72 results on '"Blijlevens NMA"'
Search Results
2. The effectiveness of ibrutinib in chronic lymphocytic leukaemia: a nationwide, population-based study in the Netherlands
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Straten, L, Levin, MD, Visser, O, Blijlevens, NMA, Cornelissen, Jan, Doorduijn, Jeanette, Kater, AP, Dinmohamed, Avinash, Straten, L, Levin, MD, Visser, O, Blijlevens, NMA, Cornelissen, Jan, Doorduijn, Jeanette, Kater, AP, and Dinmohamed, Avinash
- Published
- 2020
3. High-dose posaconazole for azole-resistant aspergillosis and other difficult-to-treat mould infections
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Schauwvlieghe, Alexander, Buil, JB, Verweij, PE, Hoek, RAS, Cornelissen, Jan, Blijlevens, NMA, Henriet, SS, Rijnders, Bart, Brüggemann, RJM, Schauwvlieghe, Alexander, Buil, JB, Verweij, PE, Hoek, RAS, Cornelissen, Jan, Blijlevens, NMA, Henriet, SS, Rijnders, Bart, and Brüggemann, RJM
- Published
- 2020
4. Primary therapy and relative survival among elderly patients with chronic myeloid leukemia: a population-based study in the Netherlands, 1989–2017
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Ector, GICG, Visser, O, Westerweel, PE, Janssen, Johan, Blijlevens, NMA, Dinmohamed, Avinash, Ector, GICG, Visser, O, Westerweel, PE, Janssen, Johan, Blijlevens, NMA, and Dinmohamed, Avinash
- Published
- 2020
5. Infections associated with immunotherapeutic and molecular targeted agents in hematology and oncology. A position paper by the European Conference on Infections in Leukemia (ECIL)
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Maschmeyer, G, De Greef, J, Mellinghoff, SC, Nosari, A, Thiebaut-Bertrand, A, Bergeron, A, Franquet, T, Blijlevens, NMA, Maertens, JA, and ECIL
- Abstract
A multitude of new agents for the treatment of hematologic malignancies has been introduced over the past decade. Hematologists, infectious disease specialists, stem cell transplant experts, pulmonologists and radiologists have met within the framework of the European Conference on Infections in Leukemia (ECIL) to provide a critical state-of-the-art on infectious complications associated with immunotherapeutic and molecular targeted agents used in clinical routine. For brentuximab vedotin, blinatumomab, CTLA4- and PD-1/PD-L1-inhibitors as well as for ibrutinib, idelalisib, HDAC inhibitors, mTOR inhibitors, ruxolitinib, and venetoclax, a detailed review of data available until August 2018 has been conducted, and specific recommendations for prophylaxis, diagnostic and differential diagnostic procedures as well as for clinical management have been developed.
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- 2019
6. Long-Term Outcome of Patients With a Hematologic Malignancy and Multiple Organ Failure Admitted at the Intensive Care
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de Vries, VA, Muller, MCA, Arbous, MS, Biemond, BJ, Blijlevens, NMA, Kusadasi, Nuray, Span, LRF, Vlaar, APJ, van Westerloo, DJ, Kluin-Nelemans, HC, Bergh, WM, Tuinman, PR, Spoelstra, A, Marijt, E, Blijlevens, N, Hilkens, M, Epker, J, Broers, A, Choi, G, Demandt, A, van Mook, W, de Vries, VA, Muller, MCA, Arbous, MS, Biemond, BJ, Blijlevens, NMA, Kusadasi, Nuray, Span, LRF, Vlaar, APJ, van Westerloo, DJ, Kluin-Nelemans, HC, Bergh, WM, Tuinman, PR, Spoelstra, A, Marijt, E, Blijlevens, N, Hilkens, M, Epker, J, Broers, A, Choi, G, Demandt, A, and van Mook, W
- Published
- 2019
7. Coronary artery spasms due to tyrosine kinase inhibitors used in chronic myeloid leukemia
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Fiets, Roel, Staal, AHJ, Cramer, GE, Blijlevens, NMA, and Hematology
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- 2018
8. The management of critically ill patients with haematological malignancies
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Kusadasi, Nuray, Muller, MCA, van Westerloo, DJ, Broers, Hilkens, M, Blijlevens, NMA, Intensive Care, and Hematology
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- 2017
9. Biomarkers and non-invasive tests for gastrointestinal mucositis
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Kuiken, NSS, Rings, Edmond, Blijlevens, NMA, Tissing, WJE, Kuiken, NSS, Rings, Edmond, Blijlevens, NMA, and Tissing, WJE
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- 2017
10. Prediction of mucositis risk secondary to cancer therapy: a systematic review of current evidence and call to action
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Nicole M. A. Blijlevens, Isoo, Karis Kin Fong Cheng, Stephen T. Sonis, Paolo Bossi, Daniel A Castillo, Sharon Elad, Y Z A Van Sebille, Erik A. H. Loeffen, L Porcello, Joanne M. Bowen, Hannah R. Wardill, Matthew A. Ciorba, Wardill, HR, Sonis, ST, Blijlevens, NMA, Van Sebille, YZA, Ciorba, MA, Loeffen, EAH, Cheng, KKF, Bossi, P, Porcello, L, Castillo, DA, Elad, S, and Bowen, JM
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personalized care ,Risk ,Mucositis ,Diarrhea ,medicine.medical_specialty ,Supportive oncology ,GENE POLYMORPHISM ,Colorectal cancer ,precision medicine ,INDUCED ORAL MUCOSITIS ,MODULATED RADIATION-THERAPY ,ACUTE GASTROINTESTINAL TOXICITY ,diarrhea ,03 medical and health sciences ,risk prediction ,0302 clinical medicine ,NECK-CANCER ,Neoplasms ,medicine ,Tumor Microenvironment ,CONCURRENT CHEMORADIOTHERAPY ,Humans ,030212 general & internal medicine ,Intensive care medicine ,RECTAL-CANCER ,Stomatitis ,business.industry ,Personalized care ,Nursing research ,Precision medicine ,Risk prediction ,Foundation (evidence) ,Cancer ,STEM-CELL TRANSPLANTATION ,Evidence-based medicine ,medicine.disease ,Call to action ,mucositis ,Oncology ,030220 oncology & carcinogenesis ,supportive oncology ,SINGLE NUCLEOTIDE POLYMORPHISMS ,business ,DOSE-VOLUME RELATIONSHIPS ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Item does not contain fulltext PURPOSE: Despite advances in personalizing the efficacy of cancer therapy, our ability to identify patients at risk of severe treatment side effects and provide individualized supportive care is limited. This is particularly the case for mucositis (oral and gastrointestinal), with no comprehensive risk evaluation strategies to identify high-risk patients. We, the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) Mucositis Study Group, therefore aimed to systematically review current evidence on that factors that influence mucositis risk to provide a foundation upon which future risk prediction studies can be based. METHODS: We identified 11,018 papers from PubMed and Web of Science, with 197 records extracted for full review and 113 meeting final eligibility criteria. Data were then synthesized into tables to highlight the level of evidence for each risk predictor. RESULTS: The strongest level of evidence supported dosimetric parameters as key predictors of mucositis risk. Genetic variants in drug-metabolizing pathways, immune signaling, and cell injury/repair mechanisms were also identified to impact mucositis risk. Factors relating to the individual were variably linked to mucositis outcomes, although female sex and smoking status showed some association with mucositis risk. CONCLUSION: Mucositis risk reflects the complex interplay between the host, tumor microenvironment, and treatment specifications, yet the large majority of studies rely on hypothesis-driven, single-candidate approaches. For significant advances in the provision of personalized supportive care, coordinated research efforts with robust multiplexed approaches are strongly advised.
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- 2020
11. The cost-effectiveness of personalized medicine strategies in acute myeloid leukemia
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van Dongen - Leunis, Annemieke, de Groot, Carin, Löwenberg, Bob, Redekop, Ken, Brouwer, Werner, van Busschbach, Jan, Blijlevens, NMA, and Health Technology Assessment (HTA)
- Published
- 2015
12. Salivary flow rate, subjective oral dryness and dental caries 5 years after haematopoietic cell transplantation.
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Bulthuis MS, van Gennip LLA, Thomas RZ, van Leeuwen SJM, Bronkhorst EM, Laheij AMGA, Raber-Durlacher JE, Blijlevens NMA, and Huysmans MDNJM
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- Humans, Female, Male, Middle Aged, Adult, Longitudinal Studies, Saliva metabolism, Secretory Rate, Netherlands, Aged, Hematopoietic Stem Cell Transplantation adverse effects, Dental Caries etiology, Xerostomia etiology, Xerostomia physiopathology
- Abstract
Background: The aim of this study was to describe salivary flow rate, subjective oral dryness and dental caries 5 years post haematopoietic cell transplantation (HCT)., Methods: HCT survivors of a previous longitudinal observational cohort study in the Netherlands (the H-OME study) were invited to participate in this additional follow-up after 5 years (the HOME2 study). During the additional follow-up appointment, stimulated (SWS) and unstimulated whole saliva (UWS) was collected, participants rated subjective oral dryness on a 0 - 10 scale, and caries lesions were assessed. Furthermore, dental records, including treatments and radiographs, were requested for the 5 years preceding and the 5 years following transplantation. Paired t-tests were performed to determine changes in UWS and SWS flow rates and subjective oral dryness from pre-HCT, and to compare the number of caries-related dental treatments (restorations, endodontic treatments or extractions) before and after HCT. Hyposalivation of UWS (< 0.2 mL/min) and SWS (< 0.7 mL/min) at 3 and 12 months, was used to explore the predictive potential of hyposalivation on a high dental treatment need (> 3 treatments) over the 5 years post-HCT., Results: Five years post-HCT, 39 HCT survivors were included. The mean UWS flow rate was 0.36 mL/min (SD 0.26) and the mean SWS flow rate 1.02 (SD 0.57); survivors were diagnosed with a median of 0 dentine lesions (range 0 - 12) and 73% reported a subjective oral dryness score ≥ 1. Survivors underwent a median of 3 (range 0 - 20) dental treatments during the 5 years following transplantation. The mean difference in UWS 5 years post-HCT compared to pre-HCT was 0.03 (95% CI: -0.07 - 10.12), the mean difference for SWS was -0.18 (95% CI: -0.45 - 0.08) and for subjective oral dryness 1.2 (95% CI: 0.2 - 2.1). In the 5 years post-HCT, non-significantly more treatments were performed compared to the 5 years pre-HCT (mean difference: 0.5, 95%CI: -1.2 - 2.2). Seventy eight percent of patients with hyposalivation of SWS at 12 months had a high dental treatment need, compared with 38% with no hyposalivation., Conclusions: Five years post-HCT, mean UWS and SWS flow rates were not significantly different from pre-HCT levels but subjective oral dryness scores were elevated., (© 2024. The Author(s).)
