Low-grade Oligodendrogliomas Research Articles

HGG-02. ADOLESCENT AND YOUNG ADULT (AYA) GLIOMA WITH BRAF V600E-MUTANTATION

BACKGROUNDBiological features of pediatric glioma differ significantly from those of adult glioma, and limited data are available on those of AYA patients. Here, we focused on AYA patients with glioma, especially those harboring BRAF V600E mutation, and investigated their clinical and genetic features. METHOD: We retrospectively analyzed AYA patients with brain tumors harboring BRAF V600E, who were treated in two hospitals in Japan.RESULTSClinical information was available for 14 patients. The median age at diagnosis was 25 years (range: 15–38). Five patients were diagnosed with glioblastoma (GBM), including one epithelioid type. These patients were over 25. Although one patient with GBM died of the disease 6.9 years after initial diagnosis, the remaining patients were alive. Two patients were alive without recurrence at 38 and 51 months after the treatment. The patient with epithelioid glioblastoma experienced early recurrence. The remaining nine patients (64%) were diagnosed with low-grade glioma, including ganglioglioma, pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, pleomorphic xanthoastrocytoma, and polymorphous low-grade neuroepithelial tumor of the young. No patients died of the disease, and four patients are alive without recurrence after initial operation without adjuvant treatment. Two patients are (epithelioid glioblastoma and ganglioglioma) currently undergoing treatment with a BRAF inhibitor for recurrent tumors.DISCUSSIONAlthough the number of this study is limited, our study suggested that the prognosis of AYA patients with BRAF-V600E positive GBM may not be as dismal as that of children or adults.

TAMI-08. A TALE OF TWO TELOMERE MAINTENANCE MECHANISMS: TERT EXPRESSION AND THE ALT PATHWAY INDUCE UNIQUE MRS-DETECTABLE METABOLIC REPROGRAMMING IN LOW-GRADE GLIOMAS

Abstract Telomeres are nucleoprotein structures at chromosomal ends that shorten with cell division and constitute a natural barrier to proliferation. In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism (TMM). Telomerase reverse transcriptase (TERT) expression is the TMM in most tumors, including low-grade oligodendrogliomas (LGOGs). In contrast, low-grade astrocytomas (LGAs) use the alternative lengthening of telomeres (ALT) pathway as their TMM. As molecular hallmarks of tumor proliferation, TMMs are attractive tumor biomarkers and therapeutic targets. Non-invasive imaging of TMM status will, therefore, allow assessment of tumor proliferation and treatment response. However, translational methods of imaging TMM status are lacking. Here, we show that TERT expression and the ALT pathway are associated with unique magnetic resonance spectroscopy (MRS)-detectable metabolic reprogramming in LGOGs and LGAs respectively. In genetically-engineered and patient-derived LGOG models, TERT expression is linked to elevated 1H-MRS-detectable NAD(P)/H, glutathione, aspartate and AXP. In contrast, the ALT pathway in LGAs is associated with higher α-ketoglutarate, glutamate, alanine and AXP. Importantly, elevated flux of hyperpolarized [1-13C]-alanine to pyruvate, which depends on α-ketoglutarate, is a non-invasive in vivo imaging biomarker of the ALT pathway in LGAs while elevated flux of hyperpolarized [1-13C]-alanine to lactate, which depends on NADH, is an imaging biomarker of TERT expression in LGOGs. Mechanistically, the ALT pathway in LGAs is linked to higher glutaminase (GLS), a key enzyme for α-ketoglutarate biosynthesis while TERT expression in LGOGs is associated with elevated nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme for NADH biosynthesis. Notably, TERT expression and the ALT pathway are linked to MRS-detectable metabolic reprogramming in LGOG and LGA patient biopsies, emphasizing the clinical validity of our observations. Collectively, we have identified unique metabolic signatures of TMM status that integrate critical oncogenic information with noninvasive imaging modalities that can improve diagnosis and treatment response monitoring for LGOG and LGA patients.

