Anaplastic Oligodendroglioma Patients Research Articles

Construction and Validation of Nomograms for Predicting Overall Survival and Cancer-Specific Survival in Patients with Primary Anaplastic Oligodendroglioma

Anaplastic oligodendroglioma (AOD) is a rare high-grade central nervous system tumor. The current research on prognostic prediction of AOD remains limited. This study aimed to identify prognostic factors and establish the nomograms to predict overall survival (OS) and cancer-specific survival (CSS) for patients with AOD. Patients diagnosed with AOD between 1992 and 2020 were extracted from the Surveillance, Epidemiology, and End Result database. We performed univariate and multivariate Cox regression analyses to identify independent prognostic factors based on the training group. Kaplan-Meier survival curves were used to compare the impact of various independent factors on patient prognosis. For OS and CSS, the nomograms were constructed and verified by the validation group. Harrell''s concordance index, receiver operating characteristic curves, calibration curves, and decision curve analyses were used to assess the discrimination, consistency, and clinical value of the nomograms. A total of 1202 AOD patients were enrolled, being randomly divided into training (n= 841) and validation (n= 361) groups (7:3 ratio). Univariate and multivariate Cox analysis identified 4 significant independent factors (tumor site, age, surgery, and chemotherapy). For OS and CSS, Harrell''s concordance index were 0.731 (0.705-0.757) and 0.728 (0.701-0.754) in the training group, 0.688 (0.646-0.731) and 0.684 (0.639-0.729) in the validation group, respectively. Receiver operating characteristic curves and Calibration curves showed good discrimination and consistency, respectively. In addition, the decision curve analyses curves showed the nomograms have good clinical benefits. We successfully established the nomograms to predict the OS and CSS for AOD patients. The nomograms showed good performance in prognostic prediction, assisting clinicians in evaluating patient prognosis and personalizing treatment plans.

T2-Fluid-attenuated inversion recovery (FLAIR) pseudoprogression in patients with anaplastic oligodendrogliomas treated with procarbazine, lomustine and vincristine (PCV) chemotherapy alone.

Pseudoprogression in gliomas has been extensively described after radiotherapy with or without chemotherapy, but not after chemotherapy alone. Here we describe the occurrence of pseudoprogression in patients with anaplastic oligodendrogliomas treated with postoperative procarbazine, lomustine and vincristine (PCV) chemotherapy alone. We retrospectively reviewed the medical and radiological files of patients with 1p/19q codeleted, IDH-mutant anaplastic oligodendrogliomas treated with PCV chemotherapy alone who presented magnetic resonance imaging (MRI) modifications suggestive of tumour progression and in whom the final diagnosis was a pseudoprogression. We identified six patients. All patients underwent a surgical resection and were treated with PCV chemotherapy without radiotherapy. After a median of 11 months following the initiation of chemotherapy (range: 3-49 months), the patients developed asymptomatic white matter MRI modifications around the surgical cavity leading to the suspicion of a tumour progression. These modifications appeared as hyperintense on T2-fluid-attenuated inversion recovery (FLAIR) sequence, hypointense on T1 sequence, and lacked mass effect (0/6), contrast enhancement (0/6), restriction on diffusion-weighted imaging (0/4), relative cerebral blood volume (rCBV) increase on perfusion MRI (0/4), and hypermetabolism on 18 F-fluoro-L-dopa positron emission tomography (18 F-DOPA PET) scan (0/3). One patient underwent a surgical resection demonstrating no tumour recurrence; the five other patients were considered as having post-therapeutic modifications based on imaging characteristics. After a median follow-up of 4 years all patients were progression-free. Anaplastic oligodendroglioma patients treated with postoperative PCV chemotherapy alone occasionally develop T2/FLAIR hyperintensities around the surgical cavity that can wrongly suggest tumour progression. Multimodal imaging and close follow-up should be considered in this situation.