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- 2024
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13. Targeted exome analysis in patients with rare bleeding disorders: data from the Rare Bleeding Disorders in the Netherlands study.
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Willems SPE, Simons A, Saes JL, Weiss M, Rijpma S, Schoormans S, Meijer K, Cnossen MH, Schutgens REG, van Es N, Nieuwenhuizen L, den Exter PL, Kruis IC, Blijlevens NMA, van Heerde WL, and Schols SEM
- Abstract
Background: Rare coagulation factor deficiencies and disorders of fibrinolysis (defined as rare bleeding disorders [RBDs]) present with a heterogeneous bleeding phenotype, and bleeding severity is difficult to predict., Objectives: Describe underlying rare genetic variants in the Dutch RBD population and investigate the relationship between genotype, laboratory phenotype, and clinical phenotype., Methods: The Rare Bleeding Disorders in the Netherlands is a cross-sectional, nationwide study conducted between October 1, 2017, and November 30, 2019. Bleeding scores and blood samples were collected during a single study visit. Coagulation factor levels were measured centrally, and targeted exome analysis was performed on 156 genes involved in thrombosis and hemostasis. Pathogenicity was assigned according to the Association for Clinical Genetic Science guidelines., Results: Rare genetic variants specific to the diagnosed RBD were found in 132 of 156 patients (85%). Of the 214 rare genetic variants identified, 57% ( n = 123) were clearly pathogenic, 19% ( n = 40) were likely pathogenic, and 24% ( n = 51) were variants of unknown significance. No explanatory genetic variants were found in patients with plasminogen activator inhibitor type 1 deficiency or hyperfibrinolysis. A correlation existed between factor activity levels and the presence of a genetic variant in the corresponding gene in patients with rare coagulation factor deficiencies and alpha-2-antiplasmin deficiency. Co-occurrence of multiple genetic variants was present in a quarter of patients, but effect on phenotype remains unclear., Conclusion: Targeted exome analysis may offer advantages over single-gene analysis, emphasized by a number of combined deficiencies in this study. Further studies are required to determine the role of co-occurring hemostasis gene variants on the bleeding phenotype in RBDs., (© 2024 The Author(s).)
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- 2024
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14. Feasibility and potential effectiveness of nurse-led video-coaching interventions for childhood, adolescent, and young adult cancer survivors: the REVIVER study.
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Bouwman E, Stollman I, Wilbers J, Claessens JJM, van Spronsen DJ, Bongaerts A, Breij D, Blijlevens NMA, Knoop H, Hermens RPMG, and Loonen JJ
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- Humans, Adolescent, Female, Male, Young Adult, Adult, Middle Aged, Telemedicine, Mentoring methods, Self Efficacy, Fatigue etiology, Neoplasms nursing, Neoplasms psychology, Cognitive Behavioral Therapy methods, Self-Management methods, Child, Motivational Interviewing methods, Cancer Survivors psychology, Feasibility Studies, Quality of Life
- Abstract
Background: Childhood, adolescent, and young adult (CAYA) cancer survivors, at risk for late effects, including cancer-related fatigue, cardiovascular issues, and psychosocial challenges, may benefit from interventions stimulating behaviour adjustments. Three nurse-led eHealth interventions (REVIVER) delivered via video calls and elaborating on person-centred care, cognitive behaviour therapy and/or motivational interviewing were developed. These interventions target: 1) fatigue management, 2) healthier lifestyle behaviours, and 3) self-efficacy and self-management. This study aimed to assess the feasibility and potential effectiveness of the REVIVER interventions for CAYA cancer survivors and healthcare professionals., Methods: In a single-group mixed methods design, CAYA cancer survivors aged 16-54, more than five years post-treatment, were enrolled. Feasibility, assessed via Bowen's outcomes for feasibility studies, included acceptability, practicality, integration and implementation, demand and adherence. Qualitative data from semi-structured interviews and a focus group interview with survivors and healthcare professionals supplemented the evaluation. Paired sample t-tests assessed changes in self-reported quality of life, fatigue, lifestyle, self-management, and self-efficacy at baseline (T0), post-intervention (T1), and 6-month follow-up (T2)., Results: The interventions and video consults were generally acceptable, practical, and successfully integrated and implemented. Success factors included the nurse consultant (i.e., communication, approach, and attitude) and the personalised approach. Barriers included sustainability concerns, technical issues, and short intervention duration. Regarding demand, 71.4%, 65.4%, and 100% of eligible CAYA cancer survivors engaged in the fatigue (N = 15), lifestyle (N = 17) and empowerment (N = 3) intervention, respectively, with 5, 5 and 2 participants interviewed, correspondingly. Low interest (demand) in the empowerment intervention (N = 3) and dropout rates of one-third for both fatigue and empowerment interventions were noted (adherence). Improvements in quality of life, fatigue (fatigue intervention), lifestyle (lifestyle intervention), self-efficacy, and self-management were evident among survivors who completed the fatigue and lifestyle interventions, with medium and large effect sizes observed immediately after the intervention and six months post-intervention., Conclusions: Our study demonstrates the feasibility of nurse-led video coaching (REVIVER interventions) despite lower demand for the empowerment intervention and lower adherence to the fatigue and empowerment interventions. The medium and high effect sizes found for those who completed the interventions hold potential clinical significance for future studies investigating the effectiveness of the REVIVER interventions., (© 2024. The Author(s).)
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- 2024
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15. Development and Validation of a Prediction Model for 1-Year Mortality in Patients With a Hematologic Malignancy Admitted to the ICU.
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Boldingh JHL, Arbous MS, Biemond BJ, Blijlevens NMA, van Bommel J, Hilkens MGEC, Kusadasi N, Muller MCA, de Vries VA, Steyerberg EW, and van den Bergh WM
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- Humans, Male, Retrospective Studies, Middle Aged, Female, Aged, Netherlands epidemiology, Adult, APACHE, Cohort Studies, Hematologic Neoplasms mortality, Hematologic Neoplasms therapy, Intensive Care Units
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Objectives: To develop and validate a prediction model for 1-year mortality in patients with a hematologic malignancy acutely admitted to the ICU., Design: A retrospective cohort study., Setting: Five university hospitals in the Netherlands between 2002 and 2015., Patients: A total of 1097 consecutive patients with a hematologic malignancy were acutely admitted to the ICU for at least 24 h., Interventions: None., Measurements and Main Results: We created a 13-variable model from 22 potential predictors. Key predictors included active disease, age, previous hematopoietic stem cell transplantation, mechanical ventilation, lowest platelet count, acute kidney injury, maximum heart rate, and type of malignancy. A bootstrap procedure reduced overfitting and improved the model's generalizability. This involved estimating the optimism in the initial model and shrinking the regression coefficients accordingly in the final model. We assessed performance using internal-external cross-validation by center and compared it with the Acute Physiology and Chronic Health Evaluation II model. Additionally, we evaluated clinical usefulness through decision curve analysis. The overall 1-year mortality rate observed in the study was 62% (95% CI, 59-65). Our 13-variable prediction model demonstrated acceptable calibration and discrimination at internal-external validation across centers ( C -statistic 0.70; 95% CI, 0.63-0.77), outperforming the Acute Physiology and Chronic Health Evaluation II model ( C -statistic 0.61; 95% CI, 0.57-0.65). Decision curve analysis indicated overall net benefit within a clinically relevant threshold probability range of 60-100% predicted 1-year mortality., Conclusions: Our newly developed 13-variable prediction model predicts 1-year mortality in hematologic malignancy patients admitted to the ICU more accurately than the Acute Physiology and Chronic Health Evaluation II model. This model may aid in shared decision-making regarding the continuation of ICU care and end-of-life considerations., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)
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- 2024
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16. Engineering of CD34+ progenitor-derived natural killer cells with higher-affinity CD16a for enhanced antibody-dependent cellular cytotoxicity.
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van Hauten PMM, Hooijmaijers L, Vidal-Manrique M, van der Waart AB, Hobo W, Wu J, Blijlevens NMA, Jansen JH, Walcheck B, Schaap NPM, de Jonge PKJD, and Dolstra H
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- Cell Adhesion Molecules metabolism, Cell Line, Tumor, Killer Cells, Natural, Receptors, Fc metabolism, Humans, Antibody-Dependent Cell Cytotoxicity, Receptors, IgG
- Abstract
Background Aims: Natural killer (NK) cell transfer is a promising cellular immunotherapy for cancer. Previously, we developed a robust method to generate large NK cell numbers from CD34
+ hematopoietic stem and progenitor cells (HSPCs), which exhibit strong anti-tumor activity. However, since these cells express low levels of the Fc receptor CD16a in vitro, antibody-dependent cellular cytotoxicity (ADCC) by these cells is limited. To broaden clinical applicability of our HSPC-NK cells toward less NK-sensitive malignancies, we aimed to improve ADCC through CD16a transduction., Methods: Using wildtype and S197P mutant greater-affinity (both with V158) CD16a retroviral transgenes (i.e., a cleavable and noncleavable CD16a upon stimulation), we generated CD16a HSPC-transduced NK cells, with CD34+ cells isolated from umbilical cord blood (UCB) or peripheral blood after G-CSF stem cell mobilization (MPB). CD16a expressing NK cells were enriched using flow cytometry-based cell sorting. Subsequently, phenotypic analyses and functional assays were performed to investigate natural cytotoxicity and ADCC activity., Results: Mean transduction efficiency was 34% for UCB-derived HSPCs and 20% for MPB-derived HSPCs, which was enriched by flow cytometry-based cell sorting to >90% for both conditions. Expression of the transgene remained stable during the entire NK expansion cell generation process. Proliferation and differentiation of HSPCs were not hampered by the transduction process, resulting in effectively differentiated CD56+ NK cells after 5 weeks. Activation of the HSPC-derived NK cells resulted in significant shedding of wildtype CD16a transcribed from the endogenous gene, but not of the noncleavable mutant CD16a protein expressed from the transduced construct. The mean increase of CD107+ IFNγ+ expressing NK cells after inducing ADCC was tenfold in enriched noncleavable CD16a HSPC-NK cells. Killing capacity of CD16a-transduced NK cells was significantly improved after addition of a tumor-targeting antibody in tumor cell lines and primary B-cell leukemia and lymphoma cells compared to unmodified HSPC-NK cells., Conclusions: Together, these data demonstrate that the applicability of adoptive NK cell immunotherapy may be broadened to less NK-sensitive malignancies by upregulation of CD16a expression in combination with the use of tumor-targeting monoclonal antibodies., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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17. The spectrum of neutralizing and non-neutralizing anti-FVIII antibodies in a nationwide cohort of 788 persons with hemophilia A.
