Oligodendroglial Subtype Research Articles

Altered metabolic landscape in IDH‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways

Heterozygous mutations in NADP‐dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D‐2‐hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient‐derived xenografts of IDH‐mutant versus IDH wild‐type glioma to profile the distribution of metabolites at high anatomical resolution in situ. This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography–mass spectrometry (LC‐MS) analysis. Selected metabolites were verified on clinical specimen. Our data identify remarkable differences in the phospholipid composition of gliomas harboring the IDH1 mutation. Moreover, we show that these tumors are characterized by reduced glucose turnover and a lower energy potential, correlating with their reduced aggressivity. Despite these differences, our data also show that D2HG overproduction does not result in a global aberration of the central carbon metabolism, indicating strong adaptive mechanisms at hand. Intriguingly, D2HG shows no quantitatively important glucose‐derived label in IDH‐mutant tumors, which suggests that the synthesis of this oncometabolite may rely on alternative carbon sources. Despite a reduction in NADPH, glutathione levels are maintained. We found that genes coding for key enzymes in de novo glutathione synthesis are highly expressed in IDH‐mutant gliomas and the expression of cystathionine‐β‐synthase (CBS) correlates with patient survival in the oligodendroglial subtype. This study provides a detailed and clinically relevant insight into the in vivo metabolism of IDH1‐mutant gliomas and points to novel metabolic vulnerabilities in these tumors.

P08.62 Salvage chemotherapy with bevacizumab and fotemustine in temozolomide-pretreated patients with recurrent grade III gliomas: a phase II study

AbstractIntroduction:Fotemustine is a nitrosourea with elevated lipophilic properties, that has shown activity as monotherapy in recurrent grade III gliomas, but few data are available on the association with the antiangiogenic drug bevacizumab.Method:From July 2008 to November 2015 we accrued, in this single arm phase II study, patients with an histological diagnosis of grade III glioma (according to WHO, 2007) at relapse after radiotherapy and/or temozolomide and we treated them with a combination of bevacizumab and fotemustine. The primary endpoint was 6-month progression-free survival (PFS-6), while secondary endpoints were overall survival (OS), disease control rate and toxicity.Results:Forty-six patients with grade III glioma (22 astrocytomas, 10 oligodendrogliomas and 14 oligoastrocytomas, 67% MGMT methylated and 30% 1p/19q codeleted) were enrolled. Median age was 45 years and KPS ≥ 90 in 54%. PFS-6, median PFS and OS were 45%, 5 months and 9 months, respectively. Nineteen patients (41%) had already received prior chemotherapy lines and 35% a second surgery before inclusion into the trial. We observed a 95% disease control rate (response or stable disease on MRI) after the induction phase with a neurological improvement in 40% and steroid reduction or withdrawal in 67%. In a preliminary analysis we didn’t observe significant differences in terms of clinical and/or radiological response rate, in PFS or OS according to MGMT methylation and 1p/19q codeletion status. There was a better clinical improvement in oligodendroglial subtype after induction phase (75% of patients), while no differences emerged in radiological disease control rate, PFS6, PFS or OS compared to astrocitary histotype. Survival rates of the whole cohort were 34% at 1 year, 21% at 2 years, 14% at 3 years, 7% at 4 years and 5% at 5 years. The pattern of progression was focal enhancing in 73% of tumors, diffuse non-enhancing (gliomatosis-like) in 12%, multicentric in 10% and local plus leptomeningeal in 5%.Twenty-two percent of patients discontinued fotemustine for grade 3/4 myelotoxicity. We did not observe any additional toxicity from the combination.Conclusions:The combination of bevacizumab and fotemustine as salvage treatment for grade III gliomas is safe and somewhat active in this heavily pretreated cohort. Further clinical studies should explore alternative regimens of therapy in the different molecular subgroups.

Proposed therapeutic strategy for adult low-grade glioma based on aggressive tumor resection.