Is chemotherapy alone an option as initial treatment for low-grade oligodendrogliomas?

The management of low-grade (grade II) oligodendrogliomas is still controversial, due to their rarity and long-term survival. According to recent WHO 2016 Classification of central nervous system tumors oligodendrogliomas are defined by the coexistence of molecular alterations, such as isocitrate dehydrogenase (IDH)1/2 mutations and 1p/19q codeletion. These tumors have better outcome and higher response to chemotherapy compared with diffuse astrocytomas. The association of radiotherapy and procarbazine, lomustine (CCNU), vincristine chemotherapy in low-grade oligodendrogliomas is definitely superior over radiotherapy alone, and yields median progression-free survival and overall survival values exceeding by far 10 years. Chemotherapy alone yields results that are inferior compared with radiotherapy + procarbazine, CCNU, vincristine but may better preserve cognitive functions from radiotherapy-induced damage. Chemosensitivity of oligodendrogliomas is related to a high percentage of O6-methylguanine-DNA methyltransferase methylation and low expression of DNA repair genes. Recurrent defects in mismatch repair pathways may induce hypermutation and secondary resistance to temozolomide, but not to nitrosoureas. Reoperation at progression following initial chemotherapy is increasingly adopted, thus allowing a further delay of radiotherapy. In the future targeting IDH1/2 mutations following incomplete surgery may represent a new innovative option.

Narrowing down the Common Cytogenetic Deletion 14q to a 5.6-Mb Critical Region in 1p/19q Codeletion Oligodendroglioma-Relapsed Patients Points to Two Potential Relapse-Related Genes: SEL1L and STON2

Based on a literature review and our database, we report on the smallest 14q deletion identified in a brain tumor characterized by 1p/19q codeletion low-grade oligodendroglioma. In 2013, array-comparative genomic hybridization of the brain tumor revealed 1p/19q codeletion as a sole abnormality. In 2019, the patient relapsed showing additional abnormalities including a 14q deletion of 16.5 Mb at 14q24.2q31.3. This region overlaps with 2 previously identified minimal regions, 14q21.2q24.3 and 14q31.3q32.1, based on 142 cases of glioma. The authors reported no correlation between these 2 regions and survival. By extracting these 2 regions from our patient's deletion and comparing it to 12 other cases of 1p/19q codeletion oligodendrogliomas reported in the literature, we narrowed down the 14q loss possible critical region to 5.6 Mb mapping at 14q31.1q31.2. This region contains 2 potential relapse-related genes: SEL1L and STON2.

Eslicarbazepine in patients with brain tumor-related epilepsy: a single-center experience

Purpose Brain tumor-related epilepsy (BTRE) is frequent in patients affected with glioma. Most patients have refractory seizures and require polytherapy. Promising treatment options derive from the development of novel anti-epileptic drugs (AEDs), like Eslicarbazepine (ESL), whose role in BTRE has not yet been explored. Our aim was to report a retrospective cohort of patients affected by BTRE treated with ESL as an adjunctive therapy and to discuss the potential role of this third-generation AED in this clinical context. Methods We analyzed a single-center, retrospectively collected cohort of patients affected by glioma and BTRE, treated with ESL as an adjunctive therapy. Results Analysis included 5 males and 3 females with age ranging from 37 to 75 years (mean = 55.5). Mean baseline Karnofsky performance status was 87.5 (range 70–100). Patients were affected by diffuse astrocytoma (3), low grade oligodendroglioma (2), anaplastic glioma (2) and glioblastoma (1). Mean follow-up was 19 months (range 6–59). Mean dose at the last follow-up was 950 mg daily. Mean weekly seizures in the month before initiation of ESL numbered 17.6 (range 0.25–50). At the last follow-up, mean weekly seizures were 2.2 (range 0–10), i.e. significantly lower than baseline (p = 0.03). The mean reduction of seizures achieved after introduction of ESL was 65%, with 6/8 patients (75%) showing a reduction of more than 50%. Two patients (25%) were seizure free. Conclusions This single-center experience suggests that ESL may be a well-tolerated, efficacious option as an add-on drug in the treatment of BTRE.

