163 results on '"Scheie, D"'
Search Results
2. First-in-human study of a novel Upar-targeted imaging agent (FGO01) for visualization of malignant glioma during surgery
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Skjøth-Rasmussen, J., Azam, A., Juhl, K., Ginsborg, S., Sørensen, M. Kryspin, Sølling, C., Larsen, C.C., Scheie, D., and Kjaer, A.
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- 2022
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Catalog
3. Population-based whole-genome sequencing with constrained gene analysis identifies predisposing germline variants in children with central nervous system tumors
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Foss-Skiftesvik, J., Stoltze, U., van Overeem Hansen, T., Byrjalsen, A., Sehested, A., Scheie, D., Mikkelsen, T. Stamm, Rasmussen, S., Bak, M., Okkels, H., Callesen, M.T., Skjøth-Rasmussen, J., Gerdes, A.-M., Schmiegelow, K., Mathiasen, R., and Wadt, K. more...
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- 2022
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4. Targeted gene-expression analysis during malignant transformation in primary and secondary malignant meningioma
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Maier, A.D., Meddis, A., Haslund-Vinding, J., Mirian, C., Areskeviciute, A., Nguyen, P., Westergaard, C., Melchior, L.C., Munch, T.N., Skjøth-Rasmussen, J., Poulsgaard, L., Ziebell, M., Bartek, J., Jr., Broholm, H., Poulsen, F.R., Gerds, T.A., Scheie, D., and Mathiesen, T. more...
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- 2021
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5. Are melanomas averse to cerebellum? Cerebellar metastases in a surgical series
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Rogne, S. G., Helseth, E., Brandal, P., Scheie, D., and Meling, T. R.
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- 2014
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6. Outcome following surgery for intracranial meningiomas in the aging
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Konglund, A., Rogne, S. G., Lund-Johansen, M., Scheie, D., Helseth, E., and Meling, T. R.
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- 2013
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7. Craniotomy for brain metastases: a consecutive series of 316 patients
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Rogne, S. G., Rnning, P., Helseth, E., Johannesen, T. B., Langberg, C. W., Lote, K., Scheie, D., and Meling, T. R.
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- 2012
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8. Acute postoperative seizures after epilepsy surgery – a long-term outcome predictor?
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Alfstad, K. Å., Lossius, M. I., Rste, G. K., Mowinckel, P., Scheie, D., Borota, O. C., Larsson, P. G., and Nakken, K. O.
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- 2011
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9. Overall survival, prognostic factors, and repeated surgery in a consecutive series of 516 patients with glioblastoma multiforme
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Helseth, R., Helseth, E., Johannesen, T. B., Langberg, C. W., Lote, K., Rønning, P., Scheie, D., Vik, A., and Meling, T. R.
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- 2010
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10. Low frequency of VHL germline mutations in Norwegian patients presenting with isolated central nervous system hemangioblastomas – a population-based study
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Rønning, P., Andresen, P. A., Hald, J. K., Heimdal, K., Scheie, D., Schreiner, T., and Helseth, E.
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- 2010
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11. Intracranial tumor surgery in patients >70 years of age: is clinical practice worthwhile or futile?
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Rogne, S. G., Konglund, A., Meling, T. R., Scheie, D., Johannesen, T. B., Rønning, P., and Helseth, E.
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- 2009
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12. Can morphology predict 1p/19q loss in oligodendroglial tumours?
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Scheie, D, Cvancarova, M, Mørk, S, Skullerud, K, Andresen, P A, Benestad, I, Helseth, E, Meling, T, and Beiske, K
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- 2008
13. 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., Küsters, B., den Dunnen, W. F. A., Vos, F. Y. F. L., Wesseling, P., Leng, W. W. J., and Kristensen, B. W. more...
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METHYLATION ,CENTRAL nervous system ,TUMORS ,DNA - Abstract
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. [ABSTRACT FROM AUTHOR] more...
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- 2020
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14. Low frequency of high grade dysplasia and malignancy among resected intraductal papillary mucinous neoplasms indicates a need for an improved diagnostic algorithm
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Rift, C., Scheie, D., Lund, E., Hansen, C., and Hasselby, J.
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- 2020
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15. Surgical management of colloid cyst of the third ventricle.
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Brostigen, C. S., Meling, T. R., Marthinsen, P. B., Scheie, D., Aarhus, M., and Helseth, E.
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NEUROLOGICAL disorders ,THERAPEUTICS ,CYSTS (Pathology) ,DISEASE incidence ,CONSCIOUSNESS ,SURGICAL complications ,RETROSPECTIVE studies - Abstract
Background The aim of this study of third ventricular colloid cysts ( TVCC) from a defined population was to estimate the incidence, the presenting features, the surgical treatment, the treatment related complications, and the clinical and surgical outcomes. Methods A reprospective study of 32 consecutive primary surgeries for TVCC was performed at Oslo University Hospital in the time period 2002-2015. Results The estimated incidence rate for TVCC was 0.9 per million. Mean age was 41 years and the male-to-female ratio was 1:1.5. The most common presenting symptoms were headache (100%), ataxia (25%), reduced level of consciousness (22%), and impaired vision (19%). The surgical mortality was 0%. Gross total resection ( GTR) was achieved in 69% based on intraoperative findings and in 81% based on postoperative imaging. The rate of surgery-related complications was 13%. There was no statistically significant difference between microsurgery and endoscopic surgery with respect to surgery-related complications and grade of resection. At time of follow-up, all patients were able to care for themselves. Conclusions Due to the risk of acute neurological deterioration and sudden death, surgical treatment is recommended for patients with symptomatic TVCC. This study shows that surgical resection can be performed with a fairly low risk and with a good long-term outcome. [ABSTRACT FROM AUTHOR] more...
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- 2017
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16. Molecular Cytogenetic Analysis of a Gliosarcoma with Osseous Metaplasia.
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Dahlback, H. S. S., Gorunova, L., Micci, F., Scheie, D., Brandal, P., Meling, T. R., and S.Heim
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SARCOMA ,GLIOMAS ,HUMAN cytogenetics ,GENOMES ,KARYOTYPES ,CELL fusion ,METAPLASTIC ossification - Abstract
Gliosarcoma, a rare glioblastoma variant, is composed of a glial and a mesenchymal component. Though the mesenchymal portion most commonly resembles a fibrosarcoma, other differentiation patterns have been observed. We present the first genomic characterisation (karyotyping followed by FISH and array comparative genomic hybridisation analysis) of a gliosarcoma with osseous metaplasia. In addition to chromosomal changes often found in gliomas (+7,-10,-13, and -22), the tumour cells also harboured a hitherto unknown t(3;21)(q13∼21;q21∼22). Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR] more...
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- 2011
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17. Gliosarcoma with liposarcomatous component, bone infiltration and extracranial growth.
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Borota, O. C., Scheie, D., Bjerkhagen, B., Jacobsen, E. A., and Skullerud, K.