Large tumour volume reduction of IDH-mutated anaplastic glioma involving the insular region\xa0following radiotherapy

BackgroundThe impact of near-total resection of IDH-mutated anaplastic glioma (IDHmutAG) is well-established but there remains uncertainty of benefit in tumours of the insular cortex where the extent of safe resection may be limited. This study aimed to assess tumour volume reduction in patients following IMRT and impact of residual post-surgical volume.Methods and materialsPatients with IDHmutAG involving insular cortex managed with IMRT from 2008 to 2019 had baseline patient, tumour and treatment factors recorded. Volumetric assessment of residual disease on MRI was performed at baseline, month+ 3 and month+ 12 post-IMRT. Potential prognostic factors were analysed for tumour reduction and relapse-free survival, and assessed by log-rank and Cox regression analyses.ResultsThirty two patients with IDHmutAG of the insular cortex were managed with median follow-up post-IMRT of 67.2 months. Pathology was anaplastic astrocytoma (AAmut) in 20, and anaplastic oligodendroglioma (AOD) in 12 patients. Median pre-IMRT volume on T1 and T2Flair was 24.3cm3 and 52.2cm3. Twenty-seven patients were alive with 5-year relapse-free survival of 80%. There was a median 67 and 64% reduction from baseline occurring at 3 months post-IMRT for T1 and T2Flair respectively; and subsequent median 78 and 73% at 12 months. At 12 months AOD patients had median 83% T1 volume reduction compared to 63% in AAmut (p < 0.01). There was no difference on T2Flair volume (p = 0.64). No other pathological factors influenced volume reduction at 12 months. No factors were associated with relapse-free survival including baseline T1 (p = 0.52) and T2Flair (p = 0.93) volume.ConclusionIMRT provides large tumour volume reduction in IDHmutAG of the insular cortex. While maximal safe debulking remains standard of care when feasible, this patient cohort reported no significant negative impact of residual disease volume on relapse-free survival.

High Radiation Dose On Fornix Resulted In Symptomatic Radiation Necrosis In Patients With Anaplastic Oligodendroglioma Treated With Surgery And Radiotherapy: A Preliminary Study

The assessment of various radiation-induced effects on important white matter tracts including the limbic circuit fibers is helpful to reduce toxicity. According to long-term follow up of EORTC 26951 trials, adding 6 cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT) prolonged survival in anaplastic oligodendroglioma (AO) patients. Consequently, this raised the interest the radiation induced long-term toxicity. We aimed to analyze the relation between RT dose of fornix and symptomatic radiation necrosis (SRN) in patients with AO treated with surgery and RT in this preliminary study. A 67 AO patients treated between Feb. 2009 and Jul. 2019 were analyzed. SRN was defined when three criteria were met: (1) radiographic findings were confirmed, (2) the patient experienced new or progressive symptoms that were attributable to the progressing lesion, and (3) treatment with corticosteroids, bevacizumab, or surgical resection only resulted in improvement of symptoms without further radiographic progression of the lesion. Various contours, including fornix, corpus callosum, basal ganglia, and septum pellucidum, are delineated manually on simulation CT fused with preoperative and postoperative MRI. Patients received 3 D-CRT (n = 17, 25%) or IMRT (n = 50, 75%) with median RT dose of 60 Gy (range, 52.5-70). Univariate logistic regression models were fitted to examine whether maximum and mean radiation dose of contours and treatment variables predicted the development of SRN. Receiver operating characteristic curve (ROC) analysis was used to assess the cut-point of radiation dose predicting SRN. With median follow-up of 42 months (range 9-125) for surviving patients, median overall survival and progression survival were 74 and 74 months, respectively. Median age was 41 years (range, 17-78) and median KPS was 90 (range, 50-100). The most common tumor locations were frontal (n = 49, 60%) and parietal (n = 16, 24%). Gross total resection was done for 38 patients (57%) and subtotal resection was done for 23 patients (34%). There were 42 patients (63%) received PCV chemotherapy. There were 17 patients (25%) who had SRN. Univariate analysis revealed that maximum dose of fornix (p = 0.011), mean dose of anterior (p = 0.033) and posterior fornix (p = 0.021) predicted the development of SRN. The maximum dose of fornix (equivalent total dose in 2 Gy fraction) was found to have the largest areas under the ROC curve (0.755, 95% CI 0.628-0.883), and the cut-off values for SRN was 59 Gy (EQD2). The rate of development of SRN was significantly higher in patients whose maximum dose of fornix more than 59 Gy (13 vs. 43%, p = 0.005). In our study, maximum dose of fornix is significant factor for development of SRN and cut point is 59 Gy (EQD2). Fornix sparing using modern RT technique is helpful to maintain neurocognitive function, and additional study is needed to evaluate the difference of recurrence and survival regarding fornix sparing.

