IDH1 and IDH2 mutations in postoperative diffuse glioma-associated epilepsy

ObjectiveIsocitrate dehydrogenase 1 and 2 mutations (IDH1/2) have an established association with preoperative seizures in patients with grades II–IV diffuse gliomas. Here, we examined if IDH1/2 mutations are a biomarker of postoperative seizure frequency.MethodsThis was a retrospective study. Patients with grades II–IV supratentorial diffuse glioma, immunohistochemistry results of IDH1-R132H, and antiepileptic drug (AED) prescribed postoperatively were included. The primary outcome was seizure frequency over the first 12 postoperative months: Group A — postoperative seizure freedom; Group B — 1–11 seizures over 12 months (less than one seizure per month); and Group C — greater than one seizure per month. Rates of IDH1-R132H mutation were compared between the three outcome groups in univariate and multivariate analyses. Subgroup analysis was performed in 64 patients with IDH1/2 pyrosequencing data.ResultsOne hundred cases were included in the analysis: 30.0% grade II, 20.0% grade III, and 50.0% grade IV gliomas. Group B patients averaged 1 seizure over 12 months, compared with 2 seizures per month in Group C. Isocitrate dehydrogense 1-R132H mutation was present in 29.3% (17/58) of Group A, 18.2% (14/22) of Group B, and 70.0% (14/20) of Group C patients (p = 0.001). On multivariate analysis, after controlling for preoperative seizure, grade, and temporal tumor location, IDH1-R132H was associated with Group C when compared with both Group A (RR 4.75, p = 0.032) and Group B (RR 9.70, p = 0.012). In the subgroup with IDH1/2 molecular data, an IDH1/2 mutation was present in 64.7% (22/34) of Group A, 28.6% (4/14) of Group C, and 87.5% (14/16) of Group C patients (p = 0.004).SignificanceIn patients with supratentorial diffuse gliomas, IDH1-R132H mutations are associated with a more severe phenotype of postoperative epilepsy. These findings support further research into IDH mutations, and the potential for an antiepileptic therapeutic effect of their inhibitors, in patients with glioma-associated epilepsy.     

Evaluating angioarchitectural characteristics of glial and metastatic brain tumors with conventional magnetic resonance imaging

Primary and metastatic brain tumors can overlap in traditional imaging features detected on preoperative conventional magnetic resonance imaging (MRI). The research objective was to determine whether morphological vascular characteristics present in routine preoperative imaging using traditional MRI sequences are predictive of primary versus metastatic brain tumors; secondarily to determine association of conventional and vascular-related imaging parameters with intraoperative blood loss, pathological invasion, and World Health Organization (WHO) tumor grade. A retrospective review analyzed 100 consecutive intracranial tumor surgeries, 50 WHO grade II-IV gliomas and 50 intracranial metastases. Two blinded expert readers independently evaluated preoperative MRIs, obtained via standard morphological imaging sequences, for adjacent or intra-tumoral arterial aneurysm, peritumoral venous ectasia, prominence, or engorgement (“aberrant peritumoral vessels”), and prominent intra-tumoral flow voids. Multivariate analysis was performed to develop models predictive of glioma and glioblastoma (GBM). Aberrant peritumoral vessels and prominent intra-tumoral flow voids were statistically significant predictors of glioma in univariate analyses (p = 0.048, p = 0.001, respectively) and when combined in multivariate analysis (OR = 5.23, p = 0.001), particularly for GBM (OR = 9.08, p < 0.001). Multivariate modeling identified prominent intra-tumoral flow voids and FLAIR invasion as the strongest combined predictors of gliomas and GBM. Aberrant peritumoral vessels and larger tumor volume predicted higher intraoperative blood loss in all analyses. No vascular-related parameters predicted pathological invasion on multivariate analysis. Aberrant peritumoral vessels and prominent intra-tumoral flow voids were predictive of gliomas, specifically GBM. These vascular characteristics, evaluated on routine clinical preoperative MRI imaging, may aid in distinguishing glioma from brain metastases and may predict intraoperative blood loss.     

