487 results on '"Kusters, B."'
Search Results
2. Dystrophic Myopathy of the Diaphragm with Recurrent Severe Respiratory Failure is Congenital Myasthenic Syndrome 11
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Kramer, J.J., Boon, H.T.M., Leijten, Q.H., Laak, H.J. ter, Eshuis, L., Kusters, B., Doorn, J.L.M., Kamsteeg, E.J., Eymard, B., Doorduin, J., and Voermans, N.C.
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All institutes and research themes of the Radboud University Medical Center ,Neurology ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Neurology (clinical) ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] - Abstract
Contains fulltext : 291135.pdf (Publisher’s version ) (Open Access) We here present the case of a patient with a congenital myasthenic syndrome (CMS) due to pathogenic variants in the RAPSN gene. During childhood he experienced recurrent episodes of respiratory failure during respiratory infections. This and other cases were reported as isolated dystrophy of the diaphragmatic musculature. In adulthood, whole exome sequencing revealed two heterozygous pathogenic variants in the RAPSN gene. This led to the revision of the diagnosis to rapsyn CMS11 (OMIM:616326, MONDO:0014588). EMG, muscle ultrasound and the revision of muscle biopsies taken in childhood support this diagnosis. After the revision of the diagnosis, treatment with pyridostigmine was started. This resulted in a reduction of fatigability and an improvement in functional abilities and quality of life.
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- 2023
3. Involvement of pelvic girdle and proximal leg muscles in early oculopharyngeal muscular dystrophy
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van der Sluijs, B.M., Lassche, S., Knuiman, G.J., Kusters, B., Heerschap, A., Hopman, M., Schreuder, T.H., van Engelen, B.G.M., and Voermans, N.C.
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- 2017
- Full Text
- View/download PDF
4. The double homeodomain protein DUX4c is associated with regenerating muscle fibers and RNA-binding proteins.
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Claus, C., Slavin, M., Ansseau, E., Lancelot, C., Bah, K., Lassche, S., Fiévet, M., Greco, A., Tomaiuolo, S., Tassin, A., Dudome, V., Kusters, B., Declèves, A.E., Laoudj-Chenivesse, D., Engelen, B.G.M. van, Nonclercq, D., Belayew, A., Kalisman, N., Coppée, F., Claus, C., Slavin, M., Ansseau, E., Lancelot, C., Bah, K., Lassche, S., Fiévet, M., Greco, A., Tomaiuolo, S., Tassin, A., Dudome, V., Kusters, B., Declèves, A.E., Laoudj-Chenivesse, D., Engelen, B.G.M. van, Nonclercq, D., Belayew, A., Kalisman, N., and Coppée, F.
- Abstract
Item does not contain fulltext, BACKGROUND: We have previously demonstrated that double homeobox 4 centromeric (DUX4C) encoded for a functional DUX4c protein upregulated in dystrophic skeletal muscles. Based on gain- and loss-of-function studies we have proposed DUX4c involvement in muscle regeneration. Here, we provide further evidence for such a role in skeletal muscles from patients affected with facioscapulohumeral muscular dystrophy (FSHD). METHODS: DUX4c was studied at RNA and protein levels in FSHD muscle cell cultures and biopsies. Its protein partners were co-purified and identified by mass spectrometry. Endogenous DUX4c was detected in FSHD muscle sections with either its partners or regeneration markers using co-immunofluorescence or in situ proximity ligation assay. RESULTS: We identified new alternatively spliced DUX4C transcripts and confirmed DUX4c immunodetection in rare FSHD muscle cells in primary culture. DUX4c was detected in nuclei, cytoplasm or at cell-cell contacts between myocytes and interacted sporadically with specific RNA-binding proteins involved, a.o., in muscle differentiation, repair, and mass maintenance. In FSHD muscle sections, DUX4c was found in fibers with unusual shape or central/delocalized nuclei (a regeneration feature) staining for developmental myosin heavy chain, MYOD or presenting intense desmin labeling. Some couples of myocytes/fibers locally exhibited peripheral DUX4c-positive areas that were very close to each other, but in distinct cells. MYOD or intense desmin staining at these locations suggested an imminent muscle cell fusion. We further demonstrated DUX4c interaction with its major protein partner, C1qBP, inside myocytes/myofibers that presented features of regeneration. On adjacent muscle sections, we could unexpectedly detect DUX4 (the FSHD causal protein) and its interaction with C1qBP in fusing myocytes/fibers. CONCLUSIONS: DUX4c upregulation in FSHD muscles suggests it contributes not only to the pathology but also, based on its protein p
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- 2023
5. Superior preservation of capillaries, myofibrils and mitochondria after long-term extracorporeal perfusion of free muscle flaps - A descriptive electron microscopy study.
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Kruit, A.S., Hummelink, S., Eshuis, L., Kusters, B., Ulrich, D.J.O., Kruit, A.S., Hummelink, S., Eshuis, L., Kusters, B., and Ulrich, D.J.O.
- Abstract
Item does not contain fulltext, BACKGROUND: Extracorporeal perfusion (ECP) is a promising technique for prolonged tissue preservation, but might have side effects. For instance, increased radical oxygen species or capillary endothelial damage. OBJECTIVE: To assess ultra-morphological muscle damage during 36-hour ECP of porcine musculocutaneous flaps, hypothesizing that it would delay the onset of damage compared to static cold storage (SCS). METHODS: Bilateral flaps were retrieved from three Dutch Landrace pigs. Three flaps were preserved for 36 hours by hypothermic storage 4-6°C (control group) and three flaps by ECP with cooled University of Wisconsin solution. Muscle biopsies were taken at 0 h, 12 h and 36 h and assessed with transmission electron microscopy. RESULTS: Muscle architecture was best preserved by ECP, with a delayed onset and decreased severity of muscle damage. After 36 hours, damage was two-fold lower in ECP-flaps compared to SCS-flaps. Myofibril architecture was best preserved. Mitochondria were greatly preserved with swelling being the most prominent feature. Capillaries were moderately but differently damaged during ECP, with focal endothelial thinning as opposed to luminal obstruction in SCS-preserved flaps. CONCLUSIONS: This experiment described favourable cellular preservation of skeletal muscle flaps during ECP compared to SCS. Results showed less severe ultra-morphological damage and a later onset of damage.
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- 2023
6. Association between hypertension and neurovascular inflammation in both normal-appearing white matter and white matter hyperintensities
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Solé Guardia, G., Custers, E.M., Lange, A. de, Clijncke, Elyne, Geenen, B., Gutierrez, Jose, Kusters, B., Claassen, J.A.H.R., Leeuw, F.E. de, Wiesmann, M., Kiliaan, A.J., Solé Guardia, G., Custers, E.M., Lange, A. de, Clijncke, Elyne, Geenen, B., Gutierrez, Jose, Kusters, B., Claassen, J.A.H.R., Leeuw, F.E. de, Wiesmann, M., and Kiliaan, A.J.
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Item does not contain fulltext
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- 2023
7. Heparin-resistance in AL amyloidosis: a case report.
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Ede, E.S. van, Hoeks, M.P.A., Hofland, J., Linssen, V.D., Kuppevelt, T.H. van, Versteeg, E.M., Hafmans, T.G., Diepstra, A., Kusters, B., Vermorgen, S.M.M., Ede, E.S. van, Hoeks, M.P.A., Hofland, J., Linssen, V.D., Kuppevelt, T.H. van, Versteeg, E.M., Hafmans, T.G., Diepstra, A., Kusters, B., and Vermorgen, S.M.M.
- Abstract
Item does not contain fulltext, BACKGROUND: Non-AT-III mediated heparin-resistance during CPB occurs by complex-forming with heparin-binding proteins. Currently, there are no specific recommendations for non-AT-III mediated heparin-resistance. CASE PRESENTATION: We present a fatal case of a 70-yr-old male-patient undergoing cardiac-surgery in which refractory heparin-resistance was observed. The massive AL amyloidosis found at autopsy is thought to be responsible and illustrates that awareness and knowledge of the etiology and perioperative strategies of non-AT-III mediated heparin-resistance is important. CONCLUSION: For anticoagulation during cardiopulmonary bypass surgery in case of a non-AT-III medicated heparin resistance, we refer to the decision tree added to this manuscript and if necessary to consider direct thrombin inhibitors, such as bivalirudin or argatroban, as it bypasses the complexing pathway.