Anaplastic Oligodendroglioma – Is Adjuvant Radiotherapy Mandatory following Maximal Surgical Resection?: Grade 3 Oligo Radiotherapy

Background. Current anaplastic oligodendroglioma (AO) management strategies involve surgical resection followed by adjuvant radiotherapy and/or chemotherapy. We investigated a subset of patients at our institution with AO, who, based on their treatment preferences, received surgery without any form of adjuvant therapy. This subset of patients was compared to a cohort with AO who received adjuvant therapy in order to investigate any differences in clinical and survival outcomes.Methods. A retrospective review of all AO patients treated by the senior author was undertaken between 1994 and 2018. A total of thirty-three cases were identified. Eleven had surgery alone, and twenty-two had surgery with adjuvant therapy. Progression free (PFS) and overall survival (OS) were compared between cohorts and potential confounders were addressed.Results. Gross total resection was achieved in 29 patients, and near total resection in 4 patients. PFS was not statistically different between patients treated with surgery alone versus patients receiving surgery plus adjuvant therapy (surgery alone: 84 ± 16 months; surgery with radiotherapy: 60 ± 9 months; p = 0.08). In addition, OS was also not statistically different between these groups (surgery alone: 215 ± 17 months; surgery with therapy: 241 ± 22 months; p = 0.44).Conclusions. It is reasonable to consider a “watch and monitor” surveillance strategy in patients who decline adjuvant radiotherapy following surgical resection of their AO. Patients should be made aware that this treatment plan is not standard within current models of care for AO.

P14.76 Characteristics of anaplastic oligodendrogliomas short-term survivors: a POLA network study

Abstract BACKGROUND Although patients with 1p/19q codeleted anaplastic oligodendrogliomas (AO) usually have a prolonged survival, some patients have a poorer outcome. The aim of the present study was to analyze their characteristics. MATERIAL AND METHODS The characteristics of AO patients with a survival &lt; 5 years included in the POLA network were analyzed and compared to those of AO patients with a survival &gt; 5 years. RESULTS In January 2019, among the 519 patients AO patients included in the POLA network, 55 patients were short-term survivors and 146 patients had a survival &gt; 5 years. Among the 55 AO short-term survivors, 44 patients (80%) died from tumor progression and 11 patients (20%) from another cause (suicide n=2, toxicity n=2, intercurrent disease n=6, other n=1). Compared to &gt; 5 years survivors, short-term survivors were older (57 years vs 48 years, p&lt;0.001) and less frequently presented with isolated seizures (9% vs 33%, p=0.0017). They presented with tumors that more frequently involved multiple lobes (66% vs 47%, p=0.03), had a higher rate of nuclear atypia (80% vs 48%, p&lt;0.001), a higher proliferative index (Ki67, 26% vs 18%, p&lt;0.001), a higher level of p53 expression (10.8% vs 3.9% p&lt;0.001), and had a higher rate of chromosomal abnormalities (91% vs 71% p=0.008). Compared to &gt; 5 years survivors, short-term survivors less frequently underwent a surgical resection (64% vs 89% p&lt;0.001) and their initial treatment more frequently consisted in temozolomide chemotherapy alone (41% vs 20% p=0.008). CONCLUSION AO short-term survivors are associated with distinct clinical, radiological, histological and molecular characteristics at diagnosis.

Radiation Therapy Cytotoxicity Score Predicts Optimal Dose and Fractionation for Individual Patients