OBJECT There is no standard therapeutic strategy for low-grade glioma (LGG). The authors hypothesized that adjuvant therapy might not be necessary for LGG cases in which total radiological resection was achieved. Accordingly, they established a treatment strategy based on the extent of resection (EOR) and the MIB-1 index: patients with a high EOR and low MIB-1 index were observed without postoperative treatment, whereas those with a low EOR and/or high MIB-1 index received radiotherapy (RT) and/or chemotherapy. In the present retrospective study, the authors reviewed clinical data on patients with primarily diagnosed LGGs who had been treated according to the above-mentioned strategy, and they validated the treatment policy. Given their results, they will establish a new treatment strategy for LGGs stratified by EOR, histological subtype, and molecular status. METHODS One hundred fifty-three patients with diagnosed LGG who had undergone resection or biopsy at Tokyo Women's Medical University between January 2000 and August 2010 were analyzed. The patients consisted of 84 men and 69 women, all with ages ≥ 15 years. A total of 146 patients underwent surgical removal of the tumor, and 7 patients underwent biopsy. RESULTS Postoperative RT and nitrosourea-based chemotherapy were administered in 48 and 35 patients, respectively. Extent of resection was significantly associated with both overall survival (OS; p = 0.0096) and progression-free survival (PFS; p = 0.0007) in patients with diffuse astrocytoma but not in those with oligodendroglial subtypes. Chemotherapy significantly prolonged PFS, especially in patients with oligodendroglial subtypes (p = 0.0009). Patients with a mutant IDH1 gene had significantly longer OS (p = 0.034). Multivariate analysis did not identify MIB-1 index or RT as prognostic factors, but it did identify chemotherapy as a prognostic factor for PFS and EOR as a prognostic factor for OS and PFS. CONCLUSIONS The findings demonstrated that EOR was significantly correlated with patient survival; thus, one should aim for maximum tumor resection. In addition, patients with a higher EOR can be safely observed without adjuvant therapy. For patients with partial resection, postoperative chemotherapy should be administered for those with oligodendroglial subtypes, and repeat resection should be considered for those with astrocytic tumors. More aggressive treatment with RT and chemotherapy may be required for patients with a poor prognosis, such as those with diffuse astrocytoma, 1p/19q nondeleted tumors, or IDH1 wild-type oligodendroglial tumors with partial resection.

AT-42 * FACTORS ASSOCIATED WITH MALIGNANT TRANSFORMATION OF LOW-GRADE GLIOMA

BACKGROUND: There is no standard therapeutic regimen for low-grade glioma (LGG). We have suggested extent of resection (EOR) was strongly associated with prognosis of LGG. About half of LGG eventually show malignant transformation (MT), MT is an important factor in determining prognosis of LGG. Therefore, it is important to definite factors associated with MT. In this study, we investigated correlation between MT and genetic profile and adjuvant therapy in LGG. METHOD: 151 patients (Male: Female = 80:71) with LGG treated in our institute from 2000 to 2010 were retrospectively analyzed. Median follow-up period was 41months, follow-up ratio was 96°, and the average age was 39.1 year-old (15-65). Diffuse astrocytoma (DA) accounted 47 patients (31°), oligodendroglioma (O) was 55 patients (37°), oligoastrocytoma (OA) was 44 patients (29°). The median Mib-1 index was 4.8°. IDH1 mutation and co-deletion of 1p19q locus were analyzed by immunohistochemistry and FISH method, respectively. RESULT: The average and median EOR of T2 high area was 85° and 95°, respectively. ACNU based chemotherapy was performed in 35 patients and radiotherapy in 48 patients. IDH1 mutation and 1p19q co-deletion were 75° and 57%, respectively. 48 patients out of 151 recurred and 29 patients were MT. Patients without IDH1 mutation (P = 0.025) or 1p19q deletion (P = 0.001) showed significant higher rate of MT. In analysis of all patients, EOR strongly correlated with MT (P = 0.0002). EOR correlated with MT in DA (P = 0.0003) but not in oligodendroglial subtypes (P = 0.7). In IDH1 mutant group, chemotherapy reduced MT (P = 0.004), however, in IDH1 wild-type group, both radiotherapy (P = 0.004) and chemotherapy (P = 0.006) brought higher incidence of MT. CONCLUSION: EOR significantly prevented MT in DA. It was suggested that IDH1 was a predictive factor for MT following radiotherapy and chemotherapy in LGG. Extensive resection is required for IDH1 wild type DA.

