Publications by authors named "Rob Fijnheer"

101 Publications

Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84).

J Clin Oncol 2020 10 30;38(29):3377-3387. Epub 2020 Jul 30.

Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Purpose: Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP.

Patients And Methods: A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat.

Results: CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections.

Conclusion: Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.
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http://dx.doi.org/10.1200/JCO.19.03418DOI Listing
October 2020

Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura.

Blood 2020 07;136(3):353-361

Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.

Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.
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http://dx.doi.org/10.1182/blood.2019004221DOI Listing
July 2020

[Whether or not to use thromboprophylaxis in patients treated with chemotherapy for malignant disease].

Ned Tijdschr Geneeskd 2019 11 28;163. Epub 2019 Nov 28.

Meander Medisch Centrum, afd. Interne Geneeskunde, Amersfoort.

Case Description: A 55-year-old patient with locally advanced pancreatic carcinoma will start Folfirinox. Should he get thromboprophylaxis?

Consideration: Patients with malignant disease have increased risk of venous thromboembolism (VTE). Several types of malignancy, surgery, chemotherapy and metastasis lead to increased risk. VTE is an underdiagnosed phenomenon and the second cause of death in patients treated with chemotherapy. Therapeutic doses increase the risk of bleeding compared to prophylactic anticoagulant treatment. Even though they are less than perfect, several risk scores are able to identify patients with high risk of VTE. The AVERT and CASSINI trials showed that prophylactic doses of DOACs in cancer patients with high risk of VTE are able to significantly reduce this risk.

Conclusion: Even though there are many unresolved questions, it seems rational to start thromboprophylaxis in patients with aggressive types of cancer, preferably using DOACs, but low molecular weight heparins are possible as well. Risk scores may be helpful when selecting patients.
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November 2019

Generation of anti-idiotypic antibodies to detect anti-spacer antibody idiotopes in acute thrombotic thrombocytopenic purpura patients.

Haematologica 2019 06 6;104(6):1268-1276. Epub 2018 Dec 6.

Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Belgium

In autoantibody-mediated autoimmune diseases, autoantibody profiling allows patients to be stratified and links autoantibodies with disease severity and outcome. However, in immune-mediated thrombotic thrombocytopenic purpura (iTTP) patients, stratification according to antibody profiles and their clinical relevance has not been fully explored. We aimed to develop a new type of autoantibody profiling assay for iTTP based on the use of anti-idiotypic antibodies. Anti-idiotypic antibodies against 3 anti-spacer autoantibodies were generated in mice and were used to capture the respective anti-spacer idiotopes from 151 acute iTTP plasma samples. We next deciphered these anti-spacer idiotope profiles in iTTP patients and investigated whether these limited idiotope profiles could be linked with disease severity. We developed 3 anti-idiotypic antibodies that recognized particular idiotopes in the anti-spacer autoantibodies II-1, TTP73 or I-9, that are involved in ADAMTS13 binding; 35%, 24% and 42% of patients were positive for antibodies with the II-1, TTP73 and I-9 idiotopes, respectively. Stratifying patients according to the corresponding 8 anti-spacer idiotope profiles provided a new insight into the anti-spacer II-1, TTP73 and I-9 idiotope profiles in these patients. Finally, these limited idiotope profiles showed no association with disease severity. We successfully developed 3 anti-idiotypic antibodies that allowed us to determine the profiles of the anti-spacer II-1, TTP73 and I-9 idiotopes in iTTP patients. Increasing the number of patients and/or future development of additional anti-idiotypic antibodies against other anti-ADAMTS13 autoantibodies might allow idiotope profiles of clinical, prognostic value to be identified.
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http://dx.doi.org/10.3324/haematol.2018.205666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545854PMC
June 2019

Secondary thrombotic microangiopathy with severely reduced ADAMTS13 activity in a patient with Capnocytophaga canimorsus sepsis: a case report.

Transfusion 2018 10 17;58(10):2426-2429. Epub 2018 Sep 17.

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: The Gram-negative bacillus Capnocytophaga canimorsus may cause a severe illness resembling thrombotic thrombocytopenic purpura (TTP). The pathogenesis and optimal therapy of this secondary thrombotic microangiopathy (TMA) remain uncertain.

Case Report: A 63-year-old Caucasian man was admitted with suspicion for TTP, but blood cultures grew C. canimorsus. Initial investigations revealed severe thrombocytopenia, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity level of less than 1%, and strongly elevated D-dimer and lactate dehydrogenase levels. He made a full recovery with antibiotics and plasma infusion for 3 days. Plasmapheresis was not performed. Retrospective determination of serial ADAMTS13 activity levels revealed that ADAMTS13 activity had already increased to 25% at the start of plasma infusion.

Conclusion: This case highlights that a C. canimorsus sepsis may cause a secondary TMA with a severe ADAMTS13 deficiency. It also illustrates that the adjunctive role of plasma exchange or plasma infusion is doubtful as ADAMTS13 activity levels increased with antibiotics alone.
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http://dx.doi.org/10.1111/trf.14829DOI Listing
October 2018

Truncation of ADAMTS13 by Plasmin Enhances Its Activity in Plasma.