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- 2023
8. Dystrophic Myopathy of the Diaphragm with Recurrent Severe Respiratory Failure is Congenital Myasthenic Syndrome 11
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Kramer, J.J., primary, Boon, H.T.M., additional, Leijten, Q.H., additional, ter Laak, H., additional, Eshuis, L., additional, Kusters, B., additional, van Doorn, J.L.M., additional, Kamsteeg, E.J., additional, Eymard, B., additional, Doorduin, J., additional, and Voermans, N.C., additional
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- 2022
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9. Facioscapulohumeral dystrophy transcriptome signatures correlate with different stages of disease and are marked by different MRI biomarkers
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Heuvel, A. van den, Lassche, Saskia, Mul, K., Greco, A., Granado, David San Leon, Heerschap, A., Kusters, B., Voermans, N.C., Engelen, B.G.M. van, Maarel, Silvere M. van der, Heuvel, A. van den, Lassche, Saskia, Mul, K., Greco, A., Granado, David San Leon, Heerschap, A., Kusters, B., Voermans, N.C., Engelen, B.G.M. van, and Maarel, Silvere M. van der
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Contains fulltext : 247669.pdf (Publisher’s version ) (Open Access)
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- 2022
10. Early Restrictive Fluid Strategy Impairs the Diaphragm Force in Lambs with Acute Respiratory Distress Syndrome
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IJland, M.M., Ingelse, S.A., Loon, Lex Maxim van, Erp, M. van, Kusters, B., Ottenheijm, C.A.C., Kox, M., Heunks, L.M.A., Lemson, J., IJland, M.M., Ingelse, S.A., Loon, Lex Maxim van, Erp, M. van, Kusters, B., Ottenheijm, C.A.C., Kox, M., Heunks, L.M.A., and Lemson, J.
- Abstract
Item does not contain fulltext
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- 2022
11. Subacute parkinsonism due to systemic lupus erythematosus and catastrophic antiphospholipid syndrome
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Hebbink, J.A., Nobels-Janssen, E., Verhagen, I.A.M., Kusters, B., Pegge, S.A.H., Tuladhar, A.M., Hebbink, J.A., Nobels-Janssen, E., Verhagen, I.A.M., Kusters, B., Pegge, S.A.H., and Tuladhar, A.M.
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Item does not contain fulltext
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- 2022
12. Changes of the CYP11B2 Expressing Zona Glomerulosa in Human Adrenals From Birth to 40 Years of Age
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Wiel, E.C.J. van de, Chaman Baz, A.H., Kusters, B., Mukai, K., Bonzel, Lidia van, Erp, M. van, Deinum, J., Langenhuijsen, J.F., Wiel, E.C.J. van de, Chaman Baz, A.H., Kusters, B., Mukai, K., Bonzel, Lidia van, Erp, M. van, Deinum, J., and Langenhuijsen, J.F.
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Item does not contain fulltext
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- 2022
13. [18F]FDG Uptake and Expression of Immunohistochemical Markers Related to Glycolysis, Hypoxia, and Proliferation in Indeterminate Thyroid Nodules
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Koster, E.J. de, Engen-van Grunsven, A.C.H. van, Bussink, J., Frielink, C., Geus-Oei, L.F. de, Kusters, B., Peters, H., Oyen, W.J.G., Vriens, D., EFFECTS Trial Study Grp, Radiology and Nuclear Medicine, ANS - Brain Imaging, ANS - Compulsivity, Impulsivity & Attention, Endocrinology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Surgery, Radiology and nuclear medicine, Internal medicine, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, Amsterdam Gastroenterology Endocrinology Metabolism, and AMS - Tissue Function & Regeneration
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Cancer Research ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Immunohistochemistry ,Women's cancers Radboud Institute for Health Sciences [Radboudumc 17] ,[F]FDG-PET/CT ,All institutes and research themes of the Radboud University Medical Center ,Oncology ,Glucose Metabolism ,[F-18]FDG-PET/CT ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Radiology, Nuclear Medicine and imaging ,Thyroid Nodule ,Glycolysis ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Purpose The current study explored the association between 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) uptake and the quantitative expression of immunohistochemical markers related to glucose metabolism, hypoxia, and cell proliferation in benign and malignant thyroid nodules of indeterminate cytology. Procedures Using a case–control design, 24 patients were selected from participants of a randomized controlled multicenter trial (NCT02208544) in which [18F]FDG-PET/CT and thyroid surgery were performed for Bethesda III and IV nodules. Three equally sized groups of [18F]FDG-positive malignant, [18F]FDG-positive benign, and [18F]FDG-negative benign nodules were included. Immunohistochemical staining was performed for glucose transporters (GLUT) 1, 3, and 4; hexokinases (HK) 1 and 2; hypoxia-inducible factor-1 alpha (HIF1α; monocarboxylate transporter 4 (MCT4); carbonic anhydrase IX (CA-IX); vascular endothelial growth factor (VEGF); sodium-iodide symporter (NIS); and Ki-67. Marker expression was scored using an immunoreactive score. Unsupervised cluster analysis was performed. The immunoreactive score was correlated to the maximum and peak standardized uptake values (SUVmax, SUVpeak) and SUVmax ratio (SUVmax of nodule/background SUVmax of contralateral, normal thyroid) of the [18F]FDG-PET/CT using the Spearman’s rank correlation coefficient and compared between the three groups using Kruskal–Wallis tests. Results The expression of GLUT1, GLUT3, HK2, and MCT4 was strongly positively correlated with the SUVmax, SUVpeak, and SUVmax ratio. The expression of GLUT1 (p = 0.009), HK2 (p = 0.02), MCT4 (p = 0.01), and VEGF (p = 0.007) was statistically significantly different between [18F]FDG-positive benign nodules, [18F]FDG-positive thyroid carcinomas, and [18F]FDG-negative benign nodules. In both [18F]FDG-positive benign nodules and [18F]FDG-positive thyroid carcinomas, the expression of GLUT1, HK2, and MCT4 was increased as compared to [18F]FDG-negative benign nodules. VEGF expression was higher in [18F]FDG-positive thyroid carcinomas as compared to [18F]FDG-negative and [18F]FDG-positive benign nodules. Conclusions Our results suggest that [18F]FDG-positive benign thyroid nodules undergo changes in protein expression similar to those in thyroid carcinomas. To expand the understanding of the metabolic changes in benign and malignant thyroid nodules, further research is required, including correlation with underlying genetic alterations.
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- 2022
14. Genotype-Specific Differences in the Tumor Metabolite Profile of Pheochromocytoma and Paraganglioma Using Untargeted and Targeted Metabolomics
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Rao, J. U., Engelke, U. F. H., Sweep, F. C. G. J., Pacak, K., Kusters, B., Goudswaard, A. G., Hermus, A. R. M. M., Mensenkamp, A. R., Eisenhofer, G., Qin, N., Richter, S., Kunst, H. P. M., Timmers, H. J. L. M., and Wevers, R. A.
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- 2015
15. Identifying changes in the zona glomerulosa of adrenals in patients below the age of 40 years
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Chaman Baz, A.H., primary, Van De Wiel, E.J.C., additional, Kusters, B., additional, Van Bonzel, L.G., additional, Van Erp, M., additional, Deinum, J., additional, and Langenhuijsen, J.F., additional
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- 2021
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16. NEM6, KBTBD13-Related Congenital Myopathy: Myopathological Analysis in 18 Dutch Patients Reveals Ring Rods Fibers, Cores, Nuclear Clumps, and Granulo-Filamentous Protein Material
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Bouman, K., Kusters, B., Winter, J.M., Gillet, C., Kleef, E.S.B. van, Eshuis, L., Brochier, G., Madelaine, Angeline, Labasse, C., Boulogne, C., Engelen, B.G.M. van, Ottenheijm, C.A.C., Romero, N.B., Voermans, N.C., Malfatti, E., Bouman, K., Kusters, B., Winter, J.M., Gillet, C., Kleef, E.S.B. van, Eshuis, L., Brochier, G., Madelaine, Angeline, Labasse, C., Boulogne, C., Engelen, B.G.M. van, Ottenheijm, C.A.C., Romero, N.B., Voermans, N.C., and Malfatti, E.
- Abstract
Item does not contain fulltext, Nemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.
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- 2021
17. Diaphragm Pathology in Critically Ill Patients With COVID-19 and Postmortem Findings From 3 Medical Centers
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Shi, Z., Vries, H.J.C. de, Vlaar, A.P.J., Hoeven, J.G. van der, Boon, R.A., Kusters, B., Heunks, L.M.A., Ottenheijm, C.A.C., Shi, Z., Vries, H.J.C. de, Vlaar, A.P.J., Hoeven, J.G. van der, Boon, R.A., Kusters, B., Heunks, L.M.A., and Ottenheijm, C.A.C.
- Abstract
Item does not contain fulltext, This case-control study examines the association of COVID-19 with the respiratory muscles in Dutch critically ill patients.