Three-Year Survival Rate in All Kinds of Glioma Tumors in One Institution, Iran, 2001-2010

Background and Aim: The survival rate of brain tumors has not yet been reported in Iran. The purpose of this study, given the lack of such information, was to evaluate the 3-year survival rate in patients with all kinds of glioma tumors. Methods and Materials/Patients: This study was descriptive and retrospective, including 222 patients who had been diagnosed clinically with one type of glioma tumor and admitted to Al-Zahra hospital, Isfahan, Iran during 2001-2010. All patients (for minors, their parents) were contacted by phone. They were asked about the 3-year survival rate following their tumor resection surgery. Data such as patient’s age on admission, gender, histological diagnosis of tumor, and treatment regimen (surgical/non-surgical, radiation, and/or chemotherapy) were collected from medical records. The 3-year survival rate and frequency of each tumor based on age and gender were measured. Results: The 3-year survival rates for Glioblastoma Multiform (GBM) and anaplastic astrocytoma were 8.7% and 0%, respectively following surgery and chemo-radiation. These tumors were categorized as high-grade glioma with poor prognosis. The 3-year survival rate for diffuse astrocytoma, low-grade oligodendroglioma, low-grade ependymoma, and pilocytic astrocytoma following surgery and radiation were 100%, 95.2%, 100%, and 100%, respectively. These tumors were categorized as low-grade glioma, which has a good prognosis. Conclusion: In this study, the 3-year survival rate in patients with low-grade glioma following surgery and radiation was almost 100%. In contrast, the 3-year survival rate in patients with highgrade glioma following surgery and chemo-radiation was almost 0%.

How to Spare a Life at a Time, Being Mindful of the Red Flags

In an era dominated by high-yield technology and novel therapies, a clinician’s insight and mindful reasoning remain more powerful than fine point instruments. During the course of our medical training, we are taught to consider the most prevalent aetiologies upfront, since « frequent conditions are widespread ». Moreover, we are trained to develop a unicist vision in front of a clinical scenario, especially when young patients are concerned. However, we shall never forget that the exceptional case will eventually present to clinic. It is our responsibility to recognize the Red Flags. Every patient has only one life, and good clinical awareness protects those lives. The case discussed in this review is highly pertinent for numerous medical fields, mentioning: Neurology, Neurosurgery, Internal Medicine, Psychiatry, Emergency Medicine, Family Medicine, General Surgery and Endocrinology. Numerous specialists are involved in a single case. A gentleman in his early 30s presents is diagnosed with a low-grade oligodendroglioma involving unilaterally the basal ganglia, documented clinically and radiologically to be stable for years. While he recited his story, we listened carefully. This young man mentioned one sentence, which retrospectively saved his life.

Bioinformatics Analysis of Differentially Expressed Genes and miRNAs in Low-Grade Gliomas.

Low-grade glioma is the most common type of primary intracranial tumor. In the last 3 years, new observations of molecular precursors in adults with gliomas have led to a modification in the histopathologic classification of these brain tumors. Among the biomarkers that have been highlighted, we have the micro RNAs (miRNAs) which play a crucial role in the regulation of gene expression and the long noncoding RNAs (lncRNAs) controlling various cellular and metabolic pathways. In our study, large-scale data on sequenced RNA and miRNAs from 516 patients were obtained from the Cancer Genome Atlas database by the TCGAbiolinks package. We identified the differential expression of miRNAs and genes using the Limma package and then we used the ClusterProfiler package for annotations of the biological pathways of the expressed genes, the survival package to estimate the survival analysis, and the GDCRNATools package to determine miRNAs-genes and miRNAs-lncRNAs interactions. We obtained a significant correlation between the miRNAs identified and the overall survival of the patients (log-rank P < .05) and we have theoretically proposed a novel network of miRNAs involved in low-grade gliomas, specifically astrocytomas and oligodendrogliomas, which combine both genes and lncRNAs.