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SARCOMA ,BRAIN tumors ,GLIOBLASTOMA multiforme ,OSTEOSARCOMA ,NEUROBLASTOMA - Abstract
Gliosarcoma is a highly malignant brain tumor consisting of both a glioblastoma and a mesenchymal component. The latter typically resembles fibrosarcoma, but differentiation patterns resembling osteosarcoma, chondrosarcoma, angiosarcoma and rhabdomyosarcoma have also been described. Molecular-genetic studies have shown that both glioblastoma and the mesenchymal component share identical cytogenetic abnormalities or mutations, suggesting a monoclonal origin from glial cells. We report an unusual case of gliosarcoma that presented as a large intracerebral tumor with infiltration of the temporal bone and the soft tissues in the infratemporal fossa. Microscopically, the tumor consisted of alternating areas of glioblastuma and fibrosarcoma. Focally, areas of osteosarcomatuus and liposarcomatous differentiation were found. Although gliosarcoma with transcranial penetration is very rare, it should be suspected in case of intracranial tumor with glioblastoma-imaging features, infiltration of bone and extracranial growth. Our case of liposarcornatous differentiation in gliosarcoma - together with another very recently reported similar case expands the morphologic heterogeneity of this peculiar brain tumor. [ABSTRACT FROM AUTHOR] more...
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- 2006
18. Prenatal diagnosis of tracheal obstruction: possible association with maternal pertussis infection.
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Haugen, G., Jenum, P.A., Scheie, D., Sund, S., and Stray-Pedersen, B.
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TRACHEAL diseases ,RESPIRATORY obstructions ,PRENATAL diagnosis ,DIAGNOSIS - Abstract
A fetus with the sonographic appearance of echogenic and enlarged lungs and dilated trachea and bronchi, indicating laryngotracheal obstruction, is reported. Additionally, the fetus had ascites and subcutaneous edema and the amniotic fluid volume was reduced. Doppler flow investigation of the systemic venous circulation revealed signs of heart failure, and color Doppler visualized possible increased pulmonary flow. Following termination of pregnancy, autopsy confirmed the sonographic observations and revealed a hypoplastic thymus. During the present pregnancy the mother suffered from sustained cough, and serological tests revealed acute pertussis infection. Polymerase chain reaction investigation for Bordetella pertussis in the amniotic fluid was negative. The possibilities of pertussis toxins as noxious factors and of an atypical presentation of DiGeorge anomaly are discussed. [ABSTRACT FROM AUTHOR] more...
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- 2000
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19. P04.05 Targeted Gene-Expression analysis during malignant transformation in primary and secondary malignant meningioma.
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Maier, A D, Meddis, A, Haslund-Vinding, J, Mirian, C, Areskeviciute, A, Nguyen, P, Westergaard, C, Melchior, L C, Munch, T N, Skjøth-Rasmussen, J, Poulsgaard, L, Ziebell, M, Jr, J Bartek, Broholm, H, Poulsen, F R, Gerds, T A, Scheie, D, and Mathiesen, T more...
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- 2021
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20. G.P.8 06 Very early onset myopathy with structural changes in the diaphragm at autopsy consistent with myofibrillar myopathy
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Rasmussen, M. and Scheie, D.
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- 2006
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21. Genome-wide methylation profiling differentiates benign from aggressive and metastatic pituitary neuroendocrine tumors.
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Jotanovic J, Boldt HB, Burton M, Andersen MS, Bengtsson D, Bontell TO, Ekman B, Engström BE, Feldt-Rasmussen U, Heck A, Jakovcevic A, Jørgensen JOL, Kraljevic I, Kunicki J, Lindsay JR, Losa M, Loughrey PB, Maiter D, Maksymowicz M, Manojlovic-Gacic E, Pahnke J, Petersenn S, Petersson M, Popovic V, Ragnarsson O, Rasmussen ÅK, Reisz Z, Saeger W, Schalin-Jäntti C, Scheie D, Terreni MR, Tynninen O, Whitelaw B, Burman P, and Casar-Borota O more...
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- Humans, Male, Female, Middle Aged, Adult, Aged, Genome-Wide Association Study methods, Cohort Studies, Young Adult, Pituitary Neoplasms genetics, Pituitary Neoplasms pathology, DNA Methylation genetics, Neuroendocrine Tumors genetics, Neuroendocrine Tumors pathology, DNA Copy Number Variations genetics
- Abstract
Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0-2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors., (© 2024. The Author(s).) more...
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- 2024
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22. DNA methylation-array interlaboratory comparison trial demonstrates highly reproducible paediatric CNS tumour classification across 13 international centres.
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Chirica M, Jurmeister P, Teichmann D, Koch A, Perez E, Schmid S, Simon M, Driever PH, Bodden C, van Tilburg CM, Hardin EC, Lavarino C, Hench J, Scheie D, Cryan J, Vicha A, Buttarelli FR, Michiels A, Haberler C, Barahona P, Tops BBJ, Jacques T, Stokland T, Witt O, Jones DTW, and Capper D more...
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- Humans, Child, Reproducibility of Results, Male, Female, Prospective Studies, Child, Preschool, DNA Methylation, Glioma genetics, Glioma diagnosis, Glioma pathology, Brain Neoplasms genetics, Brain Neoplasms diagnosis, Brain Neoplasms pathology
- Abstract
Aims: DNA methylation profiling, recently endorsed by the World Health Organisation (WHO) as a pivotal diagnostic tool for brain tumours, most commonly relies on bead arrays. Despite its widespread use, limited data exist on the technical reproducibility and potential cross-institutional differences. The LOGGIC Core BioClinical Data Bank registry conducted a prospective laboratory comparison trial with 12 international laboratories to enhance diagnostic accuracy for paediatric low-grade gliomas, focusing on technical aspects of DNA methylation data generation and profile interpretation under clinical real-time conditions., Methods: Four representative low-grade gliomas of distinct histologies were centrally selected, and DNA extraction was performed. Participating laboratories received a DNA aliquot and performed the DNA methylation-based classification and result interpretation without knowledge of tumour histology. Additionally, participants were required to interpret the copy number profile derived from DNA methylation data and conduct DNA sequencing of the BRAF hotspot p.V600 due to its relevance for low-grade gliomas. Results had to be returned within 30 days., Results: High technical reproducibility was observed, with a median pairwise correlation of 0.99 (range 0.94-0.99) between coordinating laboratory and participants. DNA methylation-based tumour classification and copy number profile interpretation were consistent across all centres, and BRAF mutation status was accurately reported for all cases. Eleven out of 12 centres successfully reported their analysis within the 30-day timeframe., Conclusion: Our study demonstrates remarkable concordance in DNA methylation profiling and profile interpretation across 12 international centres. These findings underscore the potential contribution of DNA methylation analysis to the harmonisation of brain tumour diagnostics., (© 2024 The Author(s). Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.) more...
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- 2024
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23. Glioblastoma cells increase expression of notch signaling and synaptic genes within infiltrated brain tissue.
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Harwood DSL, Pedersen V, Bager NS, Schmidt AY, Stannius TO, Areškevičiūtė A, Josefsen K, Nørøxe DS, Scheie D, Rostalski H, Lü MJS, Locallo A, Lassen U, Bagger FO, Weischenfeldt J, Heiland DH, Vitting-Seerup K, Michaelsen SR, and Kristensen BW more...
