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5. Atypical B cells (CD21-CD27-IgD-) correlate with lack of response to checkpoint inhibitor therapy in NSCLC

Author

Belderbos, R. A., Corneth, O. B.J., Dumoulin, D., Hendriks, R. W., Aerts, J. G.J.V., Willemsen, M., Belderbos, R. A., Corneth, O. B.J., Dumoulin, D., Hendriks, R. W., Aerts, J. G.J.V., and Willemsen, M.

Abstract

Introduction: Checkpoint inhibitor (CI) therapy has revolutionized treatment for non-small cell lung cancer (NSCLC). However, a proportion of patients do not respond to CI therapy for unknown reasons. Although the current paradigm in anti-tumor immunity evolves around T cells, the presence of tertiary lymphoid structures and memory B cells has been positively correlated with response to CI therapy in NSCLC. In addition, double negative (DN) (CD27- IgD-) B cells have been shown to be abundant in NSCLC compared to healthy lung tissue and inversely correlate with the intratumoral presence of memory B cells. Nonetheless, no study has correlated DN B cells to survival in NSCLC. Methods: In this study, we evaluated the presence and phenotype of B cells in peripheral blood with flow cytometry of patients with NSCLC and mesothelioma before receiving CI therapy and correlated these with clinical outcome. Results: Non-responding patients showed decreased frequencies of B cells, yet increased frequencies of antigen-experienced CD21- DN (Atypical) B cells compared to responding patients and HC, which was confirmed in patients with mesothelioma treated with CI therapy. Conclusions: These data show that the frequency of CD21- DN B cells correlates with lack of response to CI therapy in thoracic malignancies. The mechanism by which CD21- DN B cells hamper CI therapy remains unknown. Our findings support the hypothesis that CD21- DN B cells resemble phenotypically identical exhausted B cells that are seen in chronic infection or function as antigen presenting cells that induce regulatory T cells.

Published
2024

6. Doorrekening scenario’s accijnsverhoging op tabak

Author

Over, E, de Vries, E, Geboers, C, Willemsen, M, de Wit, A, Over, E, de Vries, E, Geboers, C, Willemsen, M, and de Wit, A

Abstract

RIVM rapport:In 2018 werd het Nationaal Preventie Akkoord (NPA) ondertekend, met de ambitieuze doelstelling dat in 2040 niet meer dan 5 procent van de bevolking zou roken en dat in dat jaar geen enkele jongere meer rookt (“rookvrije generatie”). In 2014 rookte nog 25,7 procent van de volwassen bevolking. In 2018, bij de ondertekening van het NPA, rookte 22,4 procent van de Nederlanders en in 2022 was dat percentage gedaald tot 18,9 procent. Deze cijfers zijn afkomstig uit de Gezondheidsenquête (Trimbos instituut, 2023). Rokers worden hier gedefinieerd als dagelijkse en gelegenheidsrokers (nietdagelijkse rokers) en deze cijfers zijn gebaseerd op zelfrapportage.