Previously, we proposed the radiosensitivity index (RSI) and the genomic-adjusted dose (GARD) as a model to biologically-optimize radiotherapy (RT) dose, based on conventional fractionation (CF). We aimed to develop a new model to biologically-optimize fractionation. We utilize public data for the NCI60 cancer cell lines, including gene expression (GE, Affymetrix U133 2.0) and survival curves. Alpha (α) and beta (β) were calculated based on the linear quadratic model (LQ). Two machine learning models to predict α and β (RSIα/β) were developed using GE and support vector machines using six-fold cross validation. RT cytotoxicity score (RT-CTS) was calculated using RSIα/β, the LQ and each patient’s dose/fractionation to predict the number of clones killed. We calibrated RT-CTS in 58 patients with stage III NSCLC treated with post-op RT and identified thresholds that distinguished clinical outcome. The locked-down RT-CTS was tested in two independent cohorts, including 596 breast cancer patients treated with surgery +/- RT (median f/u=8 yrs) and 44 anaplastic oligodendroglioma (AO) patients from EORTC 26951, a Phase 3 clinical trial. In the breast cohort, patients received RT with CF (n=336, median 60Gy), accelerated partial breast RT (n=75 APBI, median 34 Gy) or no RT (n=260). In AO patients received 59.4 Gy. The lung/breast cohorts were from our IRB-approved biorepository. GE was from Affymetrix Hu-RSTA (breast, lung) and U133 Plus (AO). Time to event analysis was with Kaplan-Meier estimates and log-rank test. RT-CTS and outcomes were explored with univariable and multi-variable (MVA) Cox regression. The predicted median RSIα/β for lung, breast and AO was 4.5, 7.3 and 6.0, respectively. In the calibration cohort (NSCLC), patients with a predicted RT-CTS > 10-12 (RT-CTS12) had an improved 1-yr local control (LC) (84.3% vs 57.1% p<0.001) and overall survival (OS) (4.8 vs 1.9 yrs p=0.04). In patients with ≥ R1 resection, a predicted RT-CTS > 10-18 (RT-CTS18) showed improved 1-yr LC (91% vs 69.2% p=0.005) and OS (5.1 vs 2.6 yrs p=0.049). In EORTC 26951 patients that achieved RT-CTS18 had superior OS (5.7 vs 2.6 yrs p=0.02). In the RT breast cohort, patients who achieved RT-CTS12 had superior 8 yr LC (91% vs 72% p=0.03) that is significant on MVA (HR 0.29, p<0.014). In non-RT patients, RT-CTS12 (generated by simulating CF (50Gy)) did not predict 8 yr LC (p=0.95). The median α/β ratio of locally controlled patients with APBI was lower than CF (5.5 vs 7.9 p<0.001). We compared RT-CTS in breast patients (n=596) simulated with CF (50Gy) and IORT (20Gy). In CF, RT-CTS12 is not achieved in 21% but is achieved if treated with IORT. Conversely, 33% who do not achieve RT-CTS12 with IORT are rescued with CF. We develop and validate a clinically-actionable machine learning model that predicts RT-CTS, an individualized RT cytotoxicity score. RT-CTS predicts no fractionation approach is universally optimal and provides a basis to biologically-tailor RT dose and fractionation.

Prognostic factors associated with survival in patients with anaplastic oligodendroglioma.

Anaplastic oligodendroglioma is a rare disease with an inadequately understood prognosis. The aim of this study was to investigate factors associated with survival outcome in anaplastic oligodendroglioma patients. A population-based cohort study was conducted based on the Surveillance, Epidemiology, and End Results program. In total, 1899 patients with a histological diagnosis of anaplastic oligodendroglioma from 1973 to 2015 were included. Mean age at diagnosis was 49.2 years, and 56.19% were male. In our study, 62.40% of patients were married, and 87.05% were white. Most patients (90.42%) were diagnosed with anaplastic oligodendroglioma as their first malignant primary tumor, but 9.58% had a diagnosis of at least one other primary malignancy; 87.89% of patients had received cancer-directed surgery. Patients receiving surgery had a better prognosis for overall survival compared to those not receiving surgery after propensity score matching analysis (p<0.05). The overall 1-, 3-, 5-, and 10-year survival of anaplastic oligodendroglioma was 78.7%, 60%, 50.2%, and 36.2%, respectively. Kaplan-Meier analysis indicated that age, marital status, presence of multiple primary malignancies, and surgical treatment were associated with overall survival, whereas sex and race were not. Moreover, age at diagnosis of 52 years was calculated as an optimal cutoff value to distinguish better and worse overall survival. Multivariate Cox proportional hazard analysis indicated that older age (OR 1.040, 95%CI1.035–1.045), single patients (OR 1.293, 95%CI 1.103–1.515), and presence of multiple primary malignancies (OR 1.501, 95%CI 1.238–1.820) were significantly associated with worse overall survival, whereas surgery (OR 0.584, 95%CI 0.494–0.689) was associated with better overall survival. A nomogram predicting 5-, and 10-year survival probability for anaplastic oligodendroglioma was constructed based on these variables. In conclusion, age, marital status, presence of multiple primary malignancies, and surgical treatment were associated with survival of anaplastic oligodendroglioma.