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- Humans, Transcriptome, Synapses metabolism, Male, Female, Cell Line, Tumor, Neuroglia metabolism, Neuroglia pathology, Cell Differentiation genetics, Glioblastoma genetics, Glioblastoma pathology, Glioblastoma metabolism, Brain Neoplasms genetics, Brain Neoplasms pathology, Brain Neoplasms metabolism, Signal Transduction, Receptors, Notch metabolism, Receptors, Notch genetics, Brain metabolism, Brain pathology, Gene Expression Regulation, Neoplastic
- Abstract
Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, accompanied by chemotherapy and radiotherapy. Malignant cells escape surgical resection by migrating into the surrounding healthy brain tissue, where they give rise to the recurrent tumor. Based on gene expression, tumor cores can be subtyped into mesenchymal, proneural, and classical tumors, each being associated with differences in genetic alterations and cellular composition. In contrast, the adjacent brain parenchyma where infiltrating malignant cells escape surgical resection is less characterized in patients. Using spatial transcriptomics (n = 11), we show that malignant cells within proneural or mesenchymal tumor cores display spatially organized differences in gene expression, although such differences decrease within the infiltrated brain tissue. Malignant cells residing in infiltrated brain tissue have increased expression of genes related to neurodevelopmental pathways and glial cell differentiation. Our findings provide an updated view of the spatial landscape of glioblastomas and further our understanding of the malignant cells that infiltrate the healthy brain, providing new avenues for the targeted therapy of these cells after surgical resection., (© 2024. The Author(s).) more...
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- 2024
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24. Intracranial Mesenchymal Tumor, FET-CREB Fusion Positive, Evaluated With 18 F-FET and 18 F-FDG PET/CT.
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Engkebølle C, Elisabeth Engelmann B, Scheie D, Fugleholm K, and Law I
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- Humans, Male, Middle Aged, Cyclic AMP Response Element-Binding Protein metabolism, Positron Emission Tomography Computed Tomography, Fluorodeoxyglucose F18, Brain Neoplasms diagnostic imaging
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Abstract: Intracranial mesenchymal tumor, FET-CREB fusion positive, is a newly recognized and rare CNS tumor that occurs primarily in children and young adults. It is regarded as the intracranial variant of angiomatoid fibrous histiocytoma. Extracranial angiomatoid fibrous histiocytomas are typically located in the extremities and usually discernible on a 18 F-FDG PET/CT scanning. We present a 50-year-old man with recurrence of a primary intracranial mesenchymal tumor with equivocal 18 F-FDG PET/CT findings but with subsequent highly increased metabolic activity using 18 F-FET PET/CT confirming tumor recurrence. This case highlights the importance of 18 F-FET PET/CT, as opposed to 18 F-FDG, in the clinical evaluation of this rare intracranial mesenchymal tumor., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.) more...
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- 2024
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25. Clival chordomas and chondrosarcomas in Denmark-Outcomes in 33 patients following the national centralization of treatment in 2010.
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Skotting MB, Poulsgaard L, Springborg JB, Sundbye F, Engelmann BE, Scheie D, Ciochon UM, Guldberg F, and Fugleholm K
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- Humans, Middle Aged, Adult, Male, Female, Aged, Denmark epidemiology, Young Adult, Retrospective Studies, Adolescent, Aged, 80 and over, Treatment Outcome, Skull Base Neoplasms pathology, Skull Base Neoplasms surgery, Chondrosarcoma surgery, Chondrosarcoma pathology, Chordoma surgery, Chordoma pathology, Chordoma radiotherapy, Cranial Fossa, Posterior pathology, Cranial Fossa, Posterior surgery
- Abstract
Purpose: This 13-year consecutive case series aims to provide a comprehensive overview of all patients operated for clival chordomas and clival chondrosarcomas in Denmark since the centralization of treatment in 2010, comparing outcomes to international series., Methods: This was a retrospective review of 33 patients with clival tumors, comprising 22 chordomas and 11 chondrosarcomas, who were treated at Copenhagen University Hospital between years 2010 and 2023. Data were collected from digital patient records and pathology reports., Results: The symptoms leading to diagnosis primarily included double vision, headaches, and dizziness. In general, patients were in good health, with a mean Charlson Comorbidity Index score of 1.6. The complication rate of the index surgery was 51.5%. Adjuvant radiotherapy was applied in 51.5% of the cases. In patients with clival chordomas, the mean age was 51.1 years, ranging from 16 to 83 years. At the time of diagnosis, the mean tumor volume was 20.9 cm
3 and the five-year overall survival rates were 79.1% (95% confidence interval (CI): 62.4-100). In patients with chondrosarcomas, the mean age was 48.2 years, ranging from 15 to 76 years. At the time of diagnosis, the mean tumor volume was 22.3 cm3 and the five-year overall survival 90% (95% CI: 73.2-100)., Conclusion: The centralized treatment of clival tumors in Denmark demonstrates incidence, survival, and complication rates comparable to those found in other international series. Given the variations in treatment strategies, tumor localizations across series, and small sample sizes, the further analysis of larger compiled multicenter datasets for clival tumors could provide more solid evidence regarding the management of these rare tumors., (© 2024. The Author(s).) more...- Published
- 2024
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26. The importance of considering competing risks in recurrence analysis of intracranial meningioma.
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Mirian C, Jensen LR, Juratli TA, Maier AD, Torp SH, Shih HA, Morshed RA, Young JS, Magill ST, Bertero L, Stummer W, Spille DC, Brokinkel B, Oya S, Miyawaki S, Saito N, Proescholdt M, Kuroi Y, Gousias K, Simon M, Moliterno J, Prat-Acin R, Goutagny S, Prabhu VC, Tsiang JT, Wach J, Güresir E, Yamamoto J, Kim YZ, Lee JH, Koshy M, Perumal K, Baskaya MK, Cannon DM, Shrieve DC, Suh CO, Chang JH, Kamenova M, Straumann S, Soleman J, Eyüpoglu IY, Catalan T, Lui A, Theodosopoulos PV, McDermott MW, Wang F, Guo F, Góes P, de Paiva Neto MA, Jamshidi A, Komotar R, Ivan M, Luther E, Souhami L, Guiot MC, Csonka T, Endo T, Barrett OC, Jensen R, Gupta T, Patel AJ, Klisch TJ, Kim JW, Maiuri F, Barresi V, Tabernero MD, Skyrman S, Broechner A, Bach MJ, Law I, Scheie D, Kristensen BW, Munch TN, Meling T, Fugleholm K, Blanche P, and Mathiesen T more...
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- Humans, Aged, Neoplasm Recurrence, Local epidemiology, Neoplasm Recurrence, Local pathology, Retrospective Studies, Risk Assessment, Meningioma pathology, Meningeal Neoplasms pathology
- Abstract
Background: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated., Methods: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions., Results: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions)., Conclusion: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions., (© 2024. The Author(s).) more...
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- 2024
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27. Clinicopathological significance of concurrent ErbB receptor expression in human meningioma.
