Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Abstract: According 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.
    Type of Publication: Journal article epub ahead of print
    PubMed ID: 29687258
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Abstract: In contrast to the relative morphological uniformity of histone H3 K27-mutant high-grade gliomas, H3 G34-mutant tumors present as a histopathologically heterogeneous group of neoplasms, with microscopic characteristics typical of either glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors (CNS-PNET). In the current study, we performed an integrative clinical, histopathological and molecular analysis of 81 G34-mutant CNS tumors. Routinely prepared tumor tissues were investigated for genomic and epigenomic alterations. Despite their divergent histopathological appearance, CNS tumors with H3.3 G34 mutations displayed uniform epigenetic signatures, suggesting a single biological origin. Comparative cytogenetic analysis with other GBM subtypes disclosed a high frequency and high specificity of 3q and 4q loss across G34-mutant tumors. PDGFRA amplification was more common in cases with GBM than with PNET morphology (36 vs. 5 %, respectively), while CCND2 amplifications showed the opposite trend (5 vs. 27 %). Survival analysis revealed the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively. No difference in outcome was found between morphological variants (GBM vs. PNET). Thus, different histological variants of G34-mutant CNS tumors likely comprise a single biological entity (high-grade glioma with H3 G34 mutation, HGG_G34), which should be outlined in future diagnostic and therapeutic classifications. Screening for H3.3 G34 mutation should therefore be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum.
    Type of Publication: Journal article published
    PubMed ID: 26482474
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
  • 4
  • 5
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; Germany ; human ; neoplasms ; PATHWAY ; PATHWAYS ; DISEASE ; DISEASES ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEIN ; RNA ; DIFFERENTIATION ; TUMORS ; ACCURACY ; PATIENT ; cell cycle ; CELL-CYCLE ; SUPPRESSION ; CANDIDATE GENE ; PROGRESSION ; MALIGNANCIES ; PATTERNS ; gene expression ; microarrays ; AGE ; CDKN2A ; TRANSFORMATION ; PROGNOSTIC FACTORS ; PREDICTION ; SERIES ; pathology ; CLINICALLY-RELEVANT ; CHROMOSOMAL IMBALANCES ; CLUSTERIN ; GENOMIC HYBRIDIZATION ; GLIOMAS ; MITOSIS ; PTEN
    Abstract: To elucidate the molecular events responsible for tumorigenesis and progression of ependymomas, we analyzed molecular alterations on the gene expression level in a series of newly diagnosed ependymal neoplasms (n = 39). To this aim, tumor RNA was hybridized to microarrays; comprising 2600 different genes with relevance to mitosis, cell-cycle control, oncogenesis, or apoptosis. For CLU, IGF-2, and RAF-1, which are apparent candidate genes because they had been previously described to be involved in tumorigenesis of other human malignancies, we found a high expression on the mRNA as well as the protein level We identified gene expression signatures for the differentiation of tumors with respect to location, grade, and patient age. Spinal ependymomas were characterized by high-expression levels of HOXB5, PLA2G, and CDKN2A and tumors in young patients (:516 years of age) by high-expression levels of LDHB and STAM Notably, we were able to classify supratentorial grade II and III tumors with 100% accuracy, whereas this did not apply for infratentorial ependymomas. The similar gene expression patterns of grade U and M infratentorial malignancies suggest that grade M tumors may develop through a secondary multistep transformation process involving genes that are related to cell proliferation (LDHA, cyclin B, ALMA) or tumor suppression (PTEN). In summary, our results provide new insight in the biochemical pathways particularly intriguing in the pathomechanism of ependymomas and suggest that this entity comprises molecularly distinct diseases
    Type of Publication: Journal article published
    PubMed ID: 14578171
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Keywords: CANCER ; EXPRESSION ; IRRADIATION ; proliferation ; SURVIVAL ; tumor ; CELL ; CELL-PROLIFERATION ; COMBINATION ; Germany ; neoplasms ; THERAPY ; COMMON ; screening ; SYSTEM ; GENE ; GENE-EXPRESSION ; GENES ; HYBRIDIZATION ; microarray ; transcription ; TISSUE ; TUMORS ; SURGERY ; STAGE ; IDENTIFICATION ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; immunohistochemistry ; MALIGNANCIES ; gene expression ; NUMBER ; AGE ; RATES ; chemotherapy ; LINE ; BLADDER-CANCER ; MARKERS ; p53 ; PROGNOSTIC-FACTORS ; RESECTION ; PARAMETERS ; CENTRAL-NERVOUS-SYSTEM ; CANCER-RESEARCH ; SERIES ; FLUORESCENCE ; PROGNOSTIC FACTOR ; MITOSIS ; CHILDHOOD ; GRADE ; CYTOGENETIC ANALYSIS ; GENE-EXPRESSION PATTERNS ; KINASE GENE ; PRIMITIVE NEUROECTODERMAL TUMORS
