Association Between IDH1 and IDH2 Mutations and Preoperative Seizures in Patients with Low-Grade Versus High-Grade Glioma: A Systematic Review and Meta-Analysis

Phan, Kevin; Lu, Victor M.; McDonald, Kerrie L.; Fairhall, Jacob; Reddy, Rajesh; Wilson, Peter

doi:10.1016/j.wneu.2017.12.112

Cited by 41 publications

(35 citation statements)

References 22 publications

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“…Itaconic acid has anti-bacterial properties which supports the notion that M1 macrophages have inflammatory function. Interestingly, IDH1 and IDH2 are the enzymes that catalyze decarboxylation of isocitrate to α-ketoglutarate outside and inside of the mitochondria, respectively ( 12 ). IDH2 plays a vital role in the formation of NADPH which is critical for ROS balance in the mitochondria ( 13 ).…”

Section: Metabolic Pathways Are Tightly Controlled In Immune Cellsmentioning

confidence: 99%

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

et al. 2018

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Lack of immune system cells or impairment in differentiation of immune cells is the basis for many chronic diseases. Metabolic changes could be the root cause for this immune cell impairment. These changes could be a result of altered transcription, cytokine production from surrounding cells, and changes in metabolic pathways. Immunity and mitochondria are interlinked with each other. An important feature of mitochondria is it can regulate activation, differentiation, and survival of immune cells. In addition, it can also release signals such as mitochondrial DNA (mtDNA) and mitochondrial ROS (mtROS) to regulate transcription of immune cells. From current literature, we found that mitochondria can regulate immunity in different ways. First, alterations in metabolic pathways (TCA cycle, oxidative phosphorylation, and FAO) and mitochondria induced transcriptional changes can lead to entirely different outcomes in immune cells. For example, M1 macrophages exhibit a broken TCA cycle and have a pro-inflammatory role. By contrast, M2 macrophages undergo β-oxidation to produce anti-inflammatory responses. In addition, amino acid metabolism, especially arginine, glutamine, serine, glycine, and tryptophan, is critical for T cell differentiation and macrophage polarization. Second, mitochondria can activate the inflammatory response. For instance, mitochondrial antiviral signaling and NLRP3 can be activated by mitochondria. Third, mitochondrial mass and mobility can be influenced by fission and fusion. Fission and fusion can influence immune functions. Finally, mitochondria are placed near the endoplasmic reticulum (ER) in immune cells. Therefore, mitochondria and ER junction signaling can also influence immune cell metabolism. Mitochondrial machinery such as metabolic pathways, amino acid metabolism, antioxidant systems, mitochondrial dynamics, mtDNA, mitophagy, and mtROS are crucial for immune functions. Here, we have demonstrated how mitochondria coordinate to alter immune responses and how changes in mitochondrial machinery contribute to alterations in immune responses. A better understanding of the molecular components of mitochondria is necessary. This can help in the development of safe and effective immune therapy or prevention of chronic diseases. In this review, we have presented an updated prospective of the mitochondrial machinery that drives various immune responses.

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Section: Metabolic Pathways Are Tightly Controlled In Immune Cellsmentioning

confidence: 99%

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

et al. 2018

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“…Mutations of isocitrate dehydrogenase 1 (IDH1) and rarely of isocitrate dehydrogenase 2 (IDH2), are driver mutations of low-grade glioma and secondary glioblastoma (GBM) 13 , 14 and associated with both seizures and better outcome. The molecular mechanism of the strong and reproducible association of IDH1 mutations and epileptic seizures remains unclear 15 – 17 . Chen et al .…”

Section: Introductionmentioning

confidence: 99%

Aberrant neuronal differentiation is common in glioma but is associated neither with epileptic seizures nor with better survival