Overexpression of tissue microRNA10b may help predict glioma prognosis

We investigated the relationship between microRNA-10b (miR-10b) expression and prognosis in human glioma patients. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to characterize the expression patterns of miR-10b in 128 glioma and 20 normal brain tissues. Clinical information – age, sex, Karnofsky Performance Status (KPS) and World Health Organization (WHO) grade – were also collected. The associations between miR-10b expression and the clinicopathological factors and outcome of glioma patients were statistically analyzed. Expression levels of miR-10b in glioma tissue were significantly higher than in normal brain tissue (P < 0.001). High-grade glioma (WHO grade III and IV) had much higher miR-10b expression levels than low-grade tumors (WHO grade I and II). Additionally, the increased miR-10b expression in the glioma tissues was significantly associated with a low KPS (P = 0.03). Kaplan–Meier survival curves and Cox regression analyses showed that overexpression of miR-10b (P = 0.01) and high grade (P = 0.02) were independent factors predicting poor outcome for glioma patients. Furthermore, subgroup analyses showed that the miR-10b expression level was significantly associated with poor overall survival in glioma patients with high grades (P < 0.001). Up-regulation of miR-10b may have value in predicting clinical outcome in glioma patients, particularly for those with high pathological grades.     

Hippocampal-sparing radiotherapy: The new standard of care for World Health Organization grade II and III gliomas?

The neurocognitive effects of cranial radiotherapy in patients with gliomas are well-recognised and may be related to the dose delivered to the hippocampi. Intensity modulated radiotherapy (IMRT) is a radiotherapy technique that can be used to selectively spare the hippocampi without compromising the dose delivered to the tumour. This study aimed to evaluate if hippocampal-sparing IMRT is achievable in patients with World Health Organization (WHO) grade II and III gliomas. A retrospective review of consecutive patients with WHO grade II and III gliomas treated with IMRT at our institution between January 2009 and August 2012 was performed. Hippocampal-sparing was defined as a mean dose to at least one hippocampus of less than 30 Gy. The dose delivered to the tumour was never compromised to achieve the hippocampal dose constraint. Logistic regression analyses were performed to identify predictive factors for achieving hippocampal-sparing treatment. Eighteen patients were identified and hippocampal-sparing was achieved in 14 (78%). The median dose prescribed was 59.4 Gy in 33 fractions and 11 patients had WHO grade III gliomas. The mean dose to the contralateral hippocampus was 24.9 Gy. Planning target volumes less than 420.5 cm³ were more likely to enable hippocampal-sparing treatment to be given (hazard ratio 1.7, p = 0.03) and there was a trend with oligodendrogliomas and anaplastic oligodendrogliomas. Hippocampal-sparing radiotherapy is feasible in patients with WHO grade II and III gliomas. Oncologic outcomes are yet to be assessed prospectively. The relationship between hippocampal dose and neurocognitive function in adults is currently under investigation.     

