3,937 results on '"Clinical Haematology"'
Search Results
2. Guidelines For The Prevention And Treatment Of Infection In Patients With An Absent Or Dysfunctional Spleen
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The British Committee For Standards In Haematology Clinical Haematology Task Force
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- 1996
3. Medical Jeopardy Quiz: Medicinal Plants
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Jain, Ankur
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- 2024
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4. Comments on COVID-19 and AL Amyloidosis, the Missing Links
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Jain, Ankur
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- 2022
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5. Lack of reproducibility of histopathological features in MYC-rearranged large B cell lymphoma using digital whole slide images
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Yasodha Natkunam, Daphne de Jong, Pedro Farinha, Philippe Gaulard, Wolfram Klapper, Andreas Rosenwald, Birgitta Sander, Reuben Tooze, Ranjana Advani, Catherine Burton, John G Gribben, Marie‐José Kersten, Eva Kimby, Georg Lenz, Thierry Molina, Franck Morschhauser, David Scott, Laurie Sehn, Wendy Stevens, Andrew Clear, Maryse Baia, Abdelmalek Habi, Mad‐Helenie Elsensohn, Carole Langlois‐Jacques, Delphine Maucort‐Boulch, Maria Calaminici, Clinical Haematology, AII - Cancer immunology, CCA - Cancer Treatment and Quality of Life, CCA - Cancer biology and immunology, and Pathology
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Histology ,FISH ,MYC-rearrangement ,General Medicine ,high-grade B cell lymphoma ,diffuse large B cell lymphoma ,Pathology and Forensic Medicine ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,digital whole slide image - Abstract
Contains fulltext : 294569.pdf (Publisher’s version ) (Open Access) AIMS: Subclassification of large B cell lymphoma (LBCL) is challenging due to the overlap in histopathological, immunophenotypical and genetic data. In particular, the criteria to separate diffuse large B cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBL) are difficult to apply in practice. The Lunenburg Lymphoma Biomarker Consortium previously reported a cohort of over 5000 LBCL that included fluorescence in-situ hybridisation (FISH) data. This cohort contained 209 cases with MYC rearrangement that were available for a validation study by a panel of eight expert haematopathologists of how various histopathological features are used. METHODS AND RESULTS: Digital whole slide images of haematoxylin and eosin-stained sections allowed the pathologists to visually score cases independently as well as participate in virtual joint review conferences. Standardised consensus guidelines were formulated for scoring histopathological features and included overall architecture/growth pattern, presence or absence of a starry-sky pattern, cell size, nuclear pleomorphism, nucleolar prominence and a range of cytological characteristics. Despite the use of consensus guidelines, the results show a high degree of discordance among the eight expert pathologists. Approximately 50% of the cases lacked a majority score, and this discordance spanned all six histopathological features. Moreover, none of the histological variables aided in prediction of MYC single versus double/triple-hit or immunoglobulin-partner FISH-based designations or clinical outcome measures. CONCLUSIONS: Our findings indicate that there are no specific conventional morphological parameters that help to subclassify MYC-rearranged LBCL or select cases for FISH analysis, and that incorporation of FISH data is essential for accurate classification and prognostication.
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- 2023
6. Nationwide study of eculizumab in paroxysmal nocturnal hemoglobinuria: Evaluation of treatment indications and outcomes
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Schaap, C.C.M., Heubel-Moenen, F.C.J.I., Nur, E., Bartels, M., Heijden, O.W.H. van der, Jonge, Emiel de, Preijers, F.W.M.B., Blijlevens, N.M.A., Langemeijer, S.M.C., MUMC+: MA Hematologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, and CCA - Cancer biology and immunology
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paroxysmal nocturnal hemoglobinuria ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,pregnancy outcomes ,PNH ,LONG-TERM SAFETY ,Hematology ,General Medicine ,treatment outcomes ,NATURAL-HISTORY ,KIDNEY-FUNCTION ,DISEASE ,hematological response ,Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2] ,All institutes and research themes of the Radboud University Medical Center ,PREGNANCY ,FUNCTIONAL ASSESSMENT ,MANAGEMENT ,eculizumab ,COMPLEMENT INHIBITOR ECULIZUMAB ,REQUIREMENTS ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 292509.pdf (Publisher’s version ) (Open Access) Eculizumab is an effective treatment for paroxysmal nocturnal hemoglobinuria (PNH). However, considering the risk of life-threatening meningococcal disease, life-long duration and costs, there are strict criteria for initiation of therapy. To evaluate the application and real-world effectiveness of eculizumab in the Netherlands, a multicenter retrospective cohort study was conducted: indications and treatment outcomes were collected for 105 Dutch PNH patients. In all patients, eculizumab was initiated conforming to indications as formulated in the Dutch PNH guideline. According to recently published response criteria, 23.4% of the patients had reached a complete hematological response, 53.2% a good or partial response, and 23.4% a minor response after 12 months of therapy. In the majority of patients the response remained stable during long-term follow-up. The degree and relevance of extravascular hemolysis significantly differed between response groups (p = 0.002). Improvements of EORTC-QLQc30 and FACIT-fatigue scores were observed, however patients reported lower scores than the general population. A detailed evaluation of 18 pregnancies during eculizumab showed no maternal or fetal deaths, and no thromboembolic events during pregnancy. This study demonstrates that the majority of patients benefit from eculizumab when adhering to the indications as formulated in the Dutch PNH guideline. However, novel therapies are needed to further improve real-world outcomes, such as hematological responses and quality of life. 01 juni 2023
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- 2023
7. Bendamustine plus rituximab for the treatment of Waldenström Macroglobulinemia
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Suzanne O. Arulogun, Duncan Brian, Harshita Goradia, Aaron Cooney, Tobias Menne, RayMun Koo, Aideen T. O'Neill, Josephine M. I. Vos, Guy Pratt, Deborah Turner, Kirsty Marshall, Kate Manos, Claire Anderson, Maria Gavriatopoulou, Charalampia Kyriakou, Marie J. Kersten, Monique C. Minnema, Eirini Koutoumanou, Dima El‐Sharkawi, Kim Linton, Dipti Talaulikar, Helen McCarthy, Mark Bishton, George Follows, Ashutosh Wechalekar, Shirley P. D'Sa, Clinical Haematology, General Internal Medicine, AII - Cancer immunology, CCA - Cancer biology and immunology, and CCA - Cancer Treatment and Quality of Life
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Hematology - Abstract
Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not well-established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively (p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m2 compared with those receiving 800–999 mg/m2 (p = 0.04). In the relapsed cohort, those who received doses of
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- 2023
8. Risk of second primary malignancies in patients with chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989-2019
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Lina van der Straten, Mark-David Levin, Manette A. W. Dinnessen, Otto Visser, Eduardus F. M. Posthuma, Jeanette K. Doorduijn, Anton W. Langerak, Arnon P. Kater, Avinash G. Dinmohamed, Immunology, Hematology, Public Health, VU University medical center, Experimental Immunology, Clinical Haematology, AII - Cancer immunology, and CCA - Cancer biology and immunology
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Oncology ,Hematology - Abstract
The longevity of patients with chronic lymphocytic leukemia (CLL) has improved progressively over the past decades, making it essential to understand long-term health outcomes, such as second primary malignancies (SPMs). Therefore, this nationwide, population-based study assessed the risk of SPM development in CLL patients diagnosed during 1989-2019 in the Netherlands compared to the expected number of malignancies in an age-, sex-, and period-matched group from the general Dutch population. In 24,815 CLL patients followed for 162,698.49 person-years, 4369 SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.63 (95% confidence interval [CI] 1.59–1.68). This elevated risk was observed for solid (SIR, 1.67; 95% CI, 1.65–1.75) and hematological SPMs (SIR 1.42; 95% CI, 1.24–1.62). The highest risk for SPMs was noted beyond five years post-diagnosis (SIR, 1.70; 95% CI, 1.62–1.77), for male individuals (SIR, 1.70; 95% CI, 1.64–1.77), and patients aged 18–69 years (SIR, 1.92; 95% CI, 1.79–2.05). The risk of SPMs was higher in CLL patients who received anti-neoplastic therapy (SIR, 2.12; 95% CI, 1.96–2.28), as compared with those who did not (SIR, 1.58; 95% CI, 1.53–1.63). Routine surveillance activities and tailored interventions to counteract the increased morbidity and excess mortality associated with SPMs are essential for improving long-term outcomes in CLL patients.
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- 2023
9. MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas
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Marthe Minderman, Hildo C. Lantermans, Leonie J. Grüneberg, Saskia A. G. M. Cillessen, Richard J. Bende, Carel J. M. van Noesel, Marie José Kersten, Steven T. Pals, Marcel Spaargaren, Graduate School, Pathology, AII - Cancer immunology, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, AII - Inflammatory diseases, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, 09 Laboratory specialisms, and Amsterdam Gastroenterology Endocrinology Metabolism
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Oncology ,Hematology - Abstract
The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is a protease and scaffold protein essential in propagating B-cell receptor (BCR) signaling to NF-κB. The deubiquitinating enzyme cylindromatosis (CYLD) is a recently discovered MALT1 target that can negatively regulate NF-κB activation. Here, we show that low expression of CYLD is associated with inferior prognosis of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients, and that chronic BCR signaling propagates MALT1-mediated cleavage and, consequently, inactivation and rapid proteasomal degradation of CYLD. Ectopic overexpression of WT CYLD or a MALT1-cleavage resistant mutant of CYLD reduced phosphorylation of IκBα, repressed transcription of canonical NF-κB target genes and impaired growth of BCR-dependent lymphoma cell lines. Furthermore, silencing of CYLD expression rendered BCR-dependent lymphoma cell lines less sensitive to inhibition of NF-κΒ signaling and cell proliferation by BCR pathway inhibitors, e.g., the BTK inhibitor ibrutinib, indicating that these effects are partially mediated by CYLD. Taken together, our findings identify an important role for MALT1-mediated CYLD cleavage in BCR signaling, NF-κB activation and cell proliferation, which provides novel insights into the underlying molecular mechanisms and clinical potential of inhibitors of MALT1 and ubiquitination enzymes as promising therapeutics for DLBCL, MCL and potentially other B-cell malignancies.