Expression of FOXP3 in Canine Gliomas: Immunohistochemical Study of Tumor-Infiltrating Regulatory Lymphocytes.

Dogs develop gliomas with similar histopathological features to human gliomas and share with them the limited success of current therapeutic regimens such as surgery and radiation. The tumor microenvironment in gliomas is influenced by immune cell infiltrates. The present study aims to immunohistochemically characterize the tumor-infiltrating lymphocyte (TIL) population of naturally occurring canine gliomas, focusing on the expression of Forkhead box P3-positive (FOXP3+) regulatory T-cells (Tregs). Forty-three canine gliomas were evaluated immunohistochemically for the presence of CD3+, FOXP3+, and CD20+ TILs. In low-grade gliomas, CD3+ TILs were found exclusively within the tumor tissue. In high-grade gliomas, they were present in significantly higher numbers throughout the tumor and in the brain-tumor junction. CD20+ TILs were rarely found in comparison to CD3+ TILs. FOXP3+ TILs shared a similar distribution with CD3+ TILs. The accumulation of FOXP3+ Tregs within the tumor was more pronounced in astrocytic gliomas than in tumors of oligodendroglial lineage and the difference in expression was significant when comparing low-grade oligodendrogliomas and high-grade astrocytomas. Only high-grade astrocytomas presented FOXP3+ cells with tumoral morphology. In spontaneous canine gliomas, TILs display similar characteristics (density and distribution) as described for human gliomas, supporting the use of the dog as an animal model for translational immunotherapeutic studies.

Ability of Radiomics in Differentiation of Anaplastic Oligodendroglioma From Atypical Low-Grade Oligodendroglioma Using Machine-Learning Approach.

Objectives: To investigate the ability of radiomics features from MRI in differentiating anaplastic oligodendroglioma (AO) from atypical low-grade oligodendroglioma using machine-learning algorithms.Methods: A total number of 101 qualified patients (50 participants with AO and 51 with atypical low-grade oligodendroglioma) were enrolled in this retrospective, single-center study. Forty radiomics features of tumor images derived from six matrices were extracted from contrast-enhanced T1-weighted (T1C) images and fluid-attenuation inversion recovery (FLAIR) images. Three selection methods were performed to select the optimal features for classifiers, including distance correlation, least absolute shrinkage and selection operator (LASSO), and gradient boosting decision tree (GBDT). Then three machine-learning classifiers were adopted to generate discriminative models, including linear discriminant analysis, support vector machine, and random forest (RF). Receiver operating characteristic analysis was conducted to evaluate the discriminative performance of each model.Results: Nine predictive models were established based on radiomics features from T1C images and FLAIR images. All of the classifiers represented feasible ability in differentiation, with AUC more than 0.840 when combined with suitable selection method. For models based on T1C images, the combination of LASSO and RF classifier represented the highest AUC of 0.904 in the validation group. For models based on FLAIR images, the combination of GBDT and RF classifier showed the highest AUC of 0.861 in the validation group.Conclusion: Radiomics-based machine-learning approach could potentially serve as a feasible method in distinguishing AO from atypical low-grade oligodendroglioma.

