20 results on '"MacKenzie, Marius A."'
Search Results
2. Castleman disease and paraneoplastic pemphigus
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Kop, Else N. and MacKenzie, Marius A.
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Pemphigus -- Care and treatment -- Risk factors -- Diagnosis -- Case studies ,Lymphoproliferative disorders -- Complications and side effects -- Diagnosis -- Care and treatment -- Case studies ,Health - Abstract
A 29-year-old woman presented with a six-month history of painful oral and vulvar erosions, and itchy erythematosquamous eroded papules grouped at multiple locations (Figures 1A and 1B). Apart from fatigue, [...]
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- 2010
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3. Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON)
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Verdonck, Leo F., Notenboom, Annelise, de Jong, Daphne D., MacKenzie, Marius A., Verhoef, Gregor E. G., Kramer, Mark H. H., Ossenkoppele, Gert J., Doorduijn, Jeanette K., Sonneveld, Pieter, and van Imhoff, Gustaaf W.
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Optimal dose and timing of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy for aggressive non-Hodgkin lymphoma (NHL) is still an unresolved issue. We assessed whether dose intensifications with cyclophosphamide and doxorubicin might improve outcome in younger patients with intermediate-risk aggressive NHL. Previously untreated patients were assigned to receive either 8 courses of standard CHOP (n = 239) or 6 courses of intensified (I)–CHOP (n = 238). Although there was a tendency in favor of I-CHOP for overall survival (OS), disease-free survival (DFS), and event-free survival (EFS), the differences were not significant. However, although these analyses were not planned, when the intermediate-risk group was divided into low-intermediate- and high-intermediate-risk patients according to the International Prognostic Index (IPI), low-intermediate-risk patients had improved 6-year OS (67% vs 52%; P = .05), DFS (58% vs 45%; P = .06), and EFS (41% vs 30%; P = .21) when they were treated with I-CHOP compared with standard CHOP. On the other hand, high-intermediate-risk patients seem to have no benefit from I-CHOP. Although clinically relevant side effects occurred more often in the I-CHOP arm, treatment-related mortality was similar. These data suggest that I-CHOP might be preferable to standard CHOP in younger patients with low-intermediate-risk aggressive NHL.
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- 2007
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4. Effect of Steady Hypothermia and Normothermia on Multimodality Evoked Potentials in Human Poikilothermia
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MacKenzie, Marius A., Vingerhoets, Dick M., Colon, Ernst J., Pinckers, Alfred J. L. G., and Notermans, Servaas L. H.
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OBJECTIVE: To assess the effects of steady-state spontaneous hypothermia on multimodality evoked potentials and on peripheral nerve conduction in human poikilothermia. DESIGN AND SETTING: Case series at a university hospital. PATIENTS: Four patients (four women, aged 28 to 37 years) with acquired poikilothermia. MAIN OUTCOME MEASURES: Short-latency somatosensory, brain-stem auditory, and visual evoked potentials as well as motor and sensory peripheral nerve conduction velocity during steady-state spontaneous hypothermia and normothermia. RESULTS: The marked latency prolongation of all evoked potentials and decreased peripheral nerve conduction velocity observed during steady-state spontaneous hypothermia (mean±SD core temperature, 33.5±0.3°C) compared with normothermia (36.9±0.4°C) agrees with previous findings during short-term induced hypothermia. CONCLUSIONS: The unequivocal effect of sustained mild spontaneous hypothermia on evoked potentials and peripheral nerve conduction velocity underlines the importance of meticulous attention to even small alterations in core temperature in interpreting neurophysiological investigations.
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- 1995
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5. Poikilothermia in Man
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Mackenzie, Marius A., Smals, Anthony G.H., Binkhorst, Rob A., Thien, Theo, and Kloppenborg, Peter W.C.
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- 1991
6. Electrocardiographic changes during steady mild hypothermia and normothermia in patients with poikilothermia
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MacKenzie, Marius A., Aengevaeren, Wim R. M., Hermus, Ad R. M. M., van der Werf, Tjeerd, Pieters, Gerlach F. F. M., Smals, Anthony G. H., and Kloppenborg, Peter W. C.
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1. ECG changes observed in short-term induced and accidental hypothermia are well known. To assess the influence of steady-state spontaneous hypothermia on the ECG, we subjected four patients with acquired poikilothermia (severe thermolability) to 24 h ECG recording, exercise testing and thermal stress. 2. Twenty-four hour Holter monitoring showed a significant reduction in heart rate and a prolongation of the QT interval during steady-state mild hypothermia (rectal temperature 33.9 ± 0.7°C, mean ± sd) compared with during normothermia; no significant changes occurred in the PR interval, QRS complex and QTc interval (QT interval corrected for heart rate). 3. Unlike during normothermia, during steady hypothermia atrioventricular Wenckebach blocks were observed in two patients, whereas another patient showed markedly more atrioventricular Wenckebach blocks during hypothermia. 4. During steady hypothermia the heart rate variability was significantly enhanced in comparison with normothermia. 5. Exercise tolerance was similar during mild hypothermia and normothermia. 6. Heat exposure (ambient temperature 40°C) induced significantly greater changes in rectal temperature, heart rate and PR interval, QRS complex and QT interval in the patients than in the control subjects (n = 8). 7. The present study reveals that even mild steady spontaneous hypothermia can elicit ECG changes, presumably mediated by relatively enhanced cardiac vagal tone. Hence, spontaneous abnormalities in core temperature should be taken into account in interpreting the ECG in clinical practice.
