Rob Fijnheer

Meander Medisch Centrum, Amersfoort, Utrecht, Netherlands

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Publications (154)678.87 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine the incidence of diffusely increased bone marrow (18) F-fluoro-2-deoxy-D-glucose (FDG) uptake at positron emission tomography (PET) in recently untreated lymphoma, and to assess the frequency of lymphoma-positive bone marrow biopsies (BMBs) in these patients. FDG-PET scans of all patients presenting with newly diagnosed or relapsed lymphoma were reviewed. Patients with non-focal, diffusely increased bone marrow FDG uptake, who had not received therapy within three months, were identified. The incidences of diffusely increased bone marrow FDG uptake, and the frequencies of positive posterior iliac crest BMBs among those cases were calculated. The incidences of diffusely increased bone marrow FDG uptake in all lymphomas, and in Hodgkin lymphoma, aggressive non-Hodgkin lymphoma (NHL), indolent NHL, and mantle cell NHL separately, were 4.2% (23/542), 9.3% (7/75), 3.4% (8/239), 3.3% (7/214), and 7.1% (1/14), respectively, and frequencies of positive BMBs among these subgroups were 55.0% (11/20), 0.0% (0/7), 83.3% (5/6), 83.3% (5/6), and 100% (1/1), respectively. The incidence of diffusely increased bone marrow FDG uptake in recently untreated lymphoma is low, albeit higher in Hodgkin lymphoma than in NHL. BMB in such patients is likely to be negative in Hodgkin lymphoma, but positive in the majority of NHL cases. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 12/2014; · 2.41 Impact Factor
  • American Journal of Hematology 12/2014; · 3.48 Impact Factor
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    ABSTRACT: To determine the prognostic value of tumor necrosis at computed tomography (CT) in newly diagnosed diffuse large B-cell lymphoma (DLBCL).
    European Journal of Radiology 12/2014; · 2.16 Impact Factor
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    ABSTRACT: Detection of bone marrow involvement using 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) has been proposed as a non-invasive alternative to standard blind bone marrow biopsy (BMB) of the posterior iliac crest in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). However, studies that directly compare FDG-PET/CT results with histopathology are currently lacking.
    Acta Radiologica 11/2014; · 1.35 Impact Factor
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    ABSTRACT: To directly compare visual and quantitative (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) to bone marrow biopsy (BMB) findings in the right posterior iliac crest in patients with newly diagnosed Hodgkin lymphoma.
    Annals of Nuclear Medicine 10/2014; · 1.51 Impact Factor
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    ABSTRACT: PurposeThis study aimed to determine the prognostic value of whole-body maximum standardized uptake value (SUVmax), whole-body metabolic tumor volume (MTV), and whole-body total lesion glycolysis (TLG) at pretreatment 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL).Materials and Methods73 patients with newly diagnosed DLBCL who had undergone FDG-PET/CT before rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (R-CHOP) immunochemotherapy were retrospectively included. All FDG-avid lesions in each patient were segmented using semi-automated software in order to calculate whole-body SUVmax, whole-body MTV, and whole-body TLG values. Cox regression analyses were used to determine the associations of whole-body SUVmax, whole-body MTV, whole-body TLG, and dichotomized National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) risk group (low risk vs. high risk) with progression-free survival (PFS) and overall survival (OS).ResultsOn univariate Cox regression analysis, only the NCCN-IPI was a significant predictor of PFS (P=0.024), and only the NCCN-IPI and whole-body MTV were significant predictors of OS (P=0.039 and P=0.043, respectively). In the multivariate Cox proportional hazards model, only the NCCN-IPI remained an independent predictive factor of PFS (P=0.024) and OS (P=0.039).Conclusion Whole-body SUVmax, whole-body MTV, and whole-body TLG do not provide any prognostic information in DLBCL beyond that which can already be obtained by the NCCN-IPI. Therefore, the NCCN-IPI remains the most important prognostic tool in this disease.This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 10/2014; · 2.41 Impact Factor
