Childhood-onset craniopharyngioma: latest insights into pathology, diagnostics, treatment, and follow-up.

INTRODUCTION: Childhood-onset craniopharyngiomas are rare embryonic tumors of low-grade histological malignancy. Severe obesity, physical fatigue, and psychosocial deficits due to hypothalamic tumor involvement have negative impact on quality of life. Initial pretreatment involvement of hypothalamic structures and/or treatment-related lesions result in sequelae clinically associated with impaired social and physical functionality and severe neuroendocrine deficiencies. Overall and progression-free survival rates are not associated with the degree of surgical resection. However, reduced overall survival rates were observed in patients with primary hypothalamic tumor involvement. Areas covered: This review discusses new perspectives on diagnostics, treatment, and follow-up of patients with childhood-onset craniopharyngioma, which were mostly published after 2010 and presented at the 5th International Multidisciplinary Postgraduate Course on Childhood Craniopharyngioma, 19-22 April 2018, at Bad Zwischenahn, Germany. Expert commentary: Percutaneous radio-oncological treatment options are effective in prevention of relapses and tumor progressions. Initial experience with proton beam therapy in childhood-onset craniopharyngioma patients shows promising results in terms of more protective radiological treatment. Recent reports on the molecular pathogenesis of craniopharyngioma open perspectives on the possibility of testing novel treatments targeting pathogenic pathways. As long as effective treatment options for hypothalamic syndrome are not available, hypothalamus-sparing treatment strategies are recommended.

Epigenetics of Epileptogenesis-Evoked Upregulation of Matrix Metalloproteinase-9 in Hippocampus.

Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms-DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45ß to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the hippocampi of pediatric and adult epileptic patients. Additionally, we have also found that despite of its transient nature, the histone modification H3S10ph is strongly and gradually accumulated during epileptogenesis in the cell nuclei and in the proximal Mmp-9 gene promoter in the hippocampus, which suggests that H3S10ph can be involved in DNA demethylation in mammals, and not only in Neurospora. The study identifies MMP-9 as the first protein coding gene which expression is regulated by DNA methylation in human epilepsy. We present a detailed epigenetic model of the epileptogenesis-evoked upregulation of MMP-9 expression in the hippocampus. To our knowledge, it is the most complex and most detailed mechanism of epigenetic regulation of gene expression ever revealed for a particular gene in epileptogenesis. Our results also suggest for the first time that dysregulation of DNA methylation found in epilepsy is a cause rather than a consequence of this condition.