Mutating Our Understanding of Brain Tumors and Seizures: Entrez IDH.
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ABSTRACT:
SUBMITTER: Lee JW
PROVIDER: S-EPMC5706359 | biostudies-literature | 2017 Nov-Dec
REPOSITORIES: biostudies-literature
Publications
Mutating Our Understanding of Brain Tumors and Seizures: Entrez IDH.
Epilepsy currents 20171101 6
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Project description:BackgroundMany low-grade gliomas (LGG) harbor isocitrate dehydrogenase (IDH) mutations. Although IDH mutation is known to be epileptogenic, the rate of refractory seizures in LGG with IDH mutation vs wild-type had not been previously compared. We therefore compared seizure pharmacoresistance in IDH-mutated and wild-type LGGs.MethodsSingle-institution retrospective study of patients with histologic proven LGG, known IDH mutation status, seizures, and ≥2 neurology clinic encounters. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥2 changes in anti-epileptic drugs were considered pharmacoresistant. Incidence rates of pharmacoresistant seizures were estimated using competing risks methodology.ResultsOf 135 patients, 25 patients (19%) had LGGs classified as IDH wild-type. Of those with IDH mutation, 104 (94.5%) were IDH1 R132H; only 6 were IDH2 R172K. 120 patients (89%) had tumor resection, and 14 (10%) had biopsy. Initial post-surgical management included observation (64%), concurrent chemoradiation (23%), chemotherapy alone (9%), and radiotherapy alone (4%). Seizures became pharmacoresistant in 24 IDH-mutated patients (22%) and in 3 IDH wild-type patients (12%). The 4-year cumulative incidence of intractable seizures was 17.6% (95% CI: 10.6%-25.9%) in IDH-mutated and 11% (95% CI: 1.3%-32.6%) in IDH wild-type LGG (Gray's P-value = .26).Conclusions22% of the IDH-mutated patients developed pharmacoresistant seizures, compared to 12% of the IDH wild-type tumors. The likelihood of developing pharmacoresistant seizures in patients with LGG-related epilepsy is independent to IDH mutation status, however, IDH-mutated tumors were approximately twice as likely to experience LGG-related pharmacoresistant seizures.
| S-EPMC8557671 | biostudies-literature
Project description:PurposeMost patients with Lower Grade Gliomas (LGG) present with epileptic seizures. Since the advent of molecular diagnostics, more homogenous sub-entities have emerged, including the isocitrate dehydrogenase-mutated (IDH-mutated) astrocytomas and 1p19q-codeleted oligodendrogliomas. We aimed to describe the occurrence of seizures in patients with molecularly defined LGG pre- and postoperatively and to analyze factors affecting seizure status postoperatively.MethodsA population-based cohort of 130 adult patients with IDH-mutated WHO grade 2 or 3 astrocytomas and oligodendrogliomas was assessed pertaining to seizure burden before and after surgery.ResultsFifty-four (79.4%) patients with astrocytoma and 45 (72.6%) patients with oligodendroglioma had a history of seizures before surgery. At 12 months postoperatively, 51/67 (76.1%) patients with astrocytoma and 47/62 (75.8%) patients with oligodendrogliomas were seizure free. In a multivariable logistic regression analysis, lower extent of resection (EOR) (OR 0.98; 95% CI 0.97-1.00, p = 0.01) and insular tumor location (OR 5.02; 95% CI 1.01-24.87, p = 0.048) were associated with presence of seizures within 1 year postoperatively in the entire LGG cohort. In sub-entities, EOR was in a similar manner associated with seizures postoperatively in astrocytomas (OR 0.98; 95% CI 0.96-0.99, p < 0.01) but not in oligodendrogliomas (p = 0.34).ConclusionOur results are well in line with data published for non-molecularly defined LGG with a large proportion of patients being seizure free at 1 year postoperative. Better seizure outcome was observed with increased EOR in astrocytomas, but this association was absent in oligodendrogliomas.
| S-EPMC9722876 | biostudies-literature
Project description:Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH-wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d-2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.