Published
2024

12. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Denomme-Pichon A. -S., Bruel A. -L., Duffourd Y., Safraou H., Thauvin-Robinet C., Tran Mau-Them F., Philippe C., Vitobello A., Jean-Marcais N., Moutton S., Thevenon J., Faivre L., Matalonga L., de Boer E., Gilissen C., Hoischen A., Kleefstra T., Pfundt R., de Vries B. B. A., Willemsen M. H., Vissers L. E. L. M., Jackson A., Banka S., Clayton-Smith J., Benetti E., Fallerini C., Renieri A., Ciolfi A., Dallapiccola B., Pizzi S., Radio F. C., Tartaglia M., Ellwanger K., Graessner H., Haack T. B., Zurek B., Havlovicova M., Macek M., Ryba L., Schwarz M., Votypka P., Lopez-Martin E., Posada M., Mencarelli M. A., Rooryck C., Trimouille A., Verloes A., Abbott K. M., Kerstjens M., Martin E. L., Maystadt I., Morleo M., Nigro V., Pinelli M., Riess O., Agathe J. -M. D. S., Santen G. W. E., Thauvin C., Torella A., Vissers L., Zguro K., Boer E. D., Cohen E., Danis D., Gao F., Horvath R., Johari M., Johanson L., Li S., Morsy H., Nelson I., Paramonov I., te Paske I. B. A. W., Robinson P., Savarese M., Steyaert W., Topf A., van der Velde J. K., Vandrovcova J., Ossowski S., Demidov G., Sturm M., Schulze-Hentrich J. M., Schule R., Xu J., Kessler C., Wayand M., Synofzik M., Wilke C., Traschutz A., Schols L., Hengel H., Lerche H., Kegele J., Heutink P., Brunner H., Scheffer H., Hoogerbrugge N., 't Hoen P. A. C., Sablauskas K., de Voer R. M., Kamsteeg E. -J., van de Warrenburg B., van Os N., Paske I. T., Janssen E., Steehouwer M., Yaldiz B., Brookes A. J., Veal C., Gibson S., Maddi V., Mehtarizadeh M., Riaz U., Warren G., Dizjikan F. Y., Shorter T., Straub V., Bettolo C. M., Manera J. D., Hambleton S., Engelhardt K., Alexander E., Peyron C., Pelissier A., Beltran S., Gut I. G., Laurie S., Piscia D., Papakonstantinou A., Bullich G., Corvo A., Fernandez-Callejo M., Hernandez C., Pico D., Lochmuller H., Gumus G., Bros-Facer V., Rath A., Hanauer M., Lagorce D., Hongnat O., Chahdil M., Lebreton E., Stevanin G., Durr A., Davoine C. -S., Guillot-Noel L., Heinzmann A., Coarelli G., Bonne G., Evangelista T., Allamand V., Ben Yaou R., Metay C., Eymard B., Atalaia A., Stojkovic T., Turnovec M., Thomasova D., Kremlikova R. P., Frankova V., Liskova P., Dolezalova P., Parkinson H., Keane T., Freeberg M., Thomas C., Spalding D., Robert G., Costa A., Patch C., Hanna M., Houlden H., Reilly M., Efthymiou S., Cali E., Magrinelli F., Sisodiya S. M., Rohrer J., Muntoni F., Zaharieva I., Sarkozy A., Timmerman V., Baets J., de Vries G., De Winter J., Beijer D., de Jonghe P., Van de Vondel L., De Ridder W., Weckhuysen S., Mutarelli M., Varavallo A., Banfi S., Musacchia F., Piluso G., Ferlini A., Selvatici R., Gualandi F., Bigoni S., Rossi R., Neri M., Aretz S., Spier I., Sommer A. K., Peters S., Oliveira C., Pelaez J. G., Matos A. R., Jose C. S., Ferreira M., Gullo I., Fernandes S., Garrido L., Ferreira P., Carneiro F., Swertz M. A., Johansson L., van der Vries G., Neerincx P. B., Ruvolo D., Kerstjens Frederikse W. S., Zonneveld-Huijssoon E., Roelofs-Prins D., van Gijn M., Kohler S., Metcalfe A., Drunat S., Heron D., Mignot C., Keren B., Lacombe D., Capella G., Valle L., Holinski-Feder E., Laner A., Steinke-Lange V., Cilio M. -R., Carpancea E., Depondt C., Lederer D., Sznajer Y., Duerinckx S., Mary S., Macaya A., Cazurro-Gutierrez A., Perez-Duenas B., Munell F., Jarava C. F., Maso L. B., Marce-Grau A., Colobran R., Hackman P., Udd B., Hemelsoet D., Dermaut B., Schuermans N., Poppe B., Verdin H., Osorio A. N., Depienne C., Roos A., Cordts I., Deschauer M., Striano P., Zara F., Riva A., Iacomino M., Uva P., Scala M., Scudieri P., Basak A. N., Claeys K., Boztug K., Haimel M., W. E G., Ruivenkamp C. A. L., Natera de Benito D., Thompson R., Polavarapu K., Grimbacher B., Zaganas I., Kokosali E., Lambros M., Evangeliou A., Spilioti M., Kapaki E., Bourbouli M., Balicza P., Molnar M. J., De la Paz M. P., Sanchez E. B., Delgado B. M., Alonso Garcia de la Rosa F. J., Schrock E., Rump A., Mei D., Vetro A., Balestrini S., Guerrini R., Chinnery P. F., Ratnaike T., Schon K., Maver A., Peterlin B., Munchau A., Lohmann K., Herzog R., Pauly M., May P., Beeson D., Cossins J., Furini S., Afenjar A., Goldenberg A., Masurel A., Phan A., Dieux-Coeslier A., Fargeot A., Guerrot A. -M., Toutain A., Molin A., Sorlin A., Putoux A., Jouret B., Laudier B., Demeer B., Doray B., Bonniaud B., Isidor B., Gilbert-Dussardier B., Leheup B., Reversade B., Paul C., Vincent-Delorme C., Neiva C., Poirsier C., Quelin C., Chiaverini C., Coubes C., Francannet C., Colson C., Desplantes C., Wells C., Goizet C., Sanlaville D., Amram D., Lehalle D., Genevieve D., Gaillard D., Zivi E., Sarrazin E., Steichen E., Schaefer E., Lacaze E., Jacquemin E., Bongers E., Kilic E., Colin E., Giuliano F., Prieur F., Laffargue F., Morice-Picard F., Petit F., Cartault F., Feillet F., Baujat G., Morin G., Diene G., Journel H., Perthus I., Lespinasse J., Alessandri J. -L., Amiel J., Martinovic J., Delanne J., Albuisson J., Lambert L., Perrin L., Ousager L. B., Van Maldergem L., Pinson L., Ruaud L., Samimi M., Bournez M., Bonnet-Dupeyron M. N., Vincent M., Jacquemont M. -L., Cordier-Alex M. -P., Gerard-Blanluet M., Willems M., Spodenkiewicz M., Doco-Fenzy M., Rossi M., Renaud M., Fradin M., Mathieu M., Holder-Espinasse M. H., Houcinat N., Hanna N., Leperrier N., Chassaing N., Philip N., Boute O., Van Kien P. K., Parent P., Bitoun P., Sarda P., Vabres P., Jouk P. -S., Touraine R., El Chehadeh S., Whalen S., Marlin S., Passemard S., Grotto S., Bellanger S. A., Blesson S., Nambot S., Naudion S., Lyonnet S., Odent S., Attie-Bitach T., Busa T., Drouin-Garraud V., Layet V., Bizaoui V., Cusin V., Capri Y., Alembik Y., Unión Europea. Comisión Europea. H2020, Unión Europea. Comisión Europea. 