CBMT-41. IMAGING A HALLMARK OF CANCER: HYPERPOLARIZED 13C-MAGNETIC RESONANCE SPECTROSCOPY CAN NON-INVASIVELY MONITOR TERT EXPRESSION IN LOW-GRADE GLIOMAS IN VIVO

Abstract Telomerase reverse transcriptase (TERT) expression is a hallmark of cancer, including in primary glioblastomas and low-grade oligodendrogliomas. Since TERT is essential for glioma proliferation and is an attractive therapeutic target, metabolic imaging of TERT status can inform on tumor progression and response to therapy. To that end, the goal of this study was to identify non-invasive, translational, hyperpolarized 13C-magnetic resonance spectroscopy-detectable metabolic imaging biomarkers of TERT in low-grade oligodendrogliomas. Unbiased metabolomic analysis of immortalized normal human astrocytes without (NHAcontrol) and with TERT (NHAtert) indicated that TERT induced unique metabolic reprogramming. Notably, TERT increased NADPH and NADH levels. Glucose flux through the pentose phosphate pathway (PPP) is a major producer of NADPH. Non-invasive imaging of PPP flux using hyperpolarized [U-13C,U-2H]-glucose indicated that production of the PPP metabolite 6-phosphogluconate (6-PG) was elevated in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [U-13C,U-2H]-glucose flux to 6-PG clearly differentiated tumor from normal brain in orthotopic NHAtert tumor xenografts. Next, we exploited the observation that TERT expression increased NADH, which is essential for the metabolism of hyperpolarized [1-13C]-alanine to lactate. Lactate production from hyperpolarized [1-13C]-alanine was higher in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [1-13C]-alanine imaging in orthotopic NHAtert tumors revealed pronounced differences in lactate production between tumor tissue and normal brain. Mechanistically, TERT increased expression of glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme for 6-PG and NADPH production, and of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme for NADH biosynthesis. Silencing TERT reversed G6PDH and NAMPT expression and normalized hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine metabolism, validating our imaging biomarkers. Finally, hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine could monitor TERT status in the clinically relevant, patient-derived BT54 oligodendroglioma model. In summary, we demonstrate, for the first time, non-invasive in vivo imaging of TERT status in gliomas that can enable longitudinal analysis of tumor burden and treatment response in the clinic.

Extent of resection and survival for oligodendroglioma: a U.S. population-based study.

National guidelines recommend maximal safe resection of low-grade and high-grade oligodendrogliomas. However, there is no level 1 evidence to support these guidelines, and recent retrospective studies on the topic have yielded mixed results. To assess the association between extent of resection (EOR) and survival for oligodendrogliomas in the general U.S. Cases diagnosed between 2004 and 2013 were selected from the Surveillance, Epidemiology, and End-Results (SEER) Program and retrospectively analyzed for treatment, prognostic factors, and survival times. Cases that did not undergo tumor de-bulking surgery (e.g. no surgery or biopsy alone) were compared to subtotal resection (resection) and gross-total resection (GTR). The primary end-points were overall survival (OS) and cause-specific survival (CSS). An external validation cohort with 1p/19q-codeleted tumors was creating using the TCGA and GSE16011 datasets. 3135 Cases were included in the final analysis. The 75% survival time (75ST) and 5-year survival rates were 47months and 70.8%, respectively. Subtotal resection (STR, 75ST = 50months) and GTR (75ST = 61months) were associated with improved survival times compared to cases that did not undergo surgical debulking (75ST = 20months, P < 0.001 for both), with reduced hazard ratios (HRs) after controlling for other factors (HR 0.81 [0.68-0.97] and HR 0.65 [0.54-0.79], respectively). GTR was associated with improved OS in both low-grade and anaplastic oligodendroglioma subgroups (HR 0.74 [0.58-0.95], HR 0.60 [0.44-0.82], respectively) while STR fell short of significance in the subgroup analysis. All findings were corroborated by multivariable analysis of CSS and externally validated in a cohort of patients with 1p19q-codeleted tumors. Greater EOR is associated with improved survival in oligodendrogliomas. Our findings in this U.S. population-based cohort support national guidelines.

Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas.

Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model describes the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, different therapeutic strategies were tried computationally on the ‘in-silico twins’ of those patients. Chemotherapy schedules with larger-than-standard rest periods between consecutive cycles had either the same or better long-term efficacy than the standard 28-day cycles. The results were confirmed in a large trial of 2000 virtual patients. These long-cycle schemes would also have reduced toxicity and defer the appearance of resistances. On the basis of those results, a combination scheme consisting of five induction TMZ cycles given monthly plus 12 maintenance cycles given every three months was found to provide substantial survival benefits for the in-silico twins of the 11 LGO patients (median 5.69 years, range: 0.67 to 68.45 years) and in a large virtual trial including 2000 patients. We used 220 sets of experiments in-silico to show that a clinical trial incorporating 100 patients per arm (standard intensive treatment versus 5 + 12 scheme) could demonstrate the superiority of the novel scheme after a follow-up period of 10 years. Thus, the proposed treatment plan could be the basis for a standardized TMZ treatment for LGO patients with survival benefits.

Genetic Abnormalities, Clonal Evolution, and Cancer Stem Cells of Brain Tumors.

Brain tumors are highly heterogeneous and have been classified by the World Health Organization in various histological and molecular subtypes. Gliomas have been classified as ranging from low-grade astrocytomas and oligodendrogliomas to high-grade astrocytomas or glioblastomas. These tumors are characterized by a peculiar pattern of genetic alterations. Pediatric high-grade gliomas are histologically indistinguishable from adult glioblastomas, but they are considered distinct from adult glioblastomas because they possess a different spectrum of driver mutations (genes encoding histones H3.3 and H3.1). Medulloblastomas, the most frequent pediatric brain tumors, are considered to be of embryonic derivation and are currently subdivided into distinct subgroups depending on histological features and genetic profiling. There is emerging evidence that brain tumors are maintained by a special neural or glial stem cell-like population that self-renews and gives rise to differentiated progeny. In many instances, the prognosis of the majority of brain tumors remains negative and there is hope that the new acquisition of information on the molecular and cellular bases of these tumors will be translated in the development of new, more active treatments.

Seizure response to temozolomide chemotherapy in patients with WHO grade II oligodendroglioma: a single-institution descriptive study.

Tumor-related epilepsy (TRE) is common in patients with low-grade oligodendrogliomas. TRE is difficult to control despite multiple antiepileptic drugs (AEDs) in up to 30% of patients. Chemotherapy has been used for treatment to avoid potential radiotherapy-related neurotoxicity. This study evaluates the effect of temozolomide on seizure frequency in a homogeneous group with World Health Organization (WHO) grade II oligodendrogliomas. A retrospective analysis was conducted of adult patients with WHO grade II oligodendrogliomas and TRE followed at Memorial Sloan Kettering between 2005 and 2015 who were treated with temozolomide alone either as initial treatment or for disease progression. All had seizures 3 months prior to starting temozolomide. Seizure frequency was reviewed every 2 cycles and at the end of temozolomide treatment. Seizure reduction of ≥50% compared to baseline was defined as improvement. Thirty-nine individuals met inclusion criteria. Median follow-up since starting temozolomide was 6 years (0.8-13 years). Reduction in seizure frequency occurred in 35 patients (89.7%). Improvement was independent of AED regimen adjustments or prior antitumor treatment in 16 (41%); of these, AED dosage was successfully reduced or completely eliminated in 10 (25.6%). Twenty-five patients (64.1%) remained on a stable AED regimen. The majority (n = 32, 82%) had radiographically stable disease, 5 (12.8%) had objective radiographic response, and 2 (5.2%) had disease progression. Temozolomide may result in reduced seizure frequency, and permit discontinuation of AEDs in patients with WHO II oligodendroglioma. Improvement was observed irrespective of objective tumor response on MRI, emphasizing the importance of incorporating seizure control in assessing response to tumor-directed therapy.