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- 1992
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7. Bortezomib Maintenance Therapy after Induction with R-CHOP, ARA-C and Autologous Stem Cell Transplantation in Newly Diagnosed MCL Patients, Results of a Multicenter Phase II HOVON Study
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Doorduijn, Jeanette K, Minnema, Monique C., Kersten, Marie Jose, Lugtenburg, Pieternella J, Schipperus, Martin R., van Marwijk Kooy, Marinus, MacKenzie, Marius, Zijlstra, Josée M, Berenschot, Henriette W, Schaafsma, M. R, Chitu, Dana A, and Kluin-Nelemans, Hanneke C.
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Doorduijn: Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Off Label Use: bortezomib maintenance in MCL. Minnema:Celgene: Consultancy; Jansen Cilag: Consultancy; Amgen: Consultancy. Kersten:janssen: Honoraria, Research Funding; takeda millennium: Research Funding; roche: Honoraria, Research Funding. Lugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Celgene: Consultancy; Roche: Consultancy. Schipperus:Novartis: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy.
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- 2015
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8. International Comparison Study of Toxic Iron Assays in Patients with Iron Overload Disorders
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De Swart, Louise, Hendriks, Jan C.M., Van der Vorm, Lisa, Cabantchik, Ioav Z., Evans, Patricia J., Hod, Eldad A., Brittenham, Gary M., Furman, Yael, Janssen, Mirian C.H., Biemond, Bart J, MacKenzie, Marius A., Mattijssen, Vera E.J.M., Origa, Raffaella, Galanello, Renzo, Hider, Robert C., and Swinkels, Dorine W.
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De Swart: Novartis Europe: Research Funding. Swinkels:Novartis Europe: Research Funding.
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- 2014
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9. A Dominant-Negative GFI1B Mutation in Gray Platelet Syndrome
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Van der Reijden, Bert A., Monteferrario, Davide, Bolar, Nikhita, Marneth, Anna, Hebeda, Konnie, Bergevoet, Saskia, Veenstra, Hans, Gorkum, Britta Laros-van, MacKenzie, Marius, Khandanpour, Cyrus, Botezatu, Lacramioara, Fransen, Erik, Van Camp, Guy, Duijnhouwer, Anthonie, Salemink, Simone, Willemsen, Brigith, Huls, Gerwin, Preijers, Franks, van Heerde, Waander L., Jansen, Joop H., Kempers, Marlies, Loeys, Bart, and Van Laer, Lut
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No relevant conflicts of interest to declare.
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- 2013
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10. A Dominant-Negative GFI1BMutation in Gray Platelet Syndrome
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Van der Reijden, Bert A., Monteferrario, Davide, Bolar, Nikhita, Marneth, Anna, Hebeda, Konnie, Bergevoet, Saskia, Veenstra, Hans, Gorkum, Britta Laros-van, MacKenzie, Marius, Khandanpour, Cyrus, Botezatu, Lacramioara, Fransen, Erik, Van Camp, Guy, Duijnhouwer, Anthonie, Salemink, Simone, Willemsen, Brigith, Huls, Gerwin, Preijers, Franks, van Heerde, Waander L., Jansen, Joop H., Kempers, Marlies, Loeys, Bart, and Van Laer, Lut
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Gray platelet syndrome (GPS) is a hereditary, usually autosomal recessive bleeding disorder caused by defective production of α-granules in platelets. GPS patients show reduced numbers of platelets that are larger and have a typical gray appearance under light microscopy, caused by the lack of α-granules. We describe a large family with an autosomal dominant type of GPS characterized by mild to severe bleeding complications. In addition to large gray platelets, other GPS-associated phenomena like myelofibrosis, thrombocytopenia, and low platelet factor 4 expression were observed in affected individuals. Histopathological examination of a BM biopsy from a patient showed a cellular marrow with increased numbers of megakaryocytes that were pleomorphic in size and shape. Megakaryocytes clustered along BM sinuses and showed dysmorphic stretched features.
