| 1. |
- Lysiak, Malgorzata, et al.
(författare)
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Deletions on Chromosome Y and Downregulation of the SRY Gene in Tumor Tissue Are Associated with Worse Survival of Glioblastoma Patients
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Biological causes of sex disparity seen in the prevalence of cancer, including glioblastoma (GBM), remain poorly understood. One of the considered aspects is the involvement of the sex chromosomes, especially loss of chromosome Y (LOY).METHODS: Tumors from 105 isocitrate dehydrogenase (IDH) wild type male GBM patients were tested with droplet digital PCR for copy number changes of ten genes on chromosome Y. Decreased gene expression, a proxy of gene loss, was then analyzed in 225 IDH wild type GBM derived from TCGA and overall survival in both cohorts was tested with Kaplan-Meier log-rank analysis and maximally selected rank statistics for cut-off determination.RESULTS: LOY was associated with significantly shorter overall survival (7 vs. 14.6 months, p = 0.0016), and among investigated individual genes survival correlated most prominently with loss of the sex-determining region Y gene (SRY) (10.8 vs. 14.8 months, p = 0.0031). Gene set enrichment analysis revealed that epidermal growth factor receptor, platelet-derived growth factor receptor, and MYC proto-oncogene signaling pathways are associated with low SRY expression.CONCLUSION: Our data show that deletions and reduced gene expression of chromosome Y genes, especially SRY, are associated with reduced survival of male GBM patients and connected to major susceptibility pathways of gliomagenesis.
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| 2. |
- Roodakker, Kenney Roy, 1989-, et al.
(författare)
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Ecstatic and gelastic seizures relate to the hypothalamus
- 2020
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Ingår i: Epilepsy & Behavior Reports. - : Elsevier BV. - 2589-9864. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Ecstatic seizures constitute a rare form of epilepsy, and the semiology is diverse. Previously, brain areas including the temporal lobe and the insula have been identified to be involved in clinical expression. The aim of this report is to review changes in ecstatic seizures in a patient before and after operation of a hypothalamic hamartoma, and to scrutinize the relation to gelastic seizures. In this case, the ecstatic seizures disappeared after surgery of the hamartoma but reappeared eleven years later. Clinical information was retrospectively obtained from medical records, interviews, and a questionnaire covering seizure semiology that pertained to ecstatic and gelastic seizures. Our findings imply a possible connection between gelastic and ecstatic seizures, originating from a hypothalamic hamartoma. To our knowledge, this location has not previously been described in ecstatic seizures. Gelastic seizures may in this case were associated with ecstatic seizures. We speclate patients with ecstatic seizures may have an ictal activation of neuronal networks that involves the insula. Our case may add information to the growing knowledge concerning ecstatic seizures.
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| 3. |
- Roodakker, Kenney Roy, 1989-, et al.
(författare)
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Ecstatic and gelastic seizures related to the hypothalamus
- 2021
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Ingår i: Epilepsy & Behavior Reports. - : Elsevier. - 2589-9864. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Ecstatic seizures constitute a rare form of epilepsy, and the semiology is diverse. Previously, brain areas including the temporal lobe and the insula have been identified to be involved in clinical expression. The aim of this report is to review changes in ecstatic seizures in a patient before and after operation for a hypothalamic hamartoma, and to scrutinize the relation to gelastic seizures. In this case, the ecstatic seizures disappeared after surgery of the hamartoma but reappeared eleven years later. Clinical information was retrospectively obtained from medical records, interviews, and a questionnaire covering seizure semiology that pertained to ecstatic and gelastic seizures. Our findings imply a possible connection between gelastic and ecstatic seizures, originating from a hypothalamic hamartoma. To our knowledge, this location has not previously been described in ecstatic seizures. Gelastic seizures may in this case be associated with ecstatic seizures. We speculate that patients with ecstatic seizures may have an ictal activation of neuronal networks that involve the insula. Our case may add information to the knowledge concerning ecstatic seizures. (C) 2020 The Authors. Published by Elsevier Inc.
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| 4. |
- Roodakker, Kenney Roy, 1989-, et al.
(författare)
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Functional Connectivity Changes of the Brain Related to Ecstatic Seizures
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION The origin of ecstatic seizures has previously been linked to the temporal lobe and/or the anteriordorsal insula. The aim of this study was to further investigate a possible anatomical–functional network, involving theinsula, possibly behind these seizures. In this article we describe changes in seizure semiology and MRI connectivityprior to and after the surgical removal of a hypothalamic hamartoma, in order to scrutinize the functional connectivitychanges of the brain related to ecstatic seizures. METHODS A clinical/neurological longitudinal follow-up study wasconducted after hamartoma removal in a patient with a history of gelastic and ecstatic seizures prior to surgery. Datafrom MRI investigations performed at three different time points were merged with clinical information on presurgicalsemiology and its development 1-year and 11-years postsurgically. Native MRI sequences were analyzed within theMontreal Neurological Institute (MNI) space to create a region of interest (ROI) of the lesion volume. The white matterarchitecture of an average brain from the Human Connectome Project (HCP) template was used to reconstruct thewhite matter bundles according to the ROI in our MRI investigations. The reconstructed white matter connectivity wasanalyzed using cortical and subcortical areas imported from Freesurfer© atlas and displayed as circle graphs.RESULTS The clinical course of the ecstatic symptoms merged with the connectivity analysis showed three potentialareas of the brain possibly involved in ecstatic seizures: the left superior frontal gyrus, the brainstem and the leftthalamus. The white matter pathways between hypothalamus-thalamus and brainstem were particularly representedwhen the ecstatic phenomena were present, whereas the absence of ecstatic seizures in the postoperative periodseemed to be connected with the predominant involvement of the fronto-thalamic-brainstem network. CONCLUSIONWe suggest that a balance of the networks between the thalamus, the brain stem and the frontal lobe is crucial inorder to experience ecstatic seizures. Our results indicate that the frontal lobe is involved in the inhibitoryeffect/negative reinforce, while the brain stem and a gelastic seizure may elicit a positive trigger/reinforce of theecstatic seizure. Additionally, our findings suggest a possible connection between gelastic and ecstatic seizures. Thisnew information about the possible functional organization supports the notion that it is a network rather than just asingle trigger zone that produces the complex pattern of symptoms seen in patients with ecstatic epileptic seizures.