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- 2023
10. Circulating Iron in Patients with Sickle Cell Disease Mediates the Release of Neutrophil Extracellular Traps
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van Avondt, Kristof, Schimmel, Marein, Bulder, Ingrid, van Mierlo, Gerard, Nur, Erfan, van Bruggen, Robin, Biemond, Bart J., Luken, Brenda M., Zeerleder, Sacha, General Paediatrics, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, CCA - Cancer biology and immunology, Landsteiner Laboratory, and AII - Inflammatory diseases
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Neutrophils ,Iron ,Sickle cell disease ,Immunology and Allergy ,Hematology ,Hemolysis ,Neutrophil extracellular traps - Abstract
Introduction: Neutrophils promote chronic inflammation and release neutrophil extracellular traps (NETs) that can drive inflammatory responses. Inflammation influences progression of sickle cell disease (SCD), and a role for NETs has been suggested in the onset of vaso-occlusive crisis (VOC). We aimed to identify factors in the circulation of these patients that provoke NET release, with a focus on triggers associated with hemolysis. Methods: Paired serum and plasma samples during VOC and steady state of 18 SCD patients (HbSS/HbSβ0-thal and HbSC/HbSβ+-thal) were collected. Cell-free heme, hemopexin, and labile plasma iron have been measured in the plasma samples of the SCD patients. NETs formation by human neutrophils from healthy donors induced by serum of SCD patients was studied using confocal microscopy and staining for extracellular DNA using Sytox, followed by quantification of surface coverage using ImageJ. Results: Eighteen patients paired samples obtained during VOC and steady state were available (11 HbSS/HbSβ0-thal and 7 HbSC/HbSβ+-thal). We observed high levels of systemic heme and iron, concomitant with low levels of the heme-scavenger hemopexin in sera of patients with SCD, both during VOC and in steady state. In our in vitro experiments, neutrophils released NETs when exposed to sera from SCD patients. The release of NETs was associated with high levels of circulating iron in these sera. Although hemin triggered NET formation in vitro, addition of hemopexin to scavenge heme did not suppress NET release in SCD sera. By contrast, the iron scavengers deferoxamine and apotransferrin attenuated NET formation in a significant proportion of SCD sera. Discussion: Our results suggest that redox-active iron in the circulation of non-transfusion-dependent SCD patients activates neutrophils to release NETs, and hence, exerts a direct pro-inflammatory effect. Thus, we propose that chelation of iron requires further investigation as a therapeutic strategy in SCD.
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- 2023
11. The association between renal function decline and disease severity in sickle cell disease
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Aafke E. Gaartman, Charlotte F. J. van Tuijn, Erfan Nur, Liffert Vogt, Bart J. Biemond, Experimental Immunology, Graduate School, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, CCA - Cancer biology and immunology, Nephrology, ACS - Microcirculation, APH - Health Behaviors & Chronic Diseases, and AII - Inflammatory diseases
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Hematology - Published
- 2023
12. Stem Cell Factor (SCF) Priming of Haematopoietic Stem Cell Grafts in Malignant Lymphoma (SCF980266)
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Herlev Hospital, Rigshospitalet, Denmark, Helsinki University Central Hospital, Turku University Hospital, University Hospital, Linkoeping, Umeå University, Oslo University Hospital, Nordic Lymphoma Group, Amgen, and Hans Erik Johnsen MD DMSc, Professor Clinical Haematology
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- 2015
13. Chronic lymphocytic leukemia presence impairs antigen-specific CD8+ T-cell responses through epigenetic reprogramming towards short-lived effectors
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Anne W. J. Martens, Inga Kavazović, Mia Krapić, Su Min Pack, Ramon Arens, Aldo Jongejan, Perry D. Moerland, Eric Eldering, Gerritje J. W. van der Windt, Felix M. Wensveen, Fleur S. Peters, Arnon P. Kater, Clinical Haematology, AII - Cancer immunology, CCA - Cancer biology and immunology, Epidemiology and Data Science, AII - Inflammatory diseases, APH - Methodology, APH - Personalized Medicine, AII - Infectious diseases, and Experimental Immunology
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Cancer Research ,Leukemia ,Oncology ,BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences ,CLL ,Effector CD8 T cells ,Hematology ,BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti - Abstract
T-cell dysregulation in chronic lymphocytic leukemia (CLL) associates with low response rates to autologous T cell-based therapies. How CLL affects antigen-specific T-cell responses remains largely unknown. We investigated (epi)genetic and functional consequences of antigen-specific T-cell responses in presence of CLL in vitro and in an adoptive-transfer murine model. Already at steady-state, antigen-experienced patient-derived T cells were skewed towards short-lived effector cells (SLEC) at the expense of memory-precursor effector cells (MPEC). Stimulation of these T cells in vitro showed rapid induction of effector genes and suppression of key memory transcription factors only in presence of CLL cells, indicating epigenetic regulation. This was investigated in vivo by following antigen-specific responses of naive OT-I CD8(+) cells to mCMV-OVA in presence/absence of TCL1 B-cell leukemia. Presence of leukemia resulted in increased SLEC formation, with disturbed inflammatory cytokine production. Chromatin and transcriptome profiling revealed strong epigenetic modifications, leading to activation of an effector and silencing of a memory profile through presence of CLL cells. Secondary challenge in vivo confirmed dysfunctional memory responses by antigen-experienced OT-I cells generated in presence of CLL. Altogether, we show that presence of CLL induces a short-lived effector phenotype and impaired memory responses by epigenetic reprogramming during primary responses.
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- 2023
14. Hyperimmune Globulin for Severely Immunocompromised Patients Hospitalized With Coronavirus Disease 2019
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Huygens, Sammy, Hofsink, Quincy, Nijhof, Inger S., Goorhuis, Abraham, Kater, Arnon P., Te Boekhorst, Peter A.W., Swaneveld, Francis, Novotný, Věra M.J., Bogers, Susanne, Welkers, Matthijs R.A., Papageorgiou, Grigorios, Rijnders, Bart J., Heijmans, Jarom, Graduate School, Clinical Haematology, Infectious diseases, APH - Aging & Later Life, APH - Global Health, AII - Infectious diseases, Experimental Immunology, AII - Cancer immunology, CCA - Cancer biology and immunology, Medical Microbiology and Infection Prevention, General Internal Medicine, Internal Medicine, Hematology, Virology, and Epidemiology
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Infectious Diseases ,SDG 3 - Good Health and Well-being ,Immunology and Allergy ,COVID-19 ,plasma-derived antibody therapy ,anti-SARS-CoV-2 hyperimmune globulin ,severely immunocompromised state ,B-cell dysfunction - Abstract
Background The aim of this randomized, controlled trial is to determine whether antisevere acute respiratory syndrome coronavirus 2 hyperimmune globulin (COVIG) protects against severe coronavirus disease 2019 (COVID-19) in severely immunocompromised, hospitalized, COVID-19 patients. Methods Patients were randomly assigned to receive COVIG or intravenous immunoglobulin (IVIG) without SARS-CoV-2 antibodies. Results Severe COVID-19 was observed in 2 of 10 (20%) patients treated with COVIG compared to 7 of 8 (88%) in the IVIG control group (P = .015, Fisher’s exact test). Conclusions Antisevere acute respiratory syndrome coronavirus 2 hyperimmune globulin may be a valuable treatment in severely immunocompromised, hospitalized, COVID-19 patients and should be considered when no monoclonal antibody therapies are available.
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- 2023
15. <scp>SMG1</scp> , a nonsense‐mediated <scp>mRNA</scp> decay ( <scp>NMD</scp> ) regulator, as a candidate therapeutic target in multiple myeloma
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Alexander C. Leeksma, Ingrid A. M. Derks, Brett Garrick, Aldo Jongejan, Martino Colombo, Timon Bloedjes, Torsten Trowe, Jim C. Leisten, Michelle Howarth, Mehnaz Malek, Deborah S. Mortensen, Kate Blease, Mathew C. Groza, Rama Krishna Narla, Remco Loos, Marie‐José Kersten, Perry D. Moerland, Jeroen E. J. Guikema, Arnon P. Kater, Eric Eldering, Ellen H. Filvaroff, Hematology, Graduate School, Experimental Immunology, CCA - Cancer biology and immunology, Epidemiology and Data Science, APH - Methodology, Pathology, CCA - Imaging and biomarkers, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, APH - Personalized Medicine, AII - Infectious diseases, and AII - Cancer immunology
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therapy ,Cancer Research ,Oncology ,SMG1 ,Genetics ,NMD ,cancer ,Molecular Medicine ,UPR ,General Medicine ,MM - Abstract
Early data suggested that CC-115, a clinical molecule, already known to inhibit the mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK) may have additional targets beyond TORK and DNA-PK. Therefore, we aimed to identify such target(s) and investigate a potential therapeutic applicability. Functional profiling of 141 cancer cell lines revealed inhibition of kinase suppressor of morphogenesis in genitalia 1 (SMG1), a key regulator of the RNA degradation mechanism nonsense-mediated mRNA decay (NMD), as an additional target of CC-115. CC-115 treatment showed a dose-dependent increase of SMG1-mediated NMD transcripts. A subset of cell lines, including multiple myeloma (MM) cell lines sensitive to the endoplasmic reticulum stress-inducing compound thapsigargin, were highly susceptible to SMG1 inhibition. CC-115 caused the induction of UPR transcripts and cell death by mitochondrial apoptosis, requiring the presence of BAX/BAK and caspase activity. Superior antitumor activity of CC-115 over TORK inhibitors in primary human MM cells and three xenograft mouse models appeared to be via inhibition of SMG1. Our data support further development of SMG1 inhibitors as possible therapeutics in MM.