Estudo exploratório da administração intranasal do monoterpeno álcool perílico em pacientes com glioma recidivante

Objetivo: Conduzimos estudo de fase I/II para avaliar atividadeantitumoral do álcool perílico (AP) por via inalatóriaem pacientes com gliomas recidivantes. Pacientes e Métodos: Trinta e sete pacientes com glioma recidivanteapós tratamento convencional foram matriculados,dos quais 29 com glioblastoma (GBM), 5 com astrocitomaanaplásico (AA) e 3 com oligodendroglioma anaplásico (OA).O objetivo foi determinar a sobrevida livre de progressão no6º mês e a toxicidade do AP administrado 4 vezes ao dia empacientes refratários ao tratamento convencional. Resultados: Os resultados mostraram no 6º mês de tratamento, resposta parcial em 1 paciente (3,4%) com GBM e 1paciente (33,3%) com OA; doença estável em 13 pacientes(44,8%) com GBM, 3 pacientes (60%) com AA e 1 paciente(33,3%) com OA; progressão da doença em 15 pacientes(51,7%) com GBM, 2 pacientes (40%) com AA e 1 paciente(33,3%) com OA. A sobrevida livre de progressão (somatóriode resposta parcial e doença estável) foi de 48,2% para pacientescom GBM, 60% para pacientes com AA e 66,6% parapacientes com OA. Conclusão: O presente trabalho mostrou pela primeira vez,que a administração intranasal de um inibidor da transduçãodo sinal, álcool perílico, é uma estratégia segura, não invasiva,de baixo custo, e a regressão do volume tumoral em algunspacientes é sugestivo de atividade antitumoral.

Genetic landscape of extreme responders with anaplastic oligodendroglioma.

BackgroundThe NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not. Methods: We performed whole exome sequencing on matched tumor and normal DNA from all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. hTERT status and rs55705857 genotypes (G-allele) were analyzed in both cohorts. Results: Six STS (survival of <7.3y) and 7 LTS (survival of ≥7.3y and no progression) had sufficient material for analysis. There was no significant difference between the groups regarding age, performance status and extent of resection. On average, STS had 7 and LTS 4 mutations. Most common mutations in STS vs. LTS were: IDH1 (67 vs. 86%), CIC (50 vs. 71%) and FUBP1 (17 vs. 71%). The hTERT promoter was mutated in 83% STS and 86% LTS. Genotyping of rs55705857 showed a higher prevalence of G allele carriers in LTS than STS (43 vs. 17%).ConclusionsThese findings confirm that IDH, CIC, FUBP1 mutations and rs55705857 genotype are common in AO. No distinct genetic signature was identified to differentiate STS and LTS.

Effects of the functional HOTAIR rs920778 and rs12826786 genetic variants in glioma susceptibility and patient prognosis.

Abnormal expression of the long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is oncogenic in several human cancers, including gliomas. The HOTAIR single nucleotide polymorphisms (SNPs) rs920778 (C > T) and rs12826786 (C > T) present in the intronic enhancer and promoter regions of HOTAIR, respectively, are associated with expression, cancer susceptibility, and patient prognosis in some tumor types. However, the relevance of these HOTAIR SNPs has not been studied in glioma. Here, we report a case-control study comprising 177 Portuguese glioma patients and 199 cancer-free controls. All subjects were genotyped by PCR and restriction fragment length polymorphism (RFLP). No statistically significant differences were found in the genotype or allele distributions of either rs920778 or rs12826786 between glioma patients and controls, suggesting these SNPs are not associated with glioma risk. No significant associations were found between rs920778 variants and HOTAIR expression levels, while rs12826786 CT genotype was associated with increased intratumoral HOTAIR RNA levels when compared to TT genotype (p-value = 0.04). Univariate (Log-rank) and multivariate (Cox proportional) analyses showed both rs920778 CT and rs12826786 CT genotypes were significantly associated with longer overall survival of WHO grade III anaplastic oligodendroglioma patients. Our results suggest that HOTAIR SNPs rs920778 and rs12826786 do not play a significant role in glioma susceptibility, but may be important prognostic factors in anaplastic oligodendroglioma patients. Future studies are warranted to validate and expand these findings, and to further dissect the importance of these SNPs in glioma.

The Correlation Between 1p/19q Codeletion, IDH1 Mutation, p53 Overexpression and Their Prognostic Roles in 41 Turkish Anaplastic Oligodendroglioma Patients.