Thromb Haemost 2018 03 13;118(3):471-479. Epub 2018 Mar 13.

Department for Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) cleaves von Willebrand Factor (VWF) multimers to control their thrombogenicity. The fibrinolytic enzyme plasmin can cleave VWF in a similar manner. However, plasmin can also cleave ADAMTS13, which ultimately inactivates it. This leaves the overall role of plasmin in primary haemostasis uncertain.We investigated the combined molecular effects of plasmin on VWF and ADAMTS13. We first identified that plasmin destroys FRETS-VWF73 substrate by cleaving the ADAMTS13 binding region in a buffered system. We next investigated how plasmin affects both VWF and ADAMTS13 under static conditions in plasma by western blotting. We found that globular VWF is largely protected from plasmin cleavage. However, ADAMTS13 is rapidly cleaved under these conditions, suggesting inactivation. Surprisingly, we observed that plasmin enhances ADAMTS13 activity in a modified two-stage FRETS-VWF73 assay that protects FRETS-VWF73 substrate from degradation. In direct binding studies under the same conditions, we found that plasmin generates multiple C-terminally truncated forms of ADAMTS13 with VWF-binding capacity. In an effort to seek evidence for this mechanism in vivo, we analysed plasma from patients with systemic amyloidosis, which is hallmarked by a hyperfibrinolytic state. We found that their plasma contained increased levels of C-terminally truncated forms of ADAMTS13, which correlated with their hyperfibrinolytic state.We propose that truncation of ADAMTS13 by plasmin abolishes intramolecular self-association, which improves interaction with unfolded VWF.
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http://dx.doi.org/10.1055/s-0038-1627460DOI Listing
March 2018

The class I scavenger receptor CD163 promotes internalization of ADAMTS13 by macrophages.

Blood Adv 2017 Jan 16;1(5):293-305. Epub 2017 Jan 16.

Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.

Internalization of ADAMTS13 by macrophages may contribute to its clearance from the circulation. Here we investigated endocytic mechanisms that contribute to the uptake of ADAMTS13 by macrophages. Human monocyte-derived macrophages were used to monitor the uptake of fluorescently labeled recombinant ADAMTS13 by flow cytometry. Internalization of ADAMTS13 was blocked upon addition of the cell-permeable dynamin inhibitor dynasore. Partial blocking of ADAMTS13 uptake was observed by using mannan; however, uptake was not affected by an antibody that blocked binding to the macrophage mannose receptor CD206, which suggests that other endocytic receptors contribute to the internalization of ADAMTS13 by macrophages. A pull-down with ADAMTS13 and subsequent mass spectrometric analysis identified the class I scavenger receptor CD163 as a candidate receptor for ADAMTS13. Blocking experiments with monoclonal anti-CD163 antibody EDHu-1 resulted in decreased ADAMTS13 internalization by macrophages. Pronounced inhibition of ADAMTS13 uptake by EDHu-1 was observed in CD163 high-expressing macrophages. In agreement with these findings, CD163-expressing Chinese hamster ovary cells were capable of rapidly internalizing ADAMTS13. Surface plasmon resonance revealed binding of ADAMTS13 to scavenger receptor cysteine-rich domains 1-9 and 1-5 of CD163. Taken together, our data identify CD163 as a major endocytic receptor for ADAMTS13 on macrophages.
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http://dx.doi.org/10.1182/bloodadvances.2016001321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744037PMC
January 2017

Thrombotic thrombocytopenic purpura related to ADAMTS13 deficiency, and successful treatment in a chimpanzee (Pan troglodytes verus).

J Med Primatol 2017 10 26;46(5):267-270. Epub 2017 May 26.

Department of Blood Coagulation, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

A 27-year-old male chimpanzee (Pan troglodytes verus) developed signs of thrombotic thrombocytopenic purpura (TTP). ADAMTS13 deficiency appeared to be the cause of disease. After treatment with high-dose prednisone, haematological values and clinical signs recovered. This is the first description of spontaneous TTP associated with ADAMTS13 deficiency in a non-human primate.
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http://dx.doi.org/10.1111/jmp.12278DOI Listing
October 2017

Where Does Diffuse Large B-Cell Lymphoma Relapse?

J Comput Assist Tomogr 2016 Jul-Aug;40(4):531-6

From the *Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht; and Departments of †Nuclear Medicine, ‡Hematology, §Radiology, and ∥Pathology, Meander Medical Center, Amersfoort, The Netherlands.

Objective: This study aimed to investigate the anatomic pattern of disease spread at first disease relapse compared with baseline in diffuse large B-cell lymphoma (DLBCL).

Materials And Methods: All patients who were newly diagnosed as having DLBCL between January 2004 and June 2014 who initially achieved complete remission but who eventually developed relapsed disease during follow-up were retrospectively identified. Available histological and imaging data were used to determine which nodal regions and extranodal locations were involved at relapse.