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    ABSTRACT: Purpose. To determine the additional value of bone marrow biopsy (BMB) in the standard staging work-up of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), in terms of risk assessment and treatment planning. Material and methods. A total of 113 consecutive patients with newly diagnosed DLBCL who had undergone standard pretreatment evaluation, including serum lactate dehydrogenase measurement, Eastern Cooperative Oncology Group performance status assessment, computed tomography or (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography, and BMB, were retrospectively included. National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) score and treatment strategy were determined in each patient, once without and once with taking into account BMB results. Numbers and percentages of BMB-induced changes on NCCN-IPI-based risk stratification (i.e. formation of low, low-intermediate, high-intermediate, and high risk groups) and choice of treatment were calculated, along with 95% confidence intervals (CIs). Results. BMB was positive in 18 of 113 patients (15.9%, 95% CI 10.2-23.9 %). BMB-induced changes on NCCI-IPI-based risk stratification occurred in 9 of 113 patients (8.0%, 95% CI 4.1-14.6%). Five patients were upstaged from low-intermediate to high-intermediate risk, and four patients were upstaged from high-intermediate to high risk. BMB findings changed treatment planning in none of the 113 patients (0.0%, 95% CI 0.0-4.0%). Conclusion. Although BMB results upstaged the NCCN-IPI-based risk stratification in a small number of cases, this did not have any therapeutic implications in our patient series. These findings support the omission of BMB from routine staging of newly diagnosed DLBCL in the current risk stratification and treatment era.
    Acta oncologica (Stockholm, Sweden) 09/2014; · 2.27 Impact Factor
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    ABSTRACT: Platelets are key cells in atherosclerosis and acute cardiovascular events. Platelet hyperreactivity and increased platelet-monocyte aggregation (PMA) are found in HIV-infected patients and may contribute to the excess cardiovascular risk. The integrase inhibitor raltegravir (RAL) has been associated with better residual viral suppression and reduction in inflammatory and coagulation biomarkers. The aim of our study was to investigate whether RAL-treated patients have reduced platelet reactivity and PMA.
    AIDS (London, England) 09/2014; 28(14):2091-2096. · 6.56 Impact Factor
  • Hematological Oncology 09/2014; · 2.36 Impact Factor
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    ABSTRACT: The majority of the patients affected by acquired thrombotic thrombocytopenic purpura (TTP) develop autoantibodies directed towards ADAMTS13 that interfere with its von Willebrand Factor (VWF) processing activity. B cell responses have been shown to primarily target the spacer domain of ADAMTS13 thereby prohibiting the binding of ADAMTS13 to VWF A2 domain. In this review we summarize recent knowledge gained on the immune recognition and processing of ADAMTS13 by antigen-presenting cells (APCs). HLA-DRB1*11 has been identified as a risk factor for acquired TTP. Analysis of MHC class II/peptide complexes of ADAMTS13 pulsed dendritic cells have shown that the CUB2 domain derived peptide FINVAPHAR is preferentially presented on HLA-DRB1*11. Based on these findings we propose a model for the initiation of the autoimmune reactivity against ADAMTS13 in previously healthy individuals. We hypothesize that mimicry between a pathogen-derived peptide and the CUB2 derived FINVAPHAR-peptide might contribute to the onset of acquired TTP.
    Blood Reviews 08/2014; · 5.45 Impact Factor
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    ABSTRACT: To determine the value of visual and quantitative (18) F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) for the detection of bone marrow involvement in follicular lymphoma, using direct histopathological examination at the right posterior iliac crest as reference standard.
    Skeletal Radiology 06/2014; · 1.74 Impact Factor
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    ABSTRACT: Acquired deficiency of ADAMTS13 causes a rare and life-threatening disorder called thrombotic thrombocytopenic purpura (TTP). Several studies have shown that aberrant glycosylation can play an important role in the pathogenesis of autoimmune diseases.N-linked glycosylation and putative O-fucosylation sites have been predicted or identified in recombinant ADAMTS13. However, it is not known which of these sites are glycosylated in plasma derived ADAMTS13.
    Journal of thrombosis and haemostasis : JTH. 05/2014; 12(5):670-9.