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- 2013
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11. Validation Of The Revised International Prognostic Scoring System (IPSS-R) In 1000 Newly Diagnosed MDS Patients With Low- and Intermediate-1 Risk MDS In The European Leukemianet MDS (EUMDS) Registry
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Swart, Louise de, Smith, Alex, Johnston, Tom, Haase, Detlef, Droste, Jackie, Fenaux, Pierre, Symeonidis, Argiris, Sanz, Guillermo, Hellström-Lindberg, Eva, Cermak, Jaroslav, Germing, Ulrich, Stauder, Reinhard, Georgescu, Otilia, MacKenzie, Marius, Malcovati, Luca, Holm, Mette Skov, Almeida, Antonio Medina, Madry, Krzysztof, Slama, Borhane, Guerci-Bresler, Agnès, Sanhes, Laurence, Beyne-Rauzy, Odile, Luño, Elisa, Bowen, David, and de Witte, Theo
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The EUMDS registry was initiated to provide an overview of the real-world demographics, diagnostics and disease-management of MDS. The first patient was registered in December 2007 and today 16 countries and 131 centers are participating. In 1997 the International Prognostic Scoring System (IPSS) was developed to predict clinical outcomes for patients with MDS and is still the most widely used prognostic scoring system. Recently, the IPSS has been revised (IPSS-R).
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- 2013
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12. Prognostic Relevance of the Kinetics of Worsening of Cytopenias in Lower-Risk MDS: A Substudy From the European Leukemianet Low Risk MDS (EUMDS) Registry
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Itzykson, Raphael, Smith, Alex, de Witte, Theo M., Droste, Jackie, Stauder, Reinhard, Symeonidis, Argyris, Hellstrom-Lindberg, Eva, Sanz, Guillermo, Cermak, Jaroslav, Georgescu, Otilia, Skov-Holm, Mette, Germing, Ulrich, MacKenzie, Marius, Beyne-Rauzy, Odile, Malcovati, Luca, Bowen, David, and Fenaux, Pierre
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Prognosis of lower (IPSS low/int-1) risk MDS is heterogeneous. Current prognostic systems rely on single time point cytopenia values (Hb level, ANC, PLT counts) at diagnosis (classical or revised IPSS [IPSS-R] Greenberg, Blood 2012) or during evolution (time-dependent IPSS/WPSS). Capturing the dynamics of continuous parameters can yield independent prognostic information as exemplified by lymphocyte time doubling in CLL. We analyzed the prognostic relevance of the kinetics of Hb, ANC and PLT in lower-risk MDS patients (pts) included in the prospective EUMDS registry.Among the first 1000 pts included in the EUMDS registry, those fulfilling the following criteria were analyzed here: a) IPSS low/int-1; b) ≥3 visits (planned every 6 months) with ≥12 months follow-up; c) not treated with hypomethylating agents, G-CSF, hydroxyurea or lenalidomide. Dynamics of Hb, ANC, and PLT were studied by deriving linear models of each variable for each pt. Only pts with ≥3 measures of Hb, ANC and PLT and with stable or worsening corresponding cytopenia (model slope ≤0) were considered in each analysis, regardless of the goodness of fit (R2) of models. Time (T) to lose 1 g/dL of Hb (THb), 1.0 x109/L of ANC (TANC) and 50 x109/L of PLT (TPLT) were derived with the formula: T ∼ 1/slope. All survival analyses were made from the date of registry entry to last follow-up, death, or progression to AML. Unless specified, survival analyses were Cox models using continuous variables accounting for interactions.530 pts met study inclusion criteria (M/F: 314/216, median age: 73y). WHO diagnosis was 5q- syndrome, RA, RARS, RCMD, RCMD-RS, RAEB-1 and MDS-U in 5, 21, 20, 38, 7, 8 and 2% respectively (resp). IPSS risk was low, int-1 and low/int-1 (cytogenetics not available) in 55%, 38% and 7% resp. At registry entry, median Hb, ANC and PLT were 10.4 g/dL, 2.4 x109/L and 187 x109/L resp. and 23% were RBC transfusion-dependent; 293 received an ESA. The median number of available blood counts was 4 (range 3–9).THb, TANC and TPLT could be determined because of a stable or worsening cytopenia (slope ≤0) in 250/508, 258/495 and 301/509 pts with ≥3 values. There was no significant correlation between the number of values available and the goodness-of-fit (R2) of linear models (all P>0.3). Median THb TANC and TPLT were 23.5 (interquartile range [IQR]: 42.2), 28.7 (IQR: 52.1) and 26.9 (IQR: 49.2) months respectively. Because these figures are derived from linear models, they can be simply rescaled by a proportional extrapolation for daily practice (eg. −1 x109/L ANC at 28.7 months = −0.41 x109/L [12/28.7] at 12 months).THb, TANC and TPLT were not correlated to age, cytogenetic risk, IPSS, IPSS-R or baseline simplified WPSS (Malcovati. Haematologica 2011; all P>0.2). TANC and TPLT (but not THb) were shorter in pts with baseline RBC transfusion dependence (P=.02 and .003, resp.).With a median follow-up of 20.9 months in the 530 pts, 19 patients have progressed (AML: 14, RAEB: 5) and 71 patients have died; 3-year estimates of overall (OS) and progression-free (PFS) survivals were 74.4% and 73.6%. All further analyses are shown for OS and give similar results for PFS. In univariate analysis, longer TANC (hazard ratio [HR] for 6-months increments: 0.88 [95% CI: 0.80–0.97], P=.008) and TPLT (HR: 