Results: A total of 21 patients with relapsed DLBCL were included, of whom 8 (38.1%) presented with disease relapse at previously involved sites only, 7 (33.3%) presented with disease relapse at both previously involved and new sites, and 6 (28.6%) presented with disease relapse at new sites only. A total of 57 nodal stations and 34 extranodal locations were involved in all 21 relapsed DLBCL patients. Of these 57 involved nodal regions, 47 (82.5%) were also involved at baseline, whereas 10 (17.5%) were not involved at baseline. Of the 34 involved extranodal locations, 17 (50.0%) were also involved at baseline, whereas 17 (50.0%) were not involved at baseline.

Conclusions: Relapsed DLBCL generally tends to affect previously involved sites, although close to one third of patients seem to have disease recurrence exclusively in previously uninvolved sites. The great majority of involved nodal stations at relapse are also involved at baseline, whereas only one half of involved extranodal locations at relapse are involved at baseline.
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http://dx.doi.org/10.1097/RCT.0000000000000395DOI Listing
January 2017

Functional recovery of stored platelets after transfusion.

Transfusion 2016 05 2;56(5):1030-7. Epub 2016 Mar 2.

Department of Clinical Chemistry and Haematology, University Medical Center, Utrecht, the Netherlands.

Background: Platelet (PLT) concentrates are prophylactically given to prevent major bleeding complications. The corrected count increment (CCI) is currently the only tool to monitor PLT transfusion efficacy. PLT function tests cannot be performed in patients with thrombocytopenia. Therefore, an optimized agonist-induced assay was used to determine PLT function, in patients with severe thrombocytopenia before and after transfusion.

Study Design And Methods: PLT reactivity toward adenosine diphosphate (ADP), thrombin receptor-activating peptide SFLLRN (TRAP), and convulxin (CVX) was assessed by flow cytometry. P-selectin expression was measured on PLTs from 11 patients with thrombocytopenia before and 1 hour after transfusion, on stored PLTs, and on stored PLTs incubated for 1 hour in whole blood from patients ex vivo.

Results: The mean (±SEM) CCI after 1 hour was 11.4 (±1.5). After transfusion, maximal agonist-induced PLT P-selectin expression was on average 29% higher for ADP (p = 0.02), 25% higher for TRAP (p = 0.007), and 24% higher for CVX (p = 0.0008). ADP-induced reactivity of stored PLTs increased with 46% after ex vivo incubation (p = 0.007). These PLTs also showed an overall higher P-selectin expression compared to PLTs 1 hour after transfusion (p = 0.005). After normalization for this background expression, a similar responsiveness was observed.

Conclusions: Our study shows recovery of PLT function after transfusion in patients with thrombocytopenia. The majority of functional PLTs measured after transfusion most likely represents stored transfused PLTs that regained functionality in vivo. The difference in baseline P-selectin expression in vivo versus ex vivo suggests a rapid clearance from circulation of PLTs with increased P-selectin expression.
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http://dx.doi.org/10.1111/trf.13544DOI Listing
May 2016

CD4+ T cells from patients with acquired thrombotic thrombocytopenic purpura recognize CUB2 domain-derived peptides.

Blood 2016 Mar 8;127(12):1606-9. Epub 2016 Jan 8.

Department of Plasma Proteins.

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder resulting from the development of autoantibodies against ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). HLA-DRB1*11 provides a risk factor for developing acquired TTP. Pulsing of antigen-presenting cells from HLA-DRB1*11- and HLA-DRB1*03-positive individuals with ADAMTS13 resulted in presentation of peptides derived from the CUB2 domain of ADAMTS13 with core sequences FINVAPHAR or ASYILIRD. Here, we assessed whether FINVAPHAR- or ASYILIRD-reactive CD4(+)T cells are present in peripheral blood mononuclear cells from HLA-DRB1*11 and HLA-DRB1*03-positive subjects with acquired TTP. The presence of ADAMTS13-reactive CD4(+)T cells was addressed by flow cytometry and the expression of activation marker CD40 ligand by CD4(+)T cells. FINVAPHAR-reactive CD4(+)T cells were identified in an HLA-DRB1*11-positive patient during the acute phase of the disease whereas ASYILIRD-positive CD4(+)T cells were identified in a DRB1*03-positive patient with acquired TTP. Frequencies of CUB2 domain-reactive CD4(+)T cells ranged from 3.3% to 4.5%. Control peptides in which the anchor residues were modified did not induce activation of CD4(+)T cells. Taken together, our data provide evidence for the involvement of CUB2 domain-reactive CD4(+)T cells in the etiology of acquired TTP.
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http://dx.doi.org/10.1182/blood-2015-10-668053DOI Listing
March 2016

Computed Tomography Observer Agreement in Staging Malignant Lymphoma.

J Comput Assist Tomogr 2016 Mar-Apr;40(2):261-5

From the *Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht; †Department of Radiology, Medical Center Haaglanden, The Hague; Departments of ‡Radiology and §Nuclear Medicine, Meander Medical Center, Amersfoort; ∥Department of Haematology, VU University Medical Center, Amsterdam; ¶Department of Hematology, Meander Medical Center, Amersfoort; and #Department of Internal Medicine, Bernhove Hospital, Uden; and Departments of **Hematology and ††Radiology, Academic Medical Center, Amsterdam, The Netherlands.

