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  • 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
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  • 2
    Abstract: Estimating the malignancy level of tumors is key to management, and has been part of oncology practice for the past approximately 100 years. A central aspect of assessing malignancy level is based on histological "grading"-a process in which a pathologist evaluates microscopic features of a tumor and interprets those findings in light of large prognostic studies. For the diffuse astrocytic gliomas, there have been many such studies over the past century and these have proven useful in estimating prognosis for patients. With the advent of molecular genetics, molecular diagnostic testing has been added to histological evaluation in the armamentarium of the pathologist, and the recent World Health Organization (WHO) Classification of Tumors of the Central Nervous System encourages testing for isocitrate dehydrogenase (IDH) gene status in the classification of diffuse astrocytic gliomas. The present review catalogues a large series of diffuse astrocytic glioma grading studies over the past few decades, and compares the prognostic value of such grading schema before and after the emergence of IDH testing. The review concludes that novel approaches to diffuse astrocytic tumor grading are required in the era of IDH testing.
    Type of Publication: Journal article published
    PubMed ID: 29548048
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  • 3
    ISSN: 1432-1106
    Keywords: Hypoglossal motoneurons ; Retrograde transport ; Synaptic interactions ; Substance P ; Cat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study has investigated the synaptic interactions between hypoglossal motoneurons and substance P (SP)-immunoreactive terminals. Cholera toxin B conjugated to horseradish peroxidase was injected into the tip of the tongue on the right side of six ketamine-anesthetized cats. Two to five days later, the animals were killed. Cells containing HRP were labeled with a histochemical reaction utilizing tetramethylbenzidine (TMB) as the chromogen. TMB forms crystalline reaction products that are very distinct at the electron microscopic level. The tissues were then processed for immunocytochemisty using an antiserum against SP. The chromogen used in this case, di-aminobenzidine, yields amorphous reaction products. At the light microscopic level, labeled cells were observed primarily ipsilaterally in both intermediate and ventrolateral subdivisions of the hypoglossal nucleus. The majority of these labeled cells were seen at the level of obex. At the electron microscopic level, both asymmetric and symmetric synapses were observed. SP-immunoreactive nerve terminals formed asymmetric synapses with labeled dendrites and symmetric synapses with labeled perikarya. SP-labeled terminals also synapsed on unlabeled dendrites and somata. These are the first ultrastructural studies demonstrating synaptic interactions between hypoglossal motoneurons and SP terminals. These studies demonstrate that hypoglossal motoneurons that innervate intrinsic tongue muscles are modulated by SP and that SP may play a role in the control of fine movements of the tongue.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Respiration Physiology 82 (1990), S. 201-215 
    ISSN: 0034-5687
    Keywords: Animal ; Carotid chemoreceptors ; Control of breathing ; Dopamine ; Hypercapnia ; Hyperoxia ; after chronic hyperoxia ; cat ; chornic ; control of breathing ; in chronic hypoxia ; ventilatory response in chronic hyperoxia
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Respiration Physiology 81 (1990), S. 337-347 
    ISSN: 0034-5687
    Keywords: Animal ; Carotid body ; Drug ; Hypercapnia ; Hypoxia ; Ion exchange, Na^+-H^+ antiporter ; amiloride ; and amiloride ; cat
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0034-5687
    Keywords: Carotid sinus nerves ; D"2 dopamine receptor ; Depressant hypoxic effect ; Hypercapnia
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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