Posterior hypothalamus-sparing surgery improves outcome after childhood craniopharyngioma.

OBJECTIVE: Quality of life (QoL) is frequently impaired in childhood-onset craniopharyngioma (CP) by hypothalamic syndrome. The debate, whether pretreatment hypothalamic involvement (HI) has apriori prognostic impact or surgical hypothalamic lesions (HL) determine outcome, is controversial. DESIGN: Survival and outcome of CPs recruited between 2007 and 2014 in KRANIOPHARYNGEOM 2007 were analyzed with regard to reference-confirmed presurgical HI and surgical HL. METHODS: Radiological findings, BMI and QoL were assessed at diagnosis and during follow-up. QoL was assessed using Pediatric Quality of Life (PEDQOL) questionnaire. RESULTS: One hundred sixty-nine CPs were included presenting with no HI (n = 11), anterior (n = 49) and anterior + posterior (a + p) HI (n = 109) prior to surgery. The latter 109 were analyzed for postoperative HL (no lesion: n = 23, anterior HL: n = 29, a + pHL: n = 57). Progression-free survival (PFS) was higher after complete resection. The highest PFS was observed in CP with a + pHL, especially when compared between non-irradiated subgroups (P = 0.006). Overall survival (OS) rates were 1.0 in all subgroups. CP with a + pHL developed higher BMI (P ≤ 0.001) during follow-up compared between subgroups. 55/109 pts with a + pHI completed PEDQOL at diagnosis (48/109 at 3 years follow-up). QoL was worse for a + pHL patients in terms of physical, social and emotional functionality when compared with the anterior HL and no HL subgroup. BMI development and QoL during follow-up were similar for patients with anterior HL and without HL. CONCLUSIONS: Posterior hypothalamus-sparing surgical strategies are associated with higher QoL, decreased development of obesity and lower PFS in CP.

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.

Long-term Effects of Growth Hormone Replacement Therapy in Childhood-onset Craniopharyngioma: Results of the German Craniopharyngioma Registry (HIT-Endo).

OBJECTIVE: Quality of survival, prognosis and long-term outcome are often severely impaired in childhood-onset craniopharyngioma patients (CP). Identification of risk factors for sequelae such as growth hormone (GH) deficiency is important for appropriate treatment and rehabilitation. DESIGN: In a cross-sectional study, 79 CP recruited in HIT-Endo before 2000 were analyzed according to GH substitution: a. CP never GH-treated (noGH); b. CP GH-treated only during childhood (pedGH); c. CP under GH, initiated at adulthood (adultGH); d. CP under GH during childhood and continued during adulthood (contGH). METHODS: Progression-free (PFS) and overall survival (OS), height, body mass index (BMI), psychosocial and neuropsychological status (EORTC QLQ-C30, MFI-20). RESULTS: OS and PFS rates were similar in all subgroups. ContGH and pedGH CP presented with increases in height (p=0.002; p=0.0001) during long-term follow-up when compared with baseline. In all subgroups except for pedGH, increases in BMI were observed when compared with BMI at diagnosis. For emotional functionality and physical fatigue, adultGH CP showed worse (p=0.037; p=0.034) response (mean: 61.4%; 12.5%) when compared with pedGH CP (mean: 83.5%; 7.7%). Observed differences were not related to irradiation and hypothalamic involvement. In terms of psychosocial status, no differences were observed between subgroups. CONCLUSIONS: We conclude that GH substitution was safe with regard to risk of tumor progression/relapse in CP. Growth was improved by GH, whereas the development of obesity was not influenced by GH substitution. However, early initiation of GH substitution after CP diagnosis might have beneficial effects on weight development and neuropsychological outcome.

HuR (Elavl1) and HuB (Elavl2) Stabilize Matrix Metalloproteinase-9 mRNA During Seizure-Induced Mmp-9 Expression in Neurons.

Matrix metalloproteinase-9 (Mmp-9) is involved in different general and cell-type-specific processes, both in neuronal and non-neuronal cells. Moreover, it is implicated in an induction or progression of various human disorders, including diseases of the central nervous system. Mechanisms regulating activity-driven Mmp-9 expression in neurons are still not fully understood. Here, we show that stabilization of Mmp-9 mRNA is one of the factors responsible for the neuronal activity-evoked upregulation of Mmp-9 mRNA expression in hippocampal neurons. Furthermore, we demonstrate that the molecular mechanism related to this stabilization is dependent on the neuronal seizure-triggered transiently increased binding of the mRNA stability-inducing protein, HuR, to ARE1 and ARE4 motifs of the 3'UTR for Mmp-9 mRNA as well as the stably augmented association of another mRNA-stabilizing protein, HuB, to the ARE1 element of the 3'UTR. Intriguingly, we demonstrate further that both HuR and HuB are crucial for an incidence of Mmp-9 mRNA stabilization after neuronal activation. This study identifies Mmp-9 mRNA as the first HuB target regulated by mRNA stabilization in neurons. Moreover, these results are the first to describe an existence of HuR-dependent mRNA stabilization in neurons of the brain.

Plasma-Induced Nonvolatile Resistive Switching with Extremely Low SET Voltage in TiOxFy with AgF Nanoparticles.

Low power consumption is crucial for the application of resistive random access memory. In this work, we present the bipolar resistive switching in an Ag/TiOxFy/Ti/Pt stack with extremely low switch-on voltage of 0.07 V. Operating current as low as 10 nA was also obtained by conductive atomic force microscopy. The highly defective TiOxFy layer was fabricated by plasma treatment using helium, oxygen, and carbon tetrafluoride orderly. During the electroforming process, AgF nanoparticles were formed due to the diffusion of Ag+ which reacted with the adsorbed F- in the TiOxFy layer. These nanoparticles are of great importance to resistive switching performance because they are believed to be conductive phases and become part of the conducting path when the sample is switched to a low-resistance state.

Bipolar resistive switching in YMnO3/Nb:SrTiO3 pn-heterojunctions.

Resistively switching oxides are promising materials for use in electronic applications such as nonvolatile memories, logic gates, and artificial synapses. This work presents the bipolar resistive switching (BRS) in YMnO3/Nb:SrTiO3 pn-heterojunctions. A thermally driven electroforming process is required prior to the observed BRS. Results indicate that the BRS in YMnO3/Nb:SrTiO3 originates from the combined effects of charge trapping and detrapping processes along with the electro-migration of charged point defects in the depletion layer of the pn-heterojunction. It is shown that the built-in voltage of the pn-heterojunctions can be tuned by the oxygen partial pressure during growth of the YMnO3 thin film and impacts the working parameters of the resistively switching cell. This study provides a guideline for material engineering of bipolar resistive switches based on pn-heterojunctions.

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.