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Oomen I, Verhagen M, Miranda M, Allacher P, Beckers EAM, Blijlevens NMA, van der Bom JG, Coppens M, Driessens M, Eikenboom JCJ, Fijnvandraat K, Hassan S, van Heerde WL, Hooimeijer HL, Jansen JH, Kaijen P, Leebeek FWG, Meijer D, Paul H, Rijpma SR, Rosendaal FR, Smit C, van Vulpen LFD, Voorberg J, Schols SEM, and Gouw SC
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- Humans, Middle Aged, Cross-Sectional Studies, Immunoglobulin G, Blood Coagulation Tests, Hemophilia A, Hemostatics
- Abstract
Objectives: Anti-factor VIII (FVIII) antibodies have been reported to exhibit both neutralizing and non-neutralizing characteristics. This is the first study investigating the full spectrum of FVIII-specific antibodies, including non-neutralizing antibodies, very-low titer inhibitors, and inhibitors, in a large nationwide population of persons with hemophilia A of all severities., Methods: All persons with hemophilia A (mild (FVIII > 5-40 IU/dL)/moderate [FVIII 1-5 IU/dL)/severe (FVIII < 1 IU/dL)] with an available plasma sample who participated in the sixth Hemophilia in the Netherlands study between 2018 and 2019 were included. The presence of anti-FVIII antibodies of the immunoglobulin A, M, and G isotypes and IgG subclasses, along with antibody titer levels, were assessed using direct-binding ELISAs. FVIII specificity was assessed using a competition-based ELISA approach. The inhibitor status was determined using the Nijmegen ultra-sensitive Bethesda assay (NusBA) and the Nijmegen Bethesda assay (NBA)., Results: In total, 788 persons with hemophilia A (336 (42.6%) mild, 123 (15.6%) moderate, 329 (41.8%) severe hemophilia) were included. The median age was 45 years (IQR 24-60), and the majority (50.9%) had over 150 exposure days to FVIII concentrates. Within our population, 144 (18.3%) individuals had non-neutralizing FVIII-specific antibodies, 10 (1.3%) had very low-titer inhibitors (NusBA positive; NBA negative), and 13 (1.6%) had inhibitors (both NusBA and NBA positive). IgG1 was the most abundant FVIII-specific antibody subclass, and the highest titer levels were found for IgG4. In individuals without a reported history of inhibitor development, no clear differences were observed in antibody patterns between those who were minimally or highly exposed to FVIII concentrates. IgG4 subclass antibodies were only observed in persons with a reported history of FVIII inhibitor or in those with a currently detected (very low-titer) inhibitor., Conclusion: In this cross-sectional study, we identified non-neutralizing antibodies in a relatively large proportion of persons with hemophilia A. In contrast, in our population, consisting of persons highly exposed to FVIII concentrates, (very low-titer) inhibitors were detected only in a small proportion of persons, reflecting a well-tolerized population. Hence, our findings suggest that only a small subpopulation of non-neutralizing FVIII-specific antibodies is associated with clinically relevant inhibitors., Competing Interests: IO was supported by an unrestricted research grant from SOBI, the EAHAD research grant, the Heimburger Award, and the Martin Villar research grant. MM received funding from the European Community H2020-MSCA-ITN-2019 project 859974 EDUC8. SG received unrestricted research funding from SOBI, EAHAD, CSL Behring Heimburger Award, Grifols Martin Villar Award, and the Netherlands Organization for Scientific Research NWO. KF has received unrestricted research grants from CSL Behring, SOBI, and Novo Nordisk and consultancy fees from SOBI, Novo Nordisk, and Roche all fees to the institution. FL has received grants/research funding from CSL Behring, UniQure, SOBI, and Takeda and consultancy fees from Biomarin, CSL Behring, Takeda, and Uniqure all fees to the institution. FL also served as a DSMB member for a study sponsored by Roche. JE received research funding from CSL Behring funds to the institution. MC has received financial support for research from Anthos, Bayer, CSL Behring, Novo Nordisk, and Roche, as well as an honoraria for lecturing or consultancy from Alexion, Bayer, CSL Behring, Daiichi Sankyo, Octapharma, Pfizer, SOBI, and Viatris. Nonfinancial conflict of interest: member of the gene therapy working group of the European Association for Haemophilia and Allied Disorders EAHAD, member of the European Reference Network ERN EuroBloodNet, chair of the working group thrombosis and hemostasis of the Dutch Society of Vascular Medicine NVIVG, part of the Dutch Internist’s Society NIV. JV is listed as an inventor on a patent application on ADAMTS13 variants. SS has received a research grant from Bayer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Oomen, Verhagen, Miranda, Allacher, Beckers, Blijlevens, Bom, Coppens, Driessens, Eikenboom, Fijnvandraat, Hassan, van Heerde, Hooimeijer, Jansen, Kaijen, Leebeek, Meijer, Paul, Rijpma, Rosendaal, Smit, van Vulpen, Voorberg, Schols and Gouw.)
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- 2024
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18. Patients with moderate hemophilia A and B with a severe bleeding phenotype have an increased burden of disease.
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Verhagen MJA, van Balen EC, Blijlevens NMA, Coppens M, van Heerde WL, Leebeek FWG, Rijpma SR, van Vulpen LFD, Gouw SC, and Schols SEM
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- Adult, Humans, Thrombin therapeutic use, Quality of Life, Hemorrhage drug therapy, Hemarthrosis prevention & control, Phenotype, Cost of Illness, Factor VIII therapeutic use, Hemophilia A complications, Hemophilia A diagnosis, Hemophilia A epidemiology
- Abstract
Background: Patients with moderate hemophilia express varying bleeding phenotypes., Objectives: To assess the burden of disease in patients with moderate hemophilia and a mild or severe phenotype incorporating the thrombin generation profile., Methods: This sub-study of the 6th Hemophilia in the Netherlands study, analyzed data of adults with moderate hemophilia A or B. Patient characteristics and information on bleeding tendency, joint status, and quality of life were obtained from electronic patient files and self-reported questionnaires. A severe bleeding phenotype was defined as an annual bleeding rate ≥5, an annual joint bleeding rate ≥3, and/or the use of secondary/tertiary prophylaxis, and a mild phenotype vice versa. TG was measured with the Nijmegen Hemostasis Assay., Results: This study included 116 patients: 21% had a severe phenotype of whom 46% used prophylaxis. Patients with a severe phenotype treated on demand reported a higher median annual bleeding rate (7), annual joint bleeding rate (3), and more frequently an impaired joint (77%) than patients with a severe phenotype on prophylaxis (2; 0; 70%) or patients with a mild phenotype (0; 0; 47%). Furthermore, patients with a severe phenotype treated on demand experienced a more decreased quality of life. Despite similar factor activity levels, patients with a severe phenotype had a lower thrombin peak height and thrombin potential (0.7%; 0.06%) than patients with a mild phenotype (21.3%; 46.8%)., Conclusion: Patients with moderate hemophilia and a severe phenotype treated on demand displayed a high burden of disease as well as a low thrombin generation profile advocating them toward more intensive prophylactic treatment., Competing Interests: Declaration of competing interests N.M.A.B, S.R.R, E.C.v.B., and M.J.A.V. have no conflicts of interest to declare. M.C. has received financial support for research from Bayer, CSL Behring, Daiichi Sankyo, Portola/Alexion, Roche, Sanquin Blood Supply, and UniQure; and consultancy or lecturing fees from Bayer, CSL Behring, Medcon International, Medtalks, Novo Nordisk, Pfizer, and Sobi. W.L.v.H. has received unrestricted grants from Bayer, Shire, Novo Nordisk, and CSL Behring; and is the founder and CSO of Enzyre BV, a Radboudumc spinoff company. F.W.G.L. has received unrestricted grants or research funding from CLS Behring, Sobi, Takeda, and Uniqure; consultancy fees from BioMarin, CLS Behring, Takeda, and Uniqure (of which all fees go to the University); and was a Data Safety Monitoring Board Member for Roche. L.F.D.v.V. has received a research grant from Griffols (fee paid to the institution). S.C.G. has received an unrestricted research grant from SOBI. S.E.M.S. has received an unrestricted research grant from Bayer., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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19. Transporter-Mediated Cellular Distribution of Tyrosine Kinase Inhibitors as a Potential Resistance Mechanism in Chronic Myeloid Leukemia.
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Verhagen NE, Koenderink JB, Blijlevens NMA, Janssen JJWM, and Russel FGM
- Abstract
Chronic myeloid leukemia (CML) is a hematologic neoplasm characterized by the expression of the BCR::ABL1 oncoprotein, a constitutively active tyrosine kinase, resulting in uncontrolled growth and proliferation of cells in the myeloid lineage. Targeted therapy using tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib and asciminib has drastically improved the life expectancy of CML patients. However, treatment resistance occurs in 10-20% of CML patients, which is a multifactorial problem that is only partially clarified by the presence of TKI inactivating BCR::ABL1 mutations. It may also be a consequence of a reduction in cytosolic TKI concentrations in the target cells due to transporter-mediated cellular distribution. This review focuses on drug-transporting proteins in stem cells and progenitor cells involved in the distribution of TKIs approved for the treatment of CML. Special attention will be given to ATP-binding cassette transporters expressed in lysosomes, which may facilitate the extracytosolic sequestration of these compounds.
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- 2023
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20. The Value of IgM Memory B-Cells in the Assessment of Splenic Function in Childhood Cancer Survivors at Risk for Splenic Dysfunction: A DCCSS-LATER Study.
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Houtman BM, Walraven I, de Grouw E, van der Maazen RWM, Kremer LCM, van Dulmen-den Broeder E, van den Heuvel-Eibrink MM, Tissing WJE, Bresters D, van der Pal HJH, de Vries ACH, Louwerens M, van der Heiden-van der Loo M, Neggers SJC, Janssens GO, Blijlevens NMA, Lambeck AJA, Preijers F, and Loonen JJ
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- Humans, Child, Spleen, Splenectomy adverse effects, Immunoglobulin M, Cancer Survivors, Neoplasms
- Abstract
Background: Childhood cancer survivors (CCS) who received radiotherapy involving the spleen or total body irradiation (TBI) might be at risk for splenic dysfunction. A comprehensive screening test for examining splenic dysfunction is lacking., Objective: We investigated whether IgM memory B-cells could be used to assess splenic dysfunction in CCS who received a splenectomy, radiotherapy involving the spleen, or TBI., Methods: All CCS were enrolled from the DCCSS-LATER cohort. We analyzed differences in IgM memory B-cells and Howell-Jolly bodies (HJB) in CCS who had a splenectomy ( n = 9), received radiotherapy involving the spleen ( n = 36), or TBI ( n = 15). IgM memory B-cells < 9 cells/ µ L was defined as abnormal., Results: We observed a higher median number of IgM memory B-cells in CCS who received radiotherapy involving the spleen (31 cells/ µ L, p =0.06) or TBI (55 cells/ µ L, p = 0.03) compared to CCS who received splenectomy (20 cells/ µ L). However, only two CCS had IgM memory B-cells below the lower limit of normal. No difference in IgM memory B-cells was observed between CCS with HJB present and absent (35 cells/ µ L vs. 44 cells/ µ L)., Conclusion: Although the number of IgM memory B-cells differed between splenectomized CCS and CCS who received radiotherapy involving the spleen or TBI, only two CCS showed abnormal values. Therefore, this assessment cannot be used to screen for splenic dysfunction., Competing Interests: The authors declare to have no competing interests., (Copyright © 2023 Bente M. Houtman et al.)