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    ABSTRACT: Severe dengue is characterised by thrombocytopenia, plasma leakage and bleeding. Platelets are important for preservation of endothelial integrity. We hypothesised that platelet activation with secondary platelet dysfunction contribute to plasma leakage. In adult Indonesian patients with acute dengue, we measured platelet activation status and the response to the platelet agonist TRAP using flow cytometer-based assays. Patients were monitored daily for plasma leakage by ultrasonography. Acute dengue was associated with platelet activation with an increased expression of the activated fibrinogen receptor (αIIbβ3), the lysosomal marker CD63 and the alpha-granule marker CD62P (P-selectin). Upon maximal platelet activation by TRAP, platelet function defects were observed with a significantly reduced maximal activated αIIbβ3 and CD63 expression and reduced platelet-monocyte and platelet-neutrophil complexes. Patients in the lowest tertile of activated αIIbβ3 and CD63 expression had an odds ratio for plasma leakage of 5.2 (95% confidence interval [CI] 1.3-22.7) and 3.9 (95% CI 1.1-13.7), respectively, compared to the highest tertile. Platelet-derived serotonin has previously been related to plasma leakage and we found increased intra-platelet serotonin concentrations in our patients. In conclusion, platelet activation with platelet function alterations can be found in patients with acute dengue and this may contribute to dengue-associated plasma leakage.
    Thrombosis and Haemostasis 04/2014; 112(2). · 5.76 Impact Factor
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    ABSTRACT: This study aimed to investigate whether visual and quantitative 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT)-based bone marrow assessment can replace blind bone marrow biopsy (BMB) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). This retrospective study included 78 patients with newly diagnosed DLBCL who had undergone both FDG-PET/CT and BMB. FDG-PET/CT images were visually evaluated for bone marrow involvement. Patient-based sensitivity of visual FDG-PET/CT assessment was calculated using BMB as reference standard. Metabolically active volume (MAV), maximum standardized uptake value (SUVmax), 3D partial volume corrected mean standardized uptake value (cSUVmean), and 3D partial volume corrected mean metabolic volume product (cMVPmean) of FDG-avid bone marrow lesions were measured. Cox regression analysis was used to determine the influence of (potential) prognostic factors (BMB status, visual [dichotomous] FDG-PET/CT bone marrow status, MAV, SUVmax, cSUVmean, cMVPmean, and International Prognostic Index score) on progression-free survival (PFS) and overall survival (OS). FDG-PET/CT detected bone marrow involvement in 34 (43.6%) cases and BMB in 16 of 78 cases (20.5), of whom 11 were also detected by FDG-PET/CT, resulting in a patient-based sensitivity of 68.8% (95% confidence interval [CI] = 44.2-86.1%) for FDG-PET/CT. In the multivariate Cox proportional hazards model, only BMB status was an independent predictive factor of PFS (P=0.016) and OS (P= P=0.004). In conclusion, FDG-PET/CT misses bone marrow involvement that has been detected by BMB in a non-negligible proportion of patients. Furthermore, both visual and quantitative FDG-PET/CT based bone marrow assessment are prognostically inferior to BMB. Therefore, FDG-PET/CT cannot replace BMB in newly diagnosed DLBCL.
    American Journal of Hematology 04/2014; · 3.48 Impact Factor
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    ABSTRACT: To determine whether full-dose contrast-enhanced computed tomography (CT) (CECT) can be omitted from an F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) (FDG-PET)/CT staging examination in newly diagnosed FDG-avid lymphoma. Twenty-nine patients with newly diagnosed FDG-avid lymphoma prospectively underwent unenhanced low-dose FDG-PET/CT and CECT. Different observers evaluated unenhanced low-dose FDG-PET/CT and CECT in a blinded manner. Ann Arbor stages according to unenhanced low-dose FDG-PET/CT and CECT were compared, and discrepancies between the 2 imaging modalities were resolved using bone marrow biopsy and posttreatment FDG-PET/CT as reference standard. Finally, it was assessed as to how many cases therapy would have been changed based on additional CECT findings. In 27 of 29 patients (93%; 95% confidence interval, 78%-98%), CECT either did not change or did not correctly change the Ann Arbor stage that was assigned according to unenhanced low-dose FDG-PET findings. In 2 of 29 patients (7%; 95% confidence interval, 2%-22%), CECT correctly provided another Ann Arbor stage than unenhanced low-dose FDG-PET/CT. In the latter 2 cases, therapy would not have been changed based on additional CECT findings. Unenhanced low-dose FDG-PET/CT alone is suggested as the primary imaging modality of choice for staging patients with newly diagnosed FDG-avid lymphoma. This diagnostic approach is particularly indicated in younger patients in whom diagnostic radiation exposure should be minimized and in patients who are at increased risk of CT contrast-induced allergic reactions or nephropathy.