Pre- and post-surgery MRSI predictive value in adult oligodendroglioma prognosis

PurposeThe aim of this study was to study the relationship between MRSI, before and after surgery, and patient survival. The accuracy of pre-operative MRSI in differentiating low- from high-grade oligodendrogliomas (ODGs) was also studied. MethodsTwo hundred patients with ODG were retrospectively included in this study between 2000 and 2016. All patients underwent MRSI before any treatment or biopsy and/or after surgery for an intra-axial brain tumour. The R software was used for statistical data analysis. p < 0.05 was considered statistically significant. Kaplan-Meier curves were calculated for patients with low-grade ODG and high-grade ODG pre- and post-operatively, to study survival (overall survival, OS). The best threshold of each MRSI metabolite ratio was obtained using receiver operating characteristic curves (ROCs). ResultsOne hundred patients underwent pre-operative MRSI and 170 post-operative MRSI. N-acetylaspartate (NAA), lactate (Lac), choline (Cho) and creatine (Cr) were measured. Kapan-Meier curves showed that survival was poorer for a nCho/Cr > 3.02 in the pre-operative and nCho/Cr > 2.04, Lac/Cr > 0.743 and nCho/NAA > 3.63 in the post-operative period. Post-operative MRSI predicts survival better than pre-operative MRSI. nCho/Cr and Lac/Cr distinguished low- from high-grade ODG with a good positive predictive value. ConclusionMRSI is associated with survival. It is a non-invasive tool which completes histopathology and can predict patients' prognosis, thus improving patient management.

Impact of 9p deletion and p16, Cyclin D1, and Myc hyperexpression on the outcome of anaplastic oligodendrogliomas.

ObjectiveTo study the presence of 9p deletion and p16, cyclin D1 and Myc expression and their respective diagnostic and prognostic interest in oligodendrogliomas.MethodsWe analyzed a retrospective series of 40 consecutive anaplastic oligodendrogliomas (OIII) from a single institution and compared them to a control series of 10 low grade oligodendrogliomas (OII). Automated FISH analysis of chromosome 9p status and immunohistochemistry for p16, cyclin D1 and Myc was performed for all cases and correlated with clinical and histological data, event free survival (EFS) and overall survival (OS).ResultsChromosome 9p deletion was observed in 55% of OIII (22/40) but not in OII. Deletion was highly correlated to EFS (median = 29 versus 53 months, p<0.0001) and OS (median = 48 versus 83 months, p<0.0001) in both the total cohort and the OIII population. In 9p non-deleted oligodendrogliomas, p16 hyperexpression correlated with a shorter OS (p = 0.02 in OII and p = 0.0001 in OIII) whereas lack of p16 expression was correlated to a shorter EFS and OS in 9p deleted OIII (p = 0.001 and p = 0.0002 respectively). Expression of Cyclin D1 was significantly higher in OIII (median expression 45% versus 14% for OII, p = 0.0006) and was correlated with MIB-1 expression (p<0.0001), vascular proliferation (p = 0.002), tumor necrosis (p = 0.04) and a shorter EFS in the total cohort (p = 0.05). Hyperexpression of Myc was correlated to grade (median expression 27% in OII versus 35% in OIII, p = 0.03), and to a shorter EFS in 9p non-deleted OIII (p = 0.01).ConclusionChromosome 9p deletion identifies a subset of OIII with significantly worse prognosis. The combination of 9p status and p16 expression level identifies two distinct OIII populations with divergent prognosis. Hyperexpression of Bcl1 and Myc appears highly linked to anaplasia but the prognostic value is unclear and should be investigated further.

Identification of Plasma Membrane Glycoproteins Specific to Human Glioblastoma Multiforme Cells Using Lectin Arrays and LC-MS/MS.