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- 2021
18. Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands
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Reumers, S.F.I., Erasmus, C.E., Bouman, K., Pennings, Maartje, Schouten, M.I., Kusters, B., Duijkers, F.A., Kooi, A. van der, Jaeger, B., Verschuuren-Bemelmans, C.C., Faber, C.G., Engelen, B.G.M. van, Kamsteeg, E.J., Jungbluth, H., Voermans, N.C., Reumers, S.F.I., Erasmus, C.E., Bouman, K., Pennings, Maartje, Schouten, M.I., Kusters, B., Duijkers, F.A., Kooi, A. van der, Jaeger, B., Verschuuren-Bemelmans, C.C., Faber, C.G., Engelen, B.G.M. van, Kamsteeg, E.J., Jungbluth, H., and Voermans, N.C.
- Abstract
Contains fulltext : 241356.pdf (Publisher’s version ) (Open Access), Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.
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- 2021
19. Diaphragm Pathology in Critically III patients with COVID-19 and Postmortem Findings From 3 Medical Centers
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Zhonghua, S., Vries, H.J.C. de, Vlaar, A.P.J., Hoeven, J.G. van der, Boon, R.A., Kusters, B., Heunks, L.M.A., Ottenheijm, C.A.C., Zhonghua, S., Vries, H.J.C. de, Vlaar, A.P.J., Hoeven, J.G. van der, Boon, R.A., Kusters, B., Heunks, L.M.A., and Ottenheijm, C.A.C.
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Item does not contain fulltext
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- 2021
20. Reduced specific force in patients with mild and severe facioscapulohumeral muscular dystrophy
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Lassche, S., Voermans, N.C., Schreuder, T.H.A., Heerschap, A., Kusters, B., Ottenheijm, C.A.C., Hopman, M.T.E., Engelen, B.G.M. van, Lassche, S., Voermans, N.C., Schreuder, T.H.A., Heerschap, A., Kusters, B., Ottenheijm, C.A.C., Hopman, M.T.E., and Engelen, B.G.M. van
- Abstract
Contains fulltext : 229514.pdf (Publisher’s version ) (Open Access), BACKGROUND: Specific force, that is the amount of force generated per unit of muscle tissue, is reduced in patients with facioscapulohumeral muscular dystrophy (FSHD). The causes of reduced specific force and its relation with FSHD disease severity are unknown. METHODS: Quantitative muscle magnetic resonance imaging (MRI), measurement of voluntary maximum force generation and quadriceps force-frequency relationship, and vastus lateralis muscle biopsies were performed in 12 genetically confirmed patients with FSHD and 12 controls. RESULTS: Specific force was reduced by ~33% in all FSHD patients independent of disease severity. Quadriceps force-frequency relationship shifted to the right in severe FSHD compared to controls. Fiber type distribution in vastus lateralis muscle biopsies did not differ between groups. CONCLUSIONS: Reduced quadriceps specific force is present in all FSHD patients regardless of disease severity or fatty infiltration. Early myopathic changes, including fibrosis, and non-muscle factors, such as physical fatigue and musculoskeletal pain, may contribute to reduced specific force.
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- 2021
21. Prognostic and Predictive Value of Integrated Qualitative and Quantitative Magnetic Resonance Imaging Analysis in Glioblastoma
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Verduin, M., Primakov, Sergey, Compter, Inge, Woodruff, Henry C., Kuijk, Sander M.J. van, Ramaekers, B.L., Laan, M. ter, Pegge, S.A.H., Meijer, F.J.A., Kusters, B., Lambin, Philippe, Hoeben, Ann, Verduin, M., Primakov, Sergey, Compter, Inge, Woodruff, Henry C., Kuijk, Sander M.J. van, Ramaekers, B.L., Laan, M. ter, Pegge, S.A.H., Meijer, F.J.A., Kusters, B., Lambin, Philippe, and Hoeben, Ann
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Contains fulltext : 231620.pdf (publisher's version ) (Open Access)
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- 2021
22. Human brain pathology in myotonic dystrophy type 1: A systematic review
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Weijs, R., Okkersen, K., Engelen, B.G.M. van, Kusters, B., Lammens, M., Aronica, E., Raaphorst, J., Cappellen van Walsum, A.M. van, Weijs, R., Okkersen, K., Engelen, B.G.M. van, Kusters, B., Lammens, M., Aronica, E., Raaphorst, J., and Cappellen van Walsum, A.M. van
- Abstract
Contains fulltext : 232905.pdf (Publisher’s version ) (Open Access), Brain involvement in myotonic dystrophy type 1 (DM1) is characterized by heterogeneous cognitive, behavioral, and affective symptoms and imaging alterations indicative of widespread grey and white matter involvement. The aim of the present study was to systematically review the literature on brain pathology in DM1. We conducted a structured search in EMBASE (index period 1974-2017) and MEDLINE (index period 1887-2017) on December 11, 2017, using free text and index search terms related to myotonic dystrophy type 1 and brain structures or regions. Eligible studies were full-text studies reporting on microscopic brain pathology of DM1 patients without potentially interfering comorbidity. We discussed the findings based on the anatomical region and the nature of the anomaly. Neuropathological findings in DM1 can be classified as follows: (1) protein and nucleotide deposits; (2) changes in neurons and glial cells; and (3) white matter alterations. Most findings are unspecific to DM1 and may occur with physiological aging, albeit to a lesser degree. There are similarities and contrasts with Alzheimer's disease; both show the appearance of neurofibrillary tangles in the limbic system without plaque occurrence. Likewise, there is myelin loss and gliosis, and there are dilated perivascular spaces in the white matter resemblant of cerebral small vessel disease. However, we did not find evidence of lacunar infarction or microbleeding. The various neuropathological findings in DM1 are reflective of the heterogeneous clinical and neuroimaging features of the disease. The strength of conclusions from this study's findings is bounded by limited numbers of participants in studies, methodological constraints, and lack of assessed associations between histopathology and clinical or neuroimaging findings.
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- 2021
23. Rectus Abdominis Flap Replantation after 18 h Hypothermic Extracorporeal Perfusion-A Porcine Model
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Kruit, A.S., Midden, D. van, Schreinemachers, M.J.M., Koers, E.J., Zegers, H.J.H., Kusters, B., Hummelink, S.L.M., Ulrich, D.J.O., Kruit, A.S., Midden, D. van, Schreinemachers, M.J.M., Koers, E.J., Zegers, H.J.H., Kusters, B., Hummelink, S.L.M., and Ulrich, D.J.O.
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Contains fulltext : 237190.pdf (Publisher’s version ) (Open Access)
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- 2021
24. Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium
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Locht, Martijn van de, Donkervoort, S., Winter, Josine M. de, Conijn, Stefan, Begthel, Leon, Kusters, B., Kamsteeg, E.J., Voermans, N.C., Bonnemann, C.G., Ottenheijm, C.A.C., Locht, Martijn van de, Donkervoort, S., Winter, Josine M. de, Conijn, Stefan, Begthel, Leon, Kusters, B., Kamsteeg, E.J., Voermans, N.C., Bonnemann, C.G., and Ottenheijm, C.A.C.
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Item does not contain fulltext
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- 2021
25. Optical genome mapping identifies a germline retrotransposon insertion in SMARCB1 in two siblings with atypical teratoid rhabdoid tumors
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Sabatella, M., Mantere, Tuomo, Waanders, E., Neveling, K., Mensenkamp, A.R., Dijk, F. van, Hehir, J.Y., Derks, R, Kwint, M.P., O'Gorman, L., Martins, M., Gidding, C.E.M., Lequin, M.H., Kusters, B., Wesseling, P., Nelen, M.R., Biegel, J.A., Hoischen, A., Jongmans, M.C.J., Kuiper, R.P., Sabatella, M., Mantere, Tuomo, Waanders, E., Neveling, K., Mensenkamp, A.R., Dijk, F. van, Hehir, J.Y., Derks, R, Kwint, M.P., O'Gorman, L., Martins, M., Gidding, C.E.M., Lequin, M.H., Kusters, B., Wesseling, P., Nelen, M.R., Biegel, J.A., Hoischen, A., Jongmans, M.C.J., and Kuiper, R.P.