7 Programa Marco, Instituto de Salud Carlos III, Instituto Nacional de Bioinformatica (España), Ministry of Health (República Checa), Ministry of Education, Youth and Sports (República Checa), Denomme-Pichon, A. -S., Bruel, A. -L., Duffourd, Y., Safraou, H., Thauvin-Robinet, C., Tran Mau-Them, F., Philippe, C., Vitobello, A., Jean-Marcais, N., Moutton, S., Thevenon, J., Faivre, L., Matalonga, L., de Boer, E., Gilissen, C., Hoischen, A., Kleefstra, T., Pfundt, R., de Vries, B. B. A., Willemsen, M. H., Vissers, L. E. L. M., Jackson, A., Banka, S., Clayton-Smith, J., Benetti, E., Fallerini, C., Renieri, A., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Ellwanger, K., Graessner, H., Haack, T. B., Zurek, B., Havlovicova, M., Macek, M., Ryba, L., Schwarz, M., Votypka, P., Lopez-Martin, E., Posada, M., Mencarelli, M. A., Rooryck, C., Trimouille, A., Verloes, A., Abbott, K. M., Kerstjens, M., Martin, E. L., Maystadt, I., Morleo, M., Nigro, V., Pinelli, M., Riess, O., Agathe, J. -M. D. S., Santen, G. W. E., Thauvin, C., Torella, A., Vissers, L., Zguro, K., Boer, E. D., Cohen, E., Danis, D., Gao, F., Horvath, R., Johari, M., Johanson, L., Li, S., Morsy, H., Nelson, I., Paramonov, I., te Paske, I. B. A. W., Robinson, P., Savarese, M., Steyaert, W., Topf, A., van der Velde, J. K., Vandrovcova, J., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Schule, R., Xu, J., Kessler, C., Wayand, M., Synofzik, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., Lerche, H., Kegele, J., Heutink, P., Brunner, H., Scheffer, H., Hoogerbrugge, N., 't Hoen, P. A. C., Sablauskas, K., de Voer, R. M., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., Paske, I. T., Janssen, E., Steehouwer, M., Yaldiz, B., Brookes, A. J., Veal, C., Gibson, S., Maddi, V., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Manera, J. D., Hambleton, S., Engelhardt, K., Alexander, E., Peyron, C., Pelissier, A., Beltran, S., Gut, I. G., Laurie, S., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Fernandez-Callejo, M., Hernandez, C., Pico, D., Lochmuller, H., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Lagorce, D., Hongnat, O., Chahdil, M., Lebreton, E., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Bonne, G., Evangelista, T., Allamand, V., Ben Yaou, R., Metay, C., Eymard, B., Atalaia, A., Stojkovic, T., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Liskova, P., Dolezalova, P., Parkinson, H., Keane, T., Freeberg, M., Thomas, C., Spalding, D., Robert, G., Costa, A., Patch, C., Hanna, M., Houlden, H., Reilly, M., Efthymiou, S., Cali, E., Magrinelli, F., Sisodiya, S. M., Rohrer, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., de Vries, G., De Winter, J., Beijer, D., de Jonghe, P., Van de Vondel, L., De Ridder, W., Weckhuysen, S., Mutarelli, M., Varavallo, A., Banfi, S., Musacchia, F., Piluso, G., Ferlini, A., Selvatici, R., Gualandi, F., Bigoni, S., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Vries, G., Neerincx, P. B., Ruvolo, D., Kerstjens Frederikse, W. S., Zonneveld-Huijssoon, E., Roelofs-Prins, D., van Gijn, M., Kohler, S., Metcalfe, A., Drunat, S., Heron, D., Mignot, C., Keren, B., Lacombe, D., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Cilio, M. -R., Carpancea, E., Depondt, C., Lederer, D., Sznajer, Y., Duerinckx, S., Mary, S., Macaya, A., Cazurro-Gutierrez, A., Perez-Duenas, B., Munell, F., Jarava, C. F., Maso, L. B., Marce-Grau, A., Colobran, R., Hackman, P., Udd, B., Hemelsoet, D., Dermaut, B., Schuermans, N., Poppe, B., Verdin, H., Osorio, A. N., Depienne, C., Roos, A., Cordts, I., Deschauer, M., Striano, P., Zara, F., Riva, A., Iacomino, M., Uva, P., Scala, M., Scudieri, P., Basak, A. N., Claeys, K., Boztug, K., Haimel, M., W. E, G., Ruivenkamp, C. A. L., Natera de Benito, D., Thompson, R., Polavarapu, K., Grimbacher, B., Zaganas, I., Kokosali, E., Lambros, M., Evangeliou, A., Spilioti, M., Kapaki, E., Bourbouli, M., Balicza, P., Molnar, M. J., De la Paz, M. P., Sanchez, E. B., Delgado, B. M., Alonso Garcia de la Rosa, F. J., Schrock, E., Rump, A., Mei, D., Vetro, A., Balestrini, S., Guerrini, R., Chinnery, P. F., Ratnaike, T., Schon, K., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., May, P., Beeson, D., Cossins, J., Furini, S., Afenjar, A., Goldenberg, A., Masurel, A., Phan, A., Dieux-Coeslier, A., Fargeot, A., Guerrot, A. -M., Toutain, A., Molin, A., Sorlin, A., Putoux, A., Jouret, B., Laudier, B., Demeer, B., Doray, B., Bonniaud, B., Isidor, B., Gilbert-Dussardier, B., Leheup, B., Reversade, B., Paul, C., Vincent-Delorme, C., Neiva, C., Poirsier, C., Quelin, C., Chiaverini, C., Coubes, C., Francannet, C., Colson, C., Desplantes, C., Wells, C., Goizet, C., Sanlaville, D., Amram, D., Lehalle, D., Genevieve, D., Gaillard, D., Zivi, E., Sarrazin, E., Steichen, E., Schaefer, E., Lacaze, E., Jacquemin, E., Bongers, E., Kilic, E., Colin, E., Giuliano, F., Prieur, F., Laffargue, F., Morice-Picard, F., Petit, F., Cartault, F., Feillet, F., Baujat, G., Morin, G., Diene, G., Journel, H., Perthus, I., Lespinasse, J., Alessandri, J. -L., Amiel, J., Martinovic, J., Delanne, J., Albuisson, J., Lambert, L., Perrin, L., Ousager, L. B., Van Maldergem, L., Pinson, L., Ruaud, L., Samimi, M., Bournez, M., Bonnet-Dupeyron, M. N., Vincent, M., Jacquemont, M. -L., Cordier-Alex, M. -P., Gerard-Blanluet, M., Willems, M., Spodenkiewicz, M., Doco-Fenzy, M., Rossi, M., Renaud, M., Fradin, M., Mathieu, M., Holder-Espinasse, M. H., Houcinat, N., Hanna, N., Leperrier, N., Chassaing, N., Philip, N., Boute, O., Van Kien, P. K., Parent, P., Bitoun, P., Sarda, P., Vabres, P., Jouk, P. -S., Touraine, R., El Chehadeh, S., Whalen, S., Marlin, S., Passemard, S., Grotto, S., Bellanger, S. A., Blesson, S., Nambot, S., Naudion, S., Lyonnet, S., Odent, S., Attie-Bitach, T., Busa, T., Drouin-Garraud, V., Layet, V., Bizaoui, V., Cusin, V., Capri, Y., Alembik, Y., and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Exome reanalysis, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Developmental disorder, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology and Life Sciences, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], ClinVar, Rare diseases, All institutes and research themes of the Radboud University Medical Center, Medicine and Health Sciences, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Multidisciplinary, general & others [D99] [Human health sciences], Exome reanalysi, Genetics (clinical)
Abstract

Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform, which received funding from the EU projects RD-Connect, Solve-RD, and European Joint Programme on Rare Diseases (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática), and ELIXIR Implementation Studies. The collaborations in this study were facilitated by the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies, one of the 24 European Reference Networks approved by the European Reference Network Board of Member States, cofunded by the European Commission. This project was supported by the Czech Ministry of Health (number 00064203) and by the Czech Ministry of Education, Youth and Sports (number - LM2018132) to M.M. Sí

Published
2023

13. Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study

Author

de Mol, C. L., Wong, Y. Y. M., van Pelt, E. D., Ketelslegers, I. A., Bakker, D. P., Boon, M., Braun, K. P. J., van Dijk, K. G. J., Eikelenboom, M. J., Engelen, M., Geleijns, K., Haaxma, C. A., Niermeijer, J. M. F., Niks, E. H., Peeters, E. A. J., Peeters-Scholte, C. M. P. C. D., Poll-The, B. T., Portier, R. P., de Rijk-van Andel, J. F., Samijn, J. P. A., Schippers, H. M., Snoeck, I. N., Stroink, H., Vermeulen, R. J., Verrips, A., Visscher, F., Vles, J. S. H., Willemsen, M. A. A. P., Catsman-Berrevoets, C. E., Hintzen, R. Q., and Neuteboom, R. F.

Published
2018
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14. Water en bodem sturend, hoe dan? : Praktijkgids voor een ontwerpende aanpak

Author

Willemsen, M., Jonge, J. de, Willemsen, M., and Jonge, J. de

Abstract

Of het nu gaat om klimaat, energie, wonen, biodiversiteit, landbouw, water of sociale rechtvaardigheid: de opgaven waarvoor we staan zijn groot. We zullen anders met onze ruimte moeten omgaan: alle claims en eisen passen simpelweg niet meer. In plaats van meer en groter, moet het anders en beter. Daarom worden water en bodem sturend bij ruimtelijke planvorming. Maar hoe doe je dat in de praktijk? Professionals in het ruimtelijk domein missen vaak nog concrete handvatten. En de verbindende schakel tussen visie en praktijk ontbreekt in veel gevallen, zo blijkt uit een inventarisatie van het College van Rijksadviseurs (CRa) van meer dan tachtig projecten over water en bodem sturend (zie kadertekst). De sleutel is een samenhangende, ontwerpende aanpak met een cyclisch proces van onderzoek, gesprek en ontwerp samen met de betrokkenen in een gebied. Zo verkennen partijen gezamenlijk de complexe opgaven en ontwikkelen zij een gedragen toekomstperspectief. Deze praktijkgids van het CRa beschrijft die ontwerpende aanpak. De uitgave is bedoeld voor professionals in het ruimtelijk domein (planologen, waterdeskundigen, landschapsarchitecten, beheerders, ontwikkelaars enz.), werkzaam bij overheden, maatschappelijke organisaties en marktpartijen. Zij vinden in deze gids zes stappen om in projecten, programma’s en bij beleidsontwikkeling te werken vanuit het principe ‘water en bodem sturend’. De stappen zijn op zich niet nieuw, het betreft gangbare gereedschappen en werkwijzen. Maar de meerwaarde zit hem in de bundeling tot samenhangende aanpak. Een aanpak die stapsgewijs concreet maakt hoe je een natuurlijk, zelfregulerend water en bodemsysteem ontwikkelt, als basis voor een toekomstgerichte, ruimtelijke ontwikkeling van een gebied.

Published
2023

15. B cell immune profiles in dysbiotic vermiform appendixes of pancreatic cancer patients

Author

Vietsch, EE, Latifi, D, Verheij, M, van der Oost, EWA, de Wilde, RF, Haen, R, van den Boom, AL, Koerkamp, BG, Doornebosch, PG, van Verschuer, VMT, Ooms, AHAG, Mohammad, F, Willemsen, M, Aerts, JGJV, Krog, RT, de Miranda, NFCC, van den Bosch, TPP, Mueller, YM, Katsikis, PD, van Eijck, CHJ, Vietsch, EE, Latifi, D, Verheij, M, van der Oost, EWA, de Wilde, RF, Haen, R, van den Boom, AL, Koerkamp, BG, Doornebosch, PG, van Verschuer, VMT, Ooms, AHAG, Mohammad, F, Willemsen, M, Aerts, JGJV, Krog, RT, de Miranda, NFCC, van den Bosch, TPP, Mueller, YM, Katsikis, PD, and van Eijck, CHJ

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies.

Published
2023

16. Educational Differences in Associations of Noticing Anti-Tobacco Information with Smoking-Related Attitudes and Quit Intentions: Findings from the International Tobacco Control Europe Surveys

Author

Springvloet, L., Willemsen, M. C., Mons, U., van den Putte, B., Kunst, A. E., Guignard, R., Hummel, K., Allwright, S., Siahpush, M., de Vries, H., and Nagelhout, G. E.

Abstract

This study examined educational differences in associations of noticing anti-tobacco information with smoking-related attitudes and quit intentions among adult smokers. Longitudinal data (N = 7571) from two waves of six countries of the International Tobacco Control (ITC) Europe Surveys were included. Generalized estimating equation analyses and multiple linear and logistic regression analyses were conducted. Higher educated smokers noticed anti-tobacco information slightly more often than lower educated smokers (F(2) = 25.78, P < 0.001). Noticing anti-tobacco information was associated with more negative smoking-related attitudes (ß = 0.05, P < 0.001) and more quit intentions (OR = 1.08, P < 0.001). Among smokers without a quit intention at baseline, a positive association was found for noticing anti-tobacco information at baseline with follow-up quit intention (OR = 1.14, P = 0.003). No other longitudinal associations were found. No educational differences were found in the association of noticing anti-tobacco information with smoking-related attitudes but associations with quit intentions were found only among low (OR = 1.12, P = 0.001) and high educated respondents (OR = 1.11, P < 0.001) and not among moderate educated respondents (OR = 1.02, P = 0.43). Noticing anti-tobacco information may positively influence quit intentions and possibly smoking-related attitudes. Lower educated smokers were as likely to be influenced by anti-tobacco information as higher educated smokers but noticed anti-tobacco information less often; increasing reach of anti-tobacco information may increase impact in this group.

