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  • 1
    Online Resource
    Online Resource
    IDH1/2 wildtype gliomas grade 2 and 3 with molecular glioblastoma-like profile have a distinct course of epilepsy compared to IDH1/2 wildtype glioblastomas
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. 4 ( 2023-04-06), p. 701-709
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. 4 ( 2023-04-06), p. 701-709
    Abstract: IDH1/2 wildtype (IDHwt) glioma WHO grade 2 and 3 patients with pTERT mutation and/or EGFR amplification and/or + 7/−10 chromosome gain/loss have a similar overall survival time as IDHwt glioblastoma patients, and are both considered glioblastoma IDHwt according to the WHO 2021 classification. However, differences in seizure onset have been observed. This study aimed to compare the course of epilepsy in the 2 glioblastoma subtypes. Methods We analyzed epilepsy data of an existing cohort including IDHwt histologically lower-grade glioma WHO grade 2 and 3 with molecular glioblastoma-like profile (IDHwt hLGG) and IDHwt glioblastoma patients. Primary outcome was the incidence proportion of epilepsy during the disease course. Secondary outcomes included, among others, onset of epilepsy, number of seizure days, and antiepileptic drug (AED) polytherapy. Results Out of 254 patients, 78% (50/64) IDHwt hLGG and 68% (129/190) IDHwt glioblastoma patients developed epilepsy during the disease (P = .121). Epilepsy onset before histopathological diagnosis occurred more frequently in IDHwt hLGG compared to IDHwt glioblastoma patients (90% vs 60%, P  & lt; .001), with a significantly longer median time to diagnosis (3.5 vs 1.3 months, P  & lt; .001). Median total seizure days was also longer for IDHwt hLGG patients (7.0 vs 3.0, P = .005), and they received more often AED polytherapy (32% vs 17%, P = .028). Conclusions Although the incidence proportion of epilepsy during the entire disease course is similar, IDHwt hLGG patients show a significantly higher incidence of epilepsy before diagnosis and a significantly longer median time between first seizure and diagnosis compared to IDHwt glioblastoma patients, indicating a distinct clinical course.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac197
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2094060-9
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  • 2
    Online Resource
    Online Resource
    Survival of diffuse astrocytic glioma, IDH1/2 wildtype, with molecular features of glioblastoma, WHO grade IV: a confirmation of the cIMPACT-NOW criteria
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. 4 ( 2020-04-15), p. 515-523
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. 4 ( 2020-04-15), p. 515-523
    Abstract: The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) has recommended that isocitrate dehydrogenase 1 and 2 wildtype (IDH1/2wt) diffuse lower-grade gliomas (LGGs) World Health Organization (WHO) grade II or III that present with (i) a telomerase reverse transcriptase promoter mutation (pTERTmt), and/or (ii) gain of chromosome 7 combined with loss of chromosome 10, and/or (iii) epidermal growth factor receptor (EGFR) amplification should be reclassified as diffuse astrocytic glioma, IDH1/2 wildtype, with molecular features of glioblastoma, WHO grade IV (IDH1/2wt astrocytomas WHO IV). This paper describes the overall survival (OS) of IDH1/2wt astrocytoma WHO IV patients, and more in detail patients with tumors with pTERTmt only. Methods In this retrospective multicenter study, we compared the OS of 71 IDH1/2wt astrocytomas WHO IV patients, with radiological characteristics of LGGs, with the OS of 197 IDH1/2wt glioblastoma patients. Moreover, we compared the OS of 22 pTERTmt only astrocytoma patients with the OS of the IDH1/2wt glioblastoma patients. Results Median OS was similar for IDH1/2wt astrocytoma WHO IV patients (23.8 mo) and IDH1/2wt glioblastoma patients (19.2 mo) (Cox proportional hazards model: hazard ratio [HR] 1.27, 95% CI: 0.85–1.88, P = 0.242). OS was also similar in patients with IDH1/2wt astrocytomas WHO IV, pTERTmt only, and IDH1/2wt glioblastomas (HR 1.15, 95% CI: 0.64–2.10, P = 0.641). Conclusions The presented data confirm the cIMPACT-NOW recommendation and we propose that IDH1/2wt astrocytomas WHO IV in the absence of other qualifying mutations should be classified as IDH1/2wt glioblastomas.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz200
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 3
    Online Resource
    Online Resource
    Intrinsic Molecular Subtypes of Glioma Are Prognostic and Predict Benefit From Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Combination With Other Prognostic Factors in Anaplastic Oligodendroglial Brain Tumors: A Report From EORTC Study 26951
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 3 ( 2013-01-20), p. 328-336
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 3 ( 2013-01-20), p. 328-336
    Abstract: Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples. Patients and Methods Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively. Results All previously identified six IGSs are present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50). Conclusion Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2012.44.1444