- Abstract
Item does not contain fulltext, In a subset of pediatric cancers, a germline cancer predisposition is highly suspected based on clinical and pathological findings, but genetic evidence is lacking, which hampers genetic counseling and predictive testing in the families involved. We describe a family with two siblings born from healthy parents who were both neonatally diagnosed with atypical teratoid rhabdoid tumor (ATRT). This rare and aggressive pediatric tumor is associated with biallelic inactivation of SMARCB1, and in 30% of the cases, a predisposing germline mutation is involved. Whereas the tumors of both siblings showed loss of expression of SMARCB1 and acquired homozygosity of the locus, whole exome and whole genome sequencing failed to identify germline or somatic SMARCB1 pathogenic mutations. We therefore hypothesized that the insertion of a pathogenic repeat-rich structure might hamper its detection, and we performed optical genome mapping (OGM) as an alternative strategy to identify structural variation in this locus. Using this approach, an insertion of ~2.8 kb within intron 2 of SMARCB1 was detected. Long-range PCR covering this region remained unsuccessful, but PacBio HiFi genome sequencing identified this insertion to be a SINE-VNTR-Alu, subfamily E (SVA-E) retrotransposon element, which was present in a mosaic state in the mother. This SVA-E insertion disrupts correct splicing of the gene, resulting in loss of a functional allele. This case demonstrates the power of OGM and long-read sequencing to identify genomic variations in high-risk cancer-predisposing genes that are refractory to detection with standard techniques, thereby completing the clinical and molecular diagnosis of such complex cases and greatly improving counseling and surveillance of the families involved. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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- 2021
26. Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1
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Sievers, P., Sill, M., Blume, C., Tauziede-Espariat, A., Schrimpf, D., Stichel, D., Reuss, D.E., Dogan, H., Hartmann, C., Mawrin, C., Hasselblatt, M., Stummer, W., Schick, U., Hench, J., Frank, S., Ketter, R., Schweizer, L., Schittenhelm, J., Puget, S., Brandner, S., Jaunmuktane, Z., Kusters, B., Abdullaev, Z., Pekmezci, M., Snuderl, M., Ratliff, M., Herold-Mende, C., Unterberg, A., Aldape, K., Ellison, D.W., Wesseling, P., Reifenberger, G., Wick, W., Perry, A., Varlet, P., Pfister, S.M., Jones, D.T.W., Deimling, A. von, Sahm, F., Sievers, P., Sill, M., Blume, C., Tauziede-Espariat, A., Schrimpf, D., Stichel, D., Reuss, D.E., Dogan, H., Hartmann, C., Mawrin, C., Hasselblatt, M., Stummer, W., Schick, U., Hench, J., Frank, S., Ketter, R., Schweizer, L., Schittenhelm, J., Puget, S., Brandner, S., Jaunmuktane, Z., Kusters, B., Abdullaev, Z., Pekmezci, M., Snuderl, M., Ratliff, M., Herold-Mende, C., Unterberg, A., Aldape, K., Ellison, D.W., Wesseling, P., Reifenberger, G., Wick, W., Perry, A., Varlet, P., Pfister, S.M., Jones, D.T.W., Deimling, A. von, and Sahm, F.
- Abstract
Contains fulltext : 232881.pdf (Publisher’s version ) (Open Access), Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.
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- 2021
27. Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study
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Bouman, K., Groothuis, J.T., Doorduin, J., Alfen, N. van, Udink ten Cate, F.E.A., Heuvel, F.M.A. van den, Nijveldt, R., Tilburg, W.C.M. van, Buckens, C.F.M., Dittrich, A.T.M., Draaisma, J.M.T., Janssen, M.C.H., Kamsteeg, E.J., Kleef, E.S.B. van, Koene, S., Smeitink, J.A.M., Kusters, B., Engelen, B.G.M. van, Erasmus, C.E., Voermans, N.C., Bouman, K., Groothuis, J.T., Doorduin, J., Alfen, N. van, Udink ten Cate, F.E.A., Heuvel, F.M.A. van den, Nijveldt, R., Tilburg, W.C.M. van, Buckens, C.F.M., Dittrich, A.T.M., Draaisma, J.M.T., Janssen, M.C.H., Kamsteeg, E.J., Kleef, E.S.B. van, Koene, S., Smeitink, J.A.M., Kusters, B., Engelen, B.G.M. van, Erasmus, C.E., and Voermans, N.C.
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Contains fulltext : 236909.pdf (Publisher’s version ) (Open Access)
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- 2021
28. Partial Adrenalectomy Carries a Considerable Risk of Incomplete Cure in Primary Aldosteronism
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Wiel, E.C.J. van de, Kusters, B., Mann, R.M., Veltien, A.A., Aalders, T.W., Verhaegh, G.W.C.T., Mukai, K., Deinum, J., Langenhuijsen, J.F., Wiel, E.C.J. van de, Kusters, B., Mann, R.M., Veltien, A.A., Aalders, T.W., Verhaegh, G.W.C.T., Mukai, K., Deinum, J., and Langenhuijsen, J.F.
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Item does not contain fulltext, PURPOSE: Laparoscopic adrenalectomy is standard treatment for patients with unilateral aldosterone-producing adenomas, but surgeons are increasingly tempted to perform partial adrenalectomy, disregarding potential multinodularity of the adrenal. We assess the diagnostic value of endoscopic ultrasound for differentiating solitary adenomas from multinodularity by examining in-depth adrenal pathology with ex vivo 11.7 T magnetic resonance imaging and immunohistochemistry. MATERIALS AND METHODS: In 15 primary aldosteronism patients, we performed intraoperative endoscopic ultrasound, ex vivo magnetic resonance imaging and histopathological examination. Every adrenal was intraoperatively and postoperatively assessed for solitary adenomas or multinodular hyperplasia. After unblinding for ex vivo magnetic resonance imaging results a second detailed histopathological examination, including immunohistochemistry analysis with CYP11B2 (aldosterone synthase) and chemokine receptor 4 (CXCR4), a new marker for aldosterone-producing adenomas, was performed. Finally, presence of somatic mutations linked to aldosterone-producing adenomas was assessed. RESULTS: The sensitivity and specificity of endoscopic ultrasound to identify multinodularity were 46% and 50%, respectively. We found multinodular hyperplasia in 87% of adrenals with ex vivo magnetic resonance imaging combined with detailed histopathology, and 6 adrenals contained multiple CYP11B2-producing nodules. Every CYP11B2 positive nodule and 61% of CYP11B2 negative nodules showed CXCR4 staining. Finally, in 4 adrenals (27%) we found somatic mutations. In multinodular glands, only 1 nodule harbored this mutation. CONCLUSIONS: Intraoperative endoscopic ultrasound in primary aldosteronism patients has low accuracy to identify multinodularity. Ex vivo magnetic resonance imaging can serve as a tool to direct detailed histopathological examination, which frequently shows CYP11B2 production in multiple nodules. Therefore, partial adre
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- 2021
29. Accuracy of Machine Learning Algorithms for the Classification of Molecular Features of Gliomas on MRI: A Systematic Literature Review and Meta-Analysis
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Kempen, E.J. van, Post, M., Mannil, M., Kusters, B., Laan, M. ter, Meijer, F.J.A., Henssen, D.J.H.A., Kempen, E.J. van, Post, M., Mannil, M., Kusters, B., Laan, M. ter, Meijer, F.J.A., and Henssen, D.J.H.A.
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Contains fulltext : 234431.pdf (Publisher’s version ) (Open Access), Treatment planning and prognosis in glioma treatment are based on the classification into low- and high-grade oligodendroglioma or astrocytoma, which is mainly based on molecular characteristics (IDH1/2- and 1p/19q codeletion status). It would be of great value if this classification could be made reliably before surgery, without biopsy. Machine learning algorithms (MLAs) could play a role in achieving this by enabling glioma characterization on magnetic resonance imaging (MRI) data without invasive tissue sampling. The aim of this study is to provide a performance evaluation and meta-analysis of various MLAs for glioma characterization. Systematic literature search and meta-analysis were performed on the aggregated data, after which subgroup analyses for several target conditions were conducted. This study is registered with PROSPERO, CRD42020191033. We identified 724 studies; 60 and 17 studies were eligible to be included in the systematic review and meta-analysis, respectively. Meta-analysis showed excellent accuracy for all subgroups, with the classification of 1p/19q codeletion status scoring significantly poorer than other subgroups (AUC: 0.748, p = 0.132). There was considerable heterogeneity among some of the included studies. Although promising results were found with regard to the ability of MLA-tools to be used for the non-invasive classification of gliomas, large-scale, prospective trials with external validation are warranted in the future.
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- 2021
30. Fever-induced recurrent rhabdomyolysis due to a novel mutation in the ryanodine receptor type 1 gene
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Molenaar, J. P., Voermans, N. C., van Hoeve, B. J., Kamsteeg, E. J., Kluijtmans, L. A., Kusters, B., Jungbluth, H. J., and van Engelen, B. G.
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- 2014
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31. The cerebral cortex and complex cerebral functions
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Donkelaar, H.J. ten, Catani, M., Domburg, P. van, Eling, P.A.T.M., Kusters, B., Hori, A., VU University medical center, and Donkelaar, H.J. ten
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Neocortex ,Neuro- en revalidatiepsychologie ,Chemistry ,Thalamus ,Neuropsychology and rehabilitation psychology ,Allocortex ,Sensory system ,medicine.anatomical_structure ,Cytoarchitecture ,Cerebral cortex ,Cortex (anatomy) ,medicine ,Neuroscience ,Motor cortex - Abstract
The cerebral cortex can be divided into a large isocortex or neocortex, a smaller allocortex (the hippocampal formation and the olfactory cortex) and a transition zone (the mesocortex) in between. The heterogeneous allocortex and the mesocortex have been discussed in Chap. 14. The various parts of the neocortex show large variations in the development of their constituent layers. The cortical areas that receive the primary sensory pathways via the thalamus form the granular cortex, in which layers II and IV are especially well developed. In the motor cortex, these layers are poorly developed (the agranular cortex), whereas the pyramidal layers III and V are well developed. Based on such differences in cytoarchitecture, Brodmann, von Economo and Koskinas and Sarkissov et al. published their brain maps (Sect. 15.2). Myeloarchitectonic maps were prepared by the Vogts and more recently by Nieuwenhuys et al. Nowadays, atlases combine data describing multiple aspects of brain structure from different subjects. The various cortical lobes are discussed in Sect. 15.3. The neocortex is the end station of all sensory projections from the thalamus and has extensive corticofugal projections via the internal capsule to the basal ganglia, the thalamus, the brain stem and the spinal cord. These connections have been extensively discussed in previous chapters. In this chapter, emphasis is on corticocortical projections, the long association and commissural tracts in particular, our knowledge of which has greatly increased (Sect. 15.4), hemispheric differences (Sect. 15.5), language and the brain (Sect. 15.6) and disorders of cortical connectivity, known as disconnection syndromes (Sect. 15.7). Classic disconnection syndromes were described in the late nineteenth century by Wernicke, Lissauer, Liepmann and Dejerine and include conduction aphasia, associative visual agnosia, apraxia and alexia without agraphia. Of some of these syndromes, old and new, the involvement of white matter tracts was studied. In 1965, Norman Geschwind reintroduced the disconnection paradigm, and, more recently, other disorders such as visual amnesia and prosopagnosia have also been attributed to disconnection mechanisms. The hodological paradigm may be extended beyond the classic disconnection syndromes by including disorders of hyperconnectivity. The term hodological syndromes was introduced to refer to cognitive and behavioural dysfunctions arising from pathologies of white matter pathways. Section 15.8 contains a discussion of the neuroanatomical basis of cognitive impairment in the primary degenerative dementias and is illustrated by a series of Clinical cases. The English terms of the Terminologia Neuroanatomica are used throughout.
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- 2020
32. Recurrence of paraproteinemic crystalline keratopathy after corneal transplantation: A case of monoclonal gammopathy of ocular significance
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Nobacht, S., Kusters, B., Breukink, M.B., Rongen, G.A., Cruysberg, J.R.M., Nobacht, S., Kusters, B., Breukink, M.B., Rongen, G.A., and Cruysberg, J.R.M.
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Contains fulltext : 225778.pdf (publisher's version ) (Open Access), PURPOSE: To report the long-term follow-up (12 years) of a 36-year-old male patient with crystalline keratopathy of both eyes, diagnosed with monoclonal gammopathy of undetermined significance (MGUS). Complete ophthalmic, systemic, and corneal immunohistochemical evaluations were performed. OBSERVATIONS: Slit-lamp examination revealed bilateral fine iridescent confluent crystalline deposits in all layers of the cornea, both peripherally and centrally. Systemic evaluation revealed abnormal M protein, IgG-kappa type, in blood and urine. Bone marrow aspiration showed a monoclonal plasma cell concentration of 2%. Consequently, the patient was diagnosed with MGUS. Because of progressive bilateral visual loss in the following 10 years, a perforating keratoplasty was performed on the left eye. Immunohistochemical analysis of the native cornea (the corneal button) revealed depositions of the same M protein type as detected in plasma and urine. Electron microscopy showed rhomboid-shaped corneal deposits of various sizes up to 4 μm. Recurrence of crystalline keratopathy was observed 9 months after keratoplasty. The monoclonal protein remained stable and the MGUS did not progress to multiple myeloma nor a related disorder. CONCLUSIONS AND IMPORTANCE: Crystalline keratopathy may be associated with MGUS in otherwise healthy individuals. If the keratopathy causes binocular visual loss, a corneal transplantation may be required. Unfortunately, recurrence of crystalline deposits in the corneal graft may occur within one year. This suggests that patients with vision impairment due to paraproteinemic keratopathy who are diagnosed as MGUS, in fact, have a monoclonal gammopathy of ocular significance (MGOS).
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- 2020
33. Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool
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Priesterbach-Ackley, L.P., Boldt, H.B., Petersen, J.K., Bervoets, N., Scheie, D., Ulhøi, B.P., Gardberg, M., Brännström, T., Torp, S.H., Aronica, E., Kusters, B., Dunnen, W.F. den, Vos, F., Wesseling, P., Leng, W.W.J. de, Kristensen, B.W., Priesterbach-Ackley, L.P., Boldt, H.B., Petersen, J.K., Bervoets, N., Scheie, D., Ulhøi, B.P., Gardberg, M., Brännström, T., Torp, S.H., Aronica, E., Kusters, B., Dunnen, W.F. den, Vos, F., Wesseling, P., Leng, W.W.J. de, and Kristensen, B.W.
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Contains fulltext : 225888.pdf (Publisher’s version ) (Open Access), AIMS: Methylation profiling (MP) is increasingly incorporated in the diagnostic process of central nervous system (CNS) tumours at our centres in The Netherlands and Scandinavia. We aimed to identify the benefits and challenges of MP as a support tool for CNS tumour diagnostics. METHODS: About 502 CNS tumour samples were analysed using (850 k) MP. Profiles were matched with the DKFZ/Heidelberg CNS Tumour Classifier. For each case, the final pathological diagnosis was compared to the diagnosis before MP. RESULTS: In 54.4% (273/502) of all analysed cases, the suggested methylation class (calibrated score ≥0.9) corresponded with the initial pathological diagnosis. The diagnosis of 24.5% of these cases (67/273) was more refined after incorporation of the MP result. In 9.8% of cases (49/502), the MP result led to a new diagnosis, resulting in an altered WHO grade in 71.4% of these cases (35/49). In 1% of cases (5/502), the suggested class based on MP was initially disregarded/interpreted as misleading, but in retrospect, the MP result predicted the right diagnosis for three of these cases. In six cases, the suggested class was interpreted as 'discrepant but noncontributory'. The remaining 33.7% of cases (169/502) had a calibrated score <0.9, including 7.8% (39/502) for which no class indication was given at all (calibrated score <0.3). CONCLUSIONS: MP is a powerful tool to confirm and fine-tune the pathological diagnosis of CNS tumours, and to avoid misdiagnoses. However, it is crucial to interpret the results in the context of clinical, radiological, histopathological and other molecular information.
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- 2020
34. Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients
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Molenaar, J.P.F., Verhoeven, J.I., Rodenburg, R.J.T., Kamsteeg, E.J., Erasmus, C.E., Vicart, S., Behin, A., Bassez, G., Magot, A., Pereon, Y., Brandom, B.W., Guglielmi, V., Vattemi, G., Chevessier, F., Mathieu, J., Franques, J., Suetterlin, K., Hanna, M.G., Guyant-Marechal, L., Snoeck, M.M., Roberts, M.E., Kuntzer, T., Fernandez-Torron, R., Martinez-Arroyo, A., Seeger, J., Kusters, B., Treves, S., Engelen, B.G.M. van, Eymard, B., Voermans, N.C., Sternberg, D., Molenaar, J.P.F., Verhoeven, J.I., Rodenburg, R.J.T., Kamsteeg, E.J., Erasmus, C.E., Vicart, S., Behin, A., Bassez, G., Magot, A., Pereon, Y., Brandom, B.W., Guglielmi, V., Vattemi, G., Chevessier, F., Mathieu, J., Franques, J., Suetterlin, K., Hanna, M.G., Guyant-Marechal, L., Snoeck, M.M., Roberts, M.E., Kuntzer, T., Fernandez-Torron, R., Martinez-Arroyo, A., Seeger, J., Kusters, B., Treves, S., Engelen, B.G.M. van, Eymard, B., Voermans, N.C., and Sternberg, D.