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- 2023
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21. High prevalence of heavy menstrual bleeding in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study.
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Maas DPMSM, Saes JL, Blijlevens NMA, Cnossen MH, den Exter PL, van der Heijden OWH, Kruis IC, Meijer K, Peters M, Schutgens REG, van Heerde WL, Nieuwenhuizen L, and Schols SEM
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- Female, Humans, Adolescent, Young Adult, Adult, Retrospective Studies, Delayed Diagnosis, Prevalence, Quality of Life, Netherlands epidemiology, Blood Coagulation Factors, Menorrhagia diagnosis, Menorrhagia drug therapy, Menorrhagia epidemiology, Hemorrhagic Disorders diagnosis, Hemorrhagic Disorders epidemiology, Blood Coagulation Disorders diagnosis, Blood Coagulation Disorders drug therapy, Blood Coagulation Disorders epidemiology
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Background: Heavy menstrual bleeding (HMB) is associated with a reduced quality of life and limitations in social and physical functioning. Data on HMB in women with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, are scarce., Objectives: To analyze the prevalence, severity, and treatment of HMB in Dutch women with an RBD., Methods: The Rare Bleeding Disorders in the Netherlands (RBiN) study included 263 patients with an RBD from all 6 hemophilia treatment centers (October 2017-November 2019). In this analysis, data of 111 women aged ≥16 years were studied. According to the International Society on Thrombosis and Haemostasis bleeding assessment tool, HMB symptoms were scored from 0 (no/trivial) to 4 (severe symptoms requiring medical intervention). HMB was defined as a score ≥1. Age at RBD diagnosis was extracted from patient files., Results: HMB was reported by 80% of women (89/111) and was more prevalent in women with a fibrinolytic disorder (33/35; 94%) than in women with a coagulation factor deficiency (56/76; 74%) (P = .011). Of the 89 women with HMB, 82% (n = 73) ever required treatment. Multiple treatment modalities were frequently used, both in severe and mild deficiencies. Hormonal treatment was mostly used (n = 64; 88%), while antifibrinolytics were prescribed less frequently (n = 18; 25%). In women with HMB since menarche (n = 61; 69%), median age at RBD diagnosis was 28 years (IQR, 14-41)., Conclusion: HMB is common in women with RBDs. Women with mild deficiencies also frequently reported HMB. Only a minority of women were treated with hemostatic agents. A significant diagnostic delay was observed after the onset of HMB symptoms., Competing Interests: Declaration of competing interests K. Meijer reports speaker fees from Bayer and Alexion, participation in trial steering committee for Bayer, consulting fees from Uniqure, participation in data monitoring and endpoint adjudication committee for Octapharma. M.H. Cnossen's institution has received investigator-initiated research and travel grants as well as speaker fees over the years from the Netherlands Organisation for Scientific Research (NWO) and Netherlands National research Agenda (NWA), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch Innovatiefonds Zorgverzekeraars, Stichting Haemophilia, Baxter/Baxalta/Shire/ Takeda, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, Roche, and Nordic Pharma, and for serving as a steering board member for Roche, Bayer and Novartis. All grants and fees go to the Erasmus MC as an institution. She is coordinator of Erasmus MC as a Health Care Provider within the European Reference Network (ERN) for rare hematological diseases EuroBloodNet and (co)leader of the local Erasmus MC Expert Centers for Rare Bleeding Disorders and Sickle Cell and Thalassemia Comprehensive Care Center. R.E.G. Schutgens reports grants from Bayer, Baxalta, Pfizer, and Novo Nordisk outside the submitted work. M. Peters reports a grant from Pfizer outside the submitted work. W.L. van Heerde reports financial support from Takeda, Bayer, Sobi and CSL Behring, and funding from Takeda and Bayer for Enzyre. The remaining authors declare no competing financial interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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22. Improvement, Implementation, and Evaluation of the CMyLife Digital Care Platform: Participatory Action Research Approach.
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Verweij L, Metsemakers SJJPM, Ector GICG, Rademaker P, Bekker CL, van Vlijmen B, van der Reijden BA, Blijlevens NMA, and Hermens RPMG
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- Humans, Emotions, Guideline Adherence, Health Personnel, Health Services Research, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
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Background: The evaluation of a continuously evolving eHealth tool in terms of improvement and implementation in daily practice is unclear. The CMyLife digital care platform provides patient-centered care by empowering patients with chronic myeloid leukemia, with a focus on making medication compliance insightful, discussable, and optimal, and achieving optimal control of the biomarker BCR-ABL1., Objective: The aim of this study was to investigate to what extent the participatory action research approach is suitable for the improvement and scientific evaluation of eHealth innovations in daily clinical practice (measured by user experiences) combined with the promotion of patient empowerment., Methods: The study used iterative cycles of planning, action, and reflection, whereby participants' experiences (patients, health care providers, the CMyLife team, and app suppliers) with the platform determined next actions. Co-design workshops were the foundation of this cyclic process. Moreover, patients filled in 2 sets of questionnaires for assessing experiences with CMyLife, the actual use of the platform, and the influence of the platform after 3 and at least 6 months. Data collected during the workshops were analyzed using content analysis, which is often used for making a practical guide to action. Descriptive statistics were used to characterize the study population in terms of information related to chronic myeloid leukemia and sociodemographics, and to describe experiences with the CMyLife digital care platform and the actual use of this platform., Results: The co-design workshops provided insights that contributed to the improvement, implementation, and evaluation of CMyLife and empowered patients with chronic myeloid leukemia (for example, simplification of language, and improvement of the user friendliness of functionalities). The results of the questionnaires indicated that (1) the platform improved information provision on chronic myeloid leukemia in 67% (33/49) of patients, (2) the use of the medication app improved medication compliance in 42% (16/38) of patients, (3) the use of the guideline app improved guideline adherence in 44% (11/25) of patients, and (4) the use of the platform caused patients to feel more empowered., Conclusions: A participatory action research approach is suited to scientifically evaluate digital care platforms in daily clinical practice in terms of improvement, implementation, and patient empowerment. Systematic iterative evaluation of users' needs and wishes is needed to keep care centered on patients and keep the innovation up-to-date and valuable for users., (©Lynn Verweij, Sanne J J P M Metsemakers, Geneviève I C G Ector, Peter Rademaker, Charlotte L Bekker, Bas van Vlijmen, Bert A van der Reijden, Nicole M A Blijlevens, Rosella P M G Hermens. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 15.09.2023.)
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- 2023
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23. The salivary proteome in relation to oral mucositis in autologous hematopoietic stem cell transplantation recipients: a labelled and label-free proteomics approach.
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van Leeuwen SJM, Proctor GB, Staes A, Laheij AMGA, Potting CMJ, Brennan MT, von Bültzingslöwen I, Rozema FR, Hazenberg MD, Blijlevens NMA, Raber-Durlacher JE, and Huysmans MCDNJM
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- Humans, Melphalan, Proteome, Proteomics, Quality of Life, Multiple Myeloma complications, Stomatitis complications, Hematopoietic Stem Cell Transplantation adverse effects, Stomatitis, Aphthous complications
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Background: Oral mucositis is a frequently seen complication in the first weeks after hematopoietic stem cell transplantation recipients which can severely affects patients quality of life. In this study, a labelled and label-free proteomics approach were used to identify differences between the salivary proteomes of autologous hematopoietic stem cell transplantation (ASCT) recipients developing ulcerative oral mucositis (ULC-OM; WHO score ≥ 2) or not (NON-OM)., Methods: In the TMT-labelled analysis we pooled saliva samples from 5 ULC-OM patients at each of 5 timepoints: baseline, 1, 2, 3 weeks and 3 months after ASCT and compared these with pooled samples from 5 NON-OM patients. For the label-free analysis we analyzed saliva samples from 9 ULC-OM and 10 NON-OM patients at 6 different timepoints (including 12 months after ASCT) with Data-Independent Acquisition (DIA). As spectral library, all samples were grouped (ULC-OM vs NON-OM) and analyzed with Data Dependent Analysis (DDA). PCA plots and a volcano plot were generated in RStudio and differently regulated proteins were analyzed using GO analysis with g:Profiler., Results: A different clustering of ULC-OM pools was found at baseline, weeks 2 and 3 after ASCT with TMT-labelled analysis. Using label-free analysis, week 1-3 samples clustered distinctly from the other timepoints. Unique and up-regulated proteins in the NON-OM group (DDA analysis) were involved in immune system-related processes, while those proteins in the ULC-OM group were intracellular proteins indicating cell lysis., Conclusions: The salivary proteome in ASCT recipients has a tissue protective or tissue-damage signature, that corresponded with the absence or presence of ulcerative oral mucositis, respectively., Trial Registration: The study is registered in the national trial register (NTR5760; automatically added to the International Clinical Trial Registry Platform)., (© 2023. The Author(s).)
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- 2023
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24. Perceived barriers and facilitators to health behaviors in European childhood cancer survivors: A qualitative PanCareFollowUp study.
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Bouwman E, Pluijm SMF, Stollman I, Araujo-Soares V, Blijlevens NMA, Follin C, Winther JF, Hjorth L, Kepak T, Kepakova K, Kremer LCM, Muraca M, van der Pal HJH, Schneider C, Uyttebroeck A, Vercruysse G, Skinner R, Brown MC, Hermens RPMG, and Loonen JJ
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- Humans, Child, Health Behavior, Qualitative Research, Focus Groups, Cancer Survivors, Neoplasms epidemiology, Neoplasms therapy
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Background: Healthy behaviors, that is, engaging in regular physical activities, maintaining a healthy diet, limiting alcohol consumption, and avoiding tobacco and drug use, decrease the risk of developing late adverse health conditions in childhood cancer survivors. However, childhood cancer survivors may experience barriers to adopting and maintaining healthy behaviors. This study aimed to assess these barriers and facilitators to health behavior adoption and maintenance in childhood cancer survivors., Methods: A focus group ( n = 12) and semi-structured telephone interviews ( n = 20) were conducted with a selected sample of European and Dutch childhood cancer survivors, respectively. The Theoretical Domains Framework (TDF) was used to inform the topic guide and analysis. Inductive thematic analysis was applied to identify categories relating to barriers and facilitators of health behavior adoption and maintenance, after which they were deductively mapped onto the TDF., Results: Ten TDF domains were identified in the data of which "Knowledge," "Beliefs about consequences," "Environmental context and resources," and "Social influences" were most commonly reported. Childhood cancer survivors expressed a need for knowledge on the importance of healthy behaviors, possibly provided by healthcare professionals. They indicated physical and long-term benefits of healthy behaviors, available professional support, and a supporting and health-consciously minded work and social environment to be facilitators. Barriers were mostly related to a lack of available time and an unhealthy environment. Lastly, (social) media was perceived as both a barrier and a facilitator to healthy behaviors., Conclusion: This study has identified education and available professional support in health behaviors and the relevance of healthy behaviors for childhood cancer survivors as key opportunities for stimulating health behavior adoption in childhood cancer survivors. Incorporating health behavior support and interventions for this population should therefore be a high priority., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2023
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25. Mucositis and Infection in Hematology Patients.