    Abstract: Medulloblastoma, a primitive neuroectodermal tumor of the cerebellum, is one of the most common central nervous system malignancies of childhood. Despite aggressive multimodal therapy, including surgery, irradiation, and chemotherapy, 5-year survival rates have only approached 50-60%. To identify potential candidate genes that predict for overall survival (OS), we performed a gene expression profiling analysis in 35 newly diagnosed medulloblastoma neoplasms. Subsequently, the nine most promising candidate genes were analyzed by immunohistochemistry and fluorescence in situ hybridization on tumor tissue microarrays representing a series of 180 tumors. We found 54 genes in which expression levels predicted for unfavorable survival in medulloblastoma. In line with the gene expression profiling analysis, a positive staining for STK15 (P = 0.0006), stathmin 1 (P = 0.001), and cyclin D1 (P = 0.03) was associated with an unfavorable OS, whereas cyclin B1, DAXX, Ki-67, MYC, NRAS. and p53 showed no statistical significant effect. In compar- ison to clinically defined parameters such as gender, age, metastatic stage, extent of tumor resection, application of chemotherapy, and tumor grade, positive staining for STK15 was identified as an independent prognostic factor for OS (P = 0.026). Moreover, additional gene copy numbers of MYC (P = 0.003) and STK15 (P = 0.05) predicted for poor survival. The combination of gene expression profiling with tissue microarray experiments allowed the identification of a series of candidate genes that predicts for survival in medulloblastoma. Of the results highlighted by the various data analysis procedures, genes associated with cell proliferation (cyclin D1), transcription (MYC), and especially mitosis (stathmin 1, STK15) appear particularly intriguing with respect to medulloblastoma pathomechanism
    Type of Publication: Journal article published
    PubMed ID: 15126347
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Keywords: SURVIVAL ; tumor ; FOLLOW-UP ; HYBRIDIZATION ; TUMORS ; TIME ; PATIENT ; IMPACT ; prognosis ; DELETION ; IN-SITU ; PROGRESSION ; AMPLIFICATION ; PATTERNS ; HUMANS ; AGE ; TUMOR PROGRESSION ; DELETIONS ; RECURRENCE ; RESECTION ; BIOPSY ; ADULT ; EGFR ; oligoastrocytoma ; oligodendroglioma ; DISEASE PROGRESSION ; HISTOLOGY ; 9P ; female ; Male ; Aged ; Middle Aged ; Predictive Value of Tests ; surgical resection ; outcome ; Genetic ; tumor grade ; GENETIC ALTERATIONS ; Disease-Free Survival ; Young Adult ; Chromosome Deletion ; Adolescent ; Brain Neoplasms/*genetics/metabolism/pathology ; Chromosomes,Human,Pair 1/*genetics ; Chromosomes,Human,Pair 19/*genetics ; Oligodendroglioma/*genetics/metabolism/pathology
    Abstract: Previous studies demonstrated that patients with oligodendroglial tumors (OT) have longer overall and recurrence free survival than patients with other glial tumors of the same grade. Recent investigations showed high influence of genetic alterations on patients' outcome: overall and recurrence free survival increased in the case of presence 1p19q deletion and decreased in the presence of 9p or 10q deletion and/or EGFR amplification. In the series of 241 cases (107 male, 134 female patients, median age -- 38 years, (16-73)) we analyzed the impact of histology, tumor grade and genetic alterations on time to tumor progression (TTP). All patients underwent surgical resection of tumor or biopsy from 2000 to 2005. 70 patterns (oligodendroglioma (O) -- 13 cases, oligoastrocytoma (OA) -- 13, anaplastic oligodendroglioma (AO) -- 30, anaplastic oligoastrocytoma (AOA) -- 14) were assessed by fluorescent in situ hybridization. Median follow up was 24 months. The type of tumor (pure or mixed) didn't influence survival. TTP of patients with grade II and grade III tumors was 37.7 and 48.2 months, respectively (p = 0.035). Deletion 1p19q was noted in 34 (49%) cases. In pure O codeletion 1p19q was detected more frequently (in O -- 75%, in AO -- 56%) than in mixed tumors (in OA -- 31%, in AOA -- 35%). Deletions 9p, 10q and EGFR amplification were noted in 5, 6 and 4 cases, respectively. None of the tumors with 1pl9q deletion had other genetic alterations. Thus, we generated three prognostic groups: A -- deletion 1p19q; B -- balanced chromosomal profile; C -- deletion 9p. Median TTP in groups A, B and C was 46.6, 25.3 and 6.4 months, respectively (p 〈 0.001). The percentage of OT with 1p19q codeletion was lower than in previous studies. Pure O more frequently had 1p19q deletion than mixed tumors. Genetic alterations predict outcome stronger than histological criteria.