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Contains fulltext : 218262.pdf (publisher's version ) (Open Access), Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequenc
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- 2020
35. Disturbed balance in the expression of MMP9 and TIMP3 in cerebral amyloid angiopathy-related intracerebral haemorrhage
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Jäkel, L., Kuiperij, B., Gerding, Lara P., Custers, Emma E.M., Berg, E. van den, Jolink, W.M.T., Schreuder, F.H.B.M., Kusters, B., Klijn, C.J.M., Verbeek, M.M., Jäkel, L., Kuiperij, B., Gerding, Lara P., Custers, Emma E.M., Berg, E. van den, Jolink, W.M.T., Schreuder, F.H.B.M., Kusters, B., Klijn, C.J.M., and Verbeek, M.M.
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Contains fulltext : 221458.pdf (publisher's version ) (Open Access)
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- 2020
36. Inclusion body myositis in patients with spinocerebellar ataxia types 3 and 6
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Rietveld, A., Gaalen, J. van, Saris, C.G.J., Okkersen, K., Kusters, B., Warrenburg, B.P.C. van de, Engelen, B.G.M. van, Sacconi, S., Raaphorst, J., Rietveld, A., Gaalen, J. van, Saris, C.G.J., Okkersen, K., Kusters, B., Warrenburg, B.P.C. van de, Engelen, B.G.M. van, Sacconi, S., and Raaphorst, J.
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Contains fulltext : 225969.pdf (Publisher’s version ) (Closed access), OBJECTIVES: To describe the combination of spinocerebellar ataxia (SCA) types 3 and 6 and sporadic inclusion body myositis (IBM). METHODS: A description of five patients with SCA type 3 and 6 who were diagnosed with IBM. We explore possible mechanisms explaining the coexistence of both diseases. RESULTS: The patients with SCA-3 (n=4) and SCA-6 (n=1) developed asymmetric muscle weakness in a pattern suggestive of IBM in the course of their disease. Based on findings of neurological examination and additional investigations (muscle ultrasound, muscle biopsy), the diagnosis of IBM was made in all patients. CONCLUSION: We report on five patients with concomitant SCA and IBM. Our cases may merely illustrate coincidental co-occurrence of IBM and SCA-3/SCA-6. However, the presence of SCA mutations could predispose to the development of IBM in some SCA patients, or, the presence of toxic aggregates and malfunctioning of cellular quality control processes in both diseases could indicate a convergence of disease mechanisms.
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- 2020
37. Preserved single muscle fiber specific force in facioscapulohumeral muscular dystrophy
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Lassche, S., Voermans, N.C., Pijl, R. van der, Berg, Marloes van den, Heerschap, A., Hees, H.W. van, Kusters, B., Maarel, Silvere M. van der, Ottenheijm, C.A.C., Engelen, B.G.M. van, Lassche, S., Voermans, N.C., Pijl, R. van der, Berg, Marloes van den, Heerschap, A., Hees, H.W. van, Kusters, B., Maarel, Silvere M. van der, Ottenheijm, C.A.C., and Engelen, B.G.M. van
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Item does not contain fulltext, OBJECTIVE: To investigate single muscle fiber contractile performance in muscle biopsies from patients with facioscapulohumeral muscular dystrophy (FSHD), one of the most common hereditary muscle disorders. METHODS: We collected 50 muscle biopsies (26 vastus lateralis, 24 tibialis anterior) from 14 patients with genetically confirmed FSHD and 12 healthy controls. Single muscle fibers (n = 547) were isolated for contractile measurements. Titin content and titin phosphorylation were examined in vastus lateralis muscle biopsies. RESULTS: Single muscle fiber specific force was intact at saturating and physiologic calcium concentrations in all FSHD biopsies, with (FSHDFAT) and without (FSHDNORMAL) fatty infiltration, compared to healthy controls. Myofilament calcium sensitivity of force is increased in single muscle fibers obtained from FSHD muscle biopsies with increased fatty infiltration, but not in FSHD muscle biopsies without fatty infiltration (pCa50: 5.77-5.80 in healthy controls, 5.74-5.83 in FSHDNORMAL, and 5.86-5.90 in FSHDFAT single muscle fibers). Cross-bridge cycling kinetics at saturating calcium concentrations and myofilament cooperativity did not differ from healthy controls. Development of single muscle fiber passive tension was changed in all FSHD vastus lateralis and in FSHDFAT tibialis anterior, resulting in increased fiber stiffness. Titin content was increased in FSHD vastus lateralis biopsies; however, titin phosphorylation did not differ from healthy controls. CONCLUSION: Muscle weakness in patients with FSHD is not caused by reduced specific force of individual muscle fibers, even in severely affected tissue with marked fatty infiltration of muscle tissue.
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- 2020
38. Correlation Between Quantitative MRI and Muscle Histopathology in Muscle Biopsies from Healthy Controls and Patients with IBM, FSHD and OPMD
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Lassche, S., Kusters, B., Heerschap, A., Schyns, M.V.P., Ottenheijm, C.A.C., Voermans, N.C., Engelen, B.G.M. van, Lassche, S., Kusters, B., Heerschap, A., Schyns, M.V.P., Ottenheijm, C.A.C., Voermans, N.C., and Engelen, B.G.M. van
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Contains fulltext : 225840.pdf (Publisher’s version ) (Open Access), BACKGROUND: Muscle MRI is increasingly used as a diagnostic and research tool in muscle disorders. However, the correlation between MRI abnormalities and histopathological severity is largely unknown. OBJECTIVE: To investigate correlations between muscle MRI abnormalities and histopathological severity in healthy controls and patients with muscle disease. METHODS: We performed quantitative MRI and histopathological analysis in 35 patients with inclusion body myositis, facioscapulohumeral muscular dystrophy or oculopharyngeal muscular dystrophy and 12 healthy controls. Participants contributed needle biopsies of the vastus lateralis and/or tibialis anterior, yielding 77 muscle biopsies with matched T1, T2 and TIRM MRI imaging. Muscle biopsies were evaluated with a semi-quantitative histopathology severity grading scale (range 0-12) and an inflammation severity grading scale (range 0-3). RESULTS: In muscle disease, histopathology sum scores ranged from 0 to 11 and correlated significantly with fat percentage as measured on MRI (Spearman's rho = 0.594, p < 0.001). Muscle edema on muscle MRI was associated with increased amounts of inflammation (p < 0.001). Mild abnormalities occured in 95% of control biopsies and were more pronounced in tibialis anterior (median sum score of 1±1 in vastus lateralis and 2±1 in tibialis anterior (p = 0.048)). CONCLUSION: In muscle disease, fatty infiltration on MRI correlates moderately with muscle histopathology. Histopathological abnormalities can occur prior to the onset of fatty infiltration. In middle-aged controls, almost all biopsies showed some histopathological abnormalities. The findings from this study may facilitate the choice for appropriate imaging sequences as outcome measures in therapeutic trials.
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- 2020
39. Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.
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Panneman, D.M., Wortmann, S.B., Haaxma, C.A., Hasselt, P.M. van, Wolf, N.I., Hendriks, Y., Kusters, B., Emst-de Vries, S.E. van, Westerlo, E.M.A. van de, Koopman, W.J.H., Wintjes, L., Brandt, F. van den, Vries, M.C. de, Lefeber, D.J., Smeitink, J.A.M., Rodenburg, R.J.T., Panneman, D.M., Wortmann, S.B., Haaxma, C.A., Hasselt, P.M. van, Wolf, N.I., Hendriks, Y., Kusters, B., Emst-de Vries, S.E. van, Westerlo, E.M.A. van de, Koopman, W.J.H., Wintjes, L., Brandt, F. van den, Vries, M.C. de, Lefeber, D.J., Smeitink, J.A.M., and Rodenburg, R.J.T.
- Abstract
1 april 2020, Contains fulltext : 218925.pdf (publisher's version ) (Open Access), NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.
- Published
- 2020
40. KBTBD13 is an actin-binding protein that modulates muscle kinetics
- Author
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Winter, Josine M. de, Molenaar, J.P., Yuen, M., Pijl, Robbert van der, Shen, S., Conijn, Stefan, Kleef, E.S.B. van, Lassche, S., Rodenburg, R.J.T., Kusters, B., Doorduin, J., Engelen, B.G.M. van, Voermans, N.C., Ottenheijm, C.A.C., Winter, Josine M. de, Molenaar, J.P., Yuen, M., Pijl, Robbert van der, Shen, S., Conijn, Stefan, Kleef, E.S.B. van, Lassche, S., Rodenburg, R.J.T., Kusters, B., Doorduin, J., Engelen, B.G.M. van, Voermans, N.C., and Ottenheijm, C.A.C.