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| 5. |
- Roodakker, Kenney Roy, 1989-
(författare)
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Towards new tools for clinical evaluation and visualization of tumor growth in patients with glioma
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gliomas are derived from glial cells and are the most common type of primary brain tumors in adults. Gliomas are classified by the World Health Organization (WHO) according to their malignancy grade and histological and molecular features. Malignancy grades range from I to IV. WHO grade I tumors are benign tumors, mostly occurring in childhood. High-grade gliomas (WHO grades III and IV) are undifferentiated and fast-growing tumors, with glioblastoma being the most common and malignant form. Patients with glioblastomas have a median survival of only 15 months. Clinical outcomes vary, however, and markers are needed to assist in the decision-making process and management of these patients. PROX1 is a transcription factor critical for embryonic development, with a role in cell cycle control and progenitor cell differentiation. Apart from its role in normal central nervous system development, PROX1 has been ascribed both tumor suppressive and oncogenic roles in several human cancers. The role of PROX1 as a prognostic factor for survival in patients with glioblastomas was the focus of paper I.Gliomas WHO grade II, also called diffuse low-grade gliomas (DLGGs), are well-differentiated tumors that occur mainly in adult life, with a peak incidence at around 30–35 years of age and a median survival of 5–10 years. DLGGs grow continuously at a rate of a few mm per year and have a strong tendency to infiltrate the white matter tracts surrounding the tumor. Eventually these tumors transform into high-grade gliomas, but, as is the case with glioblastomas, there is a large variety of clinical outcomes. For radiological diagnosis, magnetic resonance imaging (MRI) is routinely used, often in combination with advanced MRI. Positron emission tomography with amino acid tracers provides additional diagnostic accuracy. From a histological as well as imaging point of view, DLGGs are heterogeneous tumors. The heterogeneity of DLGGs, in particular the correlation between radiological and histological tumor features, was the focus of paper II & paper III.Seizures are amongst the most common presenting symptoms of patients with gliomas. Seizure semiology in patients with brain tumors and other structural brain lesions is closely related to the anatomical location of the lesion and the involvement of functional networks. A possible dynamic interplay between the anatomical region of seizure onset and connected target areas within the network was the focus of paper IV.
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| 6. |
- Zetterling, Maria, et al.
(författare)
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Extension of diffuse low-grade gliomas beyond radiological borders as shown by the coregistration of histopathological and magnetic resonance imaging data
- 2016
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Ingår i: Journal of Neurosurgery. - : AMER ASSOC NEUROLOGICAL SURGEONS. - 0022-3085 .- 1933-0693. ; 125:5, s. 1155-1166
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Tidskriftsartikel (refereegranskat)abstract
- Background: Magnetic resonance imaging tends to underestimate the extent of diffuse low-grade gliomas (DLGGs). With the aim of studying the presence of tumor cells outside the radiological border, the authors developed a method of correlating MRI findings with histological data in patients with suspected DLGGs in whom en bloc resections were performed.Methods: Five patients with suspected DLGG suitable for en bloc resection were recruited from an ongoing prospective study. Sections of the entire tumor were immunostained with antibodies against mutated IDH1 protein (IDH1-R132H). Magnetic resonance images were coregistered with corresponding IDH1 images. The growth pattern of tumor cells in white and gray matter was assessed in comparison with signal changes on corresponding MRI slices.Results: Neuropathological assessment revealed DLGG in 4 patients and progression to WHO Grade III glioma in 1 patient. The tumor core consisted of a high density of IDH1-R132H–positive tumor cells and was located in both gray and white matter. Tumor cells infiltrated along the peripheral fibers of the white matter tracts. In all cases, tumor cells were found outside the radiological tumor border delineated on T2-FLAIR MRI sequences.Conclusions: The authors present a new method for the coregistration of histological and radiological characteristics of en bloc–removed infiltrative brain tumors that discloses tumor invasion at the radiological tumor borders. This technique can be applied to evaluate the sensitivity of alternative imaging methods to detect scattered tumor cells at tumor borders. Accurate methods for detection of infiltrative tumor cells will improve the possibility of performing radical tumor resection. In future studies, the method could also be used for in vivo studies of tumor invasion.
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| 7. |
- Zhang, Lei, et al.
(författare)
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IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas
- 2018
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Ingår i: Neuro-Oncology. - : Oxford University Press (OUP). - 1522-8517 .- 1523-5866. ; 20:11, s. 1505-1516
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype.Methods: Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro.Results: Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro.Conclusion: IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.
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