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Intrinsic Gene Expression Profiles of Gliomas Are a Better Predictor of Survival than Histology
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 23 ( 2009-12-01), p. 9065-9072
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 23 ( 2009-12-01), p. 9065-9072
    Abstract: Gliomas are the most common primary brain tumors with heterogeneous morphology and variable prognosis. Treatment decisions in patients rely mainly on histologic classification and clinical parameters. However, differences between histologic subclasses and grades are subtle, and classifying gliomas is subject to a large interobserver variability. To improve current classification standards, we have performed gene expression profiling on a large cohort of glioma samples of all histologic subtypes and grades. We identified seven distinct molecular subgroups that correlate with survival. These include two favorable prognostic subgroups (median survival, & gt;4.7 years), two with intermediate prognosis (median survival, 1–4 years), two with poor prognosis (median survival, & lt;1 year), and one control group. The intrinsic molecular subtypes of glioma are different from histologic subgroups and correlate better to patient survival. The prognostic value of molecular subgroups was validated on five independent sample cohorts (The Cancer Genome Atlas, Repository for Molecular Brain Neoplasia Data, GSE12907, GSE4271, and Li and colleagues). The power of intrinsic subtyping is shown by its ability to identify a subset of prognostically favorable tumors within an external data set that contains only histologically confirmed glioblastomas (GBM). Specific genetic changes (epidermal growth factor receptor amplification, IDH1 mutation, and 1p/19q loss of heterozygosity) segregate in distinct molecular subgroups. We identified a subgroup with molecular features associated with secondary GBM, suggesting that different genetic changes drive gene expression profiles. Finally, we assessed response to treatment in molecular subgroups. Our data provide compelling evidence that expression profiling is a more accurate and objective method to classify gliomas than histologic classification. Molecular classification therefore may aid diagnosis and can guide clinical decision making. [Cancer Res 2009;69(23):9065–72]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-2307
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Abstract 3936: Identifying molecular subgroups of gliomas in formalin fixed paraffin embedded material
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3936-3936
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3936-3936
    Abstract: Gliomas are the most common primary brain tumors with heterogeneous morphology and variable prognosis. Histological classification, combined with the patients’ prognostic features, often guides treatment decisions. Unfortunately, differences in histology are subtle and therefore, diagnosis is subject to a large interobserver variability. To improve classification, we did expression profiling on fresh frozen tumor material of 276 glioma samples of all histological subtypes. This resulted in seven molecular subgroups, which correlated significantly better with survival than histology. When validated in prospective studies these molecular clusters could contribute to clinical decision making. However, there is a lack of fresh frozen glioma material, and until now clinical studies have been performed on formalin fixed paraffin embedded (FFPE) material. Therefore, we would like to see whether our molecular clusters are reproducible in FFPE material. Expression profiling was performed on 57 paired snap-frozen/FFPE glioma samples of all histological and molecular subtypes and three non-diseased brain samples. We collected FFPE material from the same patients that were included in our previous study (Gravendeel et al. Cancer Res 2009). FFPE expression profiling was performed using Hu_Ex_1.0_st “exon” arrays (Affymetrix) in combination with Nugen WT-Ovation technology (FFPE V2 and Exon modules). FFPE expression profiles were assigned to a molecular cluster based on its nearest centroid using the 20.000 most variably expressed exons. Preliminary analysis indicates that approximately 75% of all samples were assigned to the correct molecular cluster. Survival data confirmed that the molecular clusters identified using FFPE material retained significant prognostic value, similar to those obtained using fresh frozen material (p=0.0016). Our data indicate that exon arrays in combination with Nugen WT technology are a suitable platform to perform expression profiling on FFPE samples. We are currently expanding our dataset to include FFPE samples from a large phase III European trial. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3936. doi:10.1158/1538-7445.AM2011-3936
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3936
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    Online Resource
    Online Resource
    MGMT -STP27 Methylation Status as Predictive Marker for Response to PCV in Anaplastic Oligodendrogliomas and Oligoastrocytomas. A Report from EORTC Study 26951
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 19 ( 2013-10-01), p. 5513-5522