KPNA2 predicts long term survival in patients with anaplastic oligoastrocytomas

The family of karyopherins comprises importins and exportins which are both involved in nucleocytoplasmic shuttling. Increased levels of karyopherin a2/importin 1 (KPNA2) and chromosome region maintenance protein 1/exportin 1 (CRM1) have been associated with poorer prognosis in patients with infiltrative astrocytomas. Isocitrate dehydrogenase 1 gene (IDH1) R132H mutation status was also recently identified as a prognostic factor for malignant gliomas. We evaluated KPNA2 and CRM1, as well as the IDH1 mutation status, as possible novel biomarkers for World Health Organization grade III anaplastic oligoastrocytomas (AOA). We analyzed nuclear expression of KPNA2 by immunohistochemistry in 72 primary anaplastic gliomas (29 AOA, 24 anaplastic astrocytomas, 19 anaplastic oligodendrogliomas). The IDH1 mutation status was also determined in patients with anaplastic astrocytomas and AOA, and AOA patients were additionally evaluated for CRM1 nuclear expression. Long term survivors (LTS; >8 years) with AOA showed lower KPNA2 expression levels compared to non-LTS (p = 0.005). KPNA2 expression (⩾5% versus <5%, 1–<5%, median) was found to correlate inversely with overall survival (OS) and progression-free survival (PFS) in our overall series as well as in the AOA group (anaplastic gliomas: OS p = 0.017; PFS p = 0.033; AOA: OS p = 0.017, PFS p = 0.040). Mutant IDH1-R132H was detected in 69% of the AOA cohort; a combination of KPNA2 low expression and mutant IDH1-R132H was only seen in LTS (p = 0.050). No differences between the histological subtypes were observed in terms of KPNA2 expression and IDH1-R132H mutation status. To our knowledge this is the first time it has been shown that KPNA2 expression may have potential as a prognostic biomarker for AOA as well.     

IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom

IntroductionSeizures are the most common initial symptom in patients with low-grade glioma and their occurrence strongly depends on the tumor location. The majority of low-grade gliomas reveal mutations in the genes encoding isocitrate-dehydrogenase 1 (IDH1) or 2 (IDH2). These mutations are associated with metabolic changes that are potentially epileptogenic. We investigated the correlation between IDH1/2 mutations and tumor localization and seizure as the initial symptom.Materials and methodsThis retrospective study included patients with a diagnosis of WHO grade II astrocytoma and cortical infiltration and in whom initial symptoms were documented and biopsy tissue was available for IDH1/2 analysis. IDH1/2 mutation analysis was performed by direct sequencing or by immunohistochemistry with an antibody which detects mutated protein IDH1 R132H. Sequencing was carried out if immunohistochemistry was negative. IDH1/2 status was defined as mutated if either of these investigations were positive.ResultsSeventy-nine patients were included. IDH1 or IDH2 mutation was present in 63 (80%) patients who on average were younger than patients without IDH1/2 mutation (40 vs. 47 years, p = 0.0331, t-test). IDH1/2 mutations were associated with frontal tumor location (p = 0.0202). All 12 tumors in the insula revealed IDH1/2 mutations. Seizure as the initial symptom was recorded in 57 (72%) patients and was associated with IDH1 or IDH2 mutation by multivariate analysis (OR 22.563, p = 0.0019).ConclusionIn WHO grade II astrocytomas, IDH1/2 mutations mostly occur in tumors infiltrating the frontal lobe. Seizure as the initial symptom is associated with IDH1 or IDH2 mutation.     

Ki-67 overexpression in WHO grade II gliomas is associated with poor postoperative seizure control

PurposeSeizures are the most common initial symptom in patients with low-grade gliomas, and approximately 30% of these patients still suffer from epilepsy after gross-total resection of the tumour. We examined the relationship between the overexpression of ki-67 in WHO grade II gliomas and seizure control.MethodsA series of 93 histologically confirmed WHO grade II glioma tissues were analysed through immunohistochemical staining for ki-67 expression. Follow-up visits regarding seizure control were scheduled at 12 months. The Engel classification was used to categorise patients’ seizure status.ResultsOf the 93 patients analysed, 65 (66.3%) patients initially presented with seizures. A total of 36 patients were diagnosed with WHO grade II oligodendrogliomas, 29 patients had oligoastrocytomas and 28 patients had astrocytomas. Ki-67 was over-expressed in 15 patients. One year after surgery poor seizure control was observed in 11 of these patients. In contrast, low ki-67 expression (<10%) was found in 78 patients. Poor seizure control was observed in 36 patients (difference between ki-67 over- and low expression groups P = 0.002). Logistic regression analysis revealed that patients with gross-total resection achieved better seizure control while ki-67 overexpression and age below 38 years were poor seizure control factors explained of the variance of seizure outcome (OR: 0.382, 4.354 and 1.822, respectively).ConclusionsIn WHO grade II gliomas, Ki-67 is a molecular marker which predicts poor seizure control of glioma patients after the resection of the tumour. Gross-total resection, ki-67 overexpression and age below 38 years significantly affect seizure prognosis.     

Reliability of noncontrast-enhancing tumor as a biomarker of IDH1 mutation status in glioblastoma

Isocitrate dehydrogenase 1 (IDH1) mutations in gliomas have been associated with a frontal lobe location and a greater proportion of noncontrast-enhancing tumour (nCET). The purpose of our study was to validate the utility of MRI imaging features in predicting IDH1 mutations in glioblastomas. Pre-operative MRIs of new glioblastoma patients, consisting of at least FLAIR and T1-weighted post-contrast sequences, were reviewed by a neuroradiologist based primarily on the VASARI feature set. IDH1 mutation testing was performed on all patients using immunohistochemistry. 153 patients met the inclusion criteria, of whom five had IDH1 mutations (3.3%). A frontal lobe location had equivalent frequency in both the IDH1-mutated and IDH1-wildtype cohorts (p = 1.000). Three (60%) of the IDH1-mutated tumours had >33% nCET, compared to 21% of IDH1-wildtype (p = 0.073). 12 tumours had a frontal lobe epicentre and >33% nCET, all being IDH1-wildtype. All five IDH1-mutated tumours had either a frontal lobe epicentre or >33% nCET, but none had both these features. Our results question the strength of the association between frontal lobe glioblastomas with substantial nCET and IDH1 mutations, as these features are also relatively frequent in IDH1-wildtype tumours, which are much more common. MRI is thus more useful for ruling out an IDH1 mutation rather than strongly suggesting its presence: if a particular glioblastoma does not have a frontal lobe epicentre and has less than 33% nCET, it can be predicted to be IDH1-wildtype with a high degree of confidence.     

BRAF V600E mutation is a significant prognosticator of the tumour regrowth rate in brainstem gangliogliomas

BRAF V600E mutations are progression factors in paediatric low-grade gliomas. Furthermore, a high percentage of paediatric brainstem gangliogliomas have BRAF V600E mutations. However, their clinical significance, including possible connections between the biomarkers and ganglioglioma’s clinical features, especially a brainstem counterpart, is unclear. To identify potential molecular features predictive of brainstem ganglioglioma’s clinical outcomes, a retrospective cohort of 28 World Health Organization (WHO) grade I brainstem gangliogliomas was analysed for BRAF V600E, IDH1 R132H, and IDH2 R172K mutations, TERT C228T/C250T promoter mutation, H3F3A K27M mutation and MGMT methylation. The volume of tumours was calculated accurately by using 3D Slicer software. The clinical data of these patients were retrospectively analysed. In tumours with BRAF V600E mutations, the tumour regrowth rate was significantly faster than that of the wild type group (p = 0.001). Moreover, the BRAF V600E mutant group had shorter progression-free survival (PFS) compared with wild type (p = 0.012). On multivariate analysis, no factor was found to be an independent prognostic factor; however, tumours with faster regrowth rates had a strong trend towards an increased risk for shorter PFS (HR = 1.027, p = 0.056). No statistical analysis could be performed to evaluate factors affecting overall survival (OS). These data suggest that BRAF V600E can predict the regrowth rate of brainstem gangliogliomas after microsurgery, and a BRAF V600E-targeted therapeutic may be a promising early intervention measure for patients who harbour BRAF V600E mutation after microsurgery.     