    Journal of computer assisted tomography 03/2014; · 1.38 Impact Factor
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    ABSTRACT: Von Willebrand factor (VWF) multimer size is controlled through continuous proteolysis by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type I motif, member 13). This prevents spontaneous platelet agglutination and microvascular obstructions. ADAMTS13 deficiency is associated with thrombotic thrombocytopenic purpura (TTP), where life-threatening episodes of microangiopathy damage kidneys, heart and brain. Enigmatically, a complete ADAMTS13 deficiency does not lead to continuous microangiopathy. We hypothesized that plasmin, the key enzyme of the fibrinolytic system, serves as a physiological backup enzyme for ADAMTS13 in the degradation of pathological platelet-VWF complexes. Using real-time microscopy, we determined that plasmin rapidly degrades platelet-VWF complexes on endothelial cells in absence of ADAMTS13, after activation by urokinase plasminogen activator (uPA) or the thrombolytic agent streptokinase. Similarly, plasmin degrades platelet-VWF complexes in platelet agglutination studies. Plasminogen directly binds to VWF and its A1 domain in a lysine-dependent manner, as determined by enzyme-linked immunosorbent assay. Plasma levels of plasmin-α2-antiplasmin (PAP)-complexes increase with the extent of thrombocytopenia in patients with acute TTP episodes, independent of ADAMTS13 activity. This indicates that plasminogen activation takes place during microangiopathy. Finally, we show that the thrombolytic agent streptokinase has therapeutic value for Adamts13(-/-) mice in a model for TTP. We propose that plasminogen activation on endothelial cells acts as a natural backup for ADAMTS13 to degrade obstructive platelet-VWF complexes. Our findings indicate that thrombolytic agents may have therapeutic value in the treatment of microangiopathies and may be useful to bypass inhibitory antibodies against ADAMTS13 that cause TTP.
    Circulation 03/2014; 129:1320-1331. · 14.95 Impact Factor
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    ABSTRACT: BACKGROUND: Acquired deficiency of ADAMTS13 causes a rare and life-threatening disorder called thrombotic thrombocytopenic purpura (TTP). Several studies have shown that aberrant glycosylation can play an important role in the pathogenesis of autoimmune diseases.N-linked glycosylation and putative O-fucosylation sites have been predicted or identified in recombinant ADAMTS13. However, it is not known which of these sites are glycosylated in plasma derived ADAMTS13. OBJECTIVES: Here we investigated the presence of putative O-fucosylation, C-mannosylation and N-linked glycosylation sites on plasma derived ADAMTS13. METHODS/RESULTS: Sites of N-linked glycosylation were determined by the use of peptide N-glycosidase-F (PNGase F), which removes the entire carbohydrate from the side chain of asparagines. Nine of the 10 predicted N-linked glycosylation sites were identified in or near the metalloproteinase,spacer, thrombospondin type 1 repeat (TSR1) and the CUB domain of plasma ADAMTS13. Moreover, six putative O-fucosylated sites were identified in the TSR domains of plasma ADAMTS13 by performing searches of the tandem mass spectrometry (MS/MS) data for loss of hexose (162 Da), deoxyhexose (146 Da), or hexose deoxyhexose(308 Da). The use of electron transfer dissociation (ETD) allowed for unambiguous identification of the modified sites. In addition to putative O-fucosylation and N-linked glycosylation, two putative C-mannosylation sites were identified within the TSR1 and TSR4 domains of ADAMTS13. CONCLUSIONS: Our data identify several glycosylation sites on plasma derived ADAMTS13. We anticipate that our findings may be relevant for the initiation of autoimmune reactivity against ADAMTS13 in patients with acquired TTP.
    Journal of Thrombosis and Haemostasis 02/2014; 12(5):670-9. · 6.08 Impact Factor
  • Advances in Molecular Imaging 01/2014; 4(1):1-10.