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 19 ( 2013-10-01), p. 5513-5522
    Abstract: Purpose: The long-term follow-up results from the EORTC-26951 trial showed that the addition of procarbazine, CCNU, and vincristine (PCV) after radiotherapy increases survival in anaplastic oligodendrogliomas/oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others. Experimental Design: We conducted genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted the CpG island hypermethylated phenotype (CIMP) and MGMT promoter methylation (MGMT-STP27) status. Results: We first show that methylation profiling can be conducted on archival tissues with a performance that is similar to snap-frozen tissue samples. We then conducted methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP+ or MGMT-STP27 methylated tumors had an improved survival compared with CIMP− and/or MGMT-STP27 unmethylated tumors [median overall survival (OS), 1.05 vs. 6.46 years and 1.06 vs. 3.8 years, both P & lt; 0.0001 for CIMP and MGMT-STP27 status, respectively]. Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex, performance score, and review diagnosis in the model. CIMP+ and MGMT-STP27 methylated tumors showed a clear benefit from adjuvant PCV chemotherapy: the median OS of CIMP+ samples in the RT and RT-PCV arms was 3.27 and 9.51 years, respectively (P = 0.0033); for MGMT-STP27 methylated samples, it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P = 0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response. Conclusions: MGMT-STP27 may be used to guide treatment decisions in this tumor type. Clin Cancer Res; 19(19); 5513–22. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-1157
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 7
    Online Resource
    Online Resource
    Abstract 808: Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 808-808
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 808-808
    Abstract: Gliomas are the most common primary brain tumors with heterogeneous morphology and variable prognosis. Treatment decisions in patients rely mainly on histological classification and clinical parameters. However, differences between histological subclasses and grades are subtle, and classifying gliomas is subject to a large inter-observer variability. To improve current classification standards, we have performed gene expression profiling on a large cohort of glioma samples of all histological subtypes and grades. We identified seven distinct molecular subgroups that correlate with survival. These include two favorable prognostic subgroups (median survival & gt;4.7 years), two with intermediate prognosis (median survival 1-4 years), two with poor prognosis (median survival & lt;1 year), and one control group. The intrinsic molecular subtypes of glioma are different from histological subgroups and correlate better to patient survival. The prognostic value of molecular subgroups was validated on five independent sample cohorts (TCGA, REMBRANDT, GSE12907, GSE4271, and Li et al.). The power of intrinsic subtyping is demonstrated by its ability to identify a subset of prognostically favorable tumors within an external dataset that contains only histologically confirmed glioblastomas. Specific genetic changes (EGFR amplification, IDH1 mutation, 1p/19q LOH) segregate in distinct molecular subgroups. We identified a subgroup with molecular features associated with secondary glioblastoma, suggesting that different genetic changes drive gene expression profiles. Finally, we assessed response to treatment in molecular subgroups. Our data provides compelling evidence that expression profiling is a more accurate and objective method to classify gliomas than histological classification. Molecular classification therefore may aid diagnosis and can guide clinical decision making. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 808.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-808
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
    Online Resource
    Online Resource
    Subgroup-specific structural variation across 1,000 medulloblastoma genomes
    Springer Science and Business Media LLC ; 2012
    In:  Nature Vol. 488, No. 7409 ( 2012-8), p. 49-56
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 488, No. 7409 ( 2012-8), p. 49-56
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature11327
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 9
    Online Resource
    Online Resource
    Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis
    Springer Science and Business Media LLC ; 2011
    In:  Nature Genetics Vol. 43, No. 2 ( 2011-2), p. 121-126
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 43, No. 2 ( 2011-2), p. 121-126
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/ng.744
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 1494946-5
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    Cytogenetic Prognostication Within Medulloblastoma Subgroups
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 9 ( 2014-03-20), p. 886-896
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 9 ( 2014-03-20), p. 886-896
    Abstract: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2013.50.9539
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
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