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most malignant type of brain cancer and has poor prognosis with a median survival of less than one year. While the structural changes of tumor cell surface carbohydrates are known to be associated with invasive behavior of tumor cells, the cell surface glycoproteins to differentiate the low- and high-grade glioma cells can be potential diagnostic markers and therapeutic targets for GBMs. In the present study, lectin arrays consisting of eight lectins were employed to explore cell surface carbohydrate expression patterns on low-grade oligodendroglioma cells (Hs683) and GBM cells (T98G). Griffonia simplicifolia I (GS I) was found to selectively bind to T98G cells and not to Hs683 cells. For identification of the glioblastoma-specific cell surface markers, the glycoproteins from each cell type were captured by a GS I lectin column and analyzed by LC-MS/MS. The identified proteins from the two cell types were quantified using label-free quantitative analysis based on spectral counting. Of cell surface glycoproteins showing significant increases in T98G cells, five proteins were selected for verification of both protein and glycosylation level changes using Western blot and GS I lectin-based immunosorbent assay.

P.034 Focal cortical dysplasia type IIIb associated with oligodendroglioma in a seizure free patient: a case report

Background: Focal cortical dysplasia (FCD) refers to malformation of cortical development featuring abnormalities of cortical layering, neuronal differentiation and maturation. It is a common cause of medically refractory epilepsy. The coexistence of FCD and low-grade glial neoplasms such as ganglioglioma and dysembryoplastic neuroepithelial tumour is classified by the International League Against Epilepsy as “FCD Type IIIb”. We present a case of FCD Type IIIb associated with low grade oligodendroglioma (WHO grade II) in a seizure free patient. Methods: A 20-year-old male presented with suspected arteriovenous malformation of the right pinna. Imaging revealed an incidental right frontal lobe mass. Surgical resection was performed. Pathologic analysis revealed FCD Type IIIb associated with low grade oligodendroglioma (WHO grade II). Results: The patient recovered uneventfully. Only 4 prior cases of FCD Type IIIb associated with oligodendroglioma have been reported. This is the first reported case of FCD Type IIIb discovered incidentally in a seizure free patient. Conclusions: FCD Type IIIb associated with oligodendroglioma is rare. The mechanism(s) by which glioneuronal neoplasms and perilesional cortical tissue jointly contribute to epileptogenicity have not been clearly defined. There may be a reduced risk of seizures with oligodendroglioma rather than tumors with a neuronal component.

IDH mutant and 1p/19q co-deleted oligodendrogliomas: tumor grade stratification using diffusion-, susceptibility-, and perfusion-weighted MRI

PurposeCurrently, isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion are proven diagnostic biomarkers for both grade II and III oligodendrogliomas (ODs). Non-invasive diffusion-weighted imaging (DWI), susceptibility-weighted imaging (SWI), and dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) are widely used to provide physiological information (cellularity, hemorrhage, calcifications, and angiogenesis) of neoplastic histology and tumor grade. However, it is unclear whether DWI, SWI, and DSC-PWI are able to stratify grades of IDH-mutant and 1p/19q co-deleted ODs.MethodsWe retrospectively reviewed the conventional MRI (cMRI), DWI, SWI, and DSC-PWI obtained on 33 patients with IDH-mutated and 1p/19q co-deleted ODs. Features of cMRI, normalized ADC (nADC), intratumoral susceptibility signals (ITSSs), normalized maxim CBV (nCBV), and normalized maximum CBF (nCBF) were compared between low-grade ODs (LGOs) and high-grade ODs (HGOs). Receiver operating characteristic curve and logistic regression were applied to determine diagnostic performances.ResultsHGOs tended to present with prominent edema and enhancement. nADC, ITSSs, nCBV, and nCBF were significantly different between groups (all P < 0.05). The combination of SWI and DSC-PWI for grading resulted in sensitivity and specificity of 100.00 and 93.33%, respectively.ConclusionsIDH-mutant and 1p/19q co-deleted ODs can be stratified by grades using cMRI and advanced magnetic resonance imaging techniques including DWI, SWI, and DSC-PWI. Combined ITSSs with nCBV appear to be a promising option for grading molecularly defined ODs in clinical practice.