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    ABSTRACT: The purpose of this study was to determine the correlation between the (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) and the diffusion-weighted magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Pretreatment FDG-PET and diffusion-weighted MRI of 21 patients with histologically proven DLBCL were prospectively analyzed. In each patient, maximum, mean and peak standardized uptake value (SUV) was measured in the lesion with visually highest FDG uptake and in the largest lesion. Mean ADC (ADCmean, calculated with b-values of 0 and 1000 s/mm(2)) was measured in the same lesions. Correlations between FDG-PET metrics (SUVmax, SUVmean, SUVpeak) and ADCmean were assessed using Pearson's correlation coefficients. In the lesions with visually highest FDG uptake, no significant correlations were found between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.498, P=0.609 and P=0.595, respectively). In the largest lesions, there were no significant correlations either between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.992, P=0.843 and P=0.894, respectively). The results of this study indicate that the glycolytic rate as measured by FDG-PET and changes in water compartmentalization and water diffusion as measured by the ADC are independent biological phenomena in newly diagnosed DLBCL. Further studies are warranted to assess the complementary roles of these different imaging biomarkers in the evaluation and follow-up of DLBCL.
    American Journal of Nuclear Medicine and Molecular Imaging 01/2014; 4(3):231-8. · 3.25 Impact Factor
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    ABSTRACT: This study aimed to systematically review and meta-analyze published data on the diagnostic performance of (18)F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma, and to determine whether FDG-PET/CT can replace blind bone marrow biopsy (BMB) in these patients. The PubMed/Medline and Embase databases were systematically searched for relevant studies. Methodological quality of each study was assessed. Sensitivities and specificities of FDG-PET/CT in individual studies were calculated and underwent meta-analysis with a random effects model. A summary receiver operating characteristic curve (sROC) was constructed with the Moses-Shapiro-Littenberg method. The weighted summary proportion of FDG-PET/CT-negative patients with a positive BMB among all cases was calculated under the fixed effects model. Nine eligible studies, comprising a total of 955 patients with newly diagnosed Hodgkin lymphoma, were included. Overall, the studies were of moderate methodological quality. The sensitivity and specificity of FDG-PET/CT for the detection of bone marrow involvement ranged from 87.5% to 100% and from 86.7% to 100%, respectively, with pooled estimates of 96.9% [95% confidence interval (CI) 93.0% to 99.0%] and 99.7% (95% CI 98.9% to 100%), respectively. The area under the sROC curve was 0.9860. The weighted summary proportion of FDG-PET/CT-negative patients with a positive BMB among all cases was 1.1% (95% CI 0.6% to 2.0%). Although the methodological quality of studies that were included in this systematic review and meta-analysis was moderate, the current evidence suggests that FDG-PET/CT may be an appropriate method to replace BMB in newly diagnosed Hodgkin lymphoma.
    Annals of Oncology 12/2013; · 6.58 Impact Factor

Publication Stats

3k Citations
678.87 Total Impact Points

Institutions

  • 2009–2014
    • Meander Medisch Centrum
      Amersfoort, Utrecht, Netherlands
    • Radboud University Nijmegen
      • Department of General Internal Medicine
      Nijmegen, Provincie Gelderland, Netherlands
  • 1996–2014
    • University Medical Center Utrecht
      • • Department of Radiology
      • • Department of Clinical Chemistry and Haematology
      • • Department of Hematology
      • • Department of Neurology
      Utrecht, Utrecht, Netherlands
  • 2012
    • Universitas Diponegoro
      • Faculty of Medicine
      Semarang, Central Java, Indonesia
  • 2007
    • Jeroen Bosch Ziekenhuis
      Hertogenbosch, North Brabant, Netherlands
  • 2000
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 1999
    • Sanquin Blood Supply Foundation
      Amsterdamo, North Holland, Netherlands
  • 1990–1996
    • Hong Kong Red Cross Blood Transfusion Service
      Hong Kong, Hong Kong
  • 1991
    • University of Amsterdam
      • Central Laboratory of the Netherlands Red Cross Blood Transfusion Service
      Amsterdamo, North Holland, Netherlands