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19 Publications visible to you, out of a total of 19
Chemotherapy for intracranial ependymoma in adults.
GGN - German Glioma Network

Abstract (Expand)

BACKGROUND: Ependymal tumors in adults are rare, accounting for less than 4% of primary tumors of the central nervous system in this age group. The low prevalence of intracranial ependymoma in adults … limits the ability to perform clinical trials. Therefore, treatment decisions are based on small, mostly retrospective studies and the role of chemotherapy has remained unclear. METHODS: We performed a retrospective study on 17 adult patients diagnosed with intracranial World Health Organisation grade II or III ependymoma, who were treated with chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by applying Macdonald criteria. Progression-free (PFS) and overall survival (OS) were calculated from start of chemotherapy, using the Kaplan-Meier method. RESULTS: Eleven patients had supratentorial and 6 infratentorial tumors. Ten patients were treated with temozolomide (TMZ), 3 with procarbazine/lomustine/vincristine (PCV), 3 with platinum-based chemotherapy and 1 patient received epirubicin/ifosfamide. Response rates were as follows: TMZ 8/10 stable disease; PCV 3/3 stable disease; platinum-based chemotherapy 1/3 partial response; epirubicin/ifosfamide 1/1 complete response. PFS rates at 6, 12 and 24 months were 52.9, 35.3 and 23.5%. OS rates at 6, 12 and 24 months were 82.4, 82.4 and 70.1%. There was no indication for a favourable prognostic role of O(6)-methylguanyl-DNA-methyltransferase (MGMT) promoter methylation which was detected in 3/12 investigated tumors. CONCLUSIONS: Survival outcomes in response to chemotherapy in adult intracranial ependymoma patients vary substantially, but individual patients may respond to any kind of chemotherapy. There were too few patients to compare survival data between chemotherapeutic subgroups.

Authors: D. Gramatzki, P. Roth, J. Felsberg, S. Hofer, E. J. Rushing, B. Hentschel, M. Westphal, D. Krex, M. Simon, O. Schnell, W. Wick, G. Reifenberger, M. Weller

Date Published: 23rd Apr 2016

Publication Type: Journal article

Human Diseases: adult brain ependymoma

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups.
GGN - German Glioma Network

Abstract (Expand)

Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale … genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.

Authors: M. Weller, R. G. Weber, E. Willscher, V. Riehmer, B. Hentschel, M. Kreuz, J. Felsberg, U. Beyer, H. Loffler-Wirth, K. Kaulich, J. P. Steinbach, C. Hartmann, D. Gramatzki, J. Schramm, M. Westphal, G. Schackert, M. Simon, T. Martens, J. Bostrom, C. Hagel, M. Sabel, D. Krex, J. C. Tonn, W. Wick, S. Noell, U. Schlegel, B. Radlwimmer, T. Pietsch, M. Loeffler, A. von Deimling, H. Binder, G. Reifenberger

Date Published: 19th Mar 2015

Publication Type: Not specified

Human Diseases: brain glioma

Function Shapes Content: DNA-Methylation Marker Genes and their Impact for Molecular Mechanisms of Glioma
GGN - German Glioma Network

Abstract (Expand)

Glioma is a clinically and biologically diverse disease. It challenges diagnosis and prognosis due to its molecular heterogeneity and diverse regimes of biological dysfunctions which are driven by … genetic and epigenetic mechanisms. We discover the functional impact of sets of DNA methylation marker genes in the context of brain cancer subtypes as an exemplary approach how bioinformatics and particularly machine learning using self organizing maps (SOM) complements modern high-throughput genomic technologies. DNA methylation changes in gliomas comprise both, hyper- and hypomethylation in a subtype specific fashion. We compared pediatric (2 subtypes) and adult (4) glioblastoma and non-neoplastic brain. The functional impact of differential methylation marker sets is discovered in terms of gene set analysis which comprises a large collection of markers related to biological processes, literature data on gliomas and also chromatin states of the healthy brain. DNA methylation signature genes from alternative studies well agree with our signatures. SOM mapping of gene sets robustly identifies similarities between different marker sets even under conditions of noisy compositions. Mapping of previous sets of glioma markers reveals high redundancy and mixtures of subtypes in the reference cohorts. Consideration of the regulatory level of DNA methylation is inevitable for understanding cancer genesis and progression. It provides suited markers for diagnosis of glioma subtypes and disentangles tumor heterogeneity.

Authors: E. Willscher, H. Loffler-Wirth, H. Binder, Lydia Hopp

Date Published: 2015

Publication Type: Not specified

Human Diseases: brain glioma

Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling.
GGN - German Glioma Network

Abstract (Expand)

The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the … molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.