To observe the correlation between 1p/19q codeletion, isocytrate dehydrogenase-1 (IDH1) mutation and p53 protein overexpression and their prognostic value in Turkish anaplastic oligodendroglioma patients who were treated with adjuvant radiotherapy and temozolomide chemotherapy. We retrospectively evaluated 41 patients who were diagnosed as anaplastic oligodendroglioma. Thirty-five patients received standard radiotherapy. Twenty-six patients received standard temozolomide chemoterapy concurrent to radiotherapy. Chromosome 1p/19q codeletion was observed in 19 of 41 patients (46%) via Fluorescent In Situ Hybridisation (FISH) technique. Twenty-six patients (63%) showed positive immunoreaction with anti-IDH1 antibody. Six patients (15%) showed positive immunoreaction with anti-p53 antibody. A statistically significant correlation was determined between chromosome 1p/19q codeletion and IDH1 mutation (p < 0.0001). The patients who had tumors with chromosome 1p/19q codeletion and p53 overexpression were mutually exclusive. The mean estimated Progression Free Survival (PFS) of the patients who had tumors with chromosome 1p/19q codeletion and/or IDH1 mutation was determined to be significantly longer than that of the patients without these genetic changes, regardless of the treatment modality (p=0.006, p=0.004). PFS of the patients who received adjuvant chemotherapy and whose tumors had chromosome 1p/19q codeletion or IDH1 mutation was significantly longer than that of the patients without these genetic changes (p=0.001, p < 0.0001). Chromosome 1p/19q codeletion and/or IDH1 mutation are favorable prognostic factors in anaplastic oligodendroglioma patients, in terms of PFS.

P17.49 * TREATMENT STRATEGY FOR WHO GRADE III GLIOMAS: THE LESSONS LEARNED FROM THE RETROSPECTIVE MULTICENTER ANALYSIS OF 243 PATIENTS

OBJECTIVE: This retrospective analysis was performed to determine the efficacy, safety, and tolerability of treatment protocols including radiation therapy, concurrent chemoradiotherapy (CCRT) followed by adjuvant chemotherapy with temozolomide (TMZ), or PCV chemotherapy based on the status of molecular diagnosis in the treatment of patients with WHO grade III gliomas. MATERIALS: Two hundred forty three adult patients with WHO grade III glioma and aged > 17 years were enrolled from two institutions between 2004 and 2012. The pathological diagnoses were anaplastic astrocytomas (AA) in 150 patients and anaplastic oligodendrogliomas (AO) including anaplastic oliogoastrocytomas in 93 patients. Co-deleted group on 1p19q LOH analysis was 60 of available 183 patients and un-methylated group of MGMT promoter was 64 of available 170 patients. The AA patients received four different treatment protocols in same strategy in two institutions: radiation therapy only, CCRT with temozolomide, radiation therapy followed by PCV or temozolomide adjuvant chemotherapy, and nothing after surgery. The AO patients received also four different treatment protocols in same strategy in two institutions: radiation therapy only, CCRT with temozolomide, radiation therapy combined with PCV (neo- or) adjuvant chemotherapy, and temozolomide chemotherapy only after surgery. RESULTS: Overall survival (OS) and progression free survival (PFS) were superior in AO (98m and 61m) than in AA (34m and 23m) and 1p19q co-deleted group had significantly longer OS (98m vs 42m) and PFS regardless treatment protocols. In AA patients RT only group and CCRT with temozolomide group had the better OS and PFS than other two groups. Methylation status of MGMT promoter in these patients did not affect survival differences. In AO patients RT only group, PCV based chemotherapy group (neoadjuvant or adjuvant PCV), or CCRT with temozolomide groups had no statistically significant differences in survival data. However 1p19q co-deleted group had a much better survival data (OS 98m vs 53; PFS not reached yet vs 38m). CONCLUSION: 1p19q co-deletion (molecular diagnosis) may be more important than morphologic diagnosis in grade III gliomas. The methylation status of MGMT promoter is not important such as in case of grade IV, glioblastoma. Adjuvant PCV might improve OS and PFS in AO regardless of the timing of PCV, either pre-RTx. or post-RTx. CCRTx. with TMZ may improve OS in non co-deleted group and this will be one of good candidate for standard one. A randomized controlled study with a long-term follow-up may be mandatory to evaluate and to make a best treatment protocol for these tumors.