0.01 [95% CI: 0.001–0.30], P=.007) but not THb (P=.07) were associated with prolonged OS. Pts with a ≥1 x109/L decrease in ANC in less than the median time of 28.7 months (N=129) had a 3-year OS of 66.3% [95% CI: 55.0–79.9%] vs 89.3% [79.7–100%]. Pts with a ≥50 x109/L decrease in PLT in less than the median of 26.9 months (N=151) had a 3-year OS of 59.4% [46.8–75.4%] vs 85.6% [77.5–94.6%] (Figure, both P<10−4). There was no significant difference in the cause of death between those subgroups. In multivariate analysis, the prognostic impact of TANC and TPLT remained independent of baseline IPSS (P=.006 and P=.01 resp.) or IPSS-R (both P=.01), and of simplified time-dependent WPSS (P=.004 and P=.03). A landmark analysis at 2 years, using only retrospective data to derive TANC and TPLT is planned.In lower-risk MDS with stable or worsening cytopenias, kinetics of decline can be approximated to be linear to allow easy prognostic use in clinical practice. Faster decline of ANC and to a lesser extent of PLT counts, but not of Hb level (possibly because of transfusions and use of ESA), is associated with shorter OS and PFS, independently of IPSS, IPSS-R and WPSS.Germing: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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- 2012
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13. Early Mortality in 1000 Newly Diagnosed MDS Patients with Low- and Intermediate-1 Risk MDS in the European Leukemianet MDS (EUMDS) Registry
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de Swart, Louise, Smith, Alex, Fenaux, Pierre, Sanz, Guillermo, Hellstrom-Lindberg, Eva, Symeonidis, Argyris, Cermak, Jaroslav, Germing, Ulrich, Stauder, Reinhard, Georgescu, Otilia, MacKenzie, Marius, Malcovati, Luca, Holm, Mette Skov, Madry, Krzysztof, Park, Sophie, Beyne-Rauzy, Odile, Droste, Jackie, Bowen, David, and de Witte, Theo
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The EUMDS registry was established to obtain an overview in the real world MDS demographics, diagnostics and disease-management. From April 2008 until December 2010, 1000 newly diagnosed patients with IPSS low and int-1 risk MDS were included in 14 countries and 118 participating centers. The major clinical problems in MDS are the consequences of cytopenias and disease-progression. Therefore, the most important treatment goals are improvement of cytopenias and prevention of leukemia.To describe the causes of early mortality and to analyze the outcome of the first 1000 patients in the registry with and without disease-progression at 24 months follow-up.The median age of the population was 74 years (range 18–95), 60% were male. The most frequent co-morbidities were hypertension (46%), diabetes mellitus (18%), arrhythmias (12%), and thyroid diseases (12%). The WHO subgroups are RCMD (39%), RA (19%), RARS (17%), RAEB-1 (13%), RCMD-RS (7%), MDS-U (3%), and del5q (2%). IPSS score (n=935) was 0 in 48%, 0.5 in 31% and 1 in 14% of the patients. WPSS score (n=924) was Very Low in 32%, Low in 38%, Intermediate in 19% and High in 4% of the patients (Table1). 184 of 1000 patients (18%) had started MDS specific treatment within 3 months after diagnosis: this increased to 43% at 24 months of follow-up. 15% of the patients (in 12 of the 14 countries) started ESA treatment at registration and this increased to 31% at 24 months, combined with G-CSF in 7%. At registration, 29% of the patients had received at least one RBC transfusion with a mean pre-transfusion Hb level of 8 g/dL. The percentage of transfusion-dependent (TD) patients remained stable during follow-up with 31%, 29%, 26% and 29% at 6, 12, 18, 24 months of follow-up, respectively. At 24 months, overall survival (OS) is 83%. Median time from date of inclusion until progression to higher risk MDS or leukemia is 293 days. Most patients (123) have died without disease-progression (DP) versus 45 patients who have died after DP at 24 months (Table1). DP has been defined as an increase in bone marrow blasts to a higher WHO category. The main causes of death in patients without DP were infections (21%) and cardiovascular events (11%). The mortality rate in transfusion-independent (TI) and TD patients without DP was 5% and 24%, respectively. In TI and TD patients with DP, the mortality rate was 32% and 66%, respectively (Table1; Graph 1). To define the prognostic relevance of serum ferritin (SF) and TD, the SF levels divided in two groups (1. <1000 μg/L, 2. ≥1000 μg/L) were compared in TI and TD patients and stratified by disease-progression. The mortality rate according to SF at registration in TI patients without DP was 9% and 13%, respectively (HR 1.61, 95%CI 0.49–5.37). The mortality rate according to SF at registration in TD patients without DP was 21% and 56%, respectively (HR 4.79, 95%CI 2.56–8.96) (Table 1).The great majority of deceased lower risk MDS patients have died before they have developed clinical signs of disease-progression. Transfusion-dependent patients without disease-progression have a four times higher mortality rate than transfusion-independent patients. This indicates that the pathophysiology of cytopenias and related complications are a major point of interest in early mortality, especially in patients without disease-progression.No relevant conflicts of interest to declare.