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Blijlevens NMA and de Mooij CEM
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- Humans, Mucous Membrane, Fever etiology, Mucositis etiology, Hematologic Neoplasms complications, Hematology
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Survival in patients with hematological malignancies has improved over the years, both due to major developments in anticancer treatment, as well as in supportive care. Nevertheless, important and debilitating complications of intensive treatment regimens still frequently occur, including mucositis, fever and bloodstream infections. Exploring potential interacting mechanisms and directed therapies to counteract mucosal barrier injury is of the utmost importance if we are to continue to improve care for this increasingly growing patient population. In this perspective, I highlight recent advances in our understanding of the relation of mucositis and infection.
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- 2023
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26. Exercise-induced release of cardiac and skeletal muscle injury biomarkers in patients with chronic myeloid leukemia receiving TKI therapy.
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Janssen L, Allard NAE, Aengevaeren VL, Eijsvogels TMH, Timmers S, Blijlevens NMA, and Hopman MTE
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- Humans, Chronic Disease, Muscle, Skeletal, Biomarkers, Protein Kinase Inhibitors adverse effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid
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- 2023
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27. Oral health in patients scheduled for hematopoietic stem cell transplantation in the Orastem study.
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Skallsjö K, von Bültzingslöwen I, Hasséus B, Johansson JE, Öhman J, Raber-Durlacher JE, Huysmans MDNJM, Laheij AMGA, van Leeuwen SJM, Hovan AJ, Garming Legert K, Nguyen HM, Turk PJ, Rozema FR, Blijlevens NMA, and Brennan MT
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- Humans, Oral Health, Prospective Studies, Transplantation Conditioning adverse effects, Dental Caries complications, Mouth Diseases epidemiology, Mouth Diseases etiology, Mouth Diseases diagnosis, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Despite advances in transplant medicine, prevalence of complications after hematopoietic stem cell transplantation (HSCT) remains high. The impact of pre-HSCT oral health factors on the incidence and severity of complications post-HSCT is poorly understood. The aim of this prospective, observational study was to analyze oral health in patients planned for HSCT. Patients ≥18 years requiring HSCT were included from five sites between 2011-2018. General health, oral findings and patient-reported symptoms were registered in 272 patients. Oral symptoms around disease onset were reported by 43 patients (15.9%) and 153 patients (58.8%) reported oral complications during previous chemotherapy. One third of patients experienced oral symptoms at the oral examination before conditioning regimen and HSCT. In total, 124 (46.1%) patients had dental caries, 63 (29.0%) had ≥one tooth with deep periodontal pockets, 147 (75.0%) had ≥one tooth with bleeding on probing. Apical periodontitis was observed in almost 1/4 and partially impacted teeth in 17 (6.3%) patients. Oral mucosal lesions were observed in 84 patients (30.9%). A total of 45 (17.4%) of 259 patients had at least one acute issue to be managed prior to HSCT. In conclusion, oral symptoms and manifestations of oral disease were prevalent in patients planned for HSCT. The extent of oral and acute dental diseases calls for general oral screening of patients pre-HSCT., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Skallsjö et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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28. Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria.
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Schaap CCM, Schols SEM, Preijers FWMB, de Jonge E, Laarakkers CMM, Jansen JH, Blijlevens NMA, Swinkels DW, and Langemeijer SMC
- Abstract
Competing Interests: The authors have no conflicts of interest to disclose.
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- 2023
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29. Effectiveness of digital care platform CMyLife for patients with chronic myeloid leukemia: results of a patient-preference trial.
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Verweij L, Ector GICG, Smit Y, van Vlijmen B, van der Reijden BA, Hermens RPMG, and Blijlevens NMA
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- Humans, Chronic Disease, Pandemics, Quality of Life, COVID-19, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
- Abstract
Background: Two most important factors determining treatment success in chronic myeloid leukemia (CML) are adequate medication compliance and molecular monitoring albeit still being suboptimal. The CMyLife platform is an eHealth innovation, co-created with and for CML patients, aiming to improve their care, leading to an increased quality of life and the opportunity of hospital-free care., Objective: To explore the effectiveness of CMyLife in terms of information provision, patient empowerment, medication compliance, molecular monitoring, and quality of life., Methods: Effectiveness of CMyLife was explored using a patient-preference trial. Upon completion of the baseline questionnaire, participants actively used (intervention group) or did not actively use (questionnaire group) the CMyLife platform for at least 6 months, after which they completed the post-intervention questionnaire. Scores between the intervention group and the questionnaire group were compared with regard to the within-subject change between baseline and post-measurement using Generalized Estimating Equation models., Results: At baseline, 33 patients were enrolled in the questionnaire group and 75 in the intervention group. Online health information knowledge improved significantly when actively using CMyLife and patients felt more empowered. No significant improvements were found regarding medication compliance and molecular monitoring, which were already outstanding. Self-reported effectiveness showed that patients experienced that using CMyLife improved their medication compliance and helped them to oversee their molecular monitoring. Patients using CMyLife reported more symptoms but were better able to manage these., Conclusions: Since hospital-free care has shown to be feasible in time of the COVID-19 pandemic, eHealth-based innovations such as CMyLife could be a solution to maintain the quality of care and make current oncological health care services more sustainable., Trial Registration: ClinicalTrials.gov NCT04595955 , 22/10/2020., (© 2023. The Author(s).)
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- 2023
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30. Dose optimalization of subcutaneous ravulizumab is predicted to yield significant savings and to improve patient friendliness.
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Ter Avest M, Langemeijer SMC, Blijlevens NMA, van de Kar NCAJ, and Ter Heine R
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- Humans, Antibodies, Monoclonal, Humanized therapeutic use, Complement Inactivating Agents therapeutic use, Hemoglobinuria, Paroxysmal drug therapy
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Ravulizumab is an expensive complement C5-inhibitor for the treatment of paroxysmal nocturnal haemoglobinuria. Recently, a subcutaneous formulation has entered the market, for which the approved dosing regimen results in supratherapeutic ravulizumab concentrations in the majority of patients in the registration studies. Therefore, we explored alternative dosing regimens in silico based on the registration data of the manufacturer. Extending the interval from 1 to 2 weeks or individualized dosing based on therapeutic drug monitoring resulted in therapeutic ravulizumab concentrations and comparable predicted efficacy in terms of lactate dehydrogenase normalization, with dose reductions up to 64%. We here show that with an individualized dose, a substantial dose reduction for subcutaneous ravulizumab might be possible with improved patient-friendliness., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
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- 2023
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31. Healthcare professionals' perceived barriers and facilitators of health behavior support provision: A qualitative study.
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Bouwman E, Pluijm SMF, Stollman I, Araujo-Soares V, Blijlevens NMA, Follin C, Winther JF, Hjorth L, Kepak T, Kepakova K, Kremer LCM, Muraca M, van der Pal HJH, Schneider C, Uyttebroeck A, Vercruysse G, Skinner R, Brown MC, Hermens RPMG, and Loonen JJ
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- Humans, Child, Qualitative Research, Focus Groups, Delivery of Health Care, Health Personnel education, Health Behavior
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Background: Childhood cancer survivors (CCSs) have an increased risk of developing chronic health conditions. Evidence suggests that poor health behaviors further increase health risks. Healthcare professionals (HCPs) involved in survivorship care have a key role in providing health behavior support (HBS) but can feel limited in their ability to do so. This study aims to explore European HCPs perceived facilitators and barriers to providing HBS to CCSs., Methods: Five focus groups with 30 HCPs from survivorship care clinics across Europe were conducted. Topic guides were informed by the Theoretical Domains Framework (TDF) to capture domains that may influence provision of HBS. Focus groups were analyzed with thematic analysis. Transcripts were inductively coded, after which axial coding was applied to organize codes into categories. Finally, categories were mapped onto the TDF domains., Results: Nine TDF domains were identified in the data. The most commonly reported TDF domains were "Knowledge", "Skills", and "Environmental context and resources". HCPs indicated that their lack of knowledge of the association between late effects and health behaviors, besides time restrictions, were barriers to HBS. Facilitators for HBS included possession of skills needed to pass on health behavior information, good clinic organization, and an established network of HCPs., Conclusions: This study identified education and training of HCPs as key opportunities to improve HBS. Survivorship care clinics should work towards establishing well-integrated structured care with internal and external networks including HBS being part of routine care. Proper understanding of facilitators and barriers should lead to better survivorship care for CCSs., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
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- 2023
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32. High prevalence of postpartum hemorrhage in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study.
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Maas DPMSM, Saes JL, Blijlevens NMA, Cnossen MH, den Exter PL, van der Heijden OWH, Kruis IC, Meijer K, Peters M, Schutgens REG, van Heerde WL, Nieuwenhuizen L, and Schols SEM
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- Pregnancy, Humans, Female, Retrospective Studies, Netherlands, Prevalence, Blood Coagulation Factors therapeutic use, Postpartum Hemorrhage etiology, Hemostatics therapeutic use
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Background: Women with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, may have a higher risk of postpartum hemorrhage (PPH). Information on this patient category is lacking in the existing PPH guidelines because data on PPH in patients with RBDs are scarce., Objective: To describe the prevalence of PPH in women with an RBD and evaluate the use of peripartum hemostatic prophylaxis., Methods: In the Rare Bleeding Disorders in the Netherlands (RBiN) study, patients with RBDs (n = 263) were included from all 6 Dutch hemophilia treatment centers. Patient-reported information on delivery, peripartum hemostatic prophylaxis, and occurrence of PPH was collected retrospectively. If available, information about the precise volume of postpartum blood loss was extracted from electronic patient files. PPH was defined as blood loss ≥500 mL (World Health Organization guideline)., Results: A total of 244 pregnancies, including 193 livebirths, were reported by 85 women. A considerable proportion of these women experienced PPH, ranging from 30% in factor V deficiency to 100% in hyperfibrinolysis. Overall, PPH was reported in 44% of deliveries performed with and 53% of deliveries performed without administration of peripartum hemostatic prophylaxis. Blood loss was significantly higher in deliveries without administration of hemostatic prophylaxis (median 1000 mL) compared to deliveries with administration of prophylaxis (median 400 mL) (p = 0.011). Patients with relatively mild deficiencies also frequently experienced PPH when peripartum hemostatic prophylaxis was omitted., Conclusion: PPH is common in rare coagulation factor deficiencies, both severe and mild, and fibrinolytic disorders, especially when peripartum prophylactic hemostatic treatment was not administered. The use of prophylactic hemostatic treatment was associated with less postpartum blood loss., Competing Interests: Declaration of competing interests K.M. reports speaker fees from Bayer and Alexion, participation in trial steering committee for Bayer, consulting fees from Uniqure, and participation in data monitoring and endpoint adjudication committee for Octapharma. M.H.C. received investigator–initiated research and travel grants, as well as speaker fees, over the years from the Netherlands Organisation for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch “Innovatiefonds Zorgverzekeraars,” Baxter, Baxalta, Shire, Takeda, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma and has served as a steering board member for Roche, Bayer, and Novartis. All grants, awards, and fees go to the Erasmus MC as institution. R.E.G.S. reports grants from Bayer, Baxalta, Pfizer, and Novo Nordisk outside the submitted work. M.P. reports a grant from Pfizer outside the submitted work. W.L.v.H. reports financial support from Takeda, Bayer, Sobi, and CSL Behring and funding from Takeda and Bayer for Enzyre. The remaining authors declare no competing financial interests., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2023
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33. Effect of invasive aspergillosis on risk for different causes of death in older patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome.