Published
2015
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22. 1642TiP ENSURE: Dendritic cell therapy (MesoPher) in combination with extended-pleurectomy/decortication after chemotherapy in subjects with resectable mesothelioma: A feasibility study

Author

Cantini, L., primary, Dietz, M.V., additional, Belderbos, R.A., additional, Cornelissen, R., additional, Dumoulin, D.W., additional, Vink, M., additional, Bezemer, K., additional, Langerak, A.W., additional, von der Thüsen, J., additional, Mahtab, E.A.F., additional, Maat, L.P.W.M., additional, Stadhouders, R., additional, Hendriks, R., additional, Willemsen, M., additional, and Aerts, J.G., additional

Published
2022
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24. Immunophenotypic analysis reveals differences in circulating immune cells in the peripheral blood of patients with segmental and nonsegmental vitiligo

Author

Willemsen, M., Post, N.F., van Uden, N.O.P., Narayan, V.S., Chielie, S., Kemp, E.H., Bekkenk, M.W., and Luiten, R.M.

Abstract

Accumulating studies have indicated immune-based destruction of melanocytes in both segmental vitiligo (SV) and non-SV (NSV). Whereas SV often occurs unilaterally during childhood and stabilizes after an initial period of activity, the disease course of NSV is usually slowly progressive, with new lesions occurring bilaterally during life. This suggests an involvement of distinct pathophysiology pathways, specifically increased systemic immune activation in patients with NSV but not in patients with SV. This research aimed to identify the differences in immune cells in the blood of patients with SV and NSV through immunophenotyping of circulating cells. Regulatory T cells were unaffected in patients with SV compared with that in healthy controls but decreased in patients with NSV. In patients with NSV, the reduction in regulatory T cells was associated with the presence of other systemic autoimmune comorbidities, which were less present in SV. Similarly, the absence of a melanocyte-specific antibody response in patients with SV suggests less involvement of B-cell immunity in SV. These data show that in contrast to patients with NSV, no increased systemic immunity is found in patients with SV, indicating that SV pathogenesis is associated with a localized cytotoxic reaction targeting epidermal melanocytes.

Published
2022

25. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) in adulthood: A Dutch pilot study exploring clinical and patient-reported outcomes

Author

Tseng, L. A., Teela, L., Janssen, M. C., Bok, L. A., Willemsen, M. A.A.P., Neuteboom, R. F., Haverman, L., Gospe, S. M., Coughlin, C. R., van Karnebeek, C. D.M., Paediatrics, Paediatric Metabolic Diseases, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Paediatric Psychosocial Care, APH - Mental Health, Amsterdam Reproduction & Development (AR&D), APH - Methodology, APH - Digital Health, and Neurology

Subjects
PROMIS, All institutes and research themes of the Radboud University Medical Center, Patient-reported outcomes, Endocrinology, Genetics, Adults, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Molecular Biology, PDE-ALDH7A1
Abstract

Background: Little is known about pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) in adulthood, as the genetic basis of the disorder has only been elucidated 15 years ago. This creates a knowledge gap for physicians, pediatric patients and their parents, which was aimed to address in this study using clinical data as well as patient-reported outcome measures (PROMs) for the patient's perspective. Methods: Dutch, genetically confirmed PDE-ALDH7A1 patients ≥18 years were eligible for inclusion. Clinical data were collected as well as PROMs (PROMIS item banks Anxiety, Depression, Anger, Physical Functioning, Cognitive Functioning, Cognitive Abilities, Ability to Participate and Satisfaction with Social Roles). Results: Ten out of 11 patients agreed to participate (91% response rate). Seizure control at last follow up (median age 25.2 years, range 17.8–29.8 years) was achieved with pyridoxine monotherapy in 70%, 20% with adjunct common-anti epileptic drugs and 10% did not obtain complete seizure control. Neurologic symptoms were present in all but one patient (90%) and included tremors, noted in 40%. Neuro-imaging abnormalities were present in 80%. Intellectual disability was present in 70%. One patient (10%) attended university, three maintained a job without assistance, five maintained a job with assistance or attended social daycare, and one patient never followed regular education. The cohort scored significantly lower on the PROMIS Cognitive Functioning compared to the general (age-related) population. Distribution of scores was wide on all PROMIS item banks. Discussion & conclusion: Outcomes of this young adult cohort are heterogeneous and individualized approaches are therefore needed. Long-term seizure control with pyridoxine was achieved for almost all patients. Neurologic symptoms were noted in the majority, including tremors, as well as neuro-imaging abnormalities and intellectual disability, additionally reflected by the PROMIS Cognitive Functioning. PDE-ALDH7A1 patients scored comparable to the general population on all other PROMs, especially regarding Ability to Participate and Satisfaction with Social Roles this may indicate a positive interpretation of their functioning. The aim is to expand this pilot study to larger populations to obtain more solid data, and to advance the use of PROMs to engage patients in research and provide the opportunity for personalized care.

Published
2022

26. Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder

Author

Melland, H, Bumbak, F, Kolesnik-Taylor, A, Ng-Cordell, E, John, A, Constantinou, P, Joss, S, Larsen, M, Fagerberg, C, Laulund, LW, Thies, J, Emslie, F, Willemsen, M, Kleefstra, T, Pfundt, R, Barrick, R, Chang, R, Loong, L, Alfadhel, M, van der Smagt, J, Nizon, M, Kurian, MA, Scott, DJ, Ziarek, JJ, Gordon, SL, Baker, K, Melland, H, Bumbak, F, Kolesnik-Taylor, A, Ng-Cordell, E, John, A, Constantinou, P, Joss, S, Larsen, M, Fagerberg, C, Laulund, LW, Thies, J, Emslie, F, Willemsen, M, Kleefstra, T, Pfundt, R, Barrick, R, Chang, R, Loong, L, Alfadhel, M, van der Smagt, J, Nizon, M, Kurian, MA, Scott, DJ, Ziarek, JJ, Gordon, SL, and Baker, K

Abstract

PURPOSE: Synaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioral disturbances, and electroencephalogram abnormalities. In this study, we expand the genotypes and phenotypes and identify discriminating features of this disorder. METHODS: We describe 22 individuals with 15 de novo missense SYT1 variants. The evidence for pathogenicity is discussed, including the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioral data for 14 cases were compared with other monogenic neurodevelopmental disorders. RESULTS: Four variants were located in the C2A domain with the remainder in the C2B domain. We classified 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes included delayed developmental milestones, abnormal eye physiology, movement disorders, and sleep disturbances. Discriminating behavioral characteristics were severity of motor and communication impairment, presence of motor stereotypies, and mood instability. CONCLUSION: Neurodevelopmental disorder-associated SYT1 variants extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severities than initially reported. This study guides the diagnosis and molecular understanding of this rare neurodevelopmental disorder and highlights a key role for SYT1 function in emotional regulation, motor control, and emergent cognitive function.

Published
2022

27. Nota Voorkeursalternatief dijkverbetering Cuijk-Ravenstein : Een herkenbare dijk met veel gezichten, onderdeel van een groter geheel

Author

Cuyck, T. van, Tuijnman, V., Springer, M., Venema, A., Willemsen, M., Cuyck, T. van, Tuijnman, V., Springer, M., Venema, A., and Willemsen, M.

Abstract

Het project Cuijk-Ravenstein is het tweede project van het waterschap binnen het Hoogwaterbeschermingsprogramma. Dit project betreft een integraal dijkverbeteringsproject. Het waterschap Aa en Maas is initiatiefnemer, en zoekt samenwerking met gebiedspartners voor goede inpassing en waar mogelijk het verzilveren van meekoppelkansen.

Published
2022

29. Trends in individualised affordability of factory-made cigarettes: findings of the 2008-2020 International Tobacco Control (ITC) Netherlands Surveys.

Author

Geboers, Cloé, Candel, Math J J M, Chaloupka, Frank J, Nagelhout, Gera E, Vries, Hein de, van den Putte, Bas, Shang, Ce, Fong, Geoffrey T, Willemsen, Marc C, Geboers, C, Candel, M J J M, Chaloupka, F J, Nagelhout, G E, de Vries, H, Van den Putte, B, Shang, C, and Willemsen, M C

Subjects
CIGARETTES, GENERALIZED estimating equations, TOBACCO, INCOME, YOUNG adults
Abstract

Introduction: Cigarette affordability, the price of tobacco relative to consumer income, is a key determinant of tobacco consumption. This study examined trends over 12 years in individualised factory-made cigarette affordability in the Netherlands, and whether these trends differed by sex, age, and education.Methods: Data from 10 waves (2008-2020) of the International Tobacco Control (ITC) Netherlands Surveys were used to estimate individualised affordability, measured as the percentage of income required to buy 100 cigarette packs (Relative Income Price, RIP), using self-reported prices and income. The higher the RIP, the less affordable cigarettes are. Generalised estimating equation regression models assessed trends in individualised affordability over time and by sex, age, and education.Results: Affordability decreased significantly between 2008 and 2020, with RIP increasing from 1.89% (2008) to 2.64% (2020) (p≤.001), Except for 2008-2010, no significant year-on-year changes in affordability were found. Lower affordability was found among subgroups who have a lower income level: females (versus males), 18-24 and 25-39 year olds (versus 55 and over) and low or moderate educated individuals (versus high educated). Interactions between wave and education (p=.007) were found, but not with sex (p=.653) or age (p=.295). A decreasing linear trend in affordability was found for moderately (p=.041) and high-educated (p=.025), but not for low-educated individuals (p=.149).Conclusions: Cigarettes in the Netherlands have become less affordable between 2008 and 2020, yet this was mostly due to the decrease in affordability between 2008 and 2010. There is a need for more significant increases in tax to further decrease affordability.Implications: Our findings suggest that cigarettes have become less affordable in the Netherlands between 2008 and 2020. But, this appears to be the result of a steep decrease in affordability between 2008 and 2010. Affordability was lower among groups who have on average lower incomes (females, young adults, low- and moderate educated individuals), and differences in trends across education levels could be explained by per capita income changes. Our individualised measure indicated lower affordability than published aggregate affordability estimations. Future tax increases should be large enough to result in a lower affordability. [ABSTRACT FROM AUTHOR]

Published
2023
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31. Vitiligo and melanoma: The fine balance between autoimmunity and immune escape

Author

Willemsen, M., Luiten, R.M., Bekkenk, M.W., and Faculteit der Geneeskunde

Subjects
integumentary system, skin and connective tissue diseases
Abstract

Work over the past years has increased our understanding on the role of the immune system in the human pigment cell disorders vitiligo and melanoma. Yet, pathogenic mechanisms of vitiligo are still incompletely studied and immune evasion still occurs among immunotherapy-treated melanoma patients. The work described in this thesis therefore aimed to on the one hand investigate the role of the immune system in melanoma and vitiligo, and on the other hand study whether and, if so, how melanocytes and melanoma cells contribute to immune evasion. We demonstrate that a besides a localized cytotoxic reaction against epidermal melanocytes, a significant proportion of vitiligo patients also show systemic immune activation. In addition, melanocytes from vitiligo patients do not confer protection against the T cell attack by PD-L1 upregulation. This provides a rational to study the possibilities of immunosuppressive therapy in the treatment of vitiligo. In melanoma, tissue-resident memory T (TRM) have an important protective role in melanoma. Nonetheless, we show that TRM cells are not abundantly present in pre-cancerous tissues and suggests that T cell infiltration and TRM cell differentiation do not occur yet at the pre-malignant stage. Furthermore, we investigated melanoma heterogeneity to unravel the phenotype of tumor cells that are insufficiently targeted by current immunotherapies. Our findings contribute to a better understanding of autoimmunity in vitiligo and immune evasion in melanoma.

