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000136811 1001_ $$aShirahata, Mitsuaki$$b0
000136811 245__ $$aNovel, improved grading system(s) for IDH-mutant astrocytic gliomas.
000136811 260__ $$aBerlin$$bSpringer$$c2018
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000136811 520__ $$aAccording to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AIIIDHmut), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIIIIDHmut), and WHO grade IV glioblastoma, IDH-mutant (GBMIDHmut). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AIIIDHmut and AAIIIIDHmut have lost their significance. In contrast, GBMIDHmut still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.
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000136811 7001_ $$aOno, Takahiro$$b1
000136811 7001_ $$0P:(DE-He78)d20d08adc992abdb6ccffa1686f1ba17$$aStichel, Damian$$b2$$eFirst author
000136811 7001_ $$0P:(DE-He78)e54a1e0999c1d8c95869ef9188b794cc$$aSchrimpf, Daniel$$b3
000136811 7001_ $$0P:(DE-HGF)0$$aReuss, David E$$b4
000136811 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b5
000136811 7001_ $$0P:(DE-HGF)0$$aKoelsche, Christian$$b6
000136811 7001_ $$0P:(DE-HGF)0$$aWefers, Annika$$b7
000136811 7001_ $$0P:(DE-HGF)0$$aReinhardt, Annekathrin$$b8
000136811 7001_ $$0P:(DE-HGF)0$$aHuang, Kristin$$b9
000136811 7001_ $$0P:(DE-HGF)0$$aSievers, Philipp$$b10
000136811 7001_ $$aShimizu, Hiroaki$$b11
000136811 7001_ $$aNanjo, Hiroshi$$b12
000136811 7001_ $$aKobayashi, Yusuke$$b13
000136811 7001_ $$aMiyake, Yohei$$b14
000136811 7001_ $$aSuzuki, Tomonari$$b15
000136811 7001_ $$aAdachi, Jun-Ichi$$b16
000136811 7001_ $$aMishima, Kazuhiko$$b17
000136811 7001_ $$aSasaki, Atsushi$$b18
000136811 7001_ $$aNishikawa, Ryo$$b19
000136811 7001_ $$0P:(DE-He78)7999346780553d7fab7ba69d5afdfa71$$aBewerunge-Hudler, Melanie$$b20
000136811 7001_ $$aRyzhova, Marina$$b21
000136811 7001_ $$aAbsalyamova, Oksana$$b22
000136811 7001_ $$aGolanov, Andrey$$b23
000136811 7001_ $$aSinn, Peter$$b24
000136811 7001_ $$aPlatten, Michael$$b25
000136811 7001_ $$aJungk, Christine$$b26
000136811 7001_ $$0P:(DE-He78)6c294453ee36ad59deddc5494fa6aa4b$$aWinkler, Frank$$b27
000136811 7001_ $$0P:(DE-HGF)0$$aWick, Antje$$b28
000136811 7001_ $$aHänggi, Daniel$$b29
000136811 7001_ $$aUnterberg, Andreas$$b30
000136811 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b31
000136811 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b32
000136811 7001_ $$avan den Bent, Martin$$b33
000136811 7001_ $$aHegi, Monika$$b34
000136811 7001_ $$aFrench, Pim$$b35
000136811 7001_ $$aBaumert, Brigitta G$$b36
000136811 7001_ $$aStupp, Roger$$b37
000136811 7001_ $$aGorlia, Thierry$$b38
000136811 7001_ $$aWeller, Michael$$b39
000136811 7001_ $$0P:(DE-He78)51bf9ae9cb5771b30c483e5597ef606c$$aCapper, David$$b40
000136811 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b41
000136811 7001_ $$aHerold-Mende, Christel$$b42
000136811 7001_ $$0P:(DE-He78)92e9783ca7025f36ce14e12cd348d2ee$$aWick, Wolfgang$$b43
000136811 7001_ $$aLouis, David N$$b44
000136811 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b45$$eLast author
000136811 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-018-1849-4$$gVol. 136, no. 1, p. 153 - 166$$n1$$p153 - 166$$tActa neuropathologica$$v136$$x1432-0533$$y2018
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