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van Grootveld R, Masarotto V, von dem Borne PA, Blijlevens NMA, Chitu DA, van der Beek MT, Fiocco M, and de Boer MGJ
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- Adult, Humans, Male, Aged, Female, Cause of Death, Leukemia, Myeloid, Acute complications, Leukemia, Myeloid, Acute drug therapy, Aspergillosis complications, Invasive Fungal Infections complications, Myelodysplastic Syndromes complications
- Abstract
Purpose: Study objectives were to estimate the cumulative incidence of death due to different causes of death (CODs) and investigate the effect of invasive aspergillosis (IA) on each separate COD in a cohort of older patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS) included in the Haemato-Oncology Foundation for Adults in the Netherlands (HOVON) 43 randomized controlled trial., Methods: Pre-collected data from the trial was obtained from the HOVON data center and relevant clinical information was extracted. The cumulative incidence of death due to different CODs was estimated with a competing risk model and the association between each COD and prognostic factors, including IA, were investigated with a cause-specific hazard Cox regression model., Results: In total 806 patients were included, mean age of 70 years and 55% were male. The cumulative incidences of death due to leukaemia or infection at 3, 6, 12 and 36 months were 0.06, 0.11, 0.23, 0.42 and 0.17, 0.19, 0.22, 0.25 respectively. Incidence of IA was 21% and diagnosis of IA up until the final chemotherapy cycle was associated with an increased risk of dying from leukaemia (cause-specific hazard ratio (
CS HR): 1.75, 95% CI 1.34-2.28) and a trend was seen for infection (CS HR: 1.36, 95% CI 0.96-1.91)., Conclusion: Leukaemia was the most likely cause of death over time, however in the first year after diagnosis of AML or high-risk MDS infection was the most likely cause of death. Patients with IA had a relatively increased risk of dying from leukaemia or infection., (© 2023. The Author(s).)- Published
- 2023
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34. In patients with hemophilia, a decreased thrombin generation profile is associated with a severe bleeding phenotype.
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Verhagen MJA, van Heerde WL, van der Bom JG, Beckers EAM, Blijlevens NMA, Coppens M, Gouw SC, Jansen JH, Leebeek FWG, van Vulpen LFD, Meijer D, and Schols SEM
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Background: Heterogeneity in clinical bleeding phenotype has been observed in hemophilia patients with similar FVIII or FIX activity levels. Thrombin generation and plasmin generation, as a global hemostasis assay, may contribute to a better prediction of which patients are at an increased risk of bleeding., Objectives: The objective of this study was to describe the association between clinical bleeding phenotype and thrombin generation and plasmin generation profiles in patients with hemophilia., Methods: The Nijmegen Hemostasis Assay, which simultaneously measures thrombin and plasmin generation, was performed in plasma samples of patients with hemophilia participating in the sixth Hemophilia in the Netherlands study (HiN6). Patients receiving prophylaxis underwent a washout period. A severe clinical bleeding phenotype was defined as a self-reported annual bleeding rate of ≥5, a self-reported annual joint bleeding rate of ≥3, or the use of secondary/tertiary prophylaxis., Results: In total, 446 patients, with a median age of 44 years, were included in this substudy. Thrombin generation and plasmin generation parameters differed between patients with hemophilia and healthy individuals. The median thrombin peak height was 1.0 nM, 25.9 nM, 47.1 nM, and 143.9 nM in patients with severe, moderate, and mild hemophilia and healthy individuals, respectively. A severe bleeding phenotype was observed in patients with a thrombin peak height of <49% and a thrombin potential of <72% compared to healthy individuals, and was independent of the hemophilia severity. The median thrombin peak height was 0.70% in patients with a severe clinical bleeding phenotype and 30.3% in patients with a mild clinical bleeding phenotype. The median thrombin potentials for these patients were 0.06% and 59.3%, respectively., Conclusion: A decreased thrombin generation profile is associated with a severe clinical bleeding phenotype in patients with hemophilia. Thrombin generation in combination with bleeding severity may be a better tool to personalize prophylactic replacement therapy irrespective of hemophilia severity., (© 2023 The Author(s).)
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- 2023
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35. Treatment patterns and clinical outcomes of asciminib in a real-world multiresistant chronic myeloid leukemia patient population.
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Kockerols CCB, Janssen JJWM, Blijlevens NMA, Klein SK, Van Hussen-Daenen LGM, Van Gorkom GGY, Smit WM, Van Balen P, Biemond BJ, Cruijsen MJ, Corsten MF, Te Boekhorst PAW, Koene HR, Van Sluis GL, Cornelissen JJ, and Westerweel PE
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- Humans, Pyrazoles therapeutic use, Niacinamide therapeutic use, Protein Kinase Inhibitors therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid drug therapy
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- 2023
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36. Person-centred online lifestyle coaching in childhood, adolescent, and young adult cancer survivors: protocol of the multicentre PanCareFollowUp lifestyle intervention feasibility study.
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Bouwman E, Hermens RPMG, Brown MC, Araújo-Soares V, Blijlevens NMA, Kepak T, Kepakova K, Kremer LCM, van den Oever SR, van der Pal HJH, Skinner R, Pluijm SMF, and Loonen JJ
- Abstract
Background: Physical inactivity and unhealthy dietary habits are known to be disadvantageous for the development of late adverse effects in survivors of childhood, adolescent, and young adult cancer. To make interventions, aimed at improving lifestyle, fit into the daily life of survivors, interventions should be designed and delivered in a person-centred way with a limited time burden. As part of the European PanCareFollowUp project, an eHealth intervention was developed to support sustainable changes to physical activity levels and/or diet of childhood, adolescent, and young adult cancer survivors. This feasibility study aims to gain insight into the feasibility and potential effect sizes of the PanCareFollowUp lifestyle intervention., Methods: The PanCareFollowUp lifestyle intervention consists of person-centred 3-6 screen-to-screen sessions with a certified lifestyle coach. The intervention will be evaluated with a single-arm pre-post feasibility study conducted at two survivorship care clinics in the Netherlands. A total of 60 participants who are (i) diagnosed with cancer <25 years, (ii) ≥ 5 years post-treatment, (iii) aged 16-55 years, and (iv) have a low physical activity level and/or unhealthy dietary intake manifested by overweight will be recruited. Using reports, hospital records, and questionnaires for survivors, coaches, and late effect doctors, feasibility will be based on (i) adherence to intervention, (ii) acceptability, (iii) practicality, (iv) integration/implementation, (v) demand, and (vi) attrition. The potential effect sizes of the intervention will be explored by determining the percentage of survivors that reach the personalized lifestyle goals that were set with the coach. Physical activity level, dietary intake, BMI, general self-efficacy, self-management, and motivation level will be assessed at three time points with questionnaires, reports, and/or an accelerometer., Discussion: Data of this study will be gathered to assess the feasibility and potential effect sizes. This will allow for further intervention refinement as needed as well as to inform a future large-scale intervention study and a manual for implementation at other centres., Trial Registration: International Clinical Trial Registry Platform (ICTRP) number: NL8932 (ICTRP Search Portal (who.int)). Registered on September 29, 2020., (© 2022. The Author(s).)
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- 2022
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37. The Dutch Working Party on Antibiotic Policy (SWAB) Recommendations for the Diagnosis and Management of Febrile Neutropenia in Patients with Cancer.
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de la Court JR, Bruns AHW, Roukens AHE, Baas IO, van Steeg K, Toren-Wielema ML, Tersmette M, Blijlevens NMA, Huis In 't Veld RAG, Wolfs TFW, Tissing WJE, Kyuchukova Y, and Heijmans J
- Abstract
Introduction: This guideline was written by a multidisciplinary committee with mandated members of the Dutch Society for Infectious Diseases, Dutch Society for Hematology, Dutch Society for Medical Oncology, Dutch Association of Hospital Pharmacists, Dutch Society for Medical Microbiology, and Dutch Society for Pediatrics. The guideline is written for adults and pediatric patients., Method: The recommendations are based on the answers to nine questions formulated by the guideline committee. To provide evidence-based recommendations we used all relevant clinical guidelines published since 2010 as a source, supplemented with systematic searches and evaluation of the recent literature (2010-2020) and, where necessary, supplemented by expert-based advice., Results: For adults the guideline distinguishes between high- and standard-risk neutropenia based on expected duration of neutropenia (> 7 days versus ≤ 7 days). Where possible a distinction has been made between pediatric and adult patients., Conclusion: This guideline was written to aid diagnosis and management of patients with febrile neutropenia due to chemotherapy in the Netherlands. The guideline provides recommendation for children and adults. Adults patient are subdivided as having a standard- or high-risk neutropenic episode based on estimated duration of neutropenia. The most important recommendations are as follows. In adults with high-risk neutropenia (duration of neutropenia > 7 days) and in children with neutropenia, ceftazidime, cefepime, and piperacillin-tazobactam are all first-choice options for empirical antibiotic therapy in case of fever. In adults with standard-risk neutropenia (duration of neutropenia ≤ 7 days) the MASCC score can be used to assess the individual risk of infectious complications. For patients with a low risk of infectious complications (high MASCC score) oral antibiotic therapy in an outpatient setting is recommended. For patients with a high risk of infectious complications (low MASCC score) antibiotic therapy per protocol sepsis of unknown origin is recommended., (© 2022. The Author(s).)
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- 2022
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38. Invasive Fungal Disease in Patients with Myeloid Malignancies: A Retrospective Cohort Study of a Diagnostic-Driven Care Pathway Withholding Mould-Active Prophylaxis.