Objective: To determine pretreatment computed tomography observer agreement in patients with newly diagnosed lymphoma.

Methods: Forty-nine computed tomography scans were reviewed by 3 experienced radiologists, with each scan assessed twice by 1 observer. Predefined nodal and extranodal regions were assessed, and Ann Arbor stages were assigned. K-statistics were defined as poor (κ < 0.2), fair (κ > 0.2 to κ ≤ 0.4), moderate (κ > 0.4 to κ ≤ 0.6), substantial (κ > 0.6 to κ ≤ 0.8), and almost perfect (κ > 0.8 to κ ≤ 1).

Results: Nodal interobserver agreement varied from 0.09 for infraclavicular involvement to 0.95 for para-iliac involvement; intraobserver agreement was substantial to almost perfect, except for infraclavicular nodes. Extranodal interobserver agreement varied from 0.56 to 0.88; intraobserver agreement was substantial to almost perfect. Ann Arbor stage interobserver agreement varied from 0.57 to 0.69; intraobserver agreement was substantial.

Conclusion: Computed tomography observer agreement in staging malignant lymphoma appears to be suboptimal.
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http://dx.doi.org/10.1097/RCT.0000000000000338DOI Listing
August 2016

Keeping von Willebrand Factor under Control: Alternatives for ADAMTS13.

Semin Thromb Hemost 2016 Feb 23;42(1):9-17. Epub 2015 Nov 23.

Laboratory of Clinical Chemistry and Hematology, UMC Utrecht, Utrecht, The Netherlands.

Von Willebrand factor (VWF) is one of the most important proteins of the hemostatic system. Its multimeric state is essential for its natural function to guide platelets to sites of injury. ADAMTS13 is the key protease that regulates the multimeric state of VWF. Without ADAMTS13, VWF multimers can grow to pathologically large sizes. This is a risk factor for the life-threatening condition thrombotic thrombocytopenic purpura (TTP). In this condition, VWF-rich thrombi occlude the microvasculature of various tissues. Intriguingly, a complete ADAMTS13 deficiency does not cause continuous TTP, either in patients or genetically targeted mice. Instead, TTP occurs in episodes of disease, separated by extended periods of remission. This indicates that regulating factors beyond ADAMTS13 are likely involved in this pathologic cascade of events. This raises the question of what really happens when ADAMTS13 is (temporarily) unavailable. In this review, we explore the possible role of complementary mechanisms that are capable of modifying the thrombogenic potential of VWF.
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http://dx.doi.org/10.1055/s-0035-1564838DOI Listing
February 2016

Tumor necrosis at FDG-PET is an independent predictor of outcome in diffuse large B-cell lymphoma.

Eur J Radiol 2016 Jan 21;85(1):304-309. Epub 2015 Sep 21.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Purpose: To determine the prognostic performance of tumor necrosis at FDG-PET in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who are treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy.

Materials And Methods: 108 patients with newly diagnosed DLBCL who underwent FDG-PET before R-CHOP therapy were retrospectively included. Lymphomatous sites at FDG-PET were assessed for the presence of a photopenic area, in keeping with tumor necrosis. Univariate and multivariate Cox regression analyses were performed to determine the associations of tumor necrosis and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) with progression-free survival (PFS) and overall survival (OS).

Results: On univariate Cox regression analysis, both tumor necrosis and higher NCCN-IPI risk groups were significantly associated with PFS (P=0.024 and P<0.001, respectively) and OS (P=0.034 and P<0.001, respectively). On multivariate Cox regression analysis, both tumor necrosis and the NCCN-IPI were independent significant predictors for PFS (P=0.007, hazard ratio: 2.723 [95% confidence interval: 1.324-5.597] and P<0.001, hazard ratio: 2.952 [95% confidence interval: 1.876-4.646], respectively) and OS (P=0.009, hazard ratio: 2.794 [95% confidence interval: 1.305-5.985] and P<0.001, hazard ratio: 2.813 [95% confidence interval: 1.724-4.587], respectively).

Conclusion: Tumor necrosis at FDG-PET is an NCCN-IPI-independent predictor of outcome in DLBCL.
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http://dx.doi.org/10.1016/j.ejrad.2015.09.016DOI Listing
January 2016

Variety in bone marrow 18F-FDG uptake in Hodgkin lymphoma patients without lymphomatous bone marrow involvement: does it have an explanation?

Nucl Med Commun 2016 Jan;37(1):23-9

aDepartment of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht Departments of bNuclear Medicine cHematology dRadiology ePathology, Meander Medical Center, Amersfoort, The Netherlands.

Objective: To directly correlate fluorine-18 fluoro-2-deoxy-D-glucose (F-FDG) uptake of the iliac crest, as determined with PET, with both spatially matched histological bone marrow parameters and laboratory markers in Hodgkin lymphoma patients without lymphomatous bone marrow involvement at bone marrow biopsy.