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- 2022
16. Thrombotic and Bleeding Complications in Patients with Chronic Lymphocytic Leukemia and Severe COVID-19: A Study of Eric, the European Research Initiative on CLL
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Darko Antic, Natasa Milic, Thomas Chatzikonstantinou, Lydia Scarfò, Vladimir Otasevic, Nina Rajovic, David Allsup, Alejandro Alonso Cabrero, Martin Andres, Monica Baile Gonzales, Antonella Capasso, Rosa Collado, Raul Cordoba, Carolina Cuéllar-García, Juan Gonzalo Correa, Lorenzo De Paoli, Maria Rosaria De Paolis, Giovanni Del Poeta, Maria Dimou, Michael Doubek, Maria Efstathopoulou, Shaimaa El-Ashwah, Alicia Enrico, Blanca Espinet, Lucia Farina, Angela Ferrari, Myriam Foglietta, Alberto Lopez-Garcia, José A. García-Marco, Rocío García-Serra, Massimo Gentile, Eva Gimeno, Maria Gomes da Silva, Odit Gutwein, Yervand K. Hakobyan, Yair Herishanu, José Ángel Hernández-Rivas, Tobias Herold, Gilad Itchaki, Ozren Jaksic, Ann Janssens, Olga B. Kalashnikova, Elżbieta Kalicińska, Arnon P. Kater, Sabina Kersting, Maya Koren-Michowitz, Jorge Labrador, Deepesh Lad, Luca Laurenti, Alberto Fresa, Mark-David Levin, Carlota Mayor Bastida, Lara Malerba, Roberto Marasca, Monia Marchetti, Juan Marquet, Biljana Mihaljevic, Ivana Milosevic, Fatima Mirás, Marta Morawska, Marina Motta, Talha Munir, Roberta Murru, Raquel Nunes, Jacopo Olivieri, Miguel Arturo Pavlovsky, Inga Piskunova, Viola Maria Popov, Francesca Maria Quaglia, Giulia Quaresmini, Gianluigi Reda, Gian Matteo Rigolin, Amit Shrestha, Martin Šimkovič, Svetlana Smirnova, Martin Špaček, Paolo Sportoletti, Oana Stanca, Niki Stavroyianni, Doreen Te Raa, Kristina Tomic, Sanne Tonino, Livio Trentin, Ellen Van Der Spek, Michel van Gelder, Marzia Varettoni, Andrea Visentin, Candida Vitale, Vojin Vukovic, Ewa Wasik-Szczepanek, Tomasz Wróbel, Lucrecia Yáñez San Segundo, Mohamed Yassin, Marta Coscia, Alessandro Rambaldi, Emili Montserrat, Robin Foà, Antonio Cuneo, Marc Carrier, Paolo Ghia, Kostas Stamatopoulos, [Antic D] Lymphoma Center, Clinic for Hematology, University Clinical Center of Serbia, Belgrade, Serbia. Faculty of Medicine, University of Belgrade, Belgrade, Serbia. [Milic N, Rajovic N] Department of Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. [Chatzikonstantinou T] Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece. [Scarfò L] Università Vita-Salute San Raffaele and IRCC Ospedale San Raffaele, Milan, Italy. [Otasevic V] Lymphoma Center, Clinic for Hematology, University Clinical Center of Serbia, Belgrade, Serbia. [Cuéllar-García C] Hematology Unit Hospital de Terrassa, Consorci Sanitari de Terrassa, Terrassa, Spain, Consorci Sanitari de Terrassa, Interne Geneeskunde, MUMC+: MA Hematologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Experimental Immunology, Clinical Haematology, AII - Cancer immunology, Graduate School, CCA - Cancer Treatment and Quality of Life, and Universidad de Cantabria
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Cancer Research ,Cardiovascular Diseases::Vascular Diseases::Embolism and Thrombosis::Thrombosis [DISEASES] ,Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Hematologic Agents::Anticoagulants [CHEMICALS AND DRUGS] ,Age ,Anticoagulation therapy ,Bleeding ,CLL ,COVID-19 ,D-dimer ,LMWH ,Thromboprophylaxis ,Thrombosis ,COVID-19 (Malaltia) ,Biochemistry ,COVID-19 Testing ,virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES] ,afecciones patológicas, signos y síntomas::procesos patológicos::hemorragia [ENFERMEDADES] ,Trombosi ,Chronic ,RISK ,Leukemia ,Low-Molecular-Weight ,Pathological Conditions, Signs and Symptoms::Pathologic Processes::Hemorrhage [DISEASES] ,Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES] ,Venous Thromboembolism ,Hemorràgia ,enfermedades cardiovasculares::enfermedades vasculares::embolia y trombosis::trombosis [ENFERMEDADES] ,Hematology ,Lymphocytic ,Oncology ,Aged ,Anticoagulants ,Hemorrhage ,Heparin, Low-Molecular-Weight ,Humans ,SARS-CoV-2 ,Leukemia, Lymphocytic, Chronic, B-Cell ,Life Sciences & Biomedicine ,Immunology ,610 Medicine & health ,COVID-19/drug therapy ,Molecular Biology ,Science & Technology ,Heparin ,B-Cell ,Cell Biology ,acciones y usos químicos::acciones farmacológicas::usos terapéuticos::fármacos hematológicos::anticoagulantes [COMPUESTOS QUÍMICOS Y DROGAS] ,COVID-19 Drug Treatment ,Settore MED/15 - MALATTIE DEL SANGUE ,Anticoagulants (Medicina) ,610 Medizin und Gesundheit - Abstract
Background Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively). Conclusions Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.
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- 2022
17. Genomic and microenvironmental landscape of stage I follicular lymphoma, compared with stage III/IV
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G. Tjitske Los-de Vries, Wendy B. C. Stevens, Erik van Dijk, Carole Langois-Jacques, Andrew J. Clear, Phylicia Stathi, Margaretha G. M. Roemer, Matias Mendeville, Nathalie J. Hijmering, Birgitta Sander, Andreas Rosenwald, Maria Calaminici, Eva Hoster, Wolfgang Hiddemann, Philippe Gaulard, Gilles Salles, Heike Horn, Wolfram Klapper, Luc Xerri, Catherine Burton, Reuben M. Tooze, Alexandra G. Smith, Christian Buske, David W. Scott, Yasodha Natkunam, Ranjana Advani, Laurie H. Sehn, John Raemaekers, John Gribben, Eva Kimby, Marie José Kersten, Delphine Maucort-Boulch, Bauke Ylstra, Daphne de Jong, Pathology, CCA - Cancer biology and immunology, and Clinical Haematology
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Histones ,Proto-Oncogene Proteins c-bcl-2 ,Programmed Cell Death 1 Receptor ,Humans ,Hematology ,Genomics ,Lymphoma, Follicular ,Translocation, Genetic ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 282509.pdf (Publisher’s version ) (Open Access) Although the genomic and immune microenvironmental landscape of follicular lymphoma (FL) has been extensively investigated, little is known about the potential biological differences between stage I and stage III/IV disease. Using next-generation sequencing and immunohistochemistry, 82 FL nodal stage I cases were analyzed and compared with 139 FL stage III/IV nodal cases. Many similarities in mutations, chromosomal copy number aberrations, and microenvironmental cell populations were detected. However, there were also significant differences in microenvironmental and genomic features. CD8+ T cells (P = .02) and STAT6 mutations (false discovery rate [FDR]
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- 2022
18. Treatment patterns and clinical outcomes of asciminib in a real-world multiresistant chronic myeloid leukemia patient population
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Kockerols, Camille C.B., Janssen, Jeroen J.W.M., Blijlevens, Nicole M.A., Klein, Saskia K., van Hussen-Daenen, Laura G.M., van Gorkom, Gwendolyn G.Y., Smit, Willem M., van Balen, Peter, Biemond, Bart J., Cruijsen, Marjan J., Corsten, Maarten F., te Boekhorst, Peter A.W., Koene, Harry R., van Sluis, Geerte L., Cornelissen, Jan J., Westerweel, Peter E., Hematology, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, Clinical Haematology, AII - Inflammatory diseases, CCA - Cancer Treatment and Quality of Life, Interne Geneeskunde, MUMC+: MA Hematologie (9), and RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy
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Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2] ,All institutes and research themes of the Radboud University Medical Center ,Hematology ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 291291.pdf (Publisher’s version ) (Open Access)
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- 2022
19. Addition of the nuclear export inhibitor selinexor to standard intensive treatment for elderly patients with acute myeloid leukemia and high risk myelodysplastic syndrome
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Janssen, J J W M, Löwenberg, B, Manz, M, Biemond, B J, Westerweel, P E, Klein, S K, Fehr, M, Sinnige, H A M, Efthymiou, A, Legdeur, M C J C, Pabst, T, Gregor, M, van der Poel, M W M, Deeren, D, Tick, L W, Jongen-Lavrencic, M, van Obbergh, F, Boersma, R S, de Weerdt, O, Chalandon, Y, Heim, D, Spertini, O, van Sluis, G, Graux, C, Stüssi, G, van Norden, Y, Ossenkoppele, G J, Hematology, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'hématologie, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Hematologie (9), Hematology laboratory, and CCA - Cancer Treatment and quality of life
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Cancer Research ,Active Transport, Cell Nucleus ,Cytarabine ,Hematology ,ADULTS ,Triazoles ,Leukemia, Myeloid, Acute ,Hydrazines ,Oncology ,SDG 3 - Good Health and Well-being ,AML ,Myelodysplastic Syndromes ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,610 Medizin und Gesundheit ,RESIDUAL DISEASE DETECTION ,Aged - Abstract
Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65–80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n = 51), days 1–24. In the second cycle, cytarabine 1000 mg/m2 twice daily, days 1–6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69–91%) vs. 59% (45–72%; p = 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p = 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl).
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- 2022
20. Enhanced Costimulatory Signaling Improves CAR T-cell Effector Responses in CLL
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McKensie A. Collins, In-Young Jung, Ziran Zhao, Kimberly Apodaca, Weimin Kong, Stefan Lundh, Joseph A. Fraietta, Arnon P. Kater, Clare Sun, Adrian Wiestner, J. Joseph Melenhorst, Experimental Immunology, Clinical Haematology, AII - Cancer immunology, and CCA - Cancer biology and immunology
- Abstract
CD19-redirected chimeric antigen receptor (CAR) T cells have shown remarkable activity against B-cell cancers. While second-generation CARs induce complete remission in >80% of patients with acute lymphoblastic leukemia, similar monotherapy induces long-term remissions in only 26% of patients with chronic lymphocytic leukemia (CLL). This disparity is attributed to cell-intrinsic effector defects in autologous CLL-derived T cells. However, the mechanisms by which leukemic cells impact CAR T-cell potency are poorly understood. Herein we describe an in vitro assay that recapitulates endogenous CLL-mediated T-cell defects in healthy donor CAR T cells. Contact with CLL cells insufficiently activates, but does not irreversibly impair, CAR T-cell function. This state is rescuable by strong antigenic stimulation or IL2, and is not driven by immune suppression. Rather, this activation defect is attributable to low levels of costimulatory molecules on CLL cells, and exogenous costimulation enhanced CAR T-cell activation. We next assessed the stimulatory phenotype of CLL cells derived from different niches within the same patient. Lymph node (LN)-derived CLL cells had a strong costimulatory phenotype and promoted better CAR T-cell degranulation and cytokine production than matched peripheral blood CLL cells. Finally, in vitro CD40L-activated CLL cells acquired a costimulatory phenotype similar to the LN-derived tumor and stimulated improved CAR T-cell proliferation, cytokine production, and cytotoxicity. Together, these data identify insufficient activation as a driver of poor CAR T-cell responses in CLL. The costimulatory phenotype of CLL cells drives differential CAR T-cell responses, and can be augmented by improving costimulatory signaling. Significance: CLL cells insufficiently activate CAR T cells, driven by low levels of costimulatory molecules on the tumor. LN-derived CLL cells are more costimulatory and mediate enhanced CAR T-cell killing. This costimulatory phenotype can be modeled via CD40 L activation, and the activated tumor promotes stronger CAR T-cell responses.
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- 2022
21. Cortical myoclonic tremor after chimeric antigen receptor T-cell therapy
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Bart E. K. S. Swinnen, Anne-Fleur van Rootselaar, Anne M. Spanjaart, Rob M. A. de Bie, Marie J. Kersten, Diederik van de Beek, Matthijs C. Brouwer, Joke M. Dijk, Neurology, ANS - Brain Imaging, ANS - Neurodegeneration, Clinical Haematology, Graduate School, APH - Aging & Later Life, AII - Cancer immunology, CCA - Cancer Treatment and Quality of Life, AII - Infectious diseases, ANS - Neuroinfection & -inflammation, and Hematology
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Neurology ,Neurology (clinical) - Published
- 2022
22. Characterization of metabolic alterations of chronic lymphocytic leukemia in the lymph node microenvironment
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Zhenghao Chen, Helga Simon-Molas, Gaspard Cretenet, Beatriz Valle-Argos, Lindsay D. Smith, Francesco Forconi, Bauke V. Schomakers, Michel van Weeghel, Dean J. Bryant, Jaco A. C. van Bruggen, Fleur S. Peters, Jeffrey C. Rathmell, Gerritje J. W. van der Windt, Arnon P. Kater, Graham Packham, Eric Eldering, Graduate School, CCA - Cancer biology and immunology, Experimental Immunology, Laboratory Genetic Metabolic Diseases, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Clinical Haematology, and Hematology
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Glucose ,Glutamine ,hemic and lymphatic diseases ,Immunology ,Tumor Microenvironment ,Humans ,Receptors, Antigen, B-Cell ,Lymph Nodes ,Cell Biology ,Hematology ,CD40 Antigens ,Leukemia, Lymphocytic, Chronic, B-Cell ,Biochemistry - Abstract
Altered metabolism is a hallmark of both cell division and cancer. Chronic lymphocytic leukemia (CLL) cells circulate between peripheral blood (PB) and lymph nodes (LNs), where they receive proliferative and prosurvival signals from surrounding cells. However, insight into the metabolism of LN CLL and how this may relate to therapeutic response is lacking. To obtain insight into CLL LN metabolism, we applied a 2-tiered strategy. First, we sampled PB from 8 patients at baseline and after 3-month ibrutinib (IBR) treatment, which forces egress of CLL cells from LNs. Second, we applied in vitro B-cell receptor (BCR) or CD40 stimulation to mimic the LN microenvironment and performed metabolomic and transcriptomic analyses. The combined analyses indicated prominent changes in purine, glucose, and glutamate metabolism occurring in the LNs. CD40 signaling mostly regulated amino acid metabolism, tricarboxylic acid cycle (TCA), and energy production. BCR signaling preferably engaged glucose and glycerol metabolism and several biosynthesis routes. Pathway analyses demonstrated opposite effects of in vitro stimulation vs IBR treatment. In agreement, the metabolic regulator MYC and its target genes were induced after BCR/CD40 stimulation and suppressed by IBR. Next, 13C fluxomics performed on CD40/BCR-stimulated cells confirmed a strong contribution of glutamine as fuel for the TCA cycle, whereas glucose was mainly converted into lactate and ribose-5-phosphate. Finally, inhibition of glutamine import with V9302 attenuated CD40/BCR-induced resistance to venetoclax. Together, these data provide insight into crucial metabolic changes driven by the CLL LN microenvironment. The prominent use of amino acids as fuel for the TCA cycle suggests new therapeutic vulnerabilities.