Downregulation of chromatin remodeling factor CHD5 is associated with a poor prognosis in human glioma

Chromodomain helicase DNA-binding protein 5 (CHD5), a member of the CHD family, is involved in key cellular processes including chromatin remodeling, cell cycle regulation, and cellular adhesion. Recent studies have demonstrated that CHD5 is the product of a novel tumor suppressor gene and is implicated in certain tumor types. However, the clinicopathological significance of CHD5 expression in human malignant gliomas remains unclear. To address this problem, CHD5 expression in human gliomas and non-neoplastic brain tissues was measured using real-time quantitative polymerase chain reaction (RT–PCR) assay, Western blot, and immunohistochemistry. The association of CHD5 immunostaining with clinicopathological factors or prognosis of glioma patients was statistically analyzed. Genetic and protein expression of CHD5 were downregulated in glioma tissues compared to corresponding non-neoplastic brain tissues (both p < 0.001). Additionally, decreased expression of CHD5 in glioma was significantly associated with pathological grade (p = 0.007); high pathological grade was associated with low CHD5 expression. Loss of CHD5 protein expression was also significantly correlated with a low Karnofsky performance scale score (p = 0.01). Moreover, overall survival of patients with low CHD5 protein expression was dramatically shorter than those of patients with high CHD5 protein expression (p = 0.003). Multivariate Cox regression analysis indicated that CHD5 expression was an independent prognostic factor for patients with gliomas (p = 0.01). In conclusion, these data offer convincing evidence for the first time that CHD5 might act as a tumor suppressor in glioma, may act as a regulator of aggressive development, and is a candidate prognostic marker for this malignancy.     

Symptom resolution in infiltrating WHO grade II-IV glioma patients undergoing surgical resection

Past studies of morbidity in patients with infiltrating gliomas have focused on the impact of surgery on quality of life. Surprisingly, little attention has been given to the rate at which the presenting symptoms improve after surgery, even though this is often the patient’s first concern. This study is an initial effort to provide useful information about symptom resolution and factors predicting persistence of symptoms in glioma patients who undergo surgery. We conducted a retrospective analysis on patients who underwent surgery for World Health Organization (WHO) grade II-IV astrocytoma/oligodendroglioma/oligoastrocytoma at our institution. All patients were seen 2–4 months postoperatively, and asked about the persistence of symptoms they experienced preoperatively. Symptoms reported in clinic were assessed against symptoms reported prior to surgery. Our study includes 56 consecutive patients undergoing surgery for gliomas. Of patients who experienced symptoms initially, headache resolved in 18/27 postoperatively, weakness resolved in 8/14 postoperatively, altered mental status resolved in 8/12 postoperatively, vision problems resolved in 7/11 postoperatively, nausea resolved in 5/7 postoperatively, and ataxia resolved in 4/5 postoperatively. Headache was more likely to resolve in patients with frontal or temporal tumors (p = 0.02). Preoperative Karnofsky Performance Scale (KPS) of 70 or less was associated with longer postsurgical hospital stay (p < 0.01). Younger patients were more likely to experience a resolution of altered mental status (p = 0.04). Our analysis provides data regarding the rate at which surgery alleviates patient symptoms and considers variables predicting likelihood of symptom resolution. Some patients will experience symptom resolution following resection of WHO grade II-IV gliomas in the months following surgery.     

Outcome of resection of WHO Grade II meningioma and correlation of pathological and radiological predictive factors for recurrence

This study investigated whether extent of surgical resection (Simpson and Shinshu grade) along with pathological and radiological factors influence the tumor control and recurrence-free survival (RFS) of patients with World Health Organization (WHO) grade II meningiomas. The clinical, radiological and surgical notes on the 59 patients with WHO grade II meningioma managed at our institution over 20 years were retrospectively reviewed. In this study, median survival time was 41 months. The overall recurrence rate in Simpson grades I and II resection was 31%. In grades III and IV, the overall recurrence rate was 73%, and this high recurrence rate in these groups was confined within 5 years. In Cox regression analysis, combined data of grades (I and II)/complete resection showed a significant difference in RFS compared to grades (III and IV)/subtotal resection (p = 0.0001). A similar trend of RFS (p = 0.0001) was observed with the Shinshu grading system of resection. In addition, a Ki-67% marker for proliferation less than 15% (p = 0.029), absence of certain radiological features including heterogeneous enhancement, cyst formation and peritumoral edema (p = 0.006), and repeat surgery for recurrent meningioma was associated with better survival (p = 0.014). However, radiosurgery did not have a beneficial role in the treatment of recurrence of atypical meningioma. The Simpson grading system is the primary predictor of recurrence of WHO grade II meningioma after resection. In addition, certain pathological and radiological features need to be considered as possible factors of recurrence after resection. Lastly, depending on the likely risks and surgical morbidity, repeat surgical resection should be performed for recurrent atypical meningioma.     