| S-EPMC10266777 | biostudies-literature
Project description:BackgroundSeizures are a common presenting sign in dogs with brain tumors.Hypothesis/objectivesTo investigate the effect of radiotherapy on freedom from brain tumor-associated seizures and survival time in dogs.AnimalsThirty-two client-owned dogs with brain tumor-associated seizures; 18 received medical treatment and radiotherapy, 14 received medical treatment alone.MethodsMulticenter retrospective study. Baseline characteristics (seizure semiology, magnetic resonance imaging [MRI] characteristics, and treatment) and duration of seizure freedom were recorded for the 2 treatment groups. Duration of seizure freedom between groups was compared (log-rank test) using Cox's proportional hazard analysis, with baseline characteristics entered as covariates.ResultsThe duration of seizure freedom and survival time were significantly longer in the radiotherapy group (P < .001), with a mean of 24 months (95% confidence interval [CI], 14.3-33.8) versus 1.7 months in the control group (95% CI, 0.5-2.9) and a mean of 34.6 months (95% CI: 25.2-44.1) versus 6.2 months in the control group (95% CI, 2.6-9.7) respectively. Baseline characteristics were not associated with duration of seizure freedom after the start of treatment. In the radiotherapy group, 5 dogs were euthanized during the study period because of causes other than seizures. In the control group, recurrence of seizures was observed before death in all dogs.Conclusions and clinical importanceA longer period of seizure freedom and longer survival time was observed in dogs with brain tumors after radiotherapy compared to medical treatment only. The pathophysiological mechanisms of epileptogenesis and the effect of radiation therapy on seizure control are unclear to date. Further prospective studies are needed.
| S-EPMC7096644 | biostudies-literature
Project description:BackgroundIsocitrate dehydrogenase (IDH)-mutant tumors exhibit an altered metabolic state and are critically dependent upon nicotinamide adenine dinucleotide (NAD+) for cellular survival. NAD+ steady-state levels can be influenced by both biosynthetic and consumptive processes. Here, we investigated activation of sirtuin (SIRT) enzymes, which consume NAD+ as a coenzyme, as a potential mechanism to reduce cellular NAD+ levels in these tumors.MethodsThe effect of inhibition or activation of sirtuin activity, using (i) small molecules, (ii) clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 gene editing, and (iii) inducible overexpression, was investigated in IDH-mutant tumor lines, including patient-derived IDH-mutant glioma lines.ResultsWe found that Sirt1 activation led to marked augmentation of NAD+ depletion and accentuation of cytotoxicity when combined with inhibition of nicotinamide phosphoribosyltransferase (NAMPT), consistent with the enzymatic activity of SIRT1 as a primary cellular NAD+ consumer in IDH-mutant cells. Activation of Sirt1 through either genetic overexpression or pharmacologic Sirt1-activating compounds (STACs), an existing class of well-tolerated drugs, led to inhibition of IDH1-mutant tumor cell growth.ConclusionsActivation of Sirt1 can selectively target IDH-mutant tumors. These findings indicate that relatively nontoxic STACs, administered either alone or in combination with NAMPT inhibition, could alter the growth trajectory of IDH-mutant gliomas while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.
| S-EPMC7850026 | biostudies-literature
Project description:BackgroundAlthough IDH-mutant tumors aggregate to the frontotemporal regions, the clustering pattern of IDH-wildtype tumors is less clear. As voxel-based lesion-symptom mapping (VLSM) has several limitations for solid lesion mapping, a new technique, whole-lesion phenotype analysis (WLPA), is developed. We utilize WLPA to assess spatial clustering of tumors with IDH mutation from The Cancer Genome Atlas and The Cancer Imaging Archive.MethodsThe degree of tumor clustering segmented from T1 weighted images is measured to every other tumor by a function of lesion similarity to each other via the Hausdorff distance. Each tumor is ranked according to the degree to which its neighboring tumors show identical phenotypes, and through a permutation technique, significant tumors are determined. VLSM was applied through a previously described method.ResultsA total of 244 patients of mixed-grade gliomas (WHO II-IV) are analyzed, of which 150 were IDH-wildtype and 139 were glioblastomas. VLSM identifies frontal lobe regions that are more likely associated with the presence of IDH mutation but no regions where IDH-wildtype was more likely to be present. WLPA identifies both IDH-mutant and -wildtype tumors exhibit statistically significant spatial clustering.ConclusionWLPA may provide additional statistical power when compared with VLSM without making several potentially erroneous assumptions. WLPA identifies tumors most likely to exhibit particular phenotypes, rather than producing anatomical maps, and may be used in conjunction with VLSM to understand the relationship between tumor morphology and biologically relevant tumor phenotypes.