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- 2022
23. Treatment of an HLH-mimic disease based on HAVCR2 variants with absent TIM-3 expression
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Samantha A. M. Tromp, Marijn A. Gillissen, Sophie J. Bernelot Moens, Ester M. M. van Leeuwen, Machiel H. Jansen, Lianne Koens, Caroline E. Rutten, Taco W. Kuijpers, Pathology, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Infectious diseases, AII - Inflammatory diseases, Amsterdam Reproduction & Development (AR&D), Experimental Immunology, AII - Cancer immunology, and Clinical Haematology
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Hematology ,Hepatitis A Virus Cellular Receptor 2 - Published
- 2022
24. A non-randomized risk-adjusted comparison of lenalidomide + R-CHOP versus R-CHOP for MYC-rearranged DLBCL patients
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A. Vera de Jonge, Erik van Werkhoven, Avinash G. Dinmohamed, Marcel Nijland, Aeilko H. Zwinderman, Patrick M. Bossuyt, Martine S. Veldhuis, Emma G. G. M. Rutten, Rogier Mous, Joost S. P. Vermaat, Yorick Sandberg, Eva de Jongh, Yavuz M. Bilgin, Rinske Boersma, Harry Koene, Marie José Kersten, Daphne de Jong, Martine E. D. Chamuleau, Pathology, AII - Cancer immunology, CCA - Cancer biology and immunology, Hematology, CCA - Cancer Treatment and quality of life, Public Health, Pharmacy, General Practice, Graduate School, APH - Methodology, APH - Personalized Medicine, Epidemiology and Data Science, Clinical Haematology, and CCA - Cancer Treatment and Quality of Life
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Oncology ,Hematology - Abstract
Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYC-R DLBCL patients.
- Published
- 2023
25. Patient preferences regarding treatment options for Waldenström's macroglobulinemia: A <scp>discrete choice experiment</scp>
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Karima Amaador, Pythia T. Nieuwkerk, Monique C. Minnema, Marie José Kersten, Josephine M. I. Vos, Graduate School, Medical Psychology, APH - Aging & Later Life, APH - Personalized Medicine, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, CCA - Cancer biology and immunology, General Internal Medicine, and Hematology
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Cancer Research ,Oncology ,discrete choice experiment ,Radiology, Nuclear Medicine and imaging ,waldenstrom's ,macroglobulinemia ,patient preferences - Abstract
Introduction: Treatment options for Waldenström's Macroglobulinemia (WM) have expanded rapidly in the last decades. However, there is no consensus on a preferred treatment. Therefore, patient preferences become increasingly important in making individualized treatment plans. Still, WM patients' priorities and perspectives regarding their treatment options are unknown. We evaluated treatment preferences of WM patients using a discrete choice experiment (DCE). Methods: A mixed-method approach was utilized for identification and selection of attributes/levels. The DCE questionnaire included five attributes: type of agent (targeted versus chemotherapy); frequency and route of administration; 5-year progression-free survival (PFS); adverse events; and risk of secondary malignancies. An orthogonal design and a mixed logit panel data model were used to construct choice tasks and assess patient preferences, respectively. Results: Three hundred thirty WM patients participated in the project. In total, 214 (65%) complete questionnaires were included for data analysis. The 5-year PFS, followed by risk of secondary malignancies were the most important attributes for making treatment choices. Regarding side effects, patients chose to avoid neuropathy the most compared to nausea/vomiting and extreme fatigue. Patients preferred a fixed-duration treatment with IV/SC administration at the hospital over a continuous daily oral regimen at home. Conclusion: These are the first systematic data obtained on WM patient preferences for treatment. The results may help discussions with individual patients about their treatment choices. Also, these data can help design clinical trials in WM and inform health-care decision-making regarding outcomes that are most relevant to patients.
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- 2022
26. Proton pump inhibition for secondary hemochromatosis in hereditary anemia
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Annelies van Vuren, Jean Louis Kerkhoffs, Saskia Schols, Anita Rijneveld, Erfan Nur, Dore Peereboom, Yves Gandon, Paco Welsing, Richard van Wijk, Roger Schutgens, Wouter van Solinge, Joannes Marx, Tim Leiner, Bart Biemond, Eduard van Beers, Hematology, Internal medicine, and Clinical Haematology
- Subjects
Adult ,Cross-Over Studies ,Iron Overload ,Iron ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Anemia ,Esomeprazole ,Hematology ,Proton Pumps ,Iron Chelating Agents ,Treatment Outcome ,Double-Blind Method ,Humans ,Hemochromatosis - Abstract
Contains fulltext : 251634.pdf (Publisher’s version ) (Open Access) Iron overload is a severe general complication of hereditary anemias. Treatment with iron chelators is hampered by important side-effects, high costs, and the lack of availability in many countries with a high prevalence of hereditary anemias. In this phase III randomized placebo-controlled trial, we assigned adults with non-transfusion-dependent hereditary anemias with mild-to-moderate iron overload to receive esomeprazole (at a dose of 40 mg twice daily) or placebo for 12 months in a cross-over design. The primary end point was change of liver iron content measured by MRI. A total of 30 participants were enrolled in the trial. Treatment with esomeprazole resulted in a statistically significant reduction in liver iron content that was 0.55 mg Fe/g dw larger than after treatment with placebo (95%CI [0.05 to 1.06]; p = 0.03). Median baseline liver iron content at the start of esomeprazole was 4.99 versus 4.49 mg Fe/g dw at start of placebo. Mean delta liver iron content after esomeprazole treatment was -0.57 (SD 1.20) versus -0.11 mg Fe/g dw (SD 0.75) after placebo treatment. Esomeprazole was well tolerated, reported adverse events were mild and none of the patients withdrew from the study due to side effects. In summary, esomeprazole resulted in a significant reduction in liver iron content when compared to placebo in a heterogeneous group of patients with non-transfusion-dependent hereditary anemias. From an international perspective this result can have major implications given the fact that proton pump inhibitors may frequently be the only realistic therapy for many patients without access to or not tolerating iron chelators.
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- 2022
27. High frequency of central nervous system involvement in transformed Waldenström macroglobulinemia
- Author
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Eric Durot, Lukshe Kanagaratnam, Saurabh Zanwar, Elise Toussaint, Efstathios Kastritis, Shirley D’Sa, Miguel Alcoceba, Cécile Tomowiak, Bénédicte Hivert, Caroline Protin, Jithma P. Abeykoon, Josephine M. I. Vos, Anne-Sophie Michallet, Cyrielle Rodier, Jehan Dupuis, Stéphane Leprêtre, Fatiha Merabet, Xavier Roussel, Jean-Marc Zini, Caroline Regny, Aisha Patel, Pierre Morel, Damien Roos-Weil, Steven P. Treon, Meletios A. Dimopoulos, Ramon Garcia-Sanz, Prashant Kapoor, Jorge J. Castillo, Alain Jacques Delmer, Clinical Haematology, AII - Cancer immunology, CCA - Cancer biology and immunology, and CCA - Cancer Treatment and Quality of Life
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Central Nervous System ,Humans ,Hematology ,Waldenstrom Macroglobulinemia - Published
- 2022
28. Mapping anticipated advantages and disadvantages of implementation of extensive donor genotyping: A focus group approach
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Jessie S. Luken, Sebastien P. Ritsema, Merel M. Van der Wal, C. Ellen van der Schoot, Etiënne A. J. A. Rouwette, Masja de Haas, Mart P. Janssen, Graduate School, and Clinical Haematology
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Genetic Markers ,Blood Grouping and Crossmatching ,Genotype ,Blood Group Antigens ,Humans ,Blood Donors ,Hematology ,Focus Groups ,Institute for Management Research - Abstract
Background and objectives: Current genotyping techniques allow typing of all relevant red cell, human leukocyte and platelet antigens in a single analysis. Even genetic markers related to donor health can be added. Implementation of this technology will affect various stakeholders within the transfusion chain. This study aims to systematically map the anticipated advantages and disadvantages of a national rollout of blood group genotyping of donors, which will affect the availability of rare donors and the implementation of an extensively typed blood transfusion policy. Materials and methods: Two focus-group sessions were held with a wide representation of stakeholders, including representatives of donor and patient organisations. A dedicated software tool was used to collect the reflections of participants on genotyping for blood group antigens and extensive matching. Additionally, stakeholders and experts discussed various prepared propositions. All information collected was categorised. Results: From 162 statements collected, 59 statements (36%) were labelled as 'hopes' and 77 (48%) as 'fears'. Twenty-six (16%) statements remained unlabelled. The statements were divided in 18 categories under seven main themes: patient health, genotyping, privacy issues and ethical aspects, donor management, inventory management and logistics, hospital and transfusion laboratory and general aspects. The discussion on the propositions was analysed and summarised. Conclusion: Stakeholders believe that a genotyped donor pool can result in a reduction of alloimmunization and higher availability of typed blood products. There are concerns regarding logistics, costs, consent for extended typing, data sharing, privacy issues and donor management. These concerns need to be carefully addressed before further implementation.
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- 2022
29. Assessment of functional shunting in patients with sickle cell disease
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Bart J. Biemond, John C. Wood, Lena Vaclavu, Aart J. Nederveen, Henk J M M Mutsaerts, Anouk Schrantee, Liza Afzali-Hashemi, Graduate School, Radiology and Nuclear Medicine, Clinical Haematology, ACS - Diabetes & metabolism, AMS - Ageing & Vitality, AMS - Sports, APH - Personalized Medicine, ANS - Compulsivity, Impulsivity & Attention, APH - Mental Health, and Radiology and nuclear medicine
- Subjects
Adult ,medicine.medical_specialty ,business.industry ,Immunology ,Cell ,Brain ,Anemia, Sickle Cell ,Cerebral Infarction ,Cell Biology ,Disease ,Hematology ,Magnetic Resonance Imaging ,Biochemistry ,Acetazolamide ,Oxygen ,Shunting ,Oxygen Consumption ,medicine.anatomical_structure ,Internal medicine ,medicine ,Cardiology ,Humans ,In patient ,Child ,business - Abstract
Introduction Silent cerebral infarcts (SCI) are common in patients with sickle cell disease (SCD) and thought to be caused by a mismatch between oxygen delivery and consumption. The mechanism underlying insufficient oxygen utilization is related to severity of anemia, and paradoxically, to the elevated cerebral blood flow (CBF) observed in SCD patients. CBF is elevated as a compensatory mechanism to maintain oxygen delivery, but high CBF levels can result in rapid transit of blood through the brain capillaries, limiting offloading of oxygen to the tissue; a process called arteriovenous shunting. One way to assess functional arteriovenous shunting is to use noncontrast perfusion MRI techniques in which we can assess the signal intensity of an endogenous blood tracer when it reaches the sagittal sinus. This venous signal (VS) reflects the amount of labeled blood that has not exchanged with the brain parenchyma. Under normal physiological conditions, the VS intensity will increase approximately proportionally with CBF as we expect only some of the water to exchange with tissue as it flows by. However, it is unknown whether functional shunting scales with CBF only, or whether other hemodynamic processes play a role in patients with SCD. We hypothesize that, under pathophysiological conditions such as in SCD patients, more labeled blood may pass unexchanged through the capillaries, which results in higher VS. In the present study, we investigated functional shunting by quantifying VS and assessed its association with hemodynamic, demographic and laboratory parameters in both pediatric and adult SCD patients, and controls. In addition, VS-CBF relationship was studied by further increasing CBF after a vasodilatory challenge. Methods We included 28 children (mean age 12.7 ± 2.3, 9 F) and 38 adults (mean age 32.1 ± 11.2, 14 F) with SCD (HbSS and HbS), and 10 healthy race-matched adult controls (mean age 36.4 ± 15.9, 4 F). For the CBF and VS measurements, pseudo-continuous arterial spin labelling (pCASL) data were acquired using 3T MRI. We segmented the ASL blood pool in the sagittal sinus to determine a common region of interest for each group. We used these images as masks to calculate average VS. Notably, for the comparison between children and adults the ratio between VS to gray matter CBF was used (VGR) instead of the VS, to take into account higher CBF in children. To get more insight into the oxygen utilization, oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO 2) were calculated. In adult participants acetazolamide (ACZ) was used as a vasodilatory challenge. The hematologic laboratory parameters hemoglobin (Hb) and LDH were used as markers of anemia and hemolysis, respectively. Results VS as a marker of cerebral shunting was higher in both adult and pediatric patients with SCD as compared to controls (p Conclusion Our results show that the VS in the sagittal sinus on ASL images can be used to assess functional arteriovenous shunting in the brain. Given its negative association with CMRO 2 in combination with the negative association with hemoglobin and positive correlation with LDH, this functional shunting seems to reflect pathophysiologic shunting related to higher disease severity. Future studies will focus on the relation between functional shunting and the prevalence of SCI, investigating its link to aberrant capillary oxygen exchange in SCD. Figure 1 Figure 1. Disclosures Vaclavu: Philips Healthcare: Research Funding. Biemond: GBT: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Sanquin: Research Funding.
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- 2022
30. Early, very high-titre convalescent plasma therapy in clinically vulnerable individuals with mild COVID-19 (COVIC-19)
- Author
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Maxime Desmarets, Simone Hoffmann, Charline Vauchy, Bart J A Rijnders, Eric Toussirot, Antoine Durrbach, Sixten Körper, Eva Schrezenmeier, C Ellen van der Schoot, Heli Harvala, Gaëlle Brunotte, Thomas Appl, Erhard Seifried, Pierre Tiberghien, Daniel Bradshaw, David J Roberts, Lise J Estcourt, Hubert Schrezenmeier, Internal Medicine, Clinical Haematology, and AII - Inflammatory diseases
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Clinical trials ,Blood bank & transfusion medicine ,COVID-19 ,Respiratory infections ,General Medicine ,INFECTIOUS DISEASES - Abstract
IntroductionCOVID-19 convalescent plasma (CCP) is a possible treatment option for COVID-19. A comprehensive number of clinical trials on CCP efficacy have already been conducted. However, many aspects of CCP treatment still require investigations: in particular (1) Optimisation of the CCP product, (2) Identification of the patient population in need and most likely to benefit from this treatment approach, (3) Timing of administration and (4) CCP efficacy across viral variants in vivo. We aimed to test whether high-titre CCP, administered early, is efficacious in preventing hospitalisation or death in high-risk patients.Methods and analysisCOVIC-19 is a multicentre, randomised, open-label, adaptive superiority phase III trial comparing CCP with very high neutralising antibody titre administered within 7 days of symptom onset plus standard of care versus standard of care alone. We will enrol patients in two cohorts of vulnerable patients [(1) elderly 70+ years, or younger with comorbidities; (2) immunocompromised patients]. Up to 1020 participants will be enrolled in each cohort (at least 340 with a sample size re-estimation after reaching 102 patients). The primary endpoint is the proportion of participants with (1) Hospitalisation due to progressive COVID-19, or (2) Who died by day 28 after randomisation. Principal analysis will follow the intention-to-treat principle.Ethics and disseminationEthical approval has been granted by the University of Ulm ethics committee (#41/22) (lead ethics committee for Germany), Comité de protection des personnes Sud-Est I (CPP Sud-Est I) (#2022-A01307-36) (ethics committee for France), and ErasmusMC ethics committee (#MEC-2022-0365) (ethics committee for the Netherlands). Signed informed consent will be obtained from all included patients. The findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings.Trial registrationClinical Trials.gov (NCT05271929), EudraCT (2021-006621-22)
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- 2023
31. Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors
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van Zogchel, Lieke M. J., Lak, Nathalie S. M., Gelineau, Nina U., Sergeeva, Irina, Stelloo, Ellen, Swennenhuis, Joost, Feitsma, Harma, van Min, Max, Splinter, Erik, Bleijs, Margit, Groot Koerkamp, Marian, Breunis, Willemijn, Meister, Michael Torsten, Kholossy, Waleed Hassan, Holstege, Frank C. P., Molenaar, Jan J., de Leng, Wendy W. J., Stutterheim, Janine, van der Schoot, C. Ellen, Tytgat, Godelieve A. M., Landsteiner Laboratory, Clinical Haematology, and AII - Inflammatory diseases
- Subjects
neuroblastoma ,Cancer Research ,liquid biopsy ,Oncology ,TLA ,paediatric cancer ,cell-free DNA (cfDNA) ,patient-specific ddPCR - Abstract
BackgroundLiquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences. We investigated the feasibility to use these breakpoints to design patient-specific markers to detect tumor-derived cell-free DNA (cfDNA) in plasma from patients with pediatric solid tumors.Materials and methodsRegions of interest (ROI) were identified through standard clinical diagnostic pipelines, using SNP array for CNAs, and FISH or RT-qPCR for fusion genes. Using targeted locus amplification (TLA) on tumor organoids grown from tumor material or targeted locus capture (TLC) on FFPE material, ROI-specific primers and probes were designed, which were used to design droplet digital PCR (ddPCR) assays. cfDNA from patient plasma at diagnosis and during therapy was analyzed.ResultsTLA was performed on material from 2 rhabdomyosarcoma, 1 Ewing sarcoma and 3 neuroblastoma. FFPE-TLC was performed on 8 neuroblastoma tumors. For all patients, at least one patient-specific ddPCR was successfully designed and in all diagnostic plasma samples the patient-specific markers were detected. In the rhabdomyosarcoma and Ewing sarcoma patients, all samples after start of therapy were negative. In neuroblastoma patients, presence of patient-specific markers in cfDNA tracked tumor burden, decreasing during induction therapy, disappearing at complete remission and re-appearing at relapse.ConclusionWe demonstrate the feasibility to determine tumor-specific breakpoints using TLA/TLC in different pediatric solid tumors and use these for analysis of cfDNA from plasma. Considering the high prevalence of CNAs and fusion genes in pediatric solid tumors, this approach holds great promise and deserves further study in a larger cohort with standardized plasma sampling protocols.
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- 2023
32. Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment
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Stevens, Wendy B. C., Los-de Vries, G. Tjitske, Langois-Jacques, Carole, Clear, Andrew J., Stathi, Phylicia, Sander, Birgitta, Rosenwald, Andreas, Calaminici, Maria, Hoster, Eva, Hiddemann, Wolfgang, Gaulard, Philippe, Salles, Gilles, Klapper, Wolfram, Xerri, Luc, Burton, Catherine, Tooze, Reuben M., Smith, Alexandra G., Buske, Christian, Scott, David W., Natkunam, Yasodha, Advani, Ranjana, Sehn, Laurie H., Raemaekers, John, Gribben, John, Lockmer, Sandra, Kimby, Eva, Kersten, Marie José, Maucort-Boulch, Delphine, Ylstra, Bauke, van Dijk, Erik, de Jong, Daphne, Clinical Haematology, AII - Cancer immunology, CCA - Cancer Treatment and Quality of Life, CCA - Cancer biology and immunology, Pathology, and CCA - Imaging and biomarkers
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Hematology ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Contains fulltext : 294570.pdf (Publisher’s version ) (Open Access)
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- 2023
33. Cell-Free RNA from Plasma in Patients with Neuroblastoma: Exploring the Technical and Clinical Potential
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Lak, Nathalie S M, Seijger, Anne, van Zogchel, Lieke M J, Gelineau, Nina U, Javadi, Ahmad, Zappeij-Kannegieter, Lily, Bongiovanni, Laura, Andriessen, Anneloes, Stutterheim, Janine, van der Schoot, C Ellen, de Bruin, Alain, Tytgat, Godelieve A M, Pathobiologie, Dep Biomolecular Health Sciences, Landsteiner Laboratory, Clinical Haematology, AII - Inflammatory diseases, Pathobiologie, and Dep Biomolecular Health Sciences
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Cancer Research ,liquid biopsies ,neuroblastoma ,pediatric ,Oncology ,cell-free RNA ,solid tumors ,extracellular vesicles ,extracellularvesicles - Abstract
Neuroblastoma affects mostly young children, bearing a high morbidity and mortality. Liquid biopsies, e.g., molecular analysis of circulating tumor-derived nucleic acids in blood, offer a minimally invasive diagnostic modality. Cell-free RNA (cfRNA) is released by all cells, especially cancer. It circulates in blood packed in extracellular vesicles (EV) or attached to proteins. We studied the feasibility of analyzing cfRNA and EV, isolated by size exclusion chromatography (SEC), from platelet-poor plasma from healthy controls (n = 40) and neuroblastoma patients with localized (n = 10) and metastatic disease (n = 30). The mRNA content was determined using several multiplex droplet digital PCR (ddPCR) assays for a neuroblastoma-specific gene panel (PHOX2B, TH, CHRNA3) and a cell cycle regulation panel (E2F1, CDC6, ATAD2, H2AFZ, MCM2, DHFR). We applied corrections for the presence of platelets. We demonstrated that neuroblastoma-specific markers were present in plasma from 14/30 patients with metastatic disease and not in healthy controls and patients with localized disease. Most cell cycle markers had a higher expression in patients. The mRNA markers were mostly present in the EV-enriched SEC fractions. In conclusion, cfRNA can be isolated from plasma and EV and analyzed using multiplex ddPCR. cfRNA is an interesting novel liquid biopsy-based target to explore further.
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- 2023
34. A bispecific T cell engager recruits both type 1 NKT and Vγ9Vδ2-T cells for the treatment of CD1d-expressing hematological malignancies
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Roeland Lameris, Jurjen M. Ruben, Victoria Iglesias-Guimarais, Milon de Jong, Myrthe Veth, Fleur S. van de Bovenkamp, Iris de Weerdt, Arnon P. Kater, Sonja Zweegman, Sjeng Horbach, Thilo Riedl, Benjamin Winograd, Rob C. Roovers, Anton E.P. Adang, Tanja D. de Gruijl, Paul W.H.I. Parren, Hans J. van der Vliet, Experimental Immunology, Clinical Haematology, AII - Cancer immunology, CCA - Cancer biology and immunology, Internal medicine, Hematology, CCA - Cancer Treatment and quality of life, Medical oncology laboratory, and CCA - Imaging and biomarkers
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multiple myeloma ,bispecific T cell engagers ,Vγ9Vδ2-T cell ,type 1 NKT cell ,preclinical ,chronic lymphocytic leukemia ,non-human primate ,acute myeloid leukemia ,CD1d ,General Biochemistry, Genetics and Molecular Biology ,single-domain antibody - Abstract
Bispecific T cell engagers (bsTCEs) hold great promise for cancer treatment but face challenges due to the induction of cytokine release syndrome (CRS), on-target off-tumor toxicity, and the engagement of immunosuppressive regulatory T cells that limit efficacy. The development of Vγ9Vδ2-T cell engagers may overcome these challenges by combining high therapeutic efficacy with limited toxicity. By linking a CD1d-specific single-domain antibody (VHH) to a Vδ2-TCR-specific VHH, we create a bsTCE with trispecific properties, which engages not only Vγ9Vδ2-T cells but also type 1 NKT cells to CD1d+ tumors and triggers robust proinflammatory cytokine production, effector cell expansion, and target cell lysis in vitro. We show that CD1d is expressed by the majority of patient MM, (myelo)monocytic AML, and CLL cells and that the bsTCE triggers type 1 NKT and Vγ9Vδ2-T cell-mediated antitumor activity against these patient tumor cells and improves survival in in vivo AML, MM, and T-ALL mouse models. Evaluation of a surrogate CD1d-γδ bsTCE in NHPs shows Vγ9Vδ2-T cell engagement and excellent tolerability. Based on these results, CD1d-Vδ2 bsTCE (LAVA-051) is now evaluated in a phase 1/2a study in patients with therapy refractory CLL, MM, or AML.
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- 2023
35. Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome
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Tim Grob, Adil S. A. Al Hinai, Mathijs A. Sanders, François G. Kavelaars, Melissa Rijken, Patrycja L. Gradowska, Bart J. Biemond, Dimitri A. Breems, Johan Maertens, Marinus van Marwijk Kooy, Thomas Pabst, Okke de Weerdt, Gert J. Ossenkoppele, Arjan A. van de Loosdrecht, Gerwin A. Huls, Jan J. Cornelissen, H. Berna Beverloo, Bob Löwenberg, Mojca Jongen-Lavrencic, Peter J. M. Valk, Stem Cell Aging Leukemia and Lymphoma (SALL), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Hematology, Clinical Haematology, CCA - Cancer biology and immunology, and Hematology laboratory
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OUTCOMES ,endocrine system diseases ,ALLELE FREQUENCY ,MUTATIONS ,Immunology ,CLONAL HEMATOPOIESIS ,Cell Biology ,Hematology ,Biochemistry ,Cytogenetics ,Leukemia, Myeloid, Acute ,stomatognathic system ,Myelodysplastic Syndromes ,hemic and lymphatic diseases ,Mutation ,Humans ,Tumor Suppressor Protein p53 ,610 Medicine & health ,neoplasms - Abstract
Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity. ispartof: BLOOD vol:139 issue:15 pages:2347-2354 ispartof: location:United States status: published
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- 2022
36. Sodium stibogluconate and CD47-SIRPα blockade overcome resistance of anti-CD20–opsonized B cells to neutrophil killing
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Rees, Dieke J. van, Brinkhaus, Maximilian, Klein, Bart, Verkuijlen, Paul, Tool, Anton T.J., Schornagel, Karin, Treffers, Louise W., Houdt, Michel van, Kater, Arnon P., Vidarsson, Gestur, Gennery, Andrew R., Kuijpers, Taco W., Bruggen, Robin van, Matlung, Hanke L., Berg, Timo K. van den, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Graduate School, AII - Inflammatory diseases, AII - Cancer immunology, AII - Infectious diseases, CCA - Cancer biology and immunology, Experimental Immunology, Clinical Haematology, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, and Molecular cell biology and Immunology
- Subjects
Neutrophils ,Complement ,Phosphatase inhibitor ,Antibody-Dependent Cell Cytotoxicity ,Expression ,CD47 Antigen ,Hematology ,Fc-gamma-r ,Antimony Sodium Gluconate ,immune system diseases ,hemic and lymphatic diseases ,Cd20 ,Dependent cellular cytotoxicity ,Rituximab ,Antibody ,Sirp-alpha ,Therapeutic activity - Abstract
Anti-CD20 antibodies such as rituximab are broadly used to treat B-cell malignancies. These antibodies can induce various effector functions, including immune cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Neutrophils can induce ADCC toward solid cancer cells by trogoptosis, a cytotoxic mechanism known to be dependent on trogocytosis. However, neutrophils seem to be incapable of killing rituximab-opsonized B-cell lymphoma cells. Nevertheless, neutrophils do trogocytose rituximab-opsonized B-cell lymphoma cells, but this only reduces CD20 surface expression and is thought to render tumor cells therapeutically resistant to further rituximab-dependent destruction. Here, we demonstrate that resistance of B-cell lymphoma cells toward neutrophil killing can be overcome by a combination of CD47-SIRPα checkpoint blockade and sodium stibogluconate (SSG), an anti-leishmaniasis drug and documented inhibitor of the tyrosine phosphatase SHP-1. SSG enhanced neutrophil-mediated ADCC of solid tumor cells but enabled trogoptotic killing of B-cell lymphoma cells by turning trogocytosis from a mechanism that contributes to resistance into a cytotoxic anti-cancer mechanism. Tumor cell killing in the presence of SSG required both antibody opsonization of the target cells and disruption of CD47-SIRPα interactions. These results provide a more detailed understanding of the role of neutrophil trogocytosis in antibody-mediated destruction of B cells and clues on how to further optimize antibody therapy of B-cell malignancies.
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- 2022
37. Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe)
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Sabina Kersting, Julie Dubois, Kazem Nasserinejad, Johan A Dobber, Clemens Mellink, Anne-Marie F van der Kevie-Kersemaekers, Ludo M Evers, Fransien de Boer, Harry R Koene, John Schreurs, Marjolein van der Klift, Gerjo A Velders, Ellen van der Spek, Hanneke M van der Straaten, Mels Hoogendoorn, Michel van Gelder, Eduardus F M Posthuma, Hein P J Visser, Ilse Houtenbos, Cecile A M Idink, Djamila E Issa, Ellen C Dompeling, Henk C T van Zaanen, Hendrik Veelken, Henriette Levenga, Lidwine W Tick, Wim E Terpstra, Sanne H Tonino, Michelle Boyer, Mehrdad Mobasher, Mark-David Levin, Arnon P Kater, Human Genetics, ARD - Amsterdam Reproduction and Development, Clinical Haematology, AII - Cancer immunology, CCA - Cancer Treatment and Quality of Life, Experimental Immunology, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Hematologie (9), and Hematology
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Male ,Sulfonamides ,Adolescent ,FLOW ,MINIMAL RESIDUAL DISEASE ,Hematology ,QUANTIFICATION ,Antibodies, Monoclonal, Humanized ,Bridged Bicyclo Compounds, Heterocyclic ,GUIDELINES ,DIAGNOSIS ,Leukemia, Lymphocytic, Chronic, B-Cell ,MRD ,CHLORAMBUCIL ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,RITUXIMAB ,CLL - Abstract
Background Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status.Methods We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27).Findings Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35.2 months (IQR 31.5-41.3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths.Interpretation Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. Copyright (C) 2022 Elsevier Ltd. All rights reserved.
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- 2022
38. Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL
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Rijneveld, A.W., Holt, B. van der, Weerdt, O. de, Biemond, B.J., Loosdrecht, A.A. van de, Wagen, L.E. van der, Bellido, M., Gelder, M. van, Velden, W.J.F.M. van der, Selleslag, D., Lammeren-Venema, D. van, Halkes, C.J.M., Fijnheer, R., Havelange, V., Sluis, G.L. van, Legdeur, M.C., Deeren, D., Gadisseur, A., Sinnige, H.A.M., Breems, D.A., Jaspers, A., Legrand, O., Terpstra, W.E., Boersma, R.S., Mazure, D., Triffet, A., Tick, L.W., Beel, K., Maertens, J.A., Beverloo, H.B., Bakkus, M., Homburg, C.H.E., Haas, V. de, Velden, V.H.J. van der, Cornelissen, J.J., Dutch-Belgian HOVON Cooperative Gr, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Hematologie (9), UCL - SSS/DDUV/MEXP - Médecine expérimentale, UCL - (SLuc) Service d'hématologie, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, Dutch-Belgian HOVON Cooperative Group, Hematology, Clinical Genetics, and Immunology
- Subjects
Adult ,Neoplasm, Residual ,MINIMAL RESIDUAL DISEASE ,STANDARD-RISK ,All institutes and research themes of the Radboud University Medical Center ,Recurrence ,CYCLOPHOSPHAMIDE ,Medicine and Health Sciences ,Humans ,ONCOLOGY-GROUP ,Child ,CLINICAL-SIGNIFICANCE ,Aged ,ACUTE LYMPHOBLASTIC-LEUKEMIA ,PEDIATRIC-PATIENTS ,TRANSPLANTATION ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,STEM-CELL TRANSPLANTATION ,Hematology ,CHEMOTHERAPY ,STEM-CELL ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,PHASE-II ,Human medicine ,Clofarabine - Abstract
Clofarabine (CLO) is a nucleoside analog with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase 3 study aimed to evaluate whether CLO added to induction and whether consolidation would improve outcome in adults with newly diagnosed ALL. Treatment of younger (18-40 years) patients consisted of a pediatric-inspired protocol, and for older patients (41-70 years), a semi-intensive protocol was used. Three hundred and forty patients were randomized. After a median follow-up of 70 months, 5-year event-free survival (EFS) was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, whereas in patients >40 years, EFS was 43% in both arms. Complete remission (CR) rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD- after consolidation 1 in arm A vs 75/81 (93%) in arm B (P = .001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five-year overall survival (OS) was similar in both arms: 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and nonrelapse mortality was 16% vs 17% after CR. CLO-treated patients experienced more serious adverse events, more infections, and more often went off protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. This trial was registered at www.trialregister.nl as #NTR2004. ispartof: BLOOD ADVANCES vol:6 issue:4 pages:1115-1125 ispartof: location:United States status: published
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- 2022
39. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma
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Frederick L, Locke, David B, Miklos, Caron A, Jacobson, Miguel-Angel, Perales, Marie-José, Kersten, Olalekan O, Oluwole, Armin, Ghobadi, Aaron P, Rapoport, Joseph, McGuirk, John M, Pagel, Javier, Muñoz, Umar, Farooq, Tom, van Meerten, Patrick M, Reagan, Anna, Sureda, Ian W, Flinn, Peter, Vandenberghe, Kevin W, Song, Michael, Dickinson, Monique C, Minnema, Peter A, Riedell, Lori A, Leslie, Sridhar, Chaganti, Yin, Yang, Simone, Filosto, Jina, Shah, Marco, Schupp, Christina, To, Paul, Cheng, Leo I, Gordon, Jason R, Westin, Allen, Xue, Stem Cell Aging Leukemia and Lymphoma (SALL), Hematology, Clinical Haematology, AII - Cancer immunology, and CCA - Cancer Treatment and Quality of Life
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Adult ,Aged, 80 and over ,Male ,SALVAGE REGIMENS ,Biological Products ,OUTCOMES ,Receptors, Chimeric Antigen ,TRANSPLANTATION ,MULTICENTER ,General Medicine ,Middle Aged ,CHEMOTHERAPY ,Immunotherapy, Adoptive ,Transplantation, Autologous ,Progression-Free Survival ,Antineoplastic Agents, Immunological ,EVENT ,Drug Resistance, Neoplasm ,SURVIVAL ,Humans ,Female ,Lymphoma, Large B-Cell, Diffuse ,CHEMOIMMUNOTHERAPY ,Aged ,Stem Cell Transplantation - Abstract
BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.RESULTS: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; PCONCLUSIONS: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).