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De Kort EA, Buil JB, Schalekamp S, Schaefer-Prokop C, Verweij PE, Schaap NPM, Blijlevens NMA, and Van der Velden WJFM
- Abstract
Objectives: Patients receiving remission induction therapy for acute myeloid leukaemia (AML) are at high risk of developing invasive fungal disease (IFD). Newer therapies with targeted antileukemic agents and the emergence of azole resistance pose a challenge to the strategy of primary antifungal prophylaxis. We report the experience of a diagnostic-driven care pathway (DCP) for the management of IFD in these patients, using only culture-directed mould inactive prophylaxis., Methods: Retrospectively, we used a single-centre study of consecutive patients receiving intensive chemotherapy for myeloid malignancies between 2014 and 2021. DCP consisted of serial cultures and serum galactomannan (sGM) screening, CT imaging, and bronchoscopy to direct targeted antifungal treatment. IFD was classified according to the 2020 EORTC/MSGERC criteria., Results: A total of 192 patients with myeloid malignancies received 300 courses of intensive chemotherapy. There were 14 cases of invasive yeast infections and 18 of probable/proven invasive mould disease (IMD). The incidence of probable/proven IMD during the first cycle of remission-induction chemotherapy was 4.6% (n = 9). sGM remained negative in all cases of invasive aspergillosis (IA), with positive mycology findings in bronchoalveolar lavage. All-cause mortality was 9.4% (n = 18) 100 days after starting chemotherapy and was comparable between patients with or without IFD. The fungal-related mortality was 1% (n = 2)., Conclusion: Diagnostic-driven based management without universal mould active prophylaxis is a feasible strategy in the management of IFD and limits unnecessary antimould treatment during intensive chemotherapy. The poor performance of serial serum galactomannan screening in detecting IA warrants further investigation.
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- 2022
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39. Posaconazole bioavailability of the solid oral tablet is reduced during severe intestinal mucositis.
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Jansen AME, Muilwijk EW, van der Velden WJFM, Maertens JA, Aerts R, Colbers A, Burger D, Verweij PE, Ter Heine R, Blijlevens NMA, and Brüggemann RJM
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- Administration, Oral, Antifungal Agents, Biological Availability, Humans, Tablets adverse effects, Tablets pharmacokinetics, Triazoles, Mucositis chemically induced
- Abstract
Objectives: This study aimed to describe the absolute oral bioavailability of the solid oral formulation of posaconazole and the impact of severe intestinal mucositis in haematology patients. This study also aimed to describe posaconazole protein binding in haematology patients., Methods: A pharmacokinetic study was performed of patients receiving induction chemotherapy or a haematopoietic cell transplantation who were randomized to receive 7 days of intravenous posaconazole therapy followed by 9 days of oral therapy, or vice versa. Patients received a posaconazole licensed dose until day 12, after which a reduced once-daily dose of 200 mg was given. At days 7, 12, and 16, blood samples were obtained for pharmacokinetic curves, and trough samples were collected on all other days. Total and unbound posaconazole pharmacokinetics were analyzed by population pharmacokinetic modelling. The presence of severe intestinal mucositis was assessed by plasma citrulline levels and analyzed as a binary covariate using 10 μmol/L as the cut-off. Monte Carlo simulations were performed to simulate posaconazole exposure at a steady state., Results: Twenty-three patients were included for analysis, with 581 total posaconazole concentrations and 91 paired unbound concentrations. Absolute bioavailability in the final model was estimated at 51.4% (percentage relative standard error (%RSE): 56.5) and 67.6% (%RSE: 75.0) in patients with and without severe intestinal mucositis, respectively. Posaconazole unbound fraction was estimated at 2.7% (%RSE: 3.9)., Discussion: Posaconazole bioavailability is reduced in haematological patients with severe intestinal mucositis, requiring an increase in oral posaconazole dose to 400 mg twice daily on day 1, followed by 400 mg once daily or a switch to intravenous therapy., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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40. Combining factor VIII levels and thrombin/plasmin generation: A population pharmacokinetic-pharmacodynamic model for patients with haemophilia A.
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Bukkems LH, Valke LLFG, Barteling W, Laros-van Gorkom BAP, Blijlevens NMA, Cnossen MH, van Heerde WL, Schols SEM, and Mathôt RAA
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- Factor VIII, Fibrinolysin, Hemorrhage prevention & control, Humans, Thrombin, Hemophilia A drug therapy, Hemostatics
- Abstract
Aims: Prophylactic treatment of haemophilia A patients with factor VIII (FVIII) concentrate focuses on maintaining a minimal trough FVIII activity level to prevent bleeding. However, due to differences in bleeding tendency, the pharmacokinetic (PK)-guided dosing approach may be suboptimal. An alternative approach could be the addition of haemostatic pharmacodynamic (PD) parameters, reflecting a patient's unique haemostatic balance. Our aim was to develop a population PK/PD model, based on FVIII activity levels and Nijmegen Haemostasis Assay (NHA) patterns, a global haemostatic assay that measures thrombin/plasmin generation simultaneously., Methods: PK/PD measurements were collected from 30 patients treated with standard half-life FVIII concentrate. The relationship between FVIII activity levels and the thrombin/plasmin generation parameters (thrombin potential, thrombin peak height and plasmin peak height), were described by sigmoidal E
max functions., Results: The obtained EC50 value was smallest for the normalized thrombin potential (11.6 IU/dL), followed by normalized thrombin peak height (56.6 IU/dL) and normalized plasmin peak height (593 IU/dL), demonstrating that normalized thrombin potential showed 50% of the maximal effect at lower FVIII activity levels. Substantial inter-individual variability in the PD parameters, such as EC50 of thrombin potential (86.9%) was observed, indicating that, despite similar FVIII activity levels, haemostatic capacity varies significantly between patients., Conclusion: These data suggest that dosing based on patients' individual PK/PD parameters may be beneficial over dosing solely on individual PK parameters. This model could be used as proof-of-principle to examine the application of PK/PD-guided dosing. However, the relation between the PD parameters and bleeding has to be better defined., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2022
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41. Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra.
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Wardill HR, de Mooij CEM, Da Silva Ferreira AR, Havinga H, Harmsen HJM, van der Velden WJFM, van Groningen LFJ, Tissing WJE, and Blijlevens NMA
- Subjects
- Animals, Fever etiology, Humans, Interleukin 1 Receptor Antagonist Protein, Interleukin-1, Melphalan therapeutic use, Rats, Tumor Microenvironment, Hematopoietic Stem Cell Transplantation adverse effects, Multiple Myeloma diagnosis
- Abstract
High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100-300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776., (© 2022. The Author(s).)
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- 2022
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42. Treatment of patients with rare bleeding disorders in the Netherlands: Real-life data from the RBiN study.
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Maas DPMSM, Saes JL, Blijlevens NMA, Cnossen MH, den Exter PL, Kruis IC, Meijer K, Nieuwenhuizen L, Peters M, Schutgens REG, van Heerde WL, and Schols SEM
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- Hemorrhage, Humans, Netherlands, Rare Diseases diagnosis, Rare Diseases therapy, Factor XI Deficiency complications, Hemophilia A complications, Hemostatics adverse effects
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Background: Patients with rare inherited bleeding disorders (RBDs) exhibit hemorrhagic symptoms, varying in type and severity, often requiring only on-demand treatment. Prolonged bleeding after invasive procedures is common. Adequate peri-procedural therapy may reduce this bleeding risk., Objective: To describe general treatment plans of RBD patients and evaluate the use of peri-procedural hemostatic therapy., Methods: In the Rare Bleeding Disorders in the Netherlands (RBiN) study, RBD patients from all six Dutch Hemophilia Treatment Centers were included. General treatment plans were extracted from patient files. Patients with a dental or surgical procedure in their history were interviewed about use of peri-procedural treatment and bleeding complications., Results: Two-hundred sixty-three patients with a rare coagulation factor deficiency or fibrinolytic disorder were included. Eighty-four percent had a documented general treatment plan. General treatment plans of patients with the same RBD were heterogeneous, particularly in factor XI deficiency. Overall, 308 dental and 408 surgical procedures were reported. Bleeding occurred in 50% of dental and 53% of surgical procedures performed without hemostatic treatment and in 28% of dental and 19% of surgical procedures performed with hemostatic treatment. Not only patients with severe RBDs, but also patients with mild deficiencies, experienced increased bleeding without proper hemostatic treatment., Conclusion: Large heterogeneity in general treatment plans of RBD patients was found. Bleeding after invasive procedures was reported frequently, both before and after RBD diagnosis, irrespective of factor activity levels and particularly when peri-procedural treatment was omitted. Improved guidelines should include uniform recommendations for most appropriate hemostatic products per RBD and emphasize the relevance of individual bleeding history., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)
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- 2022
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43. Fibrinolytic assays in bleeding of unknown cause: Improvement in diagnostic yield.
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Valke LLFG, Meijer D, Nieuwenhuizen L, Laros-van Gorkom BAP, Blijlevens NMA, van Heerde WL, and Schols SEM
- Abstract
Introduction: Analysis of fibrinolytic disorders is challenging and may potentially lead to underdiagnosis of patients with an increased bleeding tendency., Aim: To compare clinical characteristics, laboratory measurements, and treatment modalities in a monocenter cohort of patients in whom fibrinolytic studies were performed., Methods: Retrospective study of patients in whom fibrinolytic studies were performed between January 2016 and February 2020 in the Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, the Netherlands. Plasminogen activator inhibitor type 1 (PAI-1) antigen and activity level, α2-antiplasmin activity, tissue plasminogen activator, and euglobulin clot lysis time (ECLT) before and after venous compression were determined in all patients. Data of bleeding assessment tool (BAT) score, clinical characteristics, results of primary and secondary hemostasis assays, and general treatment plans were collected., Results: In total, 160 patients were included: 97 (61%) without and 63 (39%) with a laboratory-based fibrinolytic disorder. Mean BAT score did not differ between the groups (9.3 vs 9.8, respectively). The presumptive fibrinolytic disorders were distributed as follows: 34 patients had an increased ECLT ratio or low baseline ECLT, 25 patients had low PAI-1 antigen and activity level, and four patients had both. The majority of these patients were treated with tranexamic acid monotherapy (60%) with only 40% additional treatment options, whereas 80% of patients without a presumptive fibrinolytic disorder had multiple treatment modalities., Discussion: Analysis of fibrinolytic disorders in selected patients has a high diagnostic yield. General incorporation of fibrinolytic analysis in the diagnostic workup of patients with bleeding of unknown cause can improve diagnosis and management of their bleeding episodes., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)
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- 2022
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44. Time trends in primary therapy and relative survival of diffuse large B-cell lymphoma by stage: a nationwide, population-based study in the Netherlands, 1989-2018.