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Torp SH, Arnli MB, and Scheie D
- Abstract
In general, human meningiomas grow slowly and have a favourable prognosis; however, some are prone to recur despite their benign histology. Therefore, knowledge of their tumour biology is essential to determine objective biomarkers that can identify cases with an increased risk for recurrence and to generate effective treatment options. Thus, studies on the epidermal growth factor receptor (EGFR) family, comprising ErbB1/EGFR, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4, are important. We have recently published papers on the expression of each of these receptor proteins in human meningiomas. The present study aimed to assess the clinicopathological significance of their concurrent expression. A total of 185 grade 1 and 2 meningiomas with robust clinical data underwent immunohistochemical analyses with antibodies against the aforementioned receptors. All meningiomas exhibited upregulation of these receptor proteins relative to normal meninges. In addition, the expression of phosphorylated/activated ErbB1/EGFR1 and phosphorylated/activated ErbB2/HER2 was significantly associated with histological malignancy grade and prognosis, respectively. The concurrent upregulation of ErbB receptors in human meningioma supports their fundamental role in the tumourigenesis of these tumours, and they could thus be exploited in diagnostics, prognosis, and ultimately, in targeted clinical interventions., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Torp et al.) more...
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- 2023
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28. DNA methylation profile of human dura and leptomeninges.
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Maier AD, Christiansen SN, Haslund-Vinding J, Krogager ME, Melchior LC, Scheie D, and Mathiesen T
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- Humans, DNA Methylation, Meninges, Dura Mater, Repressor Proteins, Forkhead Transcription Factors, Meningioma genetics, Meningeal Neoplasms genetics
- Abstract
Healthy meninges are used as control tissue in meningioma studies usually without specification of the exact meningeal layer or macroanatomical origin but the DNA methylation profile of human meninges has not been investigated on a macroanatomical level. We undertook a proof-of-principle analysis to determine whether (1) meningeal tissues show sufficiently homogenous DNA methylation profiles to function as normal control tissue without further specification and (2) if previously described location-specific molecular signatures of meningiomas correspond to region-specific DNA methylation patterns. Dura mater and arachnoid membrane specimens were dissected from 5 anatomical locations in 2 fresh human cadavers and analyzed with the Illumina Infinium MethylationEPIC array. Dura and leptomeninges showed marked differences in global DNA methylation patterns and between rostral and caudal anatomical locations. These differences did not reflect known anatomical predilection of meningioma molecular signatures. The highest numbers of differentially methylated probes were annotated to DIPC2 and FOXP1. Samples from foramen magnum showed hypomethylation of TFAP2B compared to those from remaining locations. Thus, the DNA methylation profiles of human meninges are heterogenous in terms of meningeal layer and anatomical location. The potential variability of DNA methylation data from meningiomas should be considered in studies using meningeal controls., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...
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- 2023
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29. Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions.
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Bogumil H, Sill M, Schrimpf D, Ismer B, Blume C, Rahmanzade R, Hinz F, Cherkezov A, Banan R, Friedel D, Reuss DE, Selt F, Ecker J, Milde T, Pajtler KW, Schittenhelm J, Hench J, Frank S, Boldt HB, Kristensen BW, Scheie D, Melchior LC, Olesen V, Sehested A, Boué DR, Abdullaev Z, Satgunaseelan L, Kurth I, Seidlitz A, White CL, Ng HK, Shi ZF, Haberler C, Deckert M, Timmer M, Goldbrunner R, Tauziède-Espariat A, Varlet P, Brandner S, Alexandrescu S, Snuderl M, Aldape K, Korshunov A, Witt O, Herold-Mende C, Unterberg A, Wick W, Pfister SM, von Deimling A, Jones DTW, Sahm F, and Sievers P more...
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- Humans, Young Adult, Biomarkers, Tumor genetics, Brain pathology, Gene Fusion, Receptor Protein-Tyrosine Kinases genetics, X-linked Nuclear Protein genetics, Brain Neoplasms genetics, Brain Neoplasms pathology, Central Nervous System Neoplasms, Neoplasms, Neuroepithelial genetics, Neoplasms, Neuroepithelial pathology
- Abstract
Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors., (© 2023. The Author(s).) more...
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- 2023
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30. Genetic predisposition and evolutionary traces of pediatric cancer risk: a prospective 5-year population-based genome sequencing study of children with CNS tumors.
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Stoltze UK, Foss-Skiftesvik J, van Overeem Hansen T, Byrjalsen A, Sehested A, Scheie D, Stamm Mikkelsen T, Rasmussen S, Bak M, Okkels H, Thude Callesen M, Skjøth-Rasmussen J, Gerdes AM, Schmiegelow K, Mathiasen R, and Wadt K more...
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- Adult, Child, Humans, Genetic Predisposition to Disease, Prospective Studies, Central Nervous System Neoplasms pathology, Glioma genetics, Cerebellar Neoplasms genetics
- Abstract
Background: The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking., Methods: In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives., Results: Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6-21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e-4) and all other genes (P = 5e-17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity-raising the question of the role of other highly constrained gene alterations detected., Conclusions: Approximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...
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- 2023
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31. Correction to: Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.
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Keck MK, Sill M, Wittmann A, Joshi P, Stichel D, Beck P, Okonechnikow K, Sievers P, Wefers AK, Roncaroli F, Avula S, McCabe MG, Hayden JT, Wesseling P, Øra I, Nistér M, Kranendonk MEG, Tops BBJ, Zapotocky M, Zamecnik J, Vasiljevic A, Fenouil T, Meyronet D, von Hoff K, Schüller U, Loiseau H, Figarella-Branger D, Kramm CM, Sturm D, Scheie D, Rauramaa T, Pesola J, Gojo J, Haberler C, Brandner S, Jacques T, Sexton Oates A, Saffery R, Koscielniak E, Baker SJ, Yip S, Snuderl M, Ud Din N, Samuel D, Schramm K, Blattner-Johnson M, Selt F, Ecker J, Milde T, von Deimling A, Korshunov A, Perry A, Pfister SM, Sahm F, Solomon DA, and Jones DTW more...
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- 2023
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32. Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature.
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Sievers P, Sill M, Schrimpf D, Abdullaev Z, Donson AM, Lake JA, Friedel D, Scheie D, Tynninen O, Rauramaa T, Vepsäläinen KL, Samuel D, Chapman R, Grundy RG, Pajtler KW, Tauziède-Espariat A, Métais A, Varlet P, Snuderl M, Jacques TS, Aldape K, Reuss DE, Korshunov A, Wick W, Pfister SM, von Deimling A, Sahm F, and Jones DTW more...
- Abstract
Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing. DNA and/or RNA sequencing revealed recurrent fusions involving the capicua transcriptional repressor (CIC) gene in 10/10 tumor samples analyzed, with the most common fusion being CIC::LEUTX (n = 9). In addition, a CIC::NUTM1 fusion was detected in one of the tumors. Apart from the detected fusion events, no additional oncogenic alteration was identified in these tumors. The histopathological review demonstrated a morphologically heterogeneous group of high-grade neuroepithelial tumors with positive immunostaining for markers of glial differentiation in combination with weak and focal expression of synaptophysin, CD56 and CD99. All tumors were located in the supratentorial compartment, occurred during childhood (median age 8.5 years) and typically showed early relapses. In summary, we expand the spectrum of pediatric-type tumors of the CNS by reporting a previously uncharacterized group of rare high-grade neuroepithelial tumors that share a common DNA methylation signature and recurrent gene fusions involving the transcriptional repressor CIC. Downstream functional consequences of the fusion protein CIC::LEUTX and potential therapeutic implications need to be further investigated., (© 2023. The Author(s).) more...