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- 2022
40. Conditional relative survival among patients with chronic lymphocytic leukaemia
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Lina Straten, Mark‐David Levin, Otto Visser, Eduardus F.M. Posthuma, Jeanette K. Doorduijn, Arnon P. Kater, Avinash G. Dinmohamed, Immunology, Hematology, Public Health, AII - Cancer immunology, Experimental Immunology, Clinical Haematology, and CCA - Cancer Treatment and Quality of Life
- Abstract
Studies on conditional relative survival (CRS) in chronic lymphocytic leukaemia (CLL) have hitherto been lacking in the literature. We predicted up-to-date estimates of 5-year RS at diagnosis and for each additional year survived (i.e., CRS) up to 15 years post-diagnosis among CLL patients diagnosed during 2007-2020. We showed that 5-year CRS continues to decline gradually with each additional year survived in a contemporary era with access to novel-based agents, irrespective of age. This finding indicates that CLL patients continue to experience substantial excess mortality compared to an age- and sex-matched group from the general population.
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- 2022
41. The Impact of Semiautomatic Segmentation Methods on Metabolic Tumor Volume, Intensity, and Dissemination Radiomics in 18F-FDG PET Scans of Patients with Classical Hodgkin Lymphoma
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Julia Driessen, Gerben J.C. Zwezerijnen, Heiko Schöder, Esther E.E. Drees, Marie José Kersten, Alison J. Moskowitz, Craig H. Moskowitz, Jakoba J. Eertink, Henrica C.W. de Vet, Otto S. Hoekstra, Josée M. Zijlstra, Ronald Boellaard, Pathology, Hematology, Radiology and nuclear medicine, CCA - Cancer Treatment and quality of life, Amsterdam Neuroscience - Brain Imaging, Graduate School, Clinical Haematology, and CCA - Imaging and biomarkers
- Subjects
segmentation methods ,radiomics ,18F-FDG PET/CT ,Radiology, Nuclear Medicine and imaging ,Hodgkin lymphoma ,outcome prediction - Abstract
Consensus about a standard segmentation method to derive metabolic tumor volume (MTV) in classical Hodgkin lymphoma (cHL) is lacking, and it is unknown how different segmentation methods influence quantitative PET features. Therefore, we aimed to evaluate the delineation and completeness of lesion selection and the need for manual adaptation with different segmentation methods, and to assess the influence of segmentation methods on the prognostic value of MTV, intensity, and dissemination radiomics features in cHL patients. Methods: We analyzed a total of 105 18F-FDG PET/CT scans from patients with newly diagnosed (n = 35) and relapsed/refractory (n = 70) cHL with 6 segmentation methods: 2 fixed thresholds on SUV4.0 and SUV2.5, 2 relative methods of 41% of SUVmax (41max) and a contrast-corrected 50% of SUVpeak (A50P), and 2 combination majority vote (MV) methods (MV2, MV3). Segmentation quality was assessed by 2 reviewers on the basis of predefined quality criteria: completeness of selection, the need for manual adaptation, and delineation of lesion borders. Correlations and prognostic performance of resulting radiomics features were compared among the methods. Results: SUV4.0 required the least manual adaptation but tended to underestimate MTV and often missed small lesions with low 18F-FDG uptake. SUV2.5 most frequently included all lesions but required minor manual adaptations and generally overestimated MTV. In contrast, few lesions were missed when using 41max, A50P, MV2, and MV3, but these segmentation methods required extensive manual adaptation and overestimated MTV in most cases. MTV and dissemination features significantly differed among the methods. However, correlations among methods were high for MTV and most intensity and dissemination features. There were no significant differences in prognostic performance for all features among the methods. Conclusion: A high correlation existed between MTV, intensity, and most dissemination features derived with the different segmentation methods, and the prognostic performance is similar. Despite frequently missing small lesions with low 18F-FDG avidity, segmentation with a fixed threshold of SUV4.0 required the least manual adaptation, which is critical for future research and implementation in clinical practice. However, the importance of small, low 18F-FDG-avidity lesions should be addressed in a larger cohort of cHL patients.
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- 2022
42. Confused about Confusion
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Anne M. Spanjaart, Fleur M. van der Valk, Geeske van Rooijen, Matthijs C. Brouwer, Marie J. Kersten, Hematology, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Neurology, ANS - Neuroinfection & -inflammation, Clinical Haematology, and CCA - Cancer Treatment and Quality of Life
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Receptors, Chimeric Antigen ,Herpesvirus 6, Human ,Brain ,Roseolovirus Infections ,General Medicine ,Middle Aged ,Viral Load ,Antiviral Agents ,Immunotherapy, Adoptive ,Magnetic Resonance Imaging ,Diagnosis, Differential ,Limbic Encephalitis ,Humans ,Female ,Lymphoma, Large B-Cell, Diffuse ,Confusion - Published
- 2022
43. Combining Ixazomib With Subcutaneous Rituximab and Dexamethasone in Relapsed or Refractory Waldenström's Macroglobulinemia: Final Analysis of the Phase I/II HOVON124/ECWM-R2 Study
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Fritz Offner, Karima Amaador, Kazem Nasserinejad, Dries Deeren, Efstathios Kastritis, Steven T. Pals, Willem Kraan, Jeanette K. Doorduijn, Roberto D Liu, Monique C. Minnema, Marcel Kap, Marie José Kersten, Lara H Böhmer, Lidwine W. Tick, Meletios A. Dimopoulos, Josephine M.I. Vos, Martine E D Chamuleau, Maria Gavriatopoulou, Hematology, CCA - Cancer Treatment and quality of life, Clinical Haematology, CCA - Cancer Treatment and Quality of Life, Graduate School, Pathology, and 09 Laboratory specialisms
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Male ,Cancer Research ,Time Factors ,Administration, Oral ,Infusions, Subcutaneous ,Gastroenterology ,Dexamethasone ,RECOMMENDATIONS ,Ixazomib ,chemistry.chemical_compound ,Antineoplastic Combined Chemotherapy Protocols ,Medicine and Health Sciences ,PRIMARY THERAPY ,Prospective Studies ,Aged, 80 and over ,INDUCED PERIPHERAL NEUROPATHY ,Macroglobulinemia ,Middle Aged ,Europe ,Treatment Outcome ,Oncology ,PLASMA-CELLS ,Female ,Rituximab ,Waldenstrom Macroglobulinemia ,Proteasome Inhibitors ,Polyneuropathy ,medicine.drug ,Boron Compounds ,medicine.medical_specialty ,Glycine ,BORTEZOMIB ,SDG 3 - Good Health and Well-being ,Refractory ,MULTIPLE-MYELOMA ,Internal medicine ,medicine ,Humans ,WM ,Aged ,MUTATIONS ,business.industry ,medicine.disease ,Phase i ii ,chemistry ,Feasibility Studies ,ORAL PROTEASOME INHIBITOR ,FOLLOW-UP ,business - Abstract
PURPOSE Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction ( P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.
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- 2022
44. Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial
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Veringa, A., Bruggemann, R.J., Span, L.F.R., Biemond, B.J., Boer, M.G.J. de, Heuvel, E.R. van den, Klein, S.K., Kraemer, D., Minnema, M.C., Prakken, N.H.J., Rijnders, B.J.A., Swen, J.J., Verweij, P.E., Wondergem, M.J., Ypma, P.F., Blijlevens, N., Kosterink, J.G.W., Werf, T.S. van der, Alffenaar, J.W.C., Voriconazole ZonMw Study Grp, Hematology, AII - Cancer immunology, CCA - Cancer Treatment and quality of life, CCA - Cancer biology and immunology, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), PharmacoTherapy, -Epidemiology and -Economics, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Microbes in Health and Disease (MHD), Clinical Haematology, AII - Inflammatory diseases, CCA - Cancer Treatment and Quality of Life, Cardiology, Eindhoven MedTech Innovation Center, Statistics, EAISI Foundational, EAISI Health, ICMS Core, and Internal Medicine
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Microbiology (medical) ,Adult ,Adolescent ,Voriconazole/adverse effects ,Invasive Fungal Infections/drug therapy ,Antifungal Agents/adverse effects ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,General Medicine ,Haematological malignancy ,Therapeutic drug monitoring ,SDG 3 – Goede gezondheid en welzijn ,All institutes and research themes of the Radboud University Medical Center ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Infectious Diseases ,Invasive fungal infection ,SDG 3 - Good Health and Well-being ,Aspergillosis/drug therapy ,Humans ,Pharmacology (medical) ,Prospective Studies ,Voriconazole ,Drug Monitoring ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Retrospective Studies - Abstract
Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treat-ment is superior to standard treatment for invasive aspergillosis.Methods: A multicentre ( n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged >= 18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treat-ment initiation of voriconazole and repeated during treatment in both groups. The TDM group had mea-sured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups ( P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) ( P < 0.001). Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. Clinical trial registration: ClinicalTrials.gov registration no. NCT00893555.(c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
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- 2023
45. AUTOIMMUNE HEMOLYTIC ANEMIA DURING PREGNANCY AND PUERPERIUM: AN INTERNATIONAL MULTI-CENTER EXPERIENCE
- Author
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Bruno Fattizzo, Marta Bortolotti, Norma Nadia Fantini, Andreas Glenthøj, Marc Michel, Mariasanta Napolitano, Simona Raso, Frederick Chen, Vickie McDonald, Irina Murakhovskaya, Josephine M.I. Vos, Andrea Patriarca, Maria Eva Mingot-Castellano, Giulio Giordano, Margherita Scarrone, Tomas Jose Gonzalez-Lopez, Laura Trespidi, Daniele Prati, Wilma Barcellini, Clinical Haematology, General Internal Medicine, AII - Cancer immunology, and CCA - Cancer biology and immunology
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here we report 45 pregnancies occurring in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women with AIHA diagnosis before pregnancy, 10 had a relapse. Additional 13 patients developed de novo AIHA during gestation/puerperium (two patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb 6.4 g/dL, range 3.1-8.7) and required treatment in all cases (96% steroids +/- intravenous immunoglobulin, IVIG, 58% transfusions). The response was achieved in all cases and was complete in 65% of cases. Antithrombotic prophylaxis was administered in eight patients (33%). Rituximab was administered in four patients, and cyclosporine was added in one after delivery. The rate of maternal complications was 15%, including premature rupture of membranes, placental detachment, and preeclampsia. Early miscarriages occurred in 13% of pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and two perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.