Materials And Methods: This retrospective study included 21 patients with newly diagnosed Hodgkin lymphoma who underwent F-FDG-PET and who had a lymphoma-negative bone marrow biopsy of the right posterior iliac crest. F-FDG-PET maximum standardized uptake value (SUVmax) was measured in the right posterior iliac crest and correlated to histological bone marrow parameters (cellularity, myeloid/erythroid ratio, degree of fibrosis, and reactive T- and B-lymphocytes) and laboratory markers (hemoglobin, C-reactive protein lactate dehydrogenase, and leukocyte and thrombocyte counts) using Pearson's correlation coefficient (R) for Gaussian data or Kendall's tau (τ) for non-Gaussian data.

Results: There was a significant moderate correlation between F-FDG-PET SUVmax and cellularity of the iliac crest (R=0.519, P=0.016). Furthermore, there was a significant strong inverse correlation between F-FDG-PET SUVmax of the iliac crest and hemoglobin level (R=-0.661, P=0.001) and there was a significant moderate correlation between F-FDG-PET SUVmax of the iliac crest and C-reactive protein level (τ=0.441, P=0.007). All other correlations, including F-FDG-PET SUVmax of the right iliac crest versus reactive T- and B-lymphocytes in the bone marrow, were not significant.

Conclusion: The observations suggest increased bone marrow F-FDG uptake to be caused by red marrow hyperplasia because of anemia in Hodgkin lymphoma. Increased bone marrow F-FDG uptake is unlikely to be caused by inflammatory bone marrow changes.
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http://dx.doi.org/10.1097/MNM.0000000000000400DOI Listing
January 2016

Disappearing acts of ADAMTS13.

EBioMedicine 2015 Aug 10;2(8):800-1. Epub 2015 Jul 10.

Department of Haematology, University Medical Centre Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1016/j.ebiom.2015.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4563130PMC
August 2015

Prognostic Value of Anemia and C-Reactive Protein Levels in Diffuse Large B-Cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2015 Nov 5;15(11):671-9. Epub 2015 Aug 5.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Purpose: To determine the prognostic value of pretreatment anemia, pretreatment elevated C-reactive protein (CRP) levels, and 6-month posttreatment anemia in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone (R-CHOP).

Patients And Methods: A total of 104 patients with newly diagnosed DLBCL were retrospectively included. Pretreatment hemoglobin and CRP levels and 6-month posttreatment hemoglobin levels were measured. Cox regression analyses were used to determine the associations of laboratory assessments and National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) risk groups with progression-free survival (PFS) and overall survival (OS).

Results: Pretreatment anemia, elevated pretreatment CRP levels, and higher risk NCCN-IPI groups were significantly associated with reduced PFS and OS (P = .001 and P = .003 for pretreatment anemia, P = .035 and P = .029 for elevated CRP, and P < .001 and P < .001 for higher risk NCCN-IPI groups). On multivariate Cox regression analysis, only the NCCN-IPI risk group remained as an independent significant predictor for PFS (P < .001) and OS (P < .001). In the subgroup of patients in complete remission 6 months after chemotherapy (n = 80), 6-month posttreatment anemia was significantly associated with reduced PFS (P = .046) but not OS (P = .062), and higher risk NCCN-IPI groups were significantly associated with both reduced PFS (P = .008) and OS (P = .017). On multivariate Cox regression analysis, only the NCCN-IPI group remained an independent significant predictor for PFS (P = .008) and OS (P = .017).

Conclusion: Pretreatment anemia, pretreatment CRP levels, and 6-month posttreatment anemia are significantly associated with poor outcome, but were not proven to be of additional prognostic value to the current risk stratification index for DLBCL.
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http://dx.doi.org/10.1016/j.clml.2015.07.639DOI Listing
November 2015

Is asymptomatic malaria really asymptomatic? Hematological, vascular and inflammatory effects of asymptomatic malaria parasitemia.

J Infect 2015 Nov 21;71(5):587-96. Epub 2015 Aug 21.

Department of Clinical Chemistry and Haematology, University Medical Centre, Utrecht, The Netherlands.

Asymptomatic malaria infections are highly prevalent in malaria endemic regions and most of these infections remain undiagnosed and untreated. Whereas conventional malaria symptoms are by definition absent, little is known on the more subtle health consequences of these infections. The aim of our study was to analyze the hematologic, vascular and inflammatory effects of patent and subpatent asymptomatic malaria parasitemia in children and adults on the Indonesian island Sumba. Both children and adults with parasitemia had increased high-sensitive C-reactive protein levels compared to aparasitemic individuals. In addition, children, but not adults with parasitemia also had lower platelet counts and Hb levels and higher levels of von Willebrand factor and platelet factor-4, markers of endothelial and platelet activation, respectively. These findings suggest that asymptomatic malaria infections have subtle health consequences, especially in children, and should be regarded as potentially harmful.
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http://dx.doi.org/10.1016/j.jinf.2015.08.005DOI Listing
November 2015

Brain glucose metabolism in diffuse large B-cell lymphoma patients as assessed with FDG-PET: impact on outcome and chemotherapy effects.