- Abstract
Contains fulltext : 217365.pdf (publisher's version ) (Open Access)
- Published
- 2020
41. KBTBD13 is an actin-binding protein that modulates muscle kinetics
- Author
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de Winter, J M, Molenaar, J P, Yuen, M, van der Pijl, R, Shen, S, Conijn, S, van de Locht, M, Willigenburg, M, Bogaards, S J P, van Kleef, E S B, Lassche, S, Persson, Malin, Rassier, D E, Sztal, T E, Ruparelia, A A, Oorschot, V, Ramm, G, Hall, T E, Xiong, Z, Johnson, C N, Li, F, Kiss, B, Lozano-Vidal, N, Boon, R A, Marabita, M, Nogara, L, Blaauw, B, Rodenburg, R J, Kusters, B, Doorduin, J, Beggs, A H, Granzier, H, Campbell, K, Ma, W, Irving, T, Malfatti, E, Romero, N B, Bryson-Richardson, R J, van Engelen, B G M, Voermans, N C, Ottenheijm, C A C, de Winter, J M, Molenaar, J P, Yuen, M, van der Pijl, R, Shen, S, Conijn, S, van de Locht, M, Willigenburg, M, Bogaards, S J P, van Kleef, E S B, Lassche, S, Persson, Malin, Rassier, D E, Sztal, T E, Ruparelia, A A, Oorschot, V, Ramm, G, Hall, T E, Xiong, Z, Johnson, C N, Li, F, Kiss, B, Lozano-Vidal, N, Boon, R A, Marabita, M, Nogara, L, Blaauw, B, Rodenburg, R J, Kusters, B, Doorduin, J, Beggs, A H, Granzier, H, Campbell, K, Ma, W, Irving, T, Malfatti, E, Romero, N B, Bryson-Richardson, R J, van Engelen, B G M, Voermans, N C, and Ottenheijm, C A C
- Abstract
The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13(R408c)-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology., Funding agencies:Dutch Foundation for Scientific Research VIDI 016.126.319Princess Beatrix Muscle Foundation W.OR17-08H2020-MSCA-RISE-2014 645648Advanced Photon Source DE-AC02-06CH11357Foundation Building Strength for Nemaline MyopathyNational Health and Medical Research Council (NHMRC) of Australia APP1121651 United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) NIH R01 HD075802 Muscular Dystrophy Association MDA602235 NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) NIH R01 AR053897 United States Department of Health & Human Services National Institutes of Health (NIH) - USA HL133359 United States Department of Energy (DOE) DE-AC02-06CH11357 NIH National Institute of General Medical Sciences (NIGMS)9 P41 GM103622 1S10OD018090-01
- Published
- 2020
- Full Text
- View/download PDF
42. Evaluation of 42-Day Storage of Red Cell Concentrates Collected by Spinning Membrane Technology: SP83
- Author
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Karpiel, A, Wegener, C, Madsen, J, Kusters, B, and Min, K
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- 2011
43. Compressor/cascade flow with strong shock-wave/boundary-layer interaction
- Author
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Kusters, B. and Schreiber, H.A.
- Subjects
Compressors -- Research ,Aerodynamics, Supersonic -- Research ,Fluid dynamics -- Research ,Numerical calculations -- Models ,Mathematical models -- Evaluation ,Aerospace and defense industries ,Business - Abstract
An extensive understanding of the flow phenomena/loss mechanism of transonic blade-to-blade flow is required to realize the full benefit of high-speed compressors for increased pressure ratios and a reduced number of stages without compromising the efficiency level. A study was conducted to simulate and understand the transonic flow phenomena in a highly loaded compressor cascade. The results of the study are discussed.
- Published
- 1998
44. Prognostic significance of NAB2-STAT6 fusion variants and TERT promotor mutations in solitary fibrous tumors/hemangiopericytomas of the CNS: not (yet) clear
- Author
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Vogels, R, Macagno, N, Griewank, K, Groenen, P, Verdijk, M, Fonville, J, Kusters, B, Figarella-Branger, D, Wesseling, P, Bouvier, C, Flucke, U, Cornu, P, Dufour, H, Guyotat, J, Jouvet, A, Metellus, P, Mokhtari, K, Vasiljevic, A, Varlet, P, Bekers, E, Djafarihamedani, M, Kurt, E, Kusters-Vandevelde, H, Fleischeuer, R, Leenstra, Sieger, Robe, P, Spliet, W, Troost, D, van Furth, W, Radboud University Medical Center [Nijmegen], Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de Neuropathologie [AP-HM Hôpital de la Timone], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Essen, Stichting PAMM, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Service d’Anatomie Pathologique et de Neuropathologie, APHM, Hôpital de la Timone, Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), VU University Medical Center [Amsterdam], AUTRES, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Pathology, CCA - Imaging and biomarkers, and Neurosurgery
- Subjects
Solitary fibrous tumor ,Medizin ,Clinical Neurology ,Nab2 stat6 ,Biology ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,medicine.disease_cause ,Pathology and Forensic Medicine ,Central Nervous System Neoplasms ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,Humans ,Oncogene Fusion ,Promoter Regions, Genetic ,Telomerase ,Retrospective Studies ,030304 developmental biology ,0303 health sciences ,Mutation ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Promoter ,Prognosis ,medicine.disease ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Progression-Free Survival ,3. Good health ,Clinical neurology ,Repressor Proteins ,Survival Rate ,Solitary Fibrous Tumors ,030220 oncology & carcinogenesis ,Cancer research ,Neurology (clinical) ,STAT6 Transcription Factor ,Hemangiopericytoma - Abstract
International audience; Grading of meningeal solitary fibrous tumors/hemangiopericytomas(SFTs/HPCs) of the central nervous system (CNS)is nowadays based on histologic criteria as described in therevised fourth edition of the WHO Classification of CNStumors [10] or the more recently published, updated versionof the Marseille Grading System (MGS) [11]. Histologybasedgrading of CNS SFTs/HPCs allows for discriminatingsubgroups with significant differences in prognosis. However,the often-piecemealresection of these tumors mayhamper adequate evaluation of mitotic activity and necrosis,and thereby assessment of malignancy grade. NAB2–STAT6fusion is the molecular hallmark of both soft tissue SFTs andCNS SFTs/HPCs, and the resultingfusion protein accumulatesin the nucleus and acts as a transcriptional activatorof early growth response mediated pathways with STAT6immunohistochemistry being a very sensitive and specifictool for their diagnosis [5, 8, 12, 14]. For soft tissue SFTs,particular NAB2–STAT6 fusion variants as well as telomerasereverse transcriptase (TERT) promoter mutations leadingto telomerase activity and tumor cell immortalization havebeen reported to have prognostic value. Some studies haveincluded CNS SFTs/HPCs in their cohort, but because ofsmall numbers and lack of (long term) follow-up data theprognostic value of these markers for CNS SFTs/HPCs isstill unclear.
- Published
- 2019
45. Grading of meningeal solitary fibrous tumors/hemangiopericytomas: analysis of the prognostic value of the Marseille Grading System in a cohort of 132 patients
- Author
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Macagno, Nicolas, Vogels, Rob, Appay, Romain, Colin, Carole, Mokhtari, Karima, Bouvier, Corinne, Cornu, Philippe, Dufour, Henry, Figarella-Branger, Dominique, Guyotat, Jacques, Jouvet, Anne, Metellus, Philippe, Vasiljevic, Alexandre, Varlet, Pascale, Vogels, R., Flucke, U., Kusters, B., Groenen, P., Wesseling, P., Bekers, E., Verdijk, M., Djafarihamedani, M., Kurt, E., Kusters-Vandevelde, H., Fleischeuer, R., Leenstra, S., Robe, P., Spliet, W., Troost, D., van Furth, W., Kusters, Benno, Pathology, and CCA - Cancer Treatment and quality of life
- Subjects
0301 basic medicine ,Oncology ,Male ,Solitary fibrous tumor ,medicine.medical_treatment ,Cohort Studies ,0302 clinical medicine ,Meningeal Neoplasms ,Research Articles ,Aged, 80 and over ,Univariate analysis ,General Neuroscience ,Marseille Grading System ,Middle Aged ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Prognosis ,Progression-Free Survival ,Solitary Fibrous Tumors ,Cohort ,Female ,medicine.medical_specialty ,Poor prognosis ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Malignancy ,Disease-Free Survival ,Pathology and Forensic Medicine ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,solitary fibrous tumor ,hemangiopericytoma ,Aged ,Neoplasm Staging ,Retrospective Studies ,Hemangiopericytoma ,Chemotherapy ,business.industry ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Reproducibility of Results ,prognostic factors ,grading ,medicine.disease ,central nervous system ,Radiation therapy ,Repressor Proteins ,030104 developmental biology ,MGS ,Neurology (clinical) ,business ,STAT6 Transcription Factor ,030217 neurology & neurosurgery - Abstract
Item does not contain fulltext The finding that meningeal solitary fibrous tumors (SFTs) and meningeal hemangiopericytomas (HPCs) are both characterized by NAB2-STAT6 gene fusion has pushed their inclusion in the WHO 2016 Classification of tumors of the central nervous system (CNS) as different manifestations of the same entity. Given that the clinical behavior of the CNS SFT/HPC spectrum ranges from benign to malignant, it is presently unclear whether the grading criteria are still adequate. Here, we present the results of a study that analyzed the prognostic value of an updated version of the Marseille Grading System (MGS) in a retrospectively assembled cohort of 132 primary meningeal SFTs/HPCs with nuclear overexpression of STAT6. The median patient follow-up was 64 months (range 4-274 months); 73 cases (55%) were MGS I, 50 cases (38%) MGS II and 9 cases (7%) were MGS III. Progression-free survival (PFS) and disease-specific survival (DSS) were investigated using univariate analysis: the prognostic factors for PFS included MGS, extent of surgery, radiotherapy, chemotherapy and mitotic activity >/=5/10 high-power field (HPF). Moreover, MGS, radiotherapy, mitotic activity >/=5/10 HPF, and necrosis were the prognostic factors measured for DSS. In multivariate analysis, extent of surgery, mitotic activity >/=5/10 HPF, MGS I and MGS III were the independent prognostic factors measured for PFS while necrosis, MGS III and radiotherapy were the independent prognostic factors for DSS. In conclusion, our results show that assessing the malignancy risk of SFT/HPC should not rely on one single criterion like mitotic activity. Therefore, MGS is useful as it combines the value of different criteria. In particular, the combination of a high mitotic activity and necrosis (MGS III) indicates a particularly poor prognosis.