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- 2012
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14. Transfusion-Dependency Is the Most Important Prognostic Factor for Survival in 1000 Newly Diagnosed MDS Patients with Low- and Intermediate-1 Risk MDS in the European LeukemiaNet MDS Registry
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de Swart, Louise, Smith, Alex, Fenaux, Pierre, Bowen, David, Sanz, Guillermo, Hellström-Lindberg, Eva, Symeonidis, Argyris, Cermak, Jaroslav, Germing, Ulrich, Stauder, Reinhard, Georgescu, Otilia, MacKenzie, Marius, Malcovati, Luca, Holm, Mette Skov, Park, Sophie, Beyne-Rauzy, Odile, Droste, Jackie, and de Witte, Theo
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The ELN EUMDS registry collects information about demographics and disease-management of newly diagnosed low- and intermediate-1 risk MDS patients.To define the prognostic impact of transfusion-dependency and serum ferritin levels.From April 2008 until December 2010, 1000 patients have been registered in fourteen European countries. The median age is 74 years (range 18–95), 60% are male. The WHO subgroups are RCMD (35.8%), RARS (18.2%), RA (17.6%), RAEB-1 (11.6%), del5q (6.2%), MDS-U (3.1%) and RAEB-2 (0.4%). IPSS score (n=935) is 0 in 48.8%, 0.5 in 31.2% and 1 in 13.5%. At time of registration 19% of the patients had started MDS specific treatment, increasing to 46% at 18 months of follow-up, usually consisting of erythroid-stimulating agents (ESA). At registration 29% of the patients were transfusion-dependent, which remained stable during follow-up. The number of transfusion-dependent patients with ESA treatment decreased from 58% to 27% at 18 months of follow-up.Overall survival at 18 months of follow-up was 89%. The mortality rate in transfusion-independent and transfusion-dependent patients at 18 months of follow-up was 5% and 21%, respectively (P<0.0001). Prognostic value of the IPSS score was confirmed with Cox regression analysis: the hazard ratio (HR) with IPSS score 0.5 was 2.20 (95% Confidence Intervals (CI); 1.40–3.48) and with IPSS score 1.0 was 3.08 (95% CI; 1.78–5.31) respectively, adjusted for age, sex, country and WHO category. For overall survival based on ferritin status, patients were divided in three groups according to their ferritin levels, based on expected clinical significance; group 1. ≤300 μg/L, group 2. >300 <1000 μg/L and group 3. ≥1000 μg/L. The mortality rate according to serum ferritin at registration in these groups was 6%, 14% and 23%, respectively, with HRs 1.80 (95%CI 1.06–3.03) and 3.21 (95% CI 1.66–6.20), including adjustment for transfusion status and number of transfusions. To define the relationship between serum ferritin and transfusion-dependency, the serum ferritin levels in the three groups were compared in transfusion-independent and transfusion-dependent patients. The mortality rate according to serum ferritin at registration in transfusion-independent patients was 3%, 6% and 3%, respectively (HR 2.17 and 0.95 respectively). The mortality rate according to serum ferritin at registration in transfusion-dependent patients was 14%, 21% and 35%, respectively (HR 1.69 and 3.93 respectively) (Table 1; Graph 1). To define the prognostic value of transfusion burden, patients were divided in groups based on transfusion status: 1. No transfusions, 2. Transfusions <20 units, 3. Transfusion >20 units. The mortality rate in these groups was 5%, 18% and 30%, respectively. The adjusted HRs were 3.67 (95% CI; 2.28–5.91) and 5.50 (95% CI; 3.18–9.52), respectively (Table 1).After 18 months of follow-up serum ferritin levels appear to be an important prognostic factor for transfusion-dependent patients only. However, transfusion burden is the most important prognostic factor for survival in patients with more than 20 units transfused compared to non-transfused patients. An increased risk was also apparent for moderately transfused patients (<20 units) so direct toxicity of transfusions (toxic iron radicals?), even at a relatively low iron load, might have an important adverse impact on survival.Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Germing:Celgene: Consultancy, Research Funding.