Acta Radiol 2016 Jun 20;57(6):733-41. Epub 2015 Aug 20.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: There is a lack of data on the effect of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy on brain glucose metabolism of diffuse large B-cell lymphoma (DLBCL) patients, as measured by 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Moreover, the prognostic value of brain glucose metabolism measurements is currently unknown.

Purpose: To investigate the use of FDG-PET for measurement of brain glucose metabolism in R-CHOP-treated DLBCL patients, and to assess its prognostic value.

Material And Methods: This retrospective study included DLBCL patients who underwent FDG-PET including the brain. FDG-PET metabolic volume products (MVPs) of the entire brain, cerebral cortex, basal ganglia, and cerebellum were measured, before and after R-CHOP therapy. Whole-body total lesion glycolysis (TLG) was also measured.

Results: Thirty-eight patients were included, of whom 18 had an appropriate end-of-treatment FDG-PET scan. There were no significant differences (P > 0.199) between pre- and post-treatment brain glucose metabolism metrics. Low basal ganglia MVP was associated with a significantly worse progression-free survival (PFS) and overall survival (OS) (P = 0.020 and P = 0.032), and low cerebellar MVP was associated with a significantly worse OS (P = 0.034). There were non-significant very weak correlations between pretreatment brain glucose metabolism metrics and TLG. In the multivariate Cox regression, only the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) remained an independent predictor of PFS (hazard ratio 3.787, P = 0.007) and OS (hazard ratio 2.903, P = 0.0345).

Conclusion: Brain glucose metabolism was not affected by R-CHOP therapy. Low pretreatment brain glucose metabolism was associated with a worse outcome, but did not surpass the predictive value of the NCCN-IPI.
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http://dx.doi.org/10.1177/0284185115598809DOI Listing
June 2016

Adult-onset congenital thrombotic thrombocytopenic purpura caused by a novel compound heterozygous mutation of the ADAMTS13 gene.

Int J Hematol 2015 Oct 13;102(4):477-81. Epub 2015 Aug 13.

Department of Haematology, Isala Clinics, Zwolle, The Netherlands.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease, characterized by microangiopathic hemolytic anaemia and thrombocytopenia, resulting in neurologic and/or renal abnormalities. We report a 49-year-old patient with a history of thrombotic events, renal failure, and thrombocytopenia. Blood analysis demonstrated no ADAMTS13 activity in the absence of antibodies against ADAMTS13. The complete ADAMTS13 gene was sequenced, and two mutations were identified: one mutation on exon 24 (Arg1060Asp), which had previously been described, and a mutation on exon 27 (Met1260IlefsX34), which has not been reported. For these mutations, compound heterozygosity appears to be necessary to cause TTP, as family members of the patient display only one of the mutations and all displayed normal ADAMTS13 activity.
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http://dx.doi.org/10.1007/s12185-015-1849-2DOI Listing
October 2015

Residual Anatomical Disease in Diffuse Large B-Cell Lymphoma Patients With FDG-PET-Based Complete Response After First-Line R-CHOP Therapy: Does It Have Any Prognostic Value?

J Comput Assist Tomogr 2015 Sep-Oct;39(5):810-5

From the *Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht; and Departments of †Nuclear Medicine, ‡Hematology, §Radiology, and ∥Pathology, Meander Medical Center, Amersfoort, the Netherlands.

Objective: This study aimed to determine the prognostic value of residual anatomical disease, including its size and reduction relative to baseline, in diffuse large B-cell lymphoma patients who have F-fluoro-2-deoxy-d-glucose positron emission tomography-based complete response after first-line R-CHOP therapy.

Methods: This retrospective study included 47 patients. In patients with computed tomography (CT)-based residual disease, the size of the largest residual lesion (Resmax) and the sum of the sizes of all residual lesions (Restotal) were measured, and their reductions relative to baseline (ΔResmax and ΔRestotal) were calculated.

Results: Patients with high-risk National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) scores had significantly lower progression-free survival (PFS) and overall survival (OS) than patients with low-risk NCCN-IPI scores (P = 0.032 and P = 0.022). In contrast, patients with residual lesions at CT had no significantly lower PFS and OS than those without (P = 0.531 and P = 0.801). In the subpopulation with CT-based residual disease, patients with high Resmax, high Restotal, low ΔResmax, and low ΔRestotal had no significantly different PFS and OS than those with low Resmax, low Restotal, high ΔResmax, and high ΔRestotal (P = 0.980 and P = 0.790, P = 0.423 and P = 0.229, P = 0.923 and P = 0.893, and P = 0.923 and P = 0.893, respectively).

Conclusions: The NCCN-IPI retains its prognostic value in diffuse large B-cell lymphoma patients with F-fluoro-2-deoxy-d-glucose positron emission tomography-based complete response after first-line R-CHOP therapy. However, the presence of residual anatomical disease, including its size and reduction relative to baseline, has no prognostic value in these patients.
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http://dx.doi.org/10.1097/RCT.0000000000000270DOI Listing
December 2015

Lymphoma grading with FDG-PET/CT readdressed: Direct and timely histopathological correlation study.