Beier

Rasmussen

Dahlrot

et al. 2018

Sci Rep

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The mechanisms of glioma-associated seizures (GAS) have yet to be fully elucidated. Proneural subtype, isocitrate dehydrogenase 1 (IDH1) mutations, and epileptic seizures are closely associated suggesting that aberrant neuronal differentiation contributes to glioma-associated seizures. In a population-based cohort (n = 236), lack of stem cell marker expression (nestin, musashi) was significantly associated with IDH1 mutations and GAS at diagnosis. In vitro data suggested an association of IDH1 mutations and a more differentiated phenotype. Out of eight glioma stem cell (GSC) lines, seven revealed positivity for the synaptic marker protein synaptophysin. Three had synapse-like structures identified by electron microscopy and were either vGlut1 (glutamatergic) or GAD67 (GABAergic) positive. In vivo, >10% synaptophysin-positive tumour cells were present in >90% of all gliomas. Synaptophysin expression was associated with proneural subtype and vGlut1 expression, suggesting that most synapse-like structures in glioma are glutamatergic. However, we found null associations between vGlut1 protein/mRNA expression and survival, GAS at onset, development of GAS after resection, and refractory GAS. Synapse-like structures were neither functional nor activated by spontaneous action potentials or cellular networks. Thus, aberrant neuronal differentiation including glutamatergic synapse-like structures is detectable in glioma but is associated neither with epileptic seizures nor with better survival.

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“…In our cohort of Grade III gliomas, SP was more common in IDH1mut tumors. In contrast, Phan's systematic review found near equal proportions of IDH1mut and IDH1wt in grade III SP 19 .…”

Section: Tumor Pathologymentioning

confidence: 79%

“…SP was significantly associated with increased OS independent of age, sex, tumor location, and size in the systematic review of Phan 2018 19 . However, we and others found that OS was not dependent on clinical seizure presentation 10,29,30 despite smaller tumor size in the SP group.…”

Section: Overall Survivalmentioning

confidence: 92%

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Sex Differences in Predictors of Seizure in Contrast-Enhancing Gliomas at Clinical Presentation: A Network Approach

Johnston

Khurana

Whitmire

et al. 2019

Preprint

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BackgroundBrain tumor related epilepsy (BTE) is a major co-morbidity related to the management of patients with brain cancer. Despite published practice guidelines recommending against anti-epileptic drug (AED) utilization in patients with gliomas, there is heterogeneity in prescription practices of AEDs in these patients. In an attempt to impact BTE management, we statistically analyzed clinically relevant attributes (sex, age, tumor size, tumor growth kinetics, and tumor location) pertaining to seizure at presentation and used them to build a computational machine learning model to predict the probability of a seizure (at presentation). Methods From our clinical data repository, we identified 223 patients (females, n=86; males, n=137) with pathologicallydetermined glioma and known seizure status at clinical presentation. Non-parametric and Fisher's Exact tests were used to identify statistical differences in clinical characteristics. We utilized a random forest machine learning method for generating our predictive models by entire cohort and separated by male and female. Findings Patients were divided into those that presented with seizure (SP, n=96, 43%; F, n= 28; M, n= 68) and those that presented without seizure (nSP, n=127, 57%, F n=58, M n=69). Females presented with seizures significantly less often than males (x 2 =6·28, p=0·01). SP patients had significantly smaller T1Gd radius compared to nSP (SP 11·30mm, nSP 18.66mm, p<0·0001). Tumor size and patient age were significant negative predictors for SP; patients with larger tumors, older age and less tumor diffusivity (p/D) were at lower risk for SP. Interpretation Despite heterogeneity across our patient cohort, there is strong evidence of a role for patient sex, tumor size, tumor invasion, and patient age in predicting the incidence of seizures at diagnosis. Future studies, with prospectively detailed data collection, may provide clearer insights into the incidence of seizures through a patient's treatment course.

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Association Between IDH1 and IDH2 Mutations and Preoperative Seizures in Patients with Low-Grade Versus High-Grade Glioma: A Systematic Review and Meta-Analysis

Cited by 41 publications

References 22 publications

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism

Aberrant neuronal differentiation is common in glioma but is associated neither with epileptic seizures nor with better survival

Sex Differences in Predictors of Seizure in Contrast-Enhancing Gliomas at Clinical Presentation: A Network Approach

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