AT-57 * LONG-TERM CLINICAL RESULTS OF EXTENSIVE TUMOR REMOVAL FOLLOWED BY ACNU-BASED CHEMORADIOTHERAPY FOR 147 ANAPLASTIC GLIOMAS

INTRODUCTION: Recent randomized trials showed that highly extent of resection (EOR) and PCV chemoradiotherapy had therapeutic long-term efficacy to anaplastic glioma (AG). From 2000, we have consistently enforced extensive removal and ACNU-based chemoradiotherapy for AG. We report retrospective clinical results of a single institution. METHODS: We reviewed 147 cases of primary AG between 2000 and 2011 (Male : Female = 94:53, average age; 43.9 year-old). 69 were anaplastic astrocytoma (41%), 43 were anaplastic oligoastrocytoma (29%), and 44 were anaplastic oligodendroglioma (30%). The intraoperative MRI was performed in 133 cases (90%), and awake surgery was performed in 58 cases (39%). Gross-total removal was 46 (31%), partial removal was 89 (61%), and biopsy was 12 (8%) (average; 83%, median; 95%). After resection, 60 Gy radiotherapy and ACNU or PAV chemotherapy were performed. The average Mib-1 index was 15%. The mean observation periods were 57 months and 95% follow-up rate. RESULTS: Overall survival (OS) wasn't reached median. The 3y-OS was 82%, 5y-OSs was 72%, and 10y-OS was 66%. There was no statistical significance among AA, AOA, AO (5y-OS; 64%, 79%, 77%). The each 5 years survival rate of gross-total resection, partial resection, and biopsy were 83%, 70%, 39%, and there was statistical significance (P = 0.0024). Extent of resection (EOR) correlated OS in AA (P = 0.02) but not in oligodendroglial subtypes (P = 0.6). Statistical significant factors were EOR (P = 0.0024) and Mib-1 index (P = 0.013). The significant factors in multi variable analysis were EOR (more than 95% or not, HR 2.5) and Mib-1 index (more than 13% or not, HR 2.3). The median PFS was 8.3, and 5y-PFS was 59%,and 10y-PFS was 45%. CONCLUSION: Our long-term clinical results of AG treated with extensive resection and ACNU-based chemoradiotherapy were better than previous reports. The EOR contributed better prognosis especially for AA.

Histogram Analysis of MR Imaging–Derived Cerebral Blood Volume Maps: Combined Glioma Grading and Identification of Low-Grade Oligodendroglial Subtypes

Inclusion of oligodendroglial tumors may confound the utility of MR based glioma grading. Our aim was, first, to assess retrospectively whether a histogram-analysis method of MR perfusion images may both grade gliomas and differentiate between low-grade oligodendroglial tumors with or without loss of heterozygosity (LOH) on 1p/19q and, second, to assess retrospectively whether low-grade oligodendroglial subtypes can be identified in a population of patients with high-grade and low-grade astrocytic and oligodendroglial tumors. Fifty-two patients (23 women, 29 men; mean age, 52 years; range, 19-78 years) with histologically confirmed gliomas were imaged by using dynamic susceptibility contrast MR imaging at 1.5T. Relative cerebral blood volume (rCBV) maps were created, and 4 neuroradiologists defined the glioma volumes independently. Averaged over the 4 observers, a histogram-analysis method was used to assess the normalized histogram peak height of the glioma rCBV distributions. Of the 52 patients, 22 had oligodendroglial tumors. The histogram method was able to differentiate high-grade gliomas (HGGs) from low-grade gliomas (LGGs) (Mann-Whitney U test, P < .001) and to identify low-grade oligodendroglial subtypes (P = .009). The corresponding intraclass correlation coefficients were 0.902 and 0.801, respectively. The sensitivity and specificity in terms of differentiating low-grade oligodendroglial tumors without LOH on 1p/19q from the other tumors was 100% (6/6) and 91% (42/46), respectively. With histology as a reference, our results suggest that histogram analysis of MR imaging-derived rCBV maps can differentiate HGGs from LGGs as well as low-grade oligodendroglial subtypes with high interobserver agreement. Also, the method was able to identify low-grade oligodendroglial tumors without LOH on 1p/19q in a population of patients with astrocytic and oligodendroglial tumors.

Apparent diffusion coefficients in oligodendroglial tumors characterized by genotype

To investigate whether oligodendroglial tumors with or without 1p/19q loss differ in their diffusion-weighted imaging characteristics. Oligodendroglial tumors with or without 1p/19q loss differ in their therapeutic responsiveness and prognosis, and recent reports also suggest that these tumors may differ in their magnetic resonance characteristics and blood volume. Apparent diffusion coefficients (ADCs) were assessed in three grade II oligodendrogliomas, nine grade II and five grade III oligoastrocytomas with known 1p/19q status. Regions of interest (ROIs) were placed on ADC maps: 1) around tumor margins to generate pixel histograms; 2) over minimum and maximum tumor ADC; 3) on areas comparable to the highest choline (Cho)/creatine (Cr) ratio determined from chemical shift imaging (CSI); and 4) across tumor margins to measure the ADC transition coefficient (ATC). Tumor ADC was significantly different from normal brain (P < 0.001). ADC in regions of highest Cho/Cr was greater than minimum ADC and did not correlate with the Cho/Cr ratio. ADC and ATC were not significantly different between oligodendroglial subtypes or grades. Tumors with intact 1p/19q had higher maximum (P = 0.021) and histogram ADC (P = 0.015), and greater ATC (P = 0.001) compared to those with 1p/19q loss, which may reflect differences in edema and cellularity. This preliminary study identified differences in ADC and ATC between oligodendroglial tumor genotypes that may reflect underlying biology. Confirmation in a larger series is warranted.

Gliomatosis Cerebri: A Review of 296 Cases from the ANOCEF Database and the Literature

Gliomatosis cerebri (GC) is a rare disease, defined as a diffuse neoplastic glial cell infiltration of the brain. Diagnosis and management of GC are difficult. This study analyzed 296 individual cases (90 patients followed through the ANOCEF network, and 206 cases from the literature), aged 1 month to 85 years (median 42), sex ratio=1.31. Median survival was 14.5 months. It was higher for patients younger than 42 years (17 months vs. 13 months), with performance status>or=80 (27 months vs. 9 months), low grade gliomatosis (grade 2=20 months, grade 3=11.5 months, grade 4=8.5 months), oligodendroglial subtype (36 months compared to 14 months for mixed GC and 11 months for astrocytic GC). Male population was younger (median 39 years vs. 45), had a higher incidence of oligodendroglial GC (22% vs. 13%), which may explain their better prognosis (median survival 17 months vs. 11.5 months) than female population. Despite a high rate of stabilization, the impact on survival of whole brain radiotherapy, which carries the risk of severe toxicity, is still unclear. Up-front chemotherapy benefit to some patients and may be preferred to whole brain radiotherapy. However, the many bias of such retrospective heterogeneous data claim for multicentric clinical trials in this rare disease.

Impaired Myelinogenesis and Early Maturation of Oligodendrocytes in Black Tremor Hamster with Central Nervous System Myelin Deficiency

Oligodendrocytes and myelin in the corpus callosum of black tremor and normal hamsters aged 3, 7, and 14 weeks were ultrastructurally examined to determine myelination index (ratio of myelin thickness/diameter of axon), percentage of naked axons, and proportions of oligodendroglial subtypes (light, medium and dark). The mutant hamsters were remarkably hypomyelinated, with a low myelination index and a high proportion of naked axons, but the proportions of the three subtypes in the mutants were comparable with those of normal hamsters at 3 weeks of age, suggesting the low myelinogenetic activity of oligodendrocytes in the mutant. Furthermore, oligodendrocytes of the mutant hamsters appeared to mature earlier than those of age-matched controls, since the proportions of dark inactive oligodendrocytes at 7 and 14 weeks of ages were higher than those of the control hamsters.