Spinal ependymomas: Benefits of extent of resection for different histological grades

Although the World Health Organization (WHO) categorizes spinal ependymomas into three histological grades, difference in surgical outcomes between WHO grades I and II tumors are unclear. For these benign tumors, prognosis may be best determined by factors other than tumor grade alone, such as extent of resection. To analyze the effects of the extent of resection on different grades of spinal ependymomas, we performed a comprehensive literature review to identify adult spinal ependymoma patients who received surgical resection with a clearly identifiable WHO grade. A total of 175 patients were identified. While grade III tumors carried the worst prognosis as expected (p < 0.001), grade I and II tumors did not differ significantly in outcomes following surgery. Overall, gross total resection (GTR, 68.7%, 114/166) provided significantly improved progression-free survival (PFS, p < 0.001) and overall survival (OS, p = 0.022) compared to the subtotal resection group. Surprisingly, the highest GTR rate was achieved for grade II tumors (78.8%, 78/99; p < 0.001) followed by grade I (58.9%, 33/56) and grade III tumors (27.3%, 3/11). Interestingly, PFS was significantly improved by GTR for grade II tumors (p < 0.001), but not for grade I (p = 0.705). Similar trends, although not statistically significant, were found for OS. Our results show that while GTR provides the best overall outcomes, GTR is most effective for classic grade II ependymomas, but not for grade I ependymomas. Despite having a lower WHO grade, myxopapillary ependymomas have a lower GTR rate, and benefit less from GTR.     

Quality of life,mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group

ObjectiveBrain tumor-related epilepsy (BTRE) is often drug resistant and patients can be forced to take polytherapy that can adversely affect their quality of life (QoL). Lacosamide (LCM) is a new antiepileptic drug (AED) used as adjunctive therapy in patients with partial seizures with or without secondary generalization, with a favorable pharmacokinetic profile that seems to be effective and well tolerated.Therefore it represents a possible therapeutic choice for patients with BTRE. We propose a prospective study with a historical control group to evaluate the effect of LCM as add-on therapy on seizure control and quality of life in patients with BTRE. This study has been designed to test the superiority of Lacosamide over Levetiracetam as an add-on. We compared a prospective cohort of 25 patients treated with Lacosamide with a historical control group (n = 19) treated with Levetiracetam as an add-on.MethodsWe recruited 25 adult patients (M 18, F 7; mean age 41.9) affected by BTRE with uncontrolled partial-onset seizures treated with AED polytherapy. We added LCM as an add-on. Patients were evaluated at baseline, after 3 months and at 6 months.This population has been compared with a historical control group of 19 BTRE adult patients (M 13, F 6; median age 48.0, range: 28–70) with uncontrolled partial-onset seizures treated with LEV as add-on.The patients underwent QoL, mood and adverse events tests (Adverse Event Profile-AEP) and evaluation of seizure frequency.ResultsTwelve patients had high grade gliomas, and thirteen had low grade gliomas. During follow-up, thirteen patients underwent chemotherapy, three radiotherapy and five patients had disease progression. Nine patients had simple partial seizures, eight had complex partial seizures, and eight had secondary generalized seizures. Fifteen patients were in monotherapy and ten in polytherapy with AEDs. LCM was added up to reach the maximum dosage of 400 mg/die (mean final dose 300 mg/die). Four patients dropped out due to poor compliance and 1 for inefficacy.In the historical control group treated with LEV (mean final dose 2000 mg/die) 12 patients had high-grade gliomas, and 7 had low grade gliomas. Thirteen patients were in monotherapy and 6 in polytherapy with AEDs.In the 22 patients evaluable of 25 patients treated with LCM, we observed at final follow-up 7 patients seizure free, 12 with a significant reduction of seizures ≥ 50%, 2 stable and 1 patient with number of seizures increased.Mean seizure frequency at baseline compared with baseline period: the mean number of seizures significantly decreased from baseline (9.4) to final follow-up (1.2) (P = 0.005). The Responder Rate was 86.4%.Comparing responder rate of 22 evaluable patients with LCM with responder rate of 19 patients with LEV we didn't observe significant differences (p = 0.31).In our patients treated with LCM we didn't observe significant difference at 3 and 6 months in QoL tests results; we observe a significant reduction in the mean score of Karnofsky Performance Status (KPS) and Barthel Index (BI) between baseline and 6 months of follow-up (KPS p = 0.003; BI p = 0.007).No clinical side effects were observed.ConclusionComparing the LCM with the historical group treated with LEV in add-on, we observed that LCM seems to have a higher clinical efficacy than LEV.In our patients, we did not observe any significant changes in QoL tests, indicating stability in all quality of life domains explored, despite the objective worsening in their functional status. Although this is a small series with a relatively short follow-up, our data indicates that LCM in add-on in patients with BTRE appears to be as effective as LEV in add-on, without impact on mood and quality of life.     