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- 2011
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15. Disease-Management of Low- and Intermediate-1 Risk Myelodysplastic Syndromes: Report on 800 Newly Diagnosed MDS Patients From the European LeukemiaNet MDS Registry
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de Swart, Louise, Smith, Alex, Fenaux, Pierre, Symeonidis, Argyris, Hellström-Lindberg, Eva, Sanz, Guillermo, Cermak, Jaroslav, Georgescu, Otilia, Germing, Ulrich, MacKenzie, Marius, Beyne-Rauzy, Odile, Malcovati, Luca, Stauder, Reinhard, Droste, Jackie, Bowen, David, and de Witte, Theo
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The European LeukemiaNet MDS (EUMDS) registry is designed to collect information about the demographics and disease-management of newly diagnosed low-risk and intermediate-1 risk MDS patients. From April 2008 until July 2010, 828 patients have been registered in eleven participating countries through a web-based reporting system.This report describes the disease-management of the first 800 registered patients, including transfusion-related issues like secondary iron overload and its treatment.159 of 800 patients (20%) started MDS specific treatment within three months before registration; this percentage increased to 50% at 18 months of follow-up. Most patients received erythroid-stimulating agents (ESA), like erythropoietin (Table 1). In patients with a clinical indication for ESA, the percentage of transfusion-independency was similar to the transfusion-independent group without indication for ESA at 18 months of follow-up (Table 1). Overall, 27% of the patients received blood transfusions at registration. This percentage remained stable during follow-up, probably due to the therapeutic effect of ESA (Table 1). The number of units transfused, per 6 months, in these patients increased from 5 to 13 units at 18 months of follow-up, with a mean pre-transfusion Hb level of 7.6 g/dL. The serum ferritin levels of the transfusion-dependent patients at registration were available in 159 patients. The serum ferritin level at registration was ≥2000 μg/L in 4% of the patients who received a mean number of 10 units (SD 7). This increased to 28% of the patients who received a mean number of 20 units (SD 11) at 18 months of follow-up. The percentage of patients on iron chelation therapy increased from 1% to 9% during follow-up (Table 1). In these patients the mean serum ferritin levels remained stable: 1913 μg/L (SD 1183) at registration and 1626 μg/L (SD 1232) at 18 months of follow-up. In contrast, transfusion-dependent patients not treated with iron chelation or ESA had increasing ferritin levels, with a mean ferritin of 630 μg/L (SD 597) at registration and 1586 μg/L (SD 1017) at 18 months of follow-up. 37 patients (5%) progressed to high-risk MDS or acute myeloblastic leukemia at a median of 155 days from registration. 62 patients (8%) have died within a median of 269 days from registration, 32 deaths were MDS related. The overall survival was 93% at 18 months of follow-up, with a progression-free survival of 90%. Differences in overall survival between transfusion-independent and transfusion-dependent patients were significant: 97% versus 85%, respectively (p<0.0001; Table 2). In the multivariate analysis transfusion-dependency, ferritin levels and IPSS score predicted survival (Table 2). The IPSS score had a significant prognostic impact on overall survival and progression-free survival in contrast to the WHO classification (Data not shown).Despite a high transfusion load the mean serum ferritin levels remained stable during treatment with iron chelation. Transfusion-dependent patients had a worse overall survival and progression-free survival with higher ferritin levels and higher IPSS score as compared to transfusion-independent patients. This report demonstrates the importance of detailed disease-management in low- and intermediate-1 risk MDS patients.Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Bowen:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Honoraria; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding.
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- 2010
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16. The Population-Based ‘real world’ of Low Risk Myelodysplastic Syndromes; Second Interim Analysis of the European LeukemiaNet MDS Registry at 800 Registered New Patients
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Bowen, David, Smith, Alex, Droste, Jackie, Fenaux, Pierre, Symeonidis, Argyris, Hellstrom-Lindberg, Eva, Sanz, Guillermo F, Cermak, Jaroslav, Georgescu, Otilia, Germing, Ulrich, MacKenzie, Marius, Stauder, Reinhard, Beyne-Rauzy, Odile, Malcovati, Luca, and de Witte, Theo
- Abstract
The European LeukemiaNet MDS Registry programme is the largest and most comprehensive prospective population-based registry of ‘low-risk’ MDS patients followed from diagnosis.The primary objective of this study is to describe the demographics and the disease-management of newly diagnosed MDS patients within IPSS low and intermediate-1 categories.The project recruits patients from 107 sites in 11 countries, ranging from 2–25 sites per country and including a high proportion of non-University centres in small cities. Consecutive eligible adult patients are registered within 3 months of diagnosis. Local diagnosis is accepted and a large dataset is collected including laboratory data, clinical information (including co-morbidity and concomitant medication) plus health utility (EQ-5D). Data are entered via a web portal and are source verified by study monitoring visits to sites.As of July 2010, 828 patients are registered; data are presented for the first 800 patients. Recruitment is highest from France (n=237) then UK (104), Greece (99), Spain (92), and Sweden (73). Median age is 74.2 yrs (range 18.7–95.3) and from the four largest recruiting countries is 74.6–77.1 yrs. Sixty one percent of patients are male. Twenty patients are non-Caucasian (n=763). Body mass index is overweight (WHO definition) in 43.4% pts and obese in 18.3%, comparable to WHO data for the general adult population (http://apps.who.int/bmi/index.jsp). RCMD is the largest WHO subgroup (34%), followed by RARS (19%), RA (18.4%), RAEB-1 (12.5%), del5q (5.4%), MDS-U (3.5%) and RAEB-2 (0.5%). All WHO subgroups have male predominance except del5q with a striking female excess (79%). IPSS score (n=743) is 0 (52.3%), 0.5 (33.2%), and 1 (14.4%). 