- Published
- 2019
46. Nonspecific pattern of muscular cN-1A expression in inclusion body myositis
- Author
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Rietveld, A., Oosterhof, T., Lassche, S., Engelen, B.G.M. van, Kusters, B., Saris, C.G.J., and Pruijn, G.J.M.
- Subjects
Bio-Molecular Chemistry ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] - Abstract
Contains fulltext : 214820.pdf (Publisher’s version ) (Open Access)
- Published
- 2019
47. Somatic PRKACA Mutations: Association With Transition From Pituitary-Dependent to Adrenal-Dependent Cushing Syndrome
- Author
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Dalmazi, Guido Di, Timmers, H.J.L.M., Arnaldi, Giorgio, Kusters, B., Scarpelli, M., Bathon, Kerstin, Hermus, A.R.M.M., Reincke, M., Dalmazi, Guido Di, Timmers, H.J.L.M., Arnaldi, Giorgio, Kusters, B., Scarpelli, M., Bathon, Kerstin, Hermus, A.R.M.M., and Reincke, M.
- Abstract
Item does not contain fulltext
- Published
- 2019
48. Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate to alleviate metabolic stress
- Author
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Lenting, K., Khurshed, M., Peeters, T.H., Heuvel, C.N.A.M. van den, Lith, S.A.M. van, Bitter, T.J.J. de, Hendriks, W.J.A.J., Span, P.N., Molenaar, R.J., Botman, D., Verrijp, K., Heerschap, A., Laan, M. ter, Kusters, B., Ewijk, A. van, Huynen, M.A., Noorden, C.J.F. van, Leenders, W.P.J., Lenting, K., Khurshed, M., Peeters, T.H., Heuvel, C.N.A.M. van den, Lith, S.A.M. van, Bitter, T.J.J. de, Hendriks, W.J.A.J., Span, P.N., Molenaar, R.J., Botman, D., Verrijp, K., Heerschap, A., Laan, M. ter, Kusters, B., Ewijk, A. van, Huynen, M.A., Noorden, C.J.F. van, and Leenders, W.P.J.
- Abstract
Contains fulltext : 202248.pdf (publisher's version ) (Closed access), Diffuse gliomas often carry point mutations in isocitrate dehydrogenase ( IDH1(mut)), resulting in metabolic stress. Although IDH(mut) gliomas are difficult to culture in vitro, they thrive in the brain via diffuse infiltration, suggesting brain-specific tumor-stroma interactions that can compensate for IDH-1 deficits. To elucidate the metabolic adjustments in clinical IDH(mut) gliomas that contribute to their malignancy, we applied a recently developed method of targeted quantitative RNA next-generation sequencing to 66 clinical gliomas and relevant orthotopic glioma xenografts, with and without the endogenous IDH-1(R132H) mutation. Datasets were analyzed in R using Manhattan plots to calculate distance between expression profiles, Ward's method to perform unsupervised agglomerative clustering, and the Mann Whitney U test and Fisher's exact tests for supervised group analyses. The significance of transcriptome data was investigated by protein analysis, in situ enzymatic activity mapping, and in vivo magnetic resonance spectroscopy of orthotopic IDH1(mut)- and IDH(wt)-glioma xenografts. Gene set enrichment analyses of clinical IDH1(mut) gliomas strongly suggest a role for catabolism of lactate and the neurotransmitter glutamate, whereas, in IDH(wt) gliomas, processing of glucose and glutamine are the predominant metabolic pathways. Further evidence of the differential metabolic activity in these cancers comes from in situ enzymatic mapping studies and preclinical in vivo magnetic resonance spectroscopy imaging. Our data support an evolutionary model in which IDH(mut) glioma cells exist in symbiosis with supportive neuronal cells and astrocytes as suppliers of glutamate and lactate, possibly explaining the diffuse nature of these cancers. The dependency on glutamate and lactate opens the way for novel approaches in the treatment of IDH(mut) gliomas.-Lenting, K., Khurshed, M., Peeters, T. H., van den Heuvel, C. N. A. M., van Lith, S. A. M., de Bitter, T., Hendriks, W.
- Published
- 2019
49. Prognostic significance of NAB2-STAT6 fusion variants and TERT promotor mutations in solitary fibrous tumors/hemangiopericytomas of the CNS: not (yet) clear
- Author
-
Vogels, R., Macagno, N., Griewank, K., Groenen, P.J., Verdijk, M.A.J., Fonville, J., Kusters, B., Figarella-Branger, D., Wesseling, P., Bouvier, C., Flucke, U.E., Vogels, R., Macagno, N., Griewank, K., Groenen, P.J., Verdijk, M.A.J., Fonville, J., Kusters, B., Figarella-Branger, D., Wesseling, P., Bouvier, C., and Flucke, U.E.
- Abstract
Contains fulltext : 203196.pdf (publisher's version ) (Closed access)
- Published
- 2019
50. Grading of meningeal solitary fibrous tumors/hemangiopericytomas: analysis of the prognostic value of the Marseille Grading System in a cohort of 132 patients
- Author
-
Macagno, N., Vogels, R.J.C., Appay, R., Colin, C., Mokhtari, K., Kurt, E., Kusters, B., Wesseling, P., Figarella-Branger, D., Flucke, U.E., Bouvier, C., Macagno, N., Vogels, R.J.C., Appay, R., Colin, C., Mokhtari, K., Kurt, E., Kusters, B., Wesseling, P., Figarella-Branger, D., Flucke, U.E., and Bouvier, C.
- Abstract
Item does not contain fulltext, The finding that meningeal solitary fibrous tumors (SFTs) and meningeal hemangiopericytomas (HPCs) are both characterized by NAB2-STAT6 gene fusion has pushed their inclusion in the WHO 2016 Classification of tumors of the central nervous system (CNS) as different manifestations of the same entity. Given that the clinical behavior of the CNS SFT/HPC spectrum ranges from benign to malignant, it is presently unclear whether the grading criteria are still adequate. Here, we present the results of a study that analyzed the prognostic value of an updated version of the Marseille Grading System (MGS) in a retrospectively assembled cohort of 132 primary meningeal SFTs/HPCs with nuclear overexpression of STAT6. The median patient follow-up was 64 months (range 4-274 months); 73 cases (55%) were MGS I, 50 cases (38%) MGS II and 9 cases (7%) were MGS III. Progression-free survival (PFS) and disease-specific survival (DSS) were investigated using univariate analysis: the prognostic factors for PFS included MGS, extent of surgery, radiotherapy, chemotherapy and mitotic activity >/=5/10 high-power field (HPF). Moreover, MGS, radiotherapy, mitotic activity >/=5/10 HPF, and necrosis were the prognostic factors measured for DSS. In multivariate analysis, extent of surgery, mitotic activity >/=5/10 HPF, MGS I and MGS III were the independent prognostic factors measured for PFS while necrosis, MGS III and radiotherapy were the independent prognostic factors for DSS. In conclusion, our results show that assessing the malignancy risk of SFT/HPC should not rely on one single criterion like mitotic activity. Therefore, MGS is useful as it combines the value of different criteria. In particular, the combination of a high mitotic activity and necrosis (MGS III) indicates a particularly poor prognosis.
- Published
- 2019
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