Acta Oncol 2016 15;55(3):386-90. Epub 2015 May 15.

a Department of Radiology and Nuclear Medicine , University Medical Center Utrecht , Utrecht , The Netherlands.

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http://dx.doi.org/10.3109/0284186X.2015.1041652DOI Listing
December 2016

Whole-body MRI-DWI for assessment of residual disease after completion of therapy in lymphoma: A prospective multicenter study.

J Magn Reson Imaging 2015 Dec 8;42(6):1646-55. Epub 2015 May 8.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: To assess the performance of whole-body MRI including diffusion-weighted imaging (whole-body MRI-DWI) for the detection of residual disease after completion of treatment in lymphoma patients.

Methods: Twenty-six patients with lymphoma prospectively underwent whole-body MRI-DWI (1.5 Tesla MR) and 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET)/computed tomography (CT) for posttreatment evaluation which were visually assessed. Apparent diffusion coefficient (ADC) and FDG-PET/CT standardized uptake value measurements were performed in all residual lesions. An unblinded expert panel reviewed all cases and determined the presence or absence of posttreatment residual disease using all available imaging (except for whole-body MRI-DWI), clinical, and histopathological information with a follow-up of at least 6 months. The performance of whole-body MRI-DWI was compared with this panel reference standard.

Results: Five of 26 patients were diagnosed with residual disease. Sensitivity and specificity for detection of residual disease with whole-body MRI-DWI were 100% and 62%, respectively. By ROC analysis, the optimal threshold of ADC was 1.21 × 10(-3) mm(2) /s with sensitivity and specificity of 100% and 91.7%, respectively.

Conclusion: Our initial results suggest that visual whole-body MRI-DWI analysis has a very good sensitivity for detecting viable residual lesions after completion of therapy but lacks specificity. ADC measurements could potentially increase the specificity of whole-body MRI.
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http://dx.doi.org/10.1002/jmri.24938DOI Listing
December 2015

Differential effects of platelets and platelet inhibition by ticagrelor on TLR2- and TLR4-mediated inflammatory responses.

Thromb Haemost 2015 May 26;113(5):1035-45. Epub 2015 Feb 26.

Rahajeng Tunjungputri, MD, Department of Internal Medicine (463), Radboud university medical center, PO Box 9101, 6500 HB Nijmegen, The Netherlands, Tel: +31 24 3618822, Fax: +31 24 3566336, E-mail:

Platelets and platelet-monocyte interaction play an important role in inflammation. Both pro- and anti-inflammatory effects of platelet inhibition have been reported in animal models. This study aimed to investigate the effect of platelets and platelet inhibition by the new P2Y12 receptor antagonist ticagrelor on monocyte function, as assessed by cytokine responses to Toll-like Receptor (TLR) ligands. In a set of in vitro experiments, peripheral blood mononuclear cells (PBMC) incubated with the TLR2 ligand Pam3CSK4 produced less cytokines in the presence of platelets, whereas platelets increased the production of cytokines when PBMC were exposed to TLR4 ligand lipopolysaccharide (LPS). These effects of platelets were dependent on direct platelet-leukocyte aggregation and for the Pam3CSK4-induced response, on phagocytosis of platelets by monocytes. In a double blind, placebo-controlled crossover trial in healthy volunteers, a single oral dosage of 180 mg ticagrelor reduced platelet-monocyte complex (PMC) formation. This was associated with an increase in pro-inflammatory cytokines in blood exposed to Pam3CSK4, but a decrease in these cytokines in blood exposed to LPS. These findings show that platelets differentially modulate TLR2- and TLR4-mediated cytokine responses of PBMC. Through inhibition of platelet-leukocyte interaction, P2Y12 receptor antagonists may either exert a pro- or anti-inflammatory effect during infections depending on the TLR primarily involved.
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http://dx.doi.org/10.1160/TH14-07-0579DOI Listing
May 2015

False-negative FDG-PET in histologically proven extensive large cell bone marrow involvement in diffuse large B-cell lymphoma.

Am J Hematol 2015 Jul 3;90(7):681. Epub 2015 May 3.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1002/ajh.23986DOI Listing
July 2015

CT-based versus FDG-PET/CT-based NCCN international prognostic index risk stratification in DLBCL.

J Natl Compr Canc Netw 2015 Feb;13(2):171-6

From the Departments of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, and the Departments of Nuclear Medicine, Hematology, and Pathology, Meander Medical Center, Amersfoort, The Netherlands.

Background: This study compared CT-based and (18)F-fluoro-2-deoxy-D-glucose PET/CT (FDG-PET/CT)-based NCCN International Prognostic Index (NCCN-IPI) risk stratification in newly diagnosed diffuse large B-cell lymphoma (DLBCL).