84.5% patients have IPSS ‘good’ cytogenetics. 19% patients have 0 cytopenias, 53% 1 cytopenia, 20% 2 cytopenias and 8% 3 cytopenias. WPSS category (with transfusion dependence assessed at time of registration, n=727) is Very Low (35.5%), Low (39.5%), Intermediate (21%), High (4%). Bone marrow features: mean no. of dysplastic lineages = 1.9, bone marrow ring sideroblasts percent = 0 (60% pts), <15 (11.5%), ≥15<50 (19.2%), ≥50 (9.6%). Median haemoglobin (Hb) concentration at presentation is 10.1 g/dl; 36% values were < 10 g/dl and 10% < 8 g/dl. Hb decreased with age (categorical variable Hb. <13>11.5, <11.5>10, <10; Χ2 test, P<.0001). Mean neutrophil count was 2.8 × 109/l with 27% values <1.5 × 109/l, 16% < 1 × 109/l, and 5% < 0.5 × 109/l. Median platelet count was 184 × 109/l; 5% patients had values < 50 × 109/l and 3% < 20 × 109/l. Platelet count and neutrophil count did not change with age. Median serum erythropoietin (EPO) concentration (n=418) was 49 IU/l, 81% values were <200 IU/l and 7% > 500 IU/l. Mean creatinine clearance was 71 mls/min with a marked reduction with age (P<.0001). Baseline serum EPO correlated with Hb. (r=.37, P<.0001), creatinine clearance (r=.22, P<.0001) and age (r=.1, P<.0001). The relationship between creatinine clearance, baseline EPO and response to EPO therapy will be explored.This registry records data from the ‘real world’, namely what the hematopathologists in 100 sites diagnose locally as low-risk MDS and will as such be managed as MDS. Median age is consistent with other population-based data (US Medicare, Yorkshire Haematological Malignancy Research Network [www.hmrn.org]). In comparison with registries from specialist MDS centres, median age is higher and a lower proportion have del(5q) WHO subtype.The ELN registry clearly maps the diagnosis and management of low-risk MDS in routine clinical practice in hospitals large and small, specialist and non-specialist and is a unique resource.The Steering Committee (SC) acknowledges the commitment and enthusiasm from all 107 sites contributing high quality data to the project. The SC is also grateful for the funding commitment of Novartis Oncology Europe through the University of Nijmegen.Bowen: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Honoraria; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Hellstrom-Lindberg:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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- 2010
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17. Health-Related Quality of Life In Newly Diagnosed Low Risk and Intermediate-1 Risk MDS: Report on the First 683 Patients From the European LeukemiaNet Registry
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Stauder, Reinhard, Smith, Alex, Witte, Theo de, Droste, Jackie, Fenaux, Pierre, Symeonidis, Argyris, Hellstrom-Lindberg, Eva, Sanz, Guillermo F, Cermak, Jaroslav, Georgescu, Otilia, Germing, Ulrich, MacKenzie, Marius, Beyne-Rauzy, Odile, Malcovati, Luca, and Bowen, David
- Abstract
Stauder: Celgene: Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Hellstrom-Lindberg:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bowen:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Honoraria; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding.
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- 2010
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18. European Registry for Low Risk and Intermediate-1 Risk MDS: Base Line Report On First 400 Registered Patients.
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de Witte, T. M., Smith, Alex, Droste, Jackie, Fenaux, Pierre, Symeonidis, Argyris, Hellstrom-Lindberg, Eva, Sanz, Guillermo, Cermak, Jaroslav, Georgescu, Otilia, Germing, Ulrich, MacKenzie, Marius, Stauder, Reinhard, Rauzy, Odile Beyne, and Bowen, David T.
- Abstract
The European LeukemiaNet has initiated a prospective, noninterventional registration study on newly diagnosed MDS patients with IPSS low and intermediate-1 risk in eleven participating European countries. The main objectives are to describe demographics and to collect data on clinical characteristics, disease management and relevant outcomes.The registry started accruing patients in April 2008. Until now 478 patients have been registered through a web-based reporting system. This report describes the demographic data of the first 400 registered patients with a median follow up of 177 days.The median age of the patients was 74 years. RAEB-1 was the WHO-diagnosis in 13% of the patients while the remaining patients had < 5% marrow blasts (RA: 81; RARS: 84; RCMD: 114; RCMD-RS: 26, MDS-U: 16; del(5q): 27). The majority of patients were males 250/400 except within WHO del(5q) which showed a female preponderance 21/27. Cytogenetic data were available in 93% of the patients and 77% had good risk cytogenetic characteristics. IPPS score was 0 in 50% of the patients, 0.5 in 28% patients and 1 point in 15% of the patients. The Karnofsky performance score was reported in 85% of the patients. The Karnofsky index was related to age (p<0.001) and was <80 in 20% of the patients. The EQ 5D status was reported in 82% of the patients. The median EQ 5D score was 70 (4 to 100) and ranged from 50 (40 to 80) in Austria to 87 (50 to 100) in Greece. The mean Sorror Score of Co-morbidity was 2.4 (2.0) and ranged from 1.4 (s.d.1.6) in Greece to 3.0 (s.d 1.8) in France. Cardiac disease was reported in 28% of the patients, pulmonary disease in 13%, diabetes mellitus in 16%, and thyroid disease in 12% of the patients. The Body mass Index was available in 73% of the patients. Overweight (BMI>25) was present in 60% of the reported patients. The median Erythropoietin level (N = 219) was 42 iU/l (3.5 to 2100). The iron status at diagnosis was available in 241 patients. The median serum iron level (N = 240) was 10 mmol/l (range: 3 to 57) with a median transferrin saturation level 39% (N = 107), ranging from 17% in MDS-U to 53% in RARS. The median ferritin level was 341 mg/l (n=289) ranging from 121 mg/l in del(5q) to 577 mg/l in RARS. 37% of the patients received MDS specific treatment, principally erythropoietin (31%) and G-CSF (4%). 