Yip, B H, additional, Killick, S, additional, Kušec, R, additional, Taylor, S, additional, Mills, K I, additional, Savage, K I, additional, Smith, C W J, additional, and Boultwood, J, additional

Published
2016
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49. TREATMENT OF SEVERE RESISTANT AUTOIMMUNE CYTOPENIAS WITH CAMPATH-1H

Author

Willis, F., Marsh, J, Bevan, D., Killick, S., Lucas, G., Griffiths, R., Ouwehand, W., Hale, G., Waldmann, H., and Gordon-Smith, E.

Subjects
Monoclonal antibodies -- Health aspects, Autoimmune diseases -- Care and treatment, Health, Campath (Medication) -- Evaluation -- Product/service Evaluations
Abstract

Background: Haemopoietic stem cell treatment has been proposed for severe resistant autoimmune cytopenias. An alternative and safer option may be the monoclonal antibody Campath-1H, which may reset the immune system [...]

Published
2001

50. Cardiac iron overload in transfusion-dependent patients with myelodysplastic syndromes

Author

Roy, N, Myerson, S, Schuh, A, Bignell, P, Patel, R, Wainscoat, J, McGowan, S, Marchi, E, Atoyebi, W, Littlewood, T, Chacko, J, Vyas, P, and Killick, S

Abstract

Transfusion-dependent myelodysplastic (MDS) patients are prone to iron overload. We evaluated 43 transfused MDS patients with T2* magnetic resonance imaging scans. 81% had liver and 16·8% cardiac iron overload. Liver R2* (1000/T2*), but not cardiac R2*, was correlated with number of units transfused (r=0·72, P

Published
2011

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