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- 2023
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33. Checkpoint inhibitor induced myositis - The value of MRI STIR.
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Erritzøe-Jervild M, Scheie D, and Stenør C
- Abstract
•Treatment with immune checkpoint inhibitors can cause serious adverse events.•Myositis combined with myocarditis ad adverse event have a mortality for 50%.•Early diagnosis is important for better outcome.•Employing MRI STIR can rapidly diagnose, guide biopsy, and classify cases of immune-related myositis., Competing Interests: We hereby declare that we have no conflicts of interest., (© 2023 The Authors.) more...
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- 2023
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34. Targeted next-generation sequencing of EUS-guided through-the-needle-biopsy sampling from pancreatic cystic lesions.
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Rift CV, Melchior LC, Kovacevic B, Klausen P, Toxværd A, Grossjohann H, Karstensen JG, Brink L, Hassan H, Kalaitzakis E, Storkholm J, Scheie D, Hansen CP, Lund EL, Vilmann P, and Hasselby JP
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- Humans, Cyst Fluid, Endoscopic Ultrasound-Guided Fine Needle Aspiration methods, High-Throughput Nucleotide Sequencing, Pancreas pathology, Pancreatic Cyst diagnosis, Pancreatic Cyst genetics, Pancreatic Cyst pathology, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology
- Abstract
Background and Aims: Recent advances have introduced molecular subtyping of pancreatic cystic lesions (PCLs) as a possible amendment to the diagnostic algorithm. The study evaluated the feasibility and diagnostic accuracy of molecular analysis and subtyping of PCLs using the recently introduced EUS-guided through-the-needle-biopsy (TTNB) sampling., Methods: We prospectively included 101 patients in the study who presented with PCLs >15 mm in the largest cross-section. EUS-guided TTNB samples were obtained by a micro-biopsy forceps introduced through a 19-gauge needle. The TTNB samples were analyzed by next-generation sequencing (NGS) for point mutations in tumor suppressors and oncogenes using a 51-gene customized hotspot panel. Sensitivity and specificity were calculated with the histologic diagnosis as reference., Results: After initial microscopic evaluation of the samples, 91 patients had residual TTNB samples available for NGS. Of these, 49 harbored mutations, most frequently in KRAS and GNAS, reflecting an excess frequency of intraductal papillary mucinous neoplasms (IPMNs) in the study population. A sensitivity and specificity of 83.7% (95% confidence interval [CI], 70.3-92.7) and 81.8% (95% CI, 48.2-97.7), respectively, were demonstrated for the diagnosis of a mucinous cyst and 87.2% (95% CI, 74.2-95.2) and 84.6% (95% CI, 54.5-98.1) for the diagnosis of an IPMN., Conclusions: Thus, molecular analysis of TTNB samples by NGS has high sensitivity and specificity for diagnosing mucinous cysts and IPMNs. Although the procedure comes with a risk of adverse events of 9.9%, TTNB samples are a robust alternative to cyst fluid for a combined histologic and molecular diagnosis of PCLs. (Clinical trial registration number: NCT03578445.)., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.) more...
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- 2023
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35. Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.
- Author
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Keck MK, Sill M, Wittmann A, Joshi P, Stichel D, Beck P, Okonechnikow K, Sievers P, Wefers AK, Roncaroli F, Avula S, McCabe MG, Hayden JT, Wesseling P, Øra I, Nistér M, Kranendonk MEG, Tops BBJ, Zapotocky M, Zamecnik J, Vasiljevic A, Fenouil T, Meyronet D, von Hoff K, Schüller U, Loiseau H, Figarella-Branger D, Kramm CM, Sturm D, Scheie D, Rauramaa T, Pesola J, Gojo J, Haberler C, Brandner S, Jacques T, Sexton Oates A, Saffery R, Koscielniak E, Baker SJ, Yip S, Snuderl M, Ud Din N, Samuel D, Schramm K, Blattner-Johnson M, Selt F, Ecker J, Milde T, von Deimling A, Korshunov A, Perry A, Pfister SM, Sahm F, Solomon DA, and Jones DTW more...
- Subjects
- Child, Child, Preschool, Female, Humans, Infant, Male, Cell Cycle Proteins genetics, DNA Methylation, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, Transcription Factors genetics, Transcription Factors metabolism, Tumor Suppressor Proteins genetics, Wnt Signaling Pathway genetics, Central Nervous System Neoplasms genetics, Neuroectodermal Tumors, Primitive genetics
- Abstract
Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined., (© 2022. The Author(s).) more...
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- 2023
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36. Diagnostic yield of simultaneous dynamic contrast-enhanced magnetic resonance perfusion measurements and [ 18 F]FET PET in patients with suspected recurrent anaplastic astrocytoma and glioblastoma.
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Henriksen OM, Hansen AE, Muhic A, Marner L, Madsen K, Møller S, Hasselbalch B, Lundemann MJ, Scheie D, Skjøth-Rasmussen J, Poulsen HS, Larsen VA, Larsson HBW, and Law I
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- Humans, Retrospective Studies, Positron-Emission Tomography methods, Tyrosine metabolism, Magnetic Resonance Imaging methods, Perfusion, Magnetic Resonance Spectroscopy, Glioblastoma diagnostic imaging, Brain Neoplasms pathology, Astrocytoma diagnostic imaging
- Abstract
Purpose: Both amino acid positron emission tomography (PET) and magnetic resonance imaging (MRI) blood volume (BV) measurements are used in suspected recurrent high-grade gliomas. We compared the separate and combined diagnostic yield of simultaneously acquired dynamic contrast-enhanced (DCE) perfusion MRI and O-(2-[
18 F]-fluoroethyl)-L-tyrosine ([18 F]FET) PET in patients with anaplastic astrocytoma and glioblastoma following standard therapy., Methods: A total of 76 lesions in 60 hybrid [18 F]FET PET/MRI scans with DCE MRI from patients with suspected recurrence of anaplastic astrocytoma and glioblastoma were included retrospectively. BV was measured from DCE MRI employing a 2-compartment exchange model (2CXM). Diagnostic performances of maximal tumour-to-background [18 F]FET uptake (TBRmax ), maximal BV (BVmax ) and normalised BVmax (nBVmax ) were determined by ROC analysis using 6-month histopathological (n = 28) or clinical/radiographical follow-up (n = 48) as reference. Sensitivity and specificity at optimal cut-offs were determined separately for enhancing and non-enhancing lesions., Results: In progressive lesions, all BV and [18 F]FET metrics were higher than in non-progressive lesions. ROC analyses showed higher overall ROC AUCs for TBRmax than both BVmax and nBVmax in both lesion-wise (all lesions, p = 0.04) and in patient-wise analysis (p < 0.01). Combining TBRmax with BV metrics did not increase ROC AUC. Lesion-wise positive fraction/sensitivity/specificity at optimal cut-offs were 55%/91%/84% for TBRmax , 45%/77%/84% for BVmax and 59%/84%/72% for nBVmax . Combining TBRmax and best-performing BV cut-offs yielded lesion-wise sensitivity/specificity of 75/97%. The fraction of progressive lesions was 11% in concordant negative lesions, 33% in lesions only BV positive, 64% in lesions only [18 F]FET positive and 97% in concordant positive lesions., Conclusion: The overall diagnostic accuracy of DCE BV imaging is good, but lower than that of [18 F]FET PET. Adding DCE BV imaging did not improve the overall diagnostic accuracy of [18 F]FET PET, but may improve specificity and allow better lesion-wise risk stratification than [18 F]FET PET alone., (© 2022. The Author(s).) more...- Published
- 2022
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37. Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data.