Materials And Methods: This retrospective study included 57 patients with newly diagnosed DLBCL who had undergone both (oral and intravenous contrast-enhanced full-dose) diagnostic CT and FDG-PET/CT. Diagnostic CT only and FDG-PET/CT were evaluated separately, and corresponding NCCN-IPI scores for the 2 datasets (NCCN-IPICT and NCCN-IPIPET/CT) were calculated. Percentages of agreement and weighted k statistic between NCCN-IPICT and NCCN-IPIPET/CT scoring with regard to the formation of low-, low-intermediate-, high-intermediate-, and high-risk groups were calculated.

Results: In 47 of 57 patients (82.5%; 95% CI, 70.4-90.4), diagnostic CT alone was in agreement with FDG-PET/CT with regard to the formation of low-, low-intermediate-, high-intermediate-, and high-risk NCCN-IPI groups, but not in the remaining 10 patients (17.5%; 95% CI, 9.6%-29.6%). All NCCN-IPI disagreements between diagnostic CT and FDG-PET/CT were from the detection of additional lesions by the latter, most of them being bone marrow lesions. Agreement between NCCN-IPICT and NCCN-IPIPET/CT with regard to the formation of low-, low-intermediate-, high-intermediate-, and high-risk groups was considered good (k=0.771).

Conclusions: Although agreement between NCCN-IPICT and NCCN-IPIPET/CT risk stratification is generally good, FDG-PET/CT results in higher NCCN-IPI risk stratifications in a non-negligible proportion of patients. Future studies should investigate the prognostic implications of these imaging-based differences in NCCN-IPI scoring.
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http://dx.doi.org/10.6004/jnccn.2015.0025DOI Listing
February 2015

Accuracy of whole-body MRI in the assessment of splenic involvement in lymphoma.

Acta Radiol 2016 Feb 13;57(2):142-51. Epub 2015 Feb 13.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, the Netherlands.

Background: Accurate evaluation of the spleen is an important component of staging lymphoma, because this may have prognostic and therapeutic implications.

Purpose: To determine the diagnostic value of whole-body magnetic resonance imaging (MRI), including diffusion-weighted imaging (whole-body MRI-DWI) in the detection of splenic involvement in lymphoma.

Material And Methods: This IRB approved, prospective multicenter study included a total of 107 patients with newly diagnosed, histologically proven lymphoma who underwent 1.5 T whole-body MRI-DWI and FDG-PET/CT. Whole-body MRI-DWI and FDG-PET/CT were independently evaluated by a radiologist and a nuclear medicine physician, in a blinded manner. Splenic involvement at MRI was defined as splenic index > 725 cm(3) or discrete nodules. At FDG-PET/CT splenic involvement was defined as splenic uptake greater than liver uptake or hypodense nodules at contrast-enhanced CT. FDG-PET/CT augmented with follow-up imaging after treatment was used as reference standard.

Results: Splenic involvement was detected with FDG-PET/CT in 21 patients, all demonstrating response to treatment. The sensitivity, specificity, positive predictive value, and negative predictive value of whole-body MRI-DWI for the detection of splenic involvement were 85.7 %, 96.5 %, 85.7%, and 96.5%, respectively. Three out of six discrepancies were related to suboptimal criterion of splenic size used with whole-body MRI-DWI versus the size-independent FDG uptake.

Conclusion: Whole-body MRI-DWI is reasonably accurate in the detection of splenic lymphomatous involvement.
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http://dx.doi.org/10.1177/0284185115571657DOI Listing
February 2016

Does the presence of tumor-induced cortical bone destruction at CT have any prognostic value in newly diagnosed diffuse large B-cell lymphoma?

Skeletal Radiol 2015 May 7;44(5):687-94. Epub 2015 Feb 7.

Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands,

Purpose: To determine the prognostic value of tumor-induced cortical bone destruction at computed tomography (CT) in newly diagnosed diffuse large B-cell lymphoma (DLBCL).

Materials And Methods: This retrospective study included 105 patients with newly diagnosed DLBCL who had undergone CT and bone marrow biopsy (BMB) before R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone) chemo-immunotherapy. Cox regression analyses were used to determine the associations of cortical bone status at CT (absence vs. presence of tumor-induced cortical bone destruction), BMB findings (negative vs. positive for lymphomatous involvement), and dichotomized National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) strata (low risk vs. high risk) with progression-free survival (PFS) and overall survival (OS).

Results: Univariate Cox regression analysis indicated that cortical bone status at CT was no significant predictor of either PFS or OS (p = 0.358 and p = 0.560, respectively), whereas BMB findings (p = 0.002 and p = 0.013, respectively) and dichotomized NCCN-IPI risk strata (p = 0.002 and p = 0.003, respectively) were significant predictors of both PFS and OS. In the multivariate Cox proportional hazards model, only the dichotomized NCCN-IPI score was an independent predictive factor of PFS and OS (p = 0.004 and p = 0.003, respectively).

Conclusions: The presence of tumor-induced cortical bone destruction at CT was not found to have any prognostic implications in newly diagnosed DLBCL.
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http://dx.doi.org/10.1007/s00256-015-2102-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363520PMC
May 2015