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- 2023
46. Gut microbiome in allogeneic HCT survivors: The insults are gone but the damage lingers
- Author
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Yannouck van Lier, Mette D. Hazenberg, Graduate School, Clinical Haematology, AII - Cancer immunology, CCA - Cancer biology and immunology, AII - Inflammatory diseases, and Amsterdam Gastroenterology Endocrinology Metabolism
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Hematology - Abstract
The gut microbiome is an important regulator of health and disease. The report by Hino et al. suggests that damage to the microbiome, inflicted before and soon after allogeneic haematopoietic progenitor cell transplantation, does not heal by itself, most likely with consequences for late transplantation outcomes. Commentary on: Hino et al. Prolonged gut microbial alterations in post-transplant survivors of allogeneic haematopoietic stem cell transplantation. Br J Haematol 2022 (Online ahead of print). doi: 10.1111/bjh.18574.
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- 2023
47. Development of a Core Set of Patient- and Caregiver-Reported Signs and Symptoms to Facilitate Early Recognition of Acute Chimeric Antigen Receptor T-Cell Therapy Toxicities
- Author
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Anne M. Spanjaart, Elise R.A. Pennings, Milan Kos, Pim G.N.J. Mutsaers, Pieternella J. Lugtenburg, Tom van Meerten, Jaap A. van Doesum, Monique C. Minnema, Margot Jak, Suzanne van Dorp, Joost S.P. Vermaat, Marjolein W.M. van der Poel, Martijn G.H. van Oijen, Maria T. Kuipers, Inger S. Nijhof, Marie José Kersten, Interne Geneeskunde, MUMC+: MA Hematologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Health Technology Assessment (HTA), Hematology, Internal medicine, AII - Cancer immunology, CCA - Cancer Treatment and quality of life, CCA - Cancer biology and immunology, Graduate School, Clinical Haematology, General Internal Medicine, Surgery, Oncology, APH - Methodology, APH - Quality of Care, CCA - Cancer Treatment and Quality of Life, and Stem Cell Aging Leukemia and Lymphoma (SALL)
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Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2] ,All institutes and research themes of the Radboud University Medical Center ,Oncology ,SDG 3 - Good Health and Well-being ,Oncology (nursing) ,Health Policy - Abstract
PURPOSE: Prompt recognition of acute chimeric antigen receptor T (CAR T)-cell–mediated toxicities is crucial because adequate and timely management can prevent or reverse potential life-threatening complications. In the outpatient setting, patients and informal caregivers have to recognize and report signs and symptoms marking these acute toxicities. This study provides a core set of patient- and caregiver-reported signs and symptoms (outcomes, P/CROs) and definitions of red flags warranting immediate action to include in a daily checklist for support at home, with the goal to make outpatient post–CAR T-cell care safer, optimize patient and caregiver support, and thereby facilitating an early discharge/hospital visit reduction strategy. METHODS: We performed a systematic review of phase II/III trials of US Food and Drug Administration–approved CAR T-cell products and selected all common and severe adverse events that could be translated into a P/CRO for inclusion in a two-round modified Delphi procedure. Eleven CAR T-cell–dedicated hematologists from the Dutch CAR T-cell tumorboard representing all treating centers selected P/CROs for inclusion in the core set and defined red flags. The final core set was evaluated with patients and caregivers. RESULTS: From nine clinical trials, 457 adverse events were identified of which 42 could be used as P/CRO. The final core set contains 28 items, including five signs for measurement via wearables and two signs for caregiver-performed assessments. CONCLUSION: This study provides a core set of P/CROs that can serve as a framework for (eHealth) tools that aim to enable patients and caregivers to more effectively recognize and report signs and symptoms of acute toxicities after CAR T-cell therapy, which will enhance safe outpatient treatment monitoring.
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- 2023
48. Children Newly Diagnosed with Fetal and Neonatal Alloimmune Thrombocytopenia: Neurodevelopmental Outcome at School Age
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Thijs W. de Vos, Maud van Zagten, Masja de Haas, Dick Oepkes, Ratna N.G.B. Tan, C. Ellen van der Schoot, Sylke J. Steggerda, Linda S. de Vries, Enrico Lopriore, Jeanine M.M. van Klink, Clinical Haematology, and AII - Inflammatory diseases
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fetal and neonatal alloimmune thrombocytopenia ,Pediatrics, Perinatology and Child Health ,minor neurological dysfunction ,cognitive functioning ,intracranial hemorrhage ,neurodevelopmental impairment - Abstract
Objective: To evaluate the neurodevelopmental outcome at school age in children newly diagnosed with fetal and neonatal alloimmune thrombocytopenia (FNAIT). Study design: This observational cohort study included children diagnosed with FNAIT between 2002 and 2014. Children were invited for cognitive and neurological testing. Behavioral questionnaires and school performance results were obtained. A composite outcome of neurodevelopmental impairment (NDI) was used, defined, and subdivided into mild-to-moderate and severe NDI. Primary outcome was severe NDI, defined as IQ
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- 2023
49. Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia
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Floor L.F. van Baarle, Emma K. van de Weerdt, Walter J.F.M. van der Velden, Roelof A. Ruiterkamp, Pieter R. Tuinman, Paula F. Ypma, Walter M. van den Bergh, Astrid M.P. Demandt, Emile D. Kerver, A.J. Gerard Jansen, Peter E. Westerweel, Sesmu M. Arbous, Rogier M. Determann, Walther N.K.A. van Mook, Mirelle Koeman, Anja B.U. Mäkelburg, Krijn P. van Lienden, Jan M. Binnekade, Bart J. Biemond, Alexander P.J. Vlaar, Hematology, Graduate School, AII - Inflammatory diseases, APH - Quality of Care, CCA - Cancer Treatment and Quality of Life, Intensive Care Medicine, ACS - Pulmonary hypertension & thrombosis, AII - Cancer immunology, AII - Infectious diseases, CCA - Cancer biology and immunology, Clinical Haematology, ACS - Microcirculation, and Intensive care medicine
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All institutes and research themes of the Radboud University Medical Center ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,General Medicine - Abstract
Item does not contain fulltext BACKGROUND: Transfusion guidelines regarding platelet-count thresholds before the placement of a central venous catheter (CVC) offer conflicting recommendations because of a lack of good-quality evidence. The routine use of ultrasound guidance has decreased CVC-related bleeding complications. METHODS: In a multicenter, randomized, controlled, noninferiority trial, we randomly assigned patients with severe thrombocytopenia (platelet count, 10,000 to 50,000 per cubic millimeter) who were being treated on the hematology ward or in the intensive care unit to receive either one unit of prophylactic platelet transfusion or no platelet transfusion before ultrasound-guided CVC placement. The primary outcome was catheter-related bleeding of grade 2 to 4; a key secondary outcome was grade 3 or 4 bleeding. The noninferiority margin was an upper boundary of the 90% confidence interval of 3.5 for the relative risk. RESULTS: We included 373 episodes of CVC placement involving 338 patients in the per-protocol primary analysis. Catheter-related bleeding of grade 2 to 4 occurred in 9 of 188 patients (4.8%) in the transfusion group and in 22 of 185 patients (11.9%) in the no-transfusion group (relative risk, 2.45; 90% confidence interval [CI], 1.27 to 4.70). Catheter-related bleeding of grade 3 or 4 occurred in 4 of 188 patients (2.1%) in the transfusion group and in 9 of 185 patients (4.9%) in the no-transfusion group (relative risk, 2.43; 95% CI, 0.75 to 7.93). A total of 15 adverse events were observed; of these events, 13 (all grade 3 catheter-related bleeding [4 in the transfusion group and 9 in the no-transfusion group]) were categorized as serious. The net savings of withholding prophylactic platelet transfusion before CVC placement was $410 per catheter placement. CONCLUSIONS: The withholding of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter did not meet the predefined margin for noninferiority and resulted in more CVC-related bleeding events than prophylactic platelet transfusion. (Funded by ZonMw; PACER Dutch Trial Register number, NL5534.).
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- 2023
50. Likelihood of spontaneous closure of cavernous sinus dural arteriovenous fistulas based on clinical and radiological findings
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Roy Tan, René van den Berg, Rajani P. Brandsen, Peerooz Saeed, Radiology and Nuclear Medicine, ACS - Microcirculation, ANS - Neurovascular Disorders, Graduate School, Ophthalmology, Clinical Haematology, AII - Amsterdam institute for Infection and Immunity, CCA -Cancer Center Amsterdam, and Other Research
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management workflow ,spontaneous closure ,Carotid cavernous fistula ,endovascular intervention ,General Medicine ,cavernous sinus dural arteriovenous fistula - Abstract
Background Cavernous sinus dural arteriovenous fistula (CSDAVF) is a rare condition that radiologists would encounter in their careers. We aim to describe the clinical and radiological characteristics of this condition, and to provide a management workflow. Methods In our retrospective study, we studied 27 patients with CSDAVF from January 2007 to August 2020. Patients with direct cavernous sinus AVFs and patients with incomplete date were excluded. Clinical and radiological data were collected and analyzed. Results Fourteen patients were conservatively treated with spontaneous resolution while 13 patients had endovascular intervention performed. In the intervention group, seven patients had intra-cranial reflux seen on radiological imaging and six patients had clinical deterioration, hence requiring intervention. Clinically, among our patients, 21 had proptosis, 20 had conjunctiva hyperaemia, 18 had extraocular movement limitation, 13 had raised intraocular pressure, 11 had chemosis, ten had ocular pain, nine had ocular bruit, eight had headache and six had worsening visual acuity. Radiologically, a concurrence was seen between superior ophthalmic vein thrombosis and spontaneous resolution of the CSDAVF, as compared to those who underwent intervention. A paradoxical increase of ocular symptoms was seen despite a decrease of flow or stagnation of contrast in radiological imaging of CSDAVF. Conclusions In our study, 52% of CSDAVF closed spontaneously. As deterioration of ocular symptoms in patients with CSDAVF might also reflect spontaneous progressive occlusion, it warrants dynamic vascular imaging to check the status of venous outflow. Patients with CSDAVF with corticovenous reflux or deterioration of visual acuity need more urgent (endovascular) treatment.
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- 2023
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