    Type of Publication: Journal article published
    PubMed ID: 19507310
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Electrical stimulation of the cerebellar fastigial nucleus (FN) elicits a prolonged (∼10 days) and substantial (50–80%) protection against ischemic and excitotoxic injuries. The mechanism(s) of protection are unknown. We investigated whether FN stimulation directly protects brain cells against apoptotic cell death in an in vitro rat brain slice culture model. Rats were electrically stimulated in FN or, as control, the cerebellar dentate nucleus (DN). Coronal slices through the forebrain were explanted, exposed to staurosporine, harvested, and analyzed for caspase-3 activity by a fluorescence assay. FN, but not DN, stimulation significantly reduced staurosporine-induced caspase-3 activity by 39 ± 7% at 3 h, 31 ± 3% at 6 h and 26 ± 4% at 10 h of incubation. Immunocytochemistry revealed FN-specific reductions in activated caspase-3 mainly in glial-like cells throughout the forebrain. FN stimulation also results in a 56.5% reduction in cytochrome c release upon staurosporine incubation. We conclude that neuroprotection elicited from FN stimulation can directly modify the sensitivity of brain cells to apoptotic stimuli and thereby suppress staurosporine induced apoptosis in adult rat brain slices. This model indicates that neuroprotection can be studied in vitro and provides new insight into the potential role of glial cells in ischemic protection of neurons induced by FN stimulation.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    ISSN: 0942-0940
    Keywords: Brain tumours ; computed tomography ; open stereotaxy ; computer simulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A computer-assisted technique was developed for CT-guided stereotactic microsurgical resection of small intracerebral lesions. An original stereotactic retractor was developed to work with the Riechert-Mundinger's equipment for precise localisation, safe exposure and microsurgical removal of these tumours. A software-program was developed to work on an ordinary IBM-compatible PC/AT. It assisted the procedure from treatment planning till the end, including tumour excision, and provided computerized support for the removal of pathological tissues within the CT-defined boundaries of the lesion. 6 patients, harbouring supratentorial intracerebral lesions underwent surgery using this technique. 2 of them suffered from brain metastases, in 1 patient a cavernous angioma was removed, 2 patients had glial tumours, and in the last patient only radiation necrotic tissue was found to be the cause of ring-enhanced lesion, which had been suspected to be a recurrent glioma. Their largest dimensions varied between 18 and 30 mm and the age of the patients ranged from 15 to 52 years. In 2 cases the lesions were localised deeply in the region of basal ganglia and thalamus. In the remaining patients the tumours were rather superficial, infiltrating subcortical white-matter close to the central sulci. There was no mortality nor significant morbidity following the procedure, the Karnofsky Performance Status (KPS) cumulative scores being either unchanged (in 3), or improved (in 3 patients). Current state and modern concepts in image-guided open stereotactic methodology is discussed.
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Several phosphodiester antisense oligodeoxynucleotides (ODNs) corresponding to untranslated and translated amino-terminal regions of NMDA-R1 messenger RNA7"9 were synthesized. An 18-mer, NMDARlAS/c, designed to correspond to nucleotides 4-21 (ref. 7), which directly follow the translation ...
    Type of Medium: Electronic Resource
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...