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Jensen LR, Maier AD, Lomstein A, Graillon T, Hrachova M, Bota D, Ruiz-Patiño A, Arrieta O, Cardona AF, Rudà R, Furtner J, Roeckle U, Clement P, Preusser M, Scheie D, Broholm H, Kristensen BW, Skjøth-Rasmussen J, Ziebell M, Munch TN, Fugleholm K, Walter MA, Mathiesen T, and Mirian C more...
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- Everolimus therapeutic use, Humans, Prospective Studies, Receptors, Somatostatin therapeutic use, Somatostatin therapeutic use, Meningeal Neoplasms drug therapy, Meningioma drug therapy
- Abstract
Treatment-refractory meningiomas have a dismal prognosis and limited treatment options. Meningiomas express high-densities of somatostatin receptors (SSTR), thus potentially susceptible to antitumorigenic effects of somatostatin analogues (SSA). Evidence for SSA in meningiomas is scarce, and it is unclear if published literature would either (1) support wider use of SSA, if (2) more evidence is desirable, or if (3) available evidence is sufficient to discard SSA. We addressed the need for more evidence with a systematic review and meta-analysis. We performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. We applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. We included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked "very low." Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistent study designs is warranted to assess SSA therapy for well-defined meningioma subgroups., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) more...
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- 2022
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38. Loss of H3K27me3 in WHO grade 3 meningioma.
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Maier AD, Brøchner CB, Mirian C, Haslund-Vinding J, Bartek J Jr, Ekström TJ, Poulsen FR, Scheie D, and Mathiesen T
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- Child, Histones genetics, Humans, Prognosis, World Health Organization, Meningeal Neoplasms pathology, Meningioma pathology
- Abstract
Immunohistochemical quantification of H3K27me3 was reported to distinguish meningioma patients with an unfavorable prognosis but is not yet established as a prognostic biomarker within WHO grade 3 meningiomas. We studied H3K27me3 loss in a series of biopsies from primary and secondary malignant meningioma to validate its prognostic performance and describe if loss of H3K27me3 occurs during malignant transformation. Two observers quantified H3K27me3 status as "complete loss", < 50% and > 50% stained cells in 110 tumor samples from a population-based consecutive cohort of 40 WHO grade 3 meningioma patients. We found no difference in overall survival (OS) in patients with > 50% H3K27me3 retention compared to < 50% in the cohort of patients with WHO grade 3 meningioma (Wald test p = 0.5). H3K27me3 staining showed heterogeneity in full section tumor slides while staining of the Barr body and peri-necrotic cells complicated quantification further. H3K27me3 expression differed without a discernible pattern between biopsies from repeated surgeries of meningioma recurrences. In conclusion, our results were not compatible with a systematic pattern of immunohistochemical H3K27me3 loss being associated with OS or malignant transformation of meningiomas and did not support H3K27me3 loss as a useful immunohistochemical biomarker within grade 3 meningiomas due to staining-specific challenges in quantification., (© 2022. The Author(s), under exclusive licence to The Japan Society of Brain Tumor Pathology.) more...
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- 2022
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39. Gene expression analysis during progression of malignant meningioma compared to benign meningioma.
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Maier AD, Meddis A, Mirian C, Haslund-Vinding J, Bartek J, Krog SM, Nguyen TUP, Areškevičiūtė A, Melchior LC, Heegaard S, Kristensen BW, Munch TN, Fugleholm K, Ziebell M, Raleigh DR, Poulsen FR, Gerds TA, Litman T, Scheie D, and Mathiesen T more...
- Subjects
- Humans, Gene Expression Profiling, Neoplasm Recurrence, Local pathology, Meningioma pathology, Meningeal Neoplasms pathology
- Abstract
Objective: Meningioma is the most common primary intracranial neoplasm. Only 1%-3% of meningiomas are malignant according to the 2016 WHO criteria (WHO grade III). High-grade meningiomas present specific gene expression signatures indicating aggressive growth or recurrence. However, changes in gene expression and in neuroinflammatory gene expression signatures in WHO grade III meningiomas and during progression from WHO grade I or II to grade III are unknown., Methods: The authors used a NanoString targeted gene expression panel with focus on 787 genes relevant in meningioma pathology and neuroinflammatory pathways to investigate patients with grade III meningiomas treated at Rigshospitalet from 2000 to 2020 (n = 51). A temporal dimension was added to the investigation by including samples from patients' earlier grade I and II meningiomas and grade III recurrences (n = 139 meningiomas). The authors investigated changes in neuroinflammatory gene expression signatures in 1) grade I meningiomas that later transformed into grade III meningiomas, and 2) grade III meningiomas compared with nonrecurrent grade I meningiomas., Results: The authors' data indicate that FOXM1, TOP2A, BIRC5, and MYBL2 were enriched and the HOTAIR regulatory pathway was enriched in grade III meningiomas compared with nonrecurrent grade I meningiomas. They discovered a separation of malignant and benign meningiomas based only on genes involved in microglia regulation with enrichment of P2RY12 in grade I compared with grade III meningiomas. Interestingly, FOXM1 was upregulated in premalignant grade I meningioma years before the grade III transformation., Conclusions: The authors found gene expression changes in low-grade meningiomas that predated histological transformation to grade III meningiomas. Neuroinflammation genes distinguished grade III from grade I meningiomas. more...
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- 2022
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40. Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort.
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Foss-Skiftesvik J, Stoltze UK, van Overeem Hansen T, Ahlborn LB, Sørensen E, Ostrowski SR, Kullegaard SMA, Laspiur AO, Melchior LC, Scheie D, Kristensen BW, Skjøth-Rasmussen J, Schmiegelow K, Wadt K, and Mathiasen R more...
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- Child, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, Transcription Factors genetics, Ependymoma diagnosis, Ependymoma genetics
- Abstract
Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43). Single nucleotide and structural germline variants in 457 cancer related genes and 2986 highly evolutionarily constrained genes were assessed in 37 children with normal tissue available for sequencing. Molecular ependymoma classification was performed using DNA methylation profiling for 39 children with available tumor tissue. Pathogenic germline variants in known cancer predisposition genes were detected in 11% (4/37; NF2, LZTR1, NF1 & TP53). However, DNA methylation profiling resulted in revision of the histopathological ependymoma diagnosis to non-ependymoma tumor types in 8% (3/39). This included the two children with pathogenic germline variants in TP53 and NF1 whose tumors were reclassified to a diffuse midline glioma and a rosette-forming glioneuronal tumor, respectively. Consequently, 50% (2/4) of children with pathogenic germline variants in fact had other tumor types. A meta-analysis combining our findings with pediatric pan-cancer germline sequencing studies showed an overall frequency of pathogenic germline variants of 3.4% (7/207) in children with ependymoma. In summary, less than 4% of childhood ependymoma is explained by genetic predisposition, virtually restricted to pathogenic variants in NF2 and NF1. For children with other cancer predisposition syndromes, diagnostic reconsideration is recommended for ependymomas without molecular classification. Additionally, LZTR1 is suggested as a novel putative ependymoma predisposition gene., (© 2022. The Author(s).) more...