Authors: G. Reifenberger, R. G. Weber, V. Riehmer, K. Kaulich, E. Willscher, H. Wirth, J. Gietzelt, B. Hentschel, M. Westphal, M. Simon, G. Schackert, J. Schramm, J. Matschke, M. C. Sabel, D. Gramatzki, J. Felsberg, C. Hartmann, J. P. Steinbach, U. Schlegel, W. Wick, B. Radlwimmer, T. Pietsch, J. C. Tonn, A. von Deimling, H. Binder, M. Weller, M. Loeffler

Date Published: 15th Oct 2014

Publication Type: Not specified

Human Diseases: brain glioma

Genomic profiling reveals distinctive molecular relapse patterns in IDH1/2 wild-type glioblastoma.
GGN - German Glioma Network

Abstract (Expand)

Molecular changes associated with the progression of glioblastoma after standard radiochemotherapy remain poorly understood. We compared genomic profiles of 27 paired primary and recurrent IDH1/2 … wild-type glioblastomas by genome-wide array-based comparative genomic hybridization. By bioinformatic analysis, primary and recurrent tumor profiles were normalized and segmented, chromosomal gains and losses identified taking the tumor cell content into account, and difference profiles deduced. Seven of 27 (26%) pairs lacked DNA copy number differences between primary and recurrent tumors (equal pairs). The recurrent tumors in 9/27 (33%) pairs contained all chromosomal imbalances of the primary tumors plus additional ones, suggesting a sequential acquisition of and/or selection for aberrations during progression (sequential pairs). In 11/27 (41%) pairs, the profiles of primary and recurrent tumors were divergent, i.e., the recurrent tumors contained additional aberrations but had lost others, suggesting a polyclonal composition of the primary tumors and considerable clonal evolution (discrepant pairs). Losses on 9p21.3 harboring the CDKN2A/B locus were significantly more common in primary tumors from sequential and discrepant (nonequal) pairs. Nonequal pairs showed ten regions of recurrent genomic differences between primary and recurrent tumors harboring 46 candidate genes associated with tumor recurrence. In particular, copy numbers of genes encoding apoptosis regulators were frequently changed at progression. In summary, approximately 25% of IDH1/2 wild-type glioblastoma pairs have stable genomic imbalances. In contrast, approximately 75% of IDH1/2 wild-type glioblastomas undergo further genomic aberrations and alter their clonal composition upon recurrence impacting their genomic profile, a process possibly facilitated by 9p21.3 loss in the primary tumor. (c) 2014 Wiley Periodicals, Inc.

Authors: V. Riehmer, J. Gietzelt, U. Beyer, B. Hentschel, M. Westphal, G. Schackert, M. C. Sabel, B. Radlwimmer, T. Pietsch, G. Reifenberger, M. Weller, R. G. Weber, M. Loeffler

Date Published: 8th Apr 2014

Publication Type: Not specified

Human Diseases: glioblastoma multiforme

Retrospective analysis of 104 histologically proven adult brainstem gliomas: clinical symptoms, therapeutic approaches and prognostic factors.
GGN - German Glioma Network

Abstract (Expand)

BACKGROUND: Adult brainstem gliomas are rare primary brain tumors (<2% of gliomas). The goal of this study was to analyze clinical, prognostic and therapeutic factors in a large series of histologically … proven brainstem gliomas. METHODS: Between 1997 and 2007, 104 patients with a histologically proven brainstem glioma were retrospectively analyzed. Data about clinical course of disease, neuropathological findings and therapeutic approaches were analyzed. RESULTS: The median age at diagnosis was 41 years (range 18-89 years), median KPS before any operative procedure was 80 (range 20-100) and median survival for the whole cohort was 18.8 months. Histopathological examinations revealed 16 grade I, 31 grade II, 42 grade III and 14 grade IV gliomas. Grading was not possible in 1 patient. Therapeutic concepts differed according to the histopathology of the disease. Median overall survival for grade II tumors was 26.4 months, for grade III tumors 12.9 months and for grade IV tumors 9.8 months. On multivariate analysis the relative risk to die increased with a KPS </= 70 by factor 6.7, with grade III/IV gliomas by the factor 1.8 and for age >/= 40 by the factor 1.7. External beam radiation reduced the risk to die by factor 0.4. CONCLUSION: Adult brainstem gliomas present with a wide variety of neurological symptoms and postoperative radiation remains the cornerstone of therapy with no proven benefit of adding chemotherapy. Low KPS, age >/= 40 and higher tumor grade have a negative impact on overall survival.

Authors: T. Reithmeier, A. Kuzeawu, B. Hentschel, M. Loeffler, M. Trippel, G. Nikkhah

Date Published: 21st Feb 2014

Publication Type: Not specified

Human Diseases: adult brain stem glioma

Portraying the expression landscapes of cancer subtypes. A case study of glioblastoma multiforme and prostate cancer
HNPCC-Sys - Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome, GGN - German Glioma Network

Abstract (Expand)

Self-organizing maps (SOM) portray molecular phenotypes with individual resolution. We present an analysis pipeline based on SOM machine learning which allows the comprehensive study of large scale … clinical data. The potency of the method is demonstrated in selected applications studying the diversity of gene expression in Glioblastoma Multiforme (GBM) and prostate cancer progression. Our method characterizes relationships between the samples, disentangles the expression patterns into well separated groups of co-regulated genes, extracts their functional contexts using enrichment techniques, and enables the detection of contaminations and outliers in the samples. We found that the four GBM subtypes can be divided into two “localized” and two “intermediate” ones. The localized subtypes are characterized by the antagonistic activation of processes related to immune response and cell division, commonly observed also in other cancers. In contrast, each of the “intermediate” subtypes forms a heterogeneous continuum of expression states linking the “localized” subtypes. Both “intermediate” subtypes are characterized by distinct expression patterns related to translational activity and innate immunity as well as nervous tissue and cell function. We show that SOM portraits provide a comprehensive framework for the description of the diversity of expression landscapes using concepts of molecular function.

Authors: Lydia Hopp, Henry Löffler-Wirth, M. Fasold, Hans Binder

Date Published: 27th Jan 2014

Publication Type: Not specified

Human Diseases: brain glioma, prostate cancer

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