| S-EPMC8367280 | biostudies-literature
Project description:To investigate the peri-tumoral effect of IDHmut vs IDHwt glioma, we engrafted IDHmut or IDHwt mouse glioma intracranially in C57BL/6 mice.
2024-04-21 | GSE227995 | GEO
Project description:This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.
| 92735 | ecrin-mdr-crc
Project description:Glioma is the most common malignant tumor in the central nervous system (CNS). Lower-grade gliomas (LGG) refer to Grade II and III gliomas. In LGG patients, seizure often appears as an initial symptom and play an important role in clinical performance and quality of life of the patients. To date, the relationship between the onset of seizures and the molecular pathology in gliomas is still poorly investigated. In this study, we investigate the potential relationship between isocitrate dehydrogenase (IDH)/telomerase reverse transcriptase promoter (TERTp) mutations and preoperative seizures in patients with LGG. 289 adult LGG patients were enrolled in this study. Data of clinical characteristics and molecular pathology were acquired. Sanger sequencing was used to detect IDH/TERTp mutations. Chi-square test was performed to determine if the IDH/TERTp mutations were associated with seizures and seizure types. In 289 LGG patients, preoperative seizures accounted for 25.3% (73/289), IDH mutations accounted for 34.3%(99/289), and TERTp mutations accounted for 44.3% (128/289). The correlation analysis demonstrated that IDH mutation is a significant factor influencing the occurrence of tumor-related epilepsy (P <.001, chi-square test). On the other hand, the statistical analysis revealed no significant correlation between TERTp mutations and seizure in LGG patients (P = .102, chi-square test). The tumor-related epilepsy rates vary among different subgroups according to IDH/TERTp mutations. However, there is no definite correlation between the IDH (P = 1.000, chi-square test)/TERTp (P = .613, chi-square test) mutations and the types of epileptic seizure. IDH mutations are more common in preoperative LGG patients with epileptic symptoms, suggesting that this mutation is positively correlated with seizures. However, there was no significant correlation between TERTp mutations and seizures. Different molecular pathologic types based on IDH/TERTp have different incidences of tumor-associated epilepsy in LGGs.
| S-EPMC6320119 | biostudies-literature
Project description:BackgroundSleep is an important element in health-related quality of life of cancer patients and caregivers. This study aimed to explore the experience of sleep disturbance in people with malignant brain tumors (BT) and their family caregivers.MethodsParticipants were recruited from ambulatory neuro-oncology clinics. Semi-structured interviews were conducted with 24 patients (67% with high-grade gliomas) and 14 caregivers. Data were analyzed thematically using a framework synthesis.ResultsWe identified six themes relating to perceptions of the nature, impact, causal factors, and interventions for sleep disturbance, beliefs about sleep and impact, and personal coping strategies. Participants described their sleep disturbance in terms of insomnia symptoms; most commonly difficulties initiating and maintaining sleep. Participants had varied views on causal factors including the BT diagnosis and treatment and caregiver burden. However, excessive thinking and BT-related anxiety were evident in both patients and caregivers. The described impact on daytime functioning due to non-restful sleep and fatigue appeared to be significant and many participants needed daytime naps, although they understated the impact on individual functioning. Some participants were reluctant to seek help from clinicians for sleep disturbance due to previous experiences where sleep disturbance was overlooked, or because they held negative views toward pharmacological interventions. Participants reported various coping strategies, ranging from relaxation-promoting techniques to behaviors to distract thinking at night that may instead disturb sleep.ConclusionsPsychological factors contribute to sleep disturbance in patients with BT and caregivers. This population may benefit from information about sleep disturbance and interventions targeting anxiety.
| S-EPMC8049408 | biostudies-literature