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- 2022
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41. 9p21.3 Microdeletion involving CDKN2A/2B in a young patient with multiple primary cancers and review of the literature.
- Author
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Jensen MR, Stoltze U, Hansen TVO, Bak M, Sehested A, Rechnitzer C, Mathiasen R, Scheie D, Larsen KB, Olsen TE, Muhic A, Skjøth-Rasmussen J, Rossing M, Schmiegelow K, and Wadt K
- Subjects
- Child, Chromosome Aberrations, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Female, Genes, p16, Humans, Melanoma genetics, Neoplasms, Multiple Primary genetics
- Abstract
Germline pathogenic variants in CDKN2A predispose to various cancers, including melanoma, pancreatic cancer, and neural system tumors, whereas CDKN2B variants are associated with renal cell carcinoma. A few case reports have described heterozygous germline deletions spanning both CDKN2A and CDKN2B associated with a cancer predisposition syndrome (CPS) that constitutes a risk of cancer beyond those associated with haploinsufficiency of each gene individually, indicating an additive effect or a contiguous gene deletion syndrome. We report a young woman with a de novo germline 9p21 microdeletion involving the CDKN2A / CDKN2B genes , who developed six primary cancers since childhood, including a very rare extraskeletal osteosarcoma (eOS) at the age of 8. To our knowledge this is the first report of eOS in a patient with CDKN2A / CDKN2B deletion., (© 2022 Jensen et al.; Published by Cold Spring Harbor Laboratory Press.) more...
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- 2022
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42. ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance.
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Federico A, Thomas C, Miskiewicz K, Woltering N, Zin F, Nemes K, Bison B, Johann PD, Hawes D, Bens S, Kordes U, Albrecht S, Dohmen H, Hauser P, Keyvani K, van Landeghem FKH, Lund EL, Scheie D, Mawrin C, Monoranu CM, Parm Ulhøi B, Pietsch T, Reinhard H, Riemenschneider MJ, Sehested A, Sumerauer D, Siebert R, Paulus W, Frühwald MC, Kool M, and Hasselblatt M more...
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- DNA Methylation, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Humans, Prognosis, SMARCB1 Protein genetics, SMARCB1 Protein metabolism, Central Nervous System Neoplasms genetics, Neoplasms, Neuroepithelial genetics, Rhabdoid Tumor genetics, Teratoma genetics
- Abstract
Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials., (© 2022. The Author(s).) more...
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- 2022
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43. Radiological "milky way sign" as an important pattern in progressive multifocal leukoencephalopathy in patients with or without apparent immunocompromise.
- Author
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Ciochon UM, Scheie D, and Shekhrajka N
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- Brain, Humans, Magnetic Resonance Imaging, Radiography, Leukoencephalopathy, Progressive Multifocal diagnostic imaging, Radiology
- Abstract
Competing Interests: Conflicts of interests The authors declare no conflict of interests.
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- 2022
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44. Implementation of TERT promoter mutations improve prognostication of the WHO classification in meningioma.
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Mirian C, Grell K, Juratli TA, Sahm F, Spiegl-Kreinecker S, Peyre M, Biczok A, Tonn JC, Goutagny S, Bertero L, Maier AD, Jensen LR, Schackert G, Broholm H, Scheie D, Cahill DP, Brastianos PK, Skjøth-Rasmussen J, Fugleholm K, Ziebell M, Munch TN, Kristensen BW, and Mathiesen T more...
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- Humans, Mutation, Promoter Regions, Genetic genetics, World Health Organization, Meningeal Neoplasms genetics, Meningeal Neoplasms pathology, Meningioma genetics, Meningioma pathology, Telomerase genetics
- Abstract
TERT promoter mutations have been associated with increased risk of recurrence in meningioma cohorts, thus a potential biomarker for aggressive phenotypes. A main purpose of refining tumour classification is better predictions on the patient level. We compiled data from previous published cohorts to investigate patient-level predictions of recurrence based on TERTp-mut status. Implementation of TERTp-mut into the WHO grading led to better patient prognostication by improved prediction of recurrence. Our results support implementation of TERTp-mut into diagnostics and classification of meningiomas., (© 2021 British Neuropathological Society.) more...
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- 2022
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45. Granular clinical history and outcome in 51 patients with primary and secondary malignant meningioma.
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Maier AD, Mirian C, Haslund-Vinding J, Bartek J, Guldager R, Møller S, Munch TN, Fugleholm K, Poulsgaard L, Skjøth-Rasmussen J, Ziebell M, Eriksson LE, Scheie D, Poulsen FR, and Mathiesen T
- Abstract
Objective: WHO grade III meningiomas, also known as malignant meningiomas (MMs), are rare, and the heterogenous clinical course in patients with MM is not well described. To characterize the clinical course of patients with MM, granular clinical data were gathered from 51 patients treated at the Department of Neurosurgery and Radiation Oncology, Rigshospitalet, in Copenhagen, Denmark, between 2000 and 2020., Methods: The authors investigated outcome and timing in terms of 1) tumor progression and grade transformation in patients previously diagnosed with WHO grade I or II meningiomas (patients with a secondary MM [sMM]); 2) performance status and complications following surgery; and 3) transition to noncurative treatment and ultimately death. Complications, time between recurrences, and outcome (modified Rankin Scale [mRS] score) for every surgery were analyzed, both malignant and premalignant., Results: Of the 51 patients, 24 (47%) had an sMM. The time to WHO grade III transformation in the sMM group varied widely (median 5.5 years, range 0.5-22 years), but after transformation to a WHO grade III tumor, patients with an sMM and those with a primary MM (pMM) did not differ significantly in overall survival and cumulative risk of progression. Median overall survival for all 51 patients was 4.2 years (95% CI 2.6-7.2 years). Time from the decision to shift from curative to noncurative treatment until death was 3.8 months and the 30-day mortality rate following surgery was 11.8%. From a cumulative number of 151 surgeries, 10 surgeries were followed by improvement on the mRS, mRS score was unchanged in 70, and it worsened in 71. The MM was the underlying cause of death in 30 of 31 patients who had died at the end of follow-up., Conclusions: Together, these findings clearly show a significant morbidity and mortality from the disease itself and from the treatment. These findings warrant studies of prognostic factors for earlier support and adjuvant measures in MM and identify a need for better palliative strategies in this patient group. more...
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- 2022
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46. Genetic alterations associated with malignant transformation of sporadic vestibular schwannoma.