Published
2022

35. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

Author

Hu, H, Haas, S A, Chelly, J, Van Esch, H, Raynaud, M, de Brouwer, A PM, Weinert, S, Froyen, G, Frints, S GM, Laumonnier, F, Zemojtel, T, Love, M I, Richard, H, Emde, A-K, Bienek, M, Jensen, C, Hambrock, M, Fischer, U, Langnick, C, Feldkamp, M, Wissink-Lindhout, W, Lebrun, N, Castelnau, L, Rucci, J, Montjean, R, Dorseuil, O, Billuart, P, Stuhlmann, T, Shaw, M, Corbett, M A, Gardner, A, Willis-Owen, S, Tan, C, Friend, K L, Belet, S, van Roozendaal, K EP, Jimenez-Pocquet, M, Moizard, M-P, Ronce, N, Sun, R, OʼKeeffe, S, Chenna, R, van Bömmel, A, Göke, J, Hackett, A, Field, M, Christie, L, Boyle, J, Haan, E, Nelson, J, Turner, G, Baynam, G, Gillessen-Kaesbach, G, Müller, U, Steinberger, D, Budny, B, Badura-Stronka, M, Latos-Bieleńska, A, Ousager, L B, Wieacker, P, Criado, G Rodríguez, Bondeson, M-L, Annerén, G, Dufke, A, Cohen, M, Van Maldergem, L, Vincent-Delorme, C, Echenne, B, Simon-Bouy, B, Kleefstra, T, Willemsen, M, Fryns, J-P, Devriendt, K, Ullmann, R, Vingron, M, Wrogemann, K, Wienker, T F, Tzschach, A, van Bokhoven, H, Gecz, J, Jentsch, T J, Chen, W, Ropers, H-H, and Kalscheuer, V M

Published
2016
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42. DMD – CLINICAL CARE

Author

Houwen, S., primary, Heutinck, L., additional, Jansen, M., additional, Krom, Y., additional, Cup, E., additional, Hendriksen, J., additional, Willemsen, M., additional, Verschuuren, J., additional, Niks, E., additional, and De Groot, I., additional

Published
2021
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44. Novel Protein Biomarkers of Monoamine Metabolism Defects Correlate with Disease Severity

Author

Tristán-Noguero, A. Borràs, E. Molero-Luis, M. Wassenberg, T. Peters, T. Verbeek, M.M. Willemsen, M. Opladen, T. Jeltsch, K. Pons, R. Thony, B. Horvath, G. Yapici, Z. Friedman, J. Hyland, K. Agosta, G.E. López-Laso, E. Artuch, R. Sabidó, E. García-Cazorla, À.

Abstract

Background: Genetic defects of monoamine neurotransmitters are rare neurological diseases amenable to treatment with variable response. They are major causes of early parkinsonism and other spectrum of movement disorders including dopa-responsive dystonia. Objectives: The objective of this study was to conduct proteomic studies in cerebrospinal fluid (CSF) samples of patients with monoamine defects to detect biomarkers involved in pathophysiology, clinical phenotypes, and treatment response. Methods: A total of 90 patients from diverse centers of the International Working Group on Neurotransmitter Related Disorders were included in the study (37 untreated before CSF collection, 48 treated and 5 unknown at the collection time). Clinical and molecular metadata were related to the protein abundances in the CSF. Results: Concentrations of 4 proteins were significantly altered, detected by mass spectrometry, and confirmed by immunoassays. First, decreased levels of apolipoprotein D were found in severe cases of aromatic L-amino acid decarboxylase deficiency. Second, low levels of apolipoprotein H were observed in patients with the severe phenotype of tyrosine hydroxylase deficiency, whereas increased concentrations of oligodendrocyte myelin glycoprotein were found in the same subset of patients with tyrosine hydroxylase deficiency. Third, decreased levels of collagen6A3 were observed in treated patients with tetrahydrobiopterin deficiency. Conclusion: This study with the largest cohort of patients with monoamine defects studied so far reports the proteomic characterization of CSF and identifies 4 novel biomarkers that bring new insights into the consequences of early dopaminergic deprivation in the developing brain. They open new possibilities to understand their role in the pathophysiology of these disorders, and they may serve as potential predictors of disease severity and therapies. © 2020 International Parkinson and Movement Disorder Society. © 2020 International Parkinson and Movement Disorder Society

Published
2021

46. Twee Kansrijke Alternatieven voor Dijkverbetering Cuijk-Ravenstein Nota Kansrijke Alternatieven

Author

Cuyck, T. van, Dortmont, T. van, Willemsen, M., Springer, M., Venema, A., Veelen, J.W. van, Cuyck, T. van, Dortmont, T. van, Willemsen, M., Springer, M., Venema, A., and Veelen, J.W. van

Abstract

Het project Cuijk-Ravenstein is het tweede project van het waterschap binnen het Hoogwaterbeschermingsprogramma. Dit project betreft een integraal dijkverbeteringsproject. Het waterschap Aa en Maas is initiatiefnemer, en zoekt samenwerking met gebiedspartners voor goede inpassing en waar mogelijk het verzilveren van meekoppelkansen.

Published
2021

47. Verkenning van het speelveld : Nota Mogelijke Oplossingen Dijkverbetering Cuijk-Ravenstein

Author

Cuyck, T. van, Willemsen, M., Springer, M., Venema, A., Cuyck, T. van, Willemsen, M., Springer, M., and Venema, A.

Abstract

Het klimaat verandert. Dat betekent dat het water in de Maas in de toekomst steeds vaker erg hoog staat. Het gebied moet daarnaast voldoen aan de nieuwe inzichten voor waterveiligheid en de normen die door het rijk in 2017 zijn vast gesteld. Dat is de reden waarom Waterschap Aa en Maas aan de slag gaat om de dijk tussen Cuijk en Ravenstein te verbeteren. Het dijktraject is één van de trajecten met de strengste norm langs de Maas vanwege de grote gevolgen bij een dijkdoorbraak. Het gebied dat overstroomt bij een doorbraak strekt zich uit tot en met ’s-Hertogenbosch.