Primary intracranial haemangiopericytoma: Comparison of survival outcomes and metastatic potential in WHO grade II and III variants

Primary intracranial haemangiopericytomas (HPC) are rare, highly vascular tumours with a high propensity for local recurrence and distant metastasis. Optimal treatment includes maximal surgical resection followed by adjuvant radiotherapy. In 2007, new histopathological grading criteria were introduced to differentiate between high grade (World Health Organization [WHO] grade III) and low grade (WHO grade II) tumours. Given the rarity of this tumour, there is a paucity of information regarding the prognostic significance of histological grade. We conducted a retrospective review of our 20 year experience in treating 27 patients with HPC at our institution. Statistical analysis to compare overall survival, local recurrence rate and metastatic potential between the two grades were conducted using Kaplan–Meier analysis. The estimated median survival for grade II HPC was 216 months and for grade III tumours was 142 months. On multivariate analysis, grade II tumours were associated with better survival than grade III lesions (hazard ratio = 0.16, 95% confidence interval 0.26–0.95; p = 0.044). During the study period, 33% of grade III tumours developed local recurrence compared to 21% of grade II tumours. Metastases were found in 36% of grade II patients and 25% of grade III patients. There was no significant statistical difference in local recurrence rate and metastasis between the two grades. Higher histological grading in HPC is associated with worse overall survival. However based on our series higher histological grading is not associated with higher local recurrence or distant metastatic rates.     

Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas

Somatic mutations in the IDH1 gene encoding cytosolic NADP+-dependent isocitrate dehydrogenase have been shown in the majority of astrocytomas, oligodendrogliomas and oligoastrocytomas of WHO grades II and III. IDH2 encoding mitochondrial NADP+-dependent isocitrate dehydrogenase is also mutated in these tumors, albeit at much lower frequencies. Preliminary data suggest an importance of IDH1 mutation for prognosis showing that patients with anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas harboring IDH1 mutations seem to fare much better than patients without this mutation in their tumors. To determine mutation types and their frequencies, we examined 1,010 diffuse gliomas. We detected 716 IDH1 mutations and 31 IDH2 mutations. We found 165 IDH1 (72.7%) and 2 IDH2 mutations (0.9%) in 227 diffuse astrocytomas WHO grade II, 146 IDH1 (64.0%) and 2 IDH2 mutations (0.9%) in 228 anaplastic astrocytomas WHO grade III, 105 IDH1 (82.0%) and 6 IDH2 mutations (4.7%) in 128 oligodendrogliomas WHO grade II, 121 IDH1 (69.5%) and 9 IDH2 mutations (5.2%) in 174 anaplastic oligodendrogliomas WHO grade III, 62 IDH1 (81.6%) and 1 IDH2 mutations (1.3%) in 76 oligoastrocytomas WHO grade II and 117 IDH1 (66.1%) and 11 IDH2 mutations (6.2%) in 177 anaplastic oligoastrocytomas WHO grade III. We report on an inverse association of IDH1 and IDH2 mutations in these gliomas and a non-random distribution of the mutation types within the tumor entities. IDH1 mutations of the R132C type are strongly associated with astrocytoma, while IDH2 mutations predominantly occur in oligodendroglial tumors. In addition, patients with anaplastic glioma harboring IDH1 mutations were on average 6 years younger than those without these alterations.     