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Håvik AL, Bruland O, Miletic H, Poulsgaard L, Scheie D, Fugleholm K, Lund-Johansen M, and Knappskog PM
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- Homozygote, Humans, Mutation genetics, Sequence Deletion, Vestibulocochlear Nerve, Nerve Sheath Neoplasms, Neuroma, Acoustic genetics, Neuroma, Acoustic pathology
- Abstract
Introduction: Malignant peripheral nerve sheath tumor of the vestibulocochlear nerve (VN-MPNST) is exceedingly rare and carries a poor prognosis. Little is known about its underlying genetics and in particular the process of malignant transformation. There is an ongoing debate on whether the transformation is initiated by ionizing radiation. We present here the analysis and comparison of two post-radiation VN-MPNST and one undergoing spontaneous transformation., Methods: Four tumors from three patients (radiation-naïve vestibular schwannoma before (VS) and after (VN-MPNST) malignant transformation in addition to two post-radiation VN-MPNST) were subjected to DNA whole-genome microarray and whole-exome sequencing and tumor-specific mutations were called. Mutational signatures were characterized using MuSiCa., Results: The tumor genomes were characterized predominantly by copy-number aberrations with 36-81% of the genome affected. Even the VS genome was grossly aberrated. The spontaneous malignant transformation was characterized by a near-total whole-genome doubling, disappearance of NF2 mutation and new mutations in three cancer-related genes (GNAQ, FOXO4 and PDGFRB). All tumors had homozygous loss of the tumor suppressor CDKN2A. Neither mutational signature nor copy number profile was associated with ionizing radiation., Conclusion: The VN-MPNST genome in our cases is characterized by large copy-number aberrations and homozygous deletion of CDKN2A. Our study demonstrates a VS with genetic alterations similar to its malignant counterpart, suggesting the existence of premalignant VS. No consistent mutational signature was associated with ionizing radiation., (© 2021. The Author(s).) more...
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- 2022
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47. Letter to the Editor. Copenhagen grading of meningioma.
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Mathiesen T, Haslund-Vinding J, Skjøth-Rasmussen J, Poulsgaard L, Fugleholm K, Mirian C, Daniela Maier A, Santarius T, Rom Poulsen F, Andrée Larsen V, Winther Kristensen B, Scheie D, Law I, and Ziebell M more...
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- Humans, Meningioma, Meningeal Neoplasms
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- 2022
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48. Proposal of a new grading system for meningioma resection: the Copenhagen Protocol.
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Haslund-Vinding J, Skjoth-Rasmussen J, Poulsgaard L, Fugleholm K, Mirian C, Maier AD, Santarius T, Rom Poulsen F, Meling T, Bartek JJ, Förander P, Larsen VA, Kristensen BW, Scheie D, Law I, Ziebell M, and Mathiesen T more...
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- Humans, Neoplasm Grading, Neoplasm Recurrence, Local, Positron-Emission Tomography, Prospective Studies, Retrospective Studies, Meningeal Neoplasms diagnostic imaging, Meningeal Neoplasms surgery, Meningioma diagnostic imaging, Meningioma surgery
- Abstract
Introduction: The extent of meningioma resection is the most fundamental risk factor for recurrence, and exact knowledge of extent of resection is necessary for prognostication and for planning of adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between "gross total removal" and "subtotal removal," while the latter comprises a five-tiered differentiation of the surgeon's impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging with
68 Ga-DOTATOC allows more sensitive and specific imaging than MRI following surgery of meningiomas., Objective: To develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy, and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance of68 Ga DOTATOC PET, we propose "Copenhagen Grading" for meningiomas., Results: Copenhagen Grading was described for six pilot patients with examples of positive and negative findings on histopathology and DOTATOC PET scanning. The grading could be traceably implemented and parameters of grading appeared complementary. Copenhagen Grading is prospectively implemented as a clinical standard at Rigshospitalet, Copenhagen., Conclusion: Copenhagen Grading provided a comprehensive, logical, and reproducible definition of the extent of resection. It offers promise to be the most sensitive and specific imaging modality available for meningiomas. Clinical and cost-efficacy remain to be established during prospective implementation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.) more...- Published
- 2022
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49. A new uPAR-targeting fluorescent probe for optical guided intracranial surgery in resection of a meningioma-a case report.
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Skjøth-Rasmussen J, Azam A, Larsen CC, Scheie D, Juhl K, and Kjaer A
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- Child, Fluorescent Dyes, Humans, Receptors, Urokinase Plasminogen Activator, Glioma, Meningeal Neoplasms diagnostic imaging, Meningeal Neoplasms surgery, Meningioma diagnostic imaging, Meningioma surgery
- Abstract
Meningiomas are benign lesion although anot insignificant number experiences recurrences despite Simpson grade 1 removal. FG001 is a compound with a fluorophore (ICG) that binds to a urokinase-type plasminogen activator receptor (uPAR) and is currently investigated at our institution in a first-in-human trial. The patient presented with a plausible malignant glioma but proved to be a grade 1 meningioma. FG001 could delineated the tumor not only on the surface but supplementary in the cavity to remove safely the dural attachment. We present FG001 as a new promising tool for improved surgical radicality beyond the intended indication, provided that a prospective validation in a consecutive meningioma cohort demonstrates similar results., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.) more...
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- 2022
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50. Constitutional POLE variants causing a phenotype reminiscent of constitutional mismatch repair deficiency.
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Sehested A, Meade J, Scheie D, Østrup O, Bertelsen B, Misiakou MA, Sarosiek T, Kessler E, Melchior LC, Munch-Petersen HF, Pai RK, Schmuth M, Gottschling H, Zschocke J, Gallon R, and Wimmer K
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- Adult, DNA Mismatch Repair genetics, Humans, Mutation, Phenotype, Brain Neoplasms genetics, Colorectal Neoplasms genetics, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary genetics
- Abstract
Heterozygous POLE or POLD1 germline pathogenic variants (PVs) cause polymerase proofreading associated polyposis (PPAP), a constitutional polymerase proofreading deficiency that typically presents with colorectal adenomas and carcinomas in adulthood. Constitutional mismatch-repair deficiency (CMMRD), caused by germline bi-allelic PVs affecting one of four MMR genes, results in a high propensity for the hematological, brain, intestinal tract, and other malignancies in childhood. Nonmalignant clinical features, such as skin pigmentation alterations, are found in nearly all CMMRD patients and are important diagnostic markers. Here, we excluded CMMRD in three cancer patients with highly suspect clinical phenotypes but identified in each a constitutional heterozygous POLE PV. These, and two additional POLE PVs identified in published CMMRD-like patients, have not previously been reported as germline PVs despite all being well-known somatic mutations in hyper-mutated tumors. Together, these five cases show that specific POLE PVs may have a stronger "mutator" effect than known PPAP-associated POLE PVs and may cause a CMMRD-like phenotype distinct from PPAP. The common underlying mechanism, that is, a constitutional replication error repair defect, and a similar tumor spectrum provide a good rationale for monitoring these patients with a severe constitutional polymerase proofreading deficiency according to protocols proposed for CMMRD., (© 2021 The Authors. Human Mutation published by Wiley Periodicals LLC.) more...
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- 2022
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