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Durmaz M, Visser O, Posthuma EFM, Brouwer RE, Issa DE, de Jong D, Lam KH, Blijlevens NMA, Zijlstra JM, Chamuleau MED, Lugtenburg PJ, Kersten MJ, and Dinmohamed AG
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclophosphamide therapeutic use, Doxorubicin therapeutic use, Humans, Immunotherapy, Netherlands epidemiology, Prednisone therapeutic use, Rituximab therapeutic use, Treatment Outcome, Vincristine therapeutic use, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse therapy
- Abstract
It is unclear whether survival in diffuse large B-cell lymphoma (DLBCL) continues to increase in an era where rituximab-containing chemotherapy reigns for almost two decades. Therefore, we evaluated trends in primary therapy and relative survival (RS) among Dutch DLBCL patients diagnosed between 1989 and 2018. Analyses were performed separately according to the stage I (N = 6952) and stage II-IV disease (N = 20,676), stratified by calendar period and age (18-64, 65-74, and ≥75 years). The use of chemotherapy ± radiotherapy increased over time across all age and stage groups. As of the mid-2000s, >95% of chemotherapy-treated patients received chemoimmunotherapy, irrespective of age and stage. Overall, RS increased significantly over time across all age groups, especially after 2003 when rituximab-containing chemotherapy had become the standard of care. However, RS increased less pronounced between 2003-2010 and 2011-2018 than between 1989-2002 and 2003-2010. These findings were congruent across all studied stage groups. Five-year RS across the three age groups during 2011-2018 was 96%, 84%, and 67% for stage I DLBCL and 75%, 60%, and 46% for stage II-IV DLBCL. Collectively, survival in DLBCL increased modestly beyond the initial introduction of rituximab, with apparent survival differences across age and stage that warrant novel treatment approaches., (© 2022. The Author(s).)
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- 2022
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45. Von Willebrand disease type 2M: Correlation between genotype and phenotype.
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Maas DPMSM, Atiq F, Blijlevens NMA, Brons PPT, Krouwel S, Laros-van Gorkom BAP, Leebeek FWG, Nieuwenhuizen L, Schoormans SCM, Simons A, Meijer D, van Heerde WL, and Schols SEM
- Subjects
- Genotype, Humans, Phenotype, von Willebrand Factor chemistry, von Willebrand Factor genetics, von Willebrand Disease, Type 2 diagnosis, von Willebrand Disease, Type 2 genetics, von Willebrand Diseases diagnosis, von Willebrand Diseases genetics
- Abstract
Background: An appropriate clinical diagnosis of von Willebrand disease (VWD) can be challenging because of a variable bleeding pattern and laboratory phenotype. Genotyping is a powerful diagnostic tool and may have an essential role in the diagnostic field of VWD., Objectives: To unravel the clinical and laboratory heterogeneity of genetically confirmed VWD type 2M patients and to investigate their relationship., Methods: Patients with a confirmed VWD type 2M genetic variant in the A1 or A3 domain of von Willebrand factor (VWF) and normal or only slightly aberrant VWF multimers were selected from all subjects genotyped at the Radboud university medical center because of a high suspicion of VWD. Bleeding scores and laboratory results were analyzed., Results: Fifty patients had a clinically relevant genetic variant in the A1 domain. Median bleeding score was 5. Compared with the nationwide Willebrand in the Netherlands study type 2 cohort, bleeding after surgery or delivery was reported more frequently and mucocutaneous bleedings less frequently. Median VWF activity/VWF antigen (VWF:Act/VWF:Ag) ratio was 0.32, whereas VWF collagen binding activity/VWF antigen (VWF:CB/VWF:Ag) ratio was 0.80. Variants in the A3 domain were only found in two patients with low to normal VWF:Act/VWF:Ag ratios (0.45, 1.03) and low VWF:CB/VWF:Ag ratios (0.45, 0.63)., Conclusion: Genetically confirmed VWD type 2M patients have a relatively mild clinical phenotype, except for bleeding after surgery and delivery. Laboratory phenotype is variable and depends on the underlying genetic variant. Addition of genotyping to the current phenotypic characterization may improve diagnosis and classification of VWD., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)
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- 2022
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46. Risk of second primary malignancies in patients with follicular lymphoma: a population-based study in the Netherlands, 1989-2018.
- Author
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Dinnessen MAW, Visser O, Tonino SH, Posthuma EFM, Blijlevens NMA, Kersten MJ, Lugtenburg PJ, and Dinmohamed AG
- Subjects
- Aged, Female, Follow-Up Studies, Humans, Male, Middle Aged, Netherlands, Risk Factors, Lymphoma, Follicular diagnosis, Lymphoma, Follicular drug therapy, Lymphoma, Follicular mortality, Neoplasms, Second Primary diagnosis, Neoplasms, Second Primary drug therapy, Neoplasms, Second Primary mortality
- Published
- 2021
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47. Manufacturers' views on outcome-based agreements.
- Author
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Barjestehvan Waalwijk van Doorn-Khosrovani S, Timmers L, Pisters-van Roy A, Gijzen J, Blijlevens NMA, and Bloemendal H
- Abstract
Introduction: Outcome-based agreements (OBAs) are occasionally deployed to relieve the burden of high drug prices on healthcare budgets. However, it is not clear when manufacturers are willing to collaborate in establishing such agreements. Therefore, we explored the feasibility of OBAs from the manufacturer's point of view., Methods: Dutch market-access experts from eight major pharmaceutical companies, globally active in the field of oncology, were interviewed. Opinions were compiled, and interviewees and their colleagues were then given the chance to review the manuscript for additional comments., Results: Most interviewees believe that OBAs can be useful in providing access to off-label use of authorised medicines, especially when no alternative treatment is available for seriously ill patients. For the licenced indications, manufacturers seem to be more inclined to collaborate when there is a potential incentive to improve market-access (e.g., if the product is not used because of concerns regarding its effectiveness). However, manufacturers are less likely to collaborate when there are greater financial risks for the company. Further concerns were definition of outcome or performance, the impact of compliance on the effectiveness of a drug, administrative burden, uncertainty regarding revenue recognition and the challenges of reimbursing combination therapies., Discussion: Market-access interviewees were generally positive about OBAs, however they were more reluctant towards OBAs for registered indications with low response-rate. The definition of performance or outcome and its clinical relevance and validity, the feasibility of OBAs and their administrative burden are relevant aspects that need to be addressed in advance. Ideally, countries should collaborate to share the outline of OBAs and create shared databases to accumulate evidence., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)
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- 2021
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48. Infections during eculizumab therapy in a Dutch population of patients with paroxysmal nocturnal haemoglobinuria.
- Author
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Schaap CCM, Grotens A, de Haan AFJ, Blijlevens NMA, and Langemeijer SMC
- Subjects
- Humans, Netherlands, Antibodies, Monoclonal, Humanized therapeutic use, Hemoglobinuria, Paroxysmal complications, Hemoglobinuria, Paroxysmal drug therapy, Infections epidemiology
- Published
- 2021
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49. Effect of Digital Care Platforms on Quality of Care for Oncological Patients and Barriers and Facilitators for Their Implementation: Systematic Review.
- Author
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Hopstaken JS, Verweij L, van Laarhoven CJHM, Blijlevens NMA, Stommel MWJ, and Hermens RPMG
- Subjects
- Communication, Humans, Qualitative Research, Quality of Health Care, Health Personnel, Patient Participation
- Abstract
Background: Oncological health care services are challenged by the increasing number of cancer survivors, long-term follow-up care, and fragmentation of care. Digital care platforms are potential tools to deliver affordable, patient-centered oncological care. Previous reviews evaluated only one feature of a digital care platform or did not evaluate the effect on enhancement of information, self-efficacy, continuity of care, or patient- and health care provider-reported experiences. Additionally, they have not focused on the barriers and facilitators for implementation of a digital care platform in oncological care., Objective: The aim of this systematic review was to collect the best available evidence of the effect of a digital care platform on quality of care parameters such as enhancement of available information, self-efficacy, continuity of care, and patient- and health care provider-reported experiences. Additionally, barriers and facilitators for implementation of digital care platforms were analyzed., Methods: The PubMed (Medline), Embase, CINAHL, and Cochrane Library databases were searched for the period from January 2000 to May 2020 for studies assessing the effect of a digital care platform on the predefined outcome parameters in oncological patients and studies describing barriers and facilitators for implementation. Synthesis of the results was performed qualitatively. Barriers and facilitators were categorized according to the framework of Grol and Wensing. The Mixed Methods Appraisal Tool was used for critical appraisal of the studies., Results: Seventeen studies were included for final analysis, comprising 8 clinical studies on the effectiveness of the digital care platform and 13 studies describing barriers and facilitators. Usage of a digital care platform appeared to enhance the availability of information and self-efficacy. There were no data available on the effect of a digital care platform on the continuity of care. However, based on focus group interviews, digital care platforms could potentially improve continuity of care by optimizing the exchange of patient information across institutes. Patient-reported experiences such as satisfaction with the platform were considerably positive. Most barriers for implementation were identified at the professional level, such as the concern for increased workload and unattended release of medical information to patients. Most facilitators were found at the patient and innovation levels, such as improved patient-doctor communication and patient empowerment. There were few barriers and facilitators mentioned at the economic and political levels., Conclusions: The use of digital care platforms is associated with better quality of care through enhancement of availability of information and increased self-efficacy for oncological patients. The numerous facilitators identified at the patient level illustrate that patients are positive toward a digital care platform. However, despite these favorable results, robust evidence concerning the effectiveness of digital care platforms, especially from high-quality studies, is still lacking. Future studies should therefore aim to further investigate the effectiveness of digital care platforms, and the barriers and facilitators to their implementation at the economic and political levels., (©Jana S Hopstaken, Lynn Verweij, Cees J H M van Laarhoven, Nicole M A Blijlevens, Martijn W J Stommel, Rosella P M G Hermens. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 24.09.2021.)
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- 2021
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50. The potential of individualized dosing of ravulizumab to improve patient-friendliness of paroxysmal nocturnal haemoglobinuria treatment at reduced costs.
- Author
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Ter Avest M, Langemeijer SMC, Schols SEM, Burger DM, van de Kar NCAJ, Blijlevens NMA, Kievit W, and Ter Heine R
- Subjects
- Antibodies, Monoclonal, Humanized, Complement Inactivating Agents, Cost-Benefit Analysis, Humans, Hemoglobinuria, Paroxysmal drug therapy
- Abstract
Ravulizumab is a very expensive complement C5-inhibitor for the treatment of paroxysmal nocturnal haemoglobinuria, with a fixed-dosing interval of 8 weeks. For lifelong treatment, a cost-effective and patient-friendly dosing strategy is preferred. We therefore explored alternative ravulizumab dosing regimens in silico based on the thorough dose-finding studies of the manufacturer. Extending the interval to 10 weeks or individually extending the interval to a mean of 12.8 weeks based on pharmacokinetic monitoring resulted in noninferior efficacy in terms of lactate dehydrogenase normalization, with drug cost savings up to 37%. We here show the potential of individualized ravulizumab dosing to improve patient-friendliness at reduced costs., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
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- 2021
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