Correlation of preoperative seizures with clinicopathological factors and prognosis in anaplastic gliomas: A report of 198 patients from China

PurposeSeizures are a common manifestation of many diseases and play an important role in the clinical presentation and quality of life (QOL) in patients with gliomas. The purpose of the present study was to investigate the possible correlation between tumor-related seizures and clinicopathological factors that influence preoperative seizure characteristics and relevant survival outcomes.MethodsWe retrospectively investigated the correlation of preoperative seizures with clinicopathological factors and prognosis in a cohort of 198 Chinese patients with anaplastic gliomas. Univariate and multivariate logistic regression analyses were used to identify factors associated with preoperative seizures. Survival function curves were calculated using the Kaplan–Meier method.ResultsOf the 198 patients, 68 (34.3%) patients had preoperative seizures. Among the patients with seizures, 26 (38.2%) had generalized seizures, 38 (55.9%) had simple partial seizures, and four (5.9%) complex seizures. There was a higher proportion of epidermal growth factor receptor (EGFR) amplification, frontal lobe involvement, left cerebral hemisphere involvement, and lower Ki-67 expression in patients with preoperative seizures in both univariate and multivariate analyses. Patients with preoperative seizures had a longer overall survival (OS) time compared with those without (median: 1924 days vs. 923 days, P = 0.048).ConclusionThe current study updates existing information on tumor-related seizures and clinicopathological factors in anaplastic gliomas, and suggests two putative biomarkers for preoperative seizures; Ki-67 expression and EGFR amplification. These factors may provide insights for developing effective treatment strategies aimed at prolonging patient survival.     

IDH1 mutation may not be prognostically favorable in glioblastoma when controlled for tumor location: A case-control study

Isocitrate dehydrogenase 1 (IDH1) mutation is a known prognostic factor in glioblastoma multiforme (GBM). It has been well documented that patients with IDH1 mutant (IDH1-mu) GBM have a better outcome compared to patients with IDH1 wild-type (IDH1-WT) GBM. IDH1-mu tumors have been shown to be more commonly located in the frontal lobe, and less likely to be in multiple lobes. It is unclear whether differential location is part of the prognostically favorable profile of these tumors. We performed a case-control study, matching IDH1-mu GBMs to IDH1-WT GBMs that are controlled for age, sex and tumor location. There were 21 IDH1-mu tumors and 21 matched IDH1-WT tumors. Age, sex and tumor location were matched between the two groups. After controlling for the factors described, the IDH1-mu tumors were more likely to be secondary GBM (61.9% secondary vs. 14.3%, p = 0.004). There was an insignificant trend towards smaller tumor volume in the IDH1-mu group (28.13 ± 6.56 vs. 41.8 ± 7.33 cm³, p = 0.173). Extent of surgical resection was similar in both groups (mean 84.49% vs. 89.89%, p = 0.419). There was no survival advantage for IDH1-mu tumors when controlled for location: 25.2 months overall survival for IDH1-mu patients and 23.6 for IDH1-WT patients, p = 0.794. IDH1 mutation may provide part of its prognostic significance by differential localization of tumor, both making IDH1-mu tumors more amenable to gross total resection and placing these tumors in less eloquent areas, thereby lowering neurological morbidity.