27% of the patients received transfusions at registration, ranging from 17% in Greece to 56% in the Netherlands. As expected only 12 patients (3%) received iron chelation therapy in this early phase after diagnosis. The mean ferritin level of these patients was 1638 mg/l. Thirteen patients progressed to high-risk MDS or AML after a median time of 154 days. Sixteen patients have died (9 patients due to non-MDS related causes) after a median of 175 days after diagnosis. In conclusion this European registry shows that is possible to collect detailed demographic data in eleven different countries. The preliminary data show demographic differences. This registry will show the impact of various demographic and clinical variables including socio-economic co-morbidity and health utility variables on the outcome of patients with low-risk MDS.Fenaux: Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Epicept: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Merck: Honoraria, Research Funding. Hellstrom-Lindberg:Celgene Corp.: Research Funding. Stauder:Celgene: Research Funding.
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- 2009
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19. Intra-Follicular Proliferation Rate Is a Powerful Independent Prognosticator in Follicular Lymphoma.
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Koster, Ad, Tromp, Hedwig A., Raemaekers, John M., Borm, George F., MacKenzie, Marius A., and Van Krieken, Joannes H.J.M.
- Abstract
Several prognostic scores are used to predict the outcome of patients with follicular lymphoma (FL). Histologic grading is widely used, but poorly reproducible. Scoring systems such as the (FL)IPI consist of surrogate clinical markers that probably reflect underlying biological phenomena. We hypothesized that the proliferation rate of the intra-follicular neoplastic cells in FL may predict clinical outcome. Proliferating cells were identified by using the Mib-1 antibody in pre-treatment lymph node biopsies of 51 patients. In each section 200 cells per follicle were assessed in five follicles. The proliferation ratio (PR) was defined as (no. of Mib-1 positive cells/ total no. of cells) x 100. The PR was assessed only in the follicles, since many proliferating, non-malignant cells are present in the inter-follicular area. The inter-observer variability was assessed by repeating this procedure for 25 cases by a second investigator blinded to the outcome of the first assessment, resulting in a correlation coefficient of 0.81 (p < 0.001). All patients participated in a prospective multicenter trial on first-line treatment with the combination of 8 cycles of CVP (cyclophosphamide, vincristine and prednisone) chemotherapy plus interferon-alpha2b, followed by interferon-alpha maintenance in responding patients until relapse or progression. For statistical analysis the Kaplan-Meier product limit method, the log-rank test, the Cox proportional hazard model and the Mann-Whitney-U test were used. The median age of the patients was 53.3 years; 37 patients had stage IV disease; in nine patients a wait and see interval preceded the treatment (median duration 13 months). A low IPI score was present in 27 patients, intermediate in 20 and high in one. (three patients unknown). After central revision of the original diagnosis six patients were classified as grade 3 FL, 45 as grade 1 or 2. The overall median PR was 16.9 (3.1–49.2). In grade 1 and 2 FL the median PR was 16.1, in grade 3 it was 24.2 (p = 0.02). After a median follow-up of 71 months the median progression-free survival (PFS) for all patients was 25 months. The median PFS was not reached in the patients with the PR below the median compared to only 15 months in the patients with the PR above the median (p = 0.00059). In patients with the PR below median, overall survival was not reached compared to only 42 months in patients with a high PR (p = 0.0019). The PR maintained its prognostic impact on PFS and OS when tested as a continuous variable (p = 0.016 and 0.053 resp.). When the six patients with grade 3 FL were excluded from the analysis, the results remained significant. Other parameters that were significantly associated with a worse OS in univariate analysis were male sex, the presence of bulky disease and intermediate or high IPI. In multivariate analysis the association of high PR with a worse OS remained significant. We found that in FL intra-follicular proliferation rate is a strong independent prognostic factor of PFS and OS. Grade 3 FL appeared to have a higher PR than low grade FL, although numbers are small in this study. PR assessment is easy, relatively fast and reproducible. When confirmed in larger series, the intra-follicular PR could be used instead of histologic grading in identifying the aggressive types of follicular lymphoma, requiring other types of treatment.
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- 2004
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20. Neuropsychiatric symptoms during cefepime treatment
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Diemont, Willem, MacKenzie, Marius, Sxhaap, Nicolaas, Goverde, Gerard, van Heereveld, Hedwig, Hekster, Yechiel, and van Grootheest, Kees
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- 2001
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