Published
2021

48. Nota bouwstenen : Dijkversterking Cuijk-Ravenstein

Author

Cuyck, T. van, Willemsen, M., Cuyck, T. van, and Willemsen, M.

Abstract

Dijkversterking Cuijk-Ravenstein staat aan het begin van het ontwerpproces. Het ontwerpproces bestaat uit een aantal stappen waarbij van breed kijken en veel mogelijkheden verkennen stap voor stap gewerkt wordt naar een haalbaar, betaalbaar en gedragen voorkeursalternatief. Als eerste stap in dat proces vullen we de gereedschapskist door een set bouwstenen te ontwikkelen specifiek voor het dijktraject Cuijk-Ravenstein. Deze Nota Kansrijke Bouwstenen bevat de beschrijving en verantwoording van mogelijke maatregelen voor versterking van de waterkering en verbetering van ruimtelijke kwaliteit, inclusief de maatregelen die door stakeholders in het participatieproces zijn aangedragen.

Published
2021

49. Prognostic factors for relapse and outcome in pediatric acute transverse myelitis

Author

Helfferich, Jelte, Bruijstens, Arlette L., Wong, Yu Yi M., Danielle van Pelt, E., Boon, Maartje, Neuteboom, Rinze F., Bakker, D. P., Braun, K. P.J., van Dijk, K. G.J., Eikelenboom, M. J., Engelen, M., Brandsma, R., Haaxma, C. A., Niermeijer, J. M.F., Niks, E. H., Peeters, E. A.J., Peeters-Scholte, C. M.P.C.D., Portier, R. P., de Rijk-van Andel, J. F., Samijn, J. P.A., Schippers, H. M., Sie, L. T.L., Snoeck, I. N., Vermeulen, R. J., Verrips, A., Visscher, F., Willemsen, M. A.A.P., Catsman-Berrevoets, C. E., Helfferich, Jelte, Bruijstens, Arlette L., Wong, Yu Yi M., Danielle van Pelt, E., Boon, Maartje, Neuteboom, Rinze F., Bakker, D. P., Braun, K. P.J., van Dijk, K. G.J., Eikelenboom, M. J., Engelen, M., Brandsma, R., Haaxma, C. A., Niermeijer, J. M.F., Niks, E. H., Peeters, E. A.J., Peeters-Scholte, C. M.P.C.D., Portier, R. P., de Rijk-van Andel, J. F., Samijn, J. P.A., Schippers, H. M., Sie, L. T.L., Snoeck, I. N., Vermeulen, R. J., Verrips, A., Visscher, F., Willemsen, M. A.A.P., and Catsman-Berrevoets, C. E.

Abstract

Objective: It may be difficult for clinicians to estimate the prognosis of pediatric acute transverse myelitis (ATM). The aim of this study was to define prognostic factors for relapsing disease and poor outcome in pediatric ATM. Methods: This prospective cohort study included 49 children, 18 boys and 31 girls (median age 13.1 years, IQR 6.5–16.2) with a first episode of ATM. Factors associated with relapsing disease and poor outcome (Expanded Disability Status Scale (EDSS) ≥ 4) were assessed during a median follow-up of 37 months (IQR 18–75). Results: In total, 14 patients (29%) experienced ≥ 1 relapse(s) and nine patients (18%) had a poor outcome. Factors at onset associated with relapsing disease included higher age (16.1 vs. 11.6 years, p = 0.002), longer time to maximum severity of symptoms (5.5 vs. 3 days, p = 0.01), lower maximum EDSS score (4.0 vs. 6.5, p = 0.003), short lesion on spinal MRI (64 vs. 21%, p = 0.006), abnormalities on brain MRI (93 vs. 44%, p = 0.002) and presence of oligoclonal bands in cerebrospinal fluid (67 vs. 14%, p = 0.004). The only factor associated with poor outcome was presence of a spinal cord lesion on MRI without cervical involvement (56 vs. 14%, p = 0.02). Conclusion: Pediatric ATM patients presenting with clinical, radiological and laboratory features associated with multiple sclerosis (MS) are at risk for relapsing disease. In absence of these known MS risk factors at onset of disease these patients are at low risk for relapses. Only a minority of pediatric ATM patients in this cohort have a poor outcome.

Published
2021

50. Prognostic factors for relapse and outcome in pediatric acute transverse myelitis

Author

Neurologen, Brain, Helfferich, Jelte, Bruijstens, Arlette L., Wong, Yu Yi M., Danielle van Pelt, E., Boon, Maartje, Neuteboom, Rinze F., Bakker, D. P., Braun, K. P.J., van Dijk, K. G.J., Eikelenboom, M. J., Engelen, M., Brandsma, R., Haaxma, C. A., Niermeijer, J. M.F., Niks, E. H., Peeters, E. A.J., Peeters-Scholte, C. M.P.C.D., Portier, R. P., de Rijk-van Andel, J. F., Samijn, J. P.A., Schippers, H. M., Sie, L. T.L., Snoeck, I. N., Vermeulen, R. J., Verrips, A., Visscher, F., Willemsen, M. A.A.P., Catsman-Berrevoets, C. E., Neurologen, Brain, Helfferich, Jelte, Bruijstens, Arlette L., Wong, Yu Yi M., Danielle van Pelt, E., Boon, Maartje, Neuteboom, Rinze F., Bakker, D. P., Braun, K. P.J., van Dijk, K. G.J., Eikelenboom, M. J., Engelen, M., Brandsma, R., Haaxma, C. A., Niermeijer, J. M.F., Niks, E. H., Peeters, E. A.J., Peeters-Scholte, C. M.P.C.D., Portier, R. P., de Rijk-van Andel, J. F., Samijn, J. P.A., Schippers, H. M., Sie, L. T.L., Snoeck, I. N., Vermeulen, R. J., Verrips, A., Visscher, F., Willemsen, M. A.A.P., and Catsman-Berrevoets, C. E.

Published
2021

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