O10.02 * MITOTIC INDEX, MICROVASCULAR PROLIFERATION AND NECROSIS DEFINE THREE GROUPS OF 1P/19Q CO-DELETED ANAPLASTIC OLIGODENDROGLIOMAS ASSOCIATED WITH DIFFERENT GENOMIC ALTERATIONS

BACKGROUND: The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AO). METHODS: The histological characteristics of 203 AO patients enrolled in the French national network POLA were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing. RESULTS: 1p/19q co-deletion was present in 79% of cases and was associated with alpha-internexin expression (p < 10-4), IDH1/2 mutation (p < 10-4), chromosome 4 loss (p < 10-3), and better overall survival (p < 10-4). Based on mitotic index, microvascular proliferation (MVP) and necrosis, 3 groups of 1p/19q co-deleted AO were identified: AO with more than 5 mitoses per 10-HPF, no MVP and no necrosis, (1), AO with MVP and no necrosis (2) and AO with MVP and necrosis (3). Compared to group 1, group 2 and 3 AO had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared to group 2, group 3 AO had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q co-deleted AO, chromosomal instability was associated with shorter progression free survival (p = 0.024) and shorter overall survival (p = 0.023). CONCLUSIONS: The present study shows that oligodendroglioma with classic histological features remains a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q co-deleted AO are also heterogeneous. Interestingly, mitotic index, MVP and necrosis help to classify them into three groups associated with distinct genomic alterations.

Mitotic index, microvascular proliferation, and necrosis define 3 groups of 1p/19q codeleted anaplastic oligodendrogliomas associated with different genomic alterations.

The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AOs). The histological characteristics of 203 AO patients, enrolled in the French national network POLA, were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing. 1p/19q codeletion was present in 79% of cases and was associated with alpha-internexin expression (P < 10(-4)), IDH1/2 mutation (P < 10(-4)), chromosome 4 loss (P < 10(-3)), and better overall survival (P < 10(-4)). Based on mitotic index, microvascular proliferation (MVP), and necrosis, 3 groups of 1p/19q codeleted AOs were identified: (group 1) AO with more than 5 mitoses per 10-HPF, no MVP, and no necrosis; (group 2) AO with MVP and no necrosis; and (group 3) AO with MVP and necrosis. Compared with group 1, groups 2 and 3 AOs had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared with group 2, group 3 AOs had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q codeleted AOs, chromosomal instability was associated with shorter progression-free survival (P = .024) and shorter overall survival (P = .023). The present study shows that oligodendrogliomas with classic histological features remain a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q codeleted AOs are also heterogeneous. Interestingly, mitotic index, MVP, and necrosis help to classify them into 3 groups associated with distinct genomic alterations.

Contrast enhancement in 1p/19q-codeleted anaplastic oligodendrogliomas is associated with 9p loss, genomic instability, and angiogenic gene expression

The aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs). The MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays. Most of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2. In AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.

Effectiveness of radiotherapy for elderly patients with anaplastic gliomas

Postoperative radiotherapy (RT) is utilized routinely in the management of anaplastic World Health Organization Grade III gliomas (AG), including anaplastic astrocytoma (AA) and anaplastic oligodendroglioma (AO). However, the optimal role of RT in elderly AG patients remains controversial. We evaluated the effectiveness of RT in elderly AG patients using a national cancer registry. The USA Surveillance, Epidemiology, and End Results database (1990–2008) was used to query patients over 70years of age with AA or AO. Independent predictors of overall survival were determined using a multivariate Cox proportional hazards model. Among 390 elderly patients with AG, 333 (85%) had AA and 57 (15%) had AO. Approximately two-thirds of AA patients (64%) and AO patients (65%) received RT. Most AO patients (58%) and many AA patients (41%) underwent surgical resection; the remainder had biopsy. The median overall survival for all patients who underwent RT was 6months (95% confidence interval [CI], 5–7months) versus 2months (95% CI 1–6) in patients who did not have RT. Patients who had gross total resection (GTR) plus RT had a median overall survival of 11 months (95% CI 7–14). Multivariate analysis for all patients showed that undergoing RT was significantly associated with improved survival (hazard ratio [HR] 0.52, p<.0001). AA tumor type (HR 1.37, p=.03) was associated with worse survival than AO tumor type; female sex (HR 0.59, p<.0001) and being married (HR 0.66, p=.002) significantly improved survival. Patients that underwent GTR had a significant reduction in the hazards of mortality compared to biopsy (HR 0.72, p=.04). Elderly AG patients undergoing RT had better overall survival compared to patients who did not receive RT. Treatment strategies involving maximal safe resection plus RT should be considered in the optimal management of AG in elderly patients.

Correlation of IDH1/2 mutation with clinicopathologic factors and prognosis in anaplastic gliomas: a report of 203 patients from China

Isocitrate dehydrogenase (IDH) gene mutation is one of the most exciting new advances in these years. It has been reported that IDH gene frequently altered in grade II and grade III gliomas. We aimed to identify the mutation frequency of IDH genes in Chinese anaplastic glioma patients, the association of IDH gene mutation with other clinical and molecular pathological features and the prognostic value of it. We performed polymerase chain reaction-based IDH gene mutation detection in 203 anaplastic glioma patients from China. A total of 108 and 3 patients harbored IDH1 and IDH2 gene mutation, respectively. And there was a higher proportion of MGMT promoter methylation, frontal lobe location, and better outcome and lower proportion of temporal location in IDH-mutated samples. There were hardly any significant association between protein expression level of well-known markers and IDH mutation. Anaplastic oligoastrocytoma and anaplastic astrocytoma patients with IDH gene mutation showed similar prognosis with anaplastic oligodendroglioma patients with wild-type IDH gene. IDH gene mutation is a good prognostic marker and a potential substratification factor for anaplastic glioma patients.

Survival and Prognostic Factors of Anaplastic Gliomas

The prognosis of patients with anaplastic glioma tumors is relatively favorable compared with patients with glioblastoma multiforme. To estimate survival differences between anaplastic astrocytoma (AA) and anaplastic oligodendroglioma (AO) patients and factors associated with survival prognosis. A nationwide cohort of grade III glioma patients diagnosed between 1990 and 2008 was studied using the Surveillance, Epidemiology, and End Results registry. Multivariate Cox proportional hazard models evaluated the role of patient and clinical characteristics on overall survival. A total of 1766 patients with AA and 570 patients with AO were studied. The median overall survival was 15 and 42 months among AA and AO patients, respectively. Age increments of 10 years implicated a 50% increase in mortality hazards among AA (hazard ratio [HR], 1.49; P < .001) and AO (HR, 1.51; P < .001) patients. Among AA patients, radiation (HR, 0.62; P < .001), surgery (vs biopsy; HR, 0.73; P < .001), female sex (HR, 0.87; P = .02), and married status (HR, 0.87; P = .02) were associated with a reduction in the hazard of mortality. Longer survival if diagnosed in 2000 relative to 1990 was observed (HR, 0.84; P = .004) in AA patients. Although surgery did not significantly improve survival among AO patients, gross total resection increased the median survival from 40 to 61 months (P = .001) in this cohort. First-course radiation, younger age, female sex, treatment in recent years, and surgery were associated with improved survival in AA patients. In contrast, age was the most prominent predictor of survival in AO patients. Surgery alone did not seem to benefit AO patients, and gross total resection improved survival by 21 months.

Anaplastic Oligodendroglioma: A New Treatment Paradigm and Current Controversies

Anaplastic oligodendroglial tumors have gained increasing interest with the emerging role of molecular markers and systemic chemotherapy during the past years. The long-term results of two landmark trials, RTOG 9402 and EORTC 26961, have resulted in a reconsideration of the appropriate therapeutic approaches for patients with these tumors. Both trials indicate that patients whose tumors harbor a 1p/19q co-deletion benefit particularly from the addition of procarbazine/lomustine (CCNU)/vincristine (PCV) chemotherapy to radiation therapy (RT). The median survival of patients with co-deleted tumors treated within the RTOG trial with PCV before irradiation was 14.7 years compared with 7.3 years of patients who received RT alone. Median overall survival has not been reached in the RT plus PCV arm of the EORTC trial, but a similar difference can be anticipated after a follow-up of more than 12 years. In contrast, no such benefit was observed for patients with tumors lacking 1p/19q co-deletion. Outside clinical trials, patients with anaplastic oligodendroglial tumors, and 1p/19q co-deletion therefore should be offered a combined treatment modality regimen, including radio- and chemotherapy. PCV, however, is associated with significant hematological toxicity and also nonhematological side effects, which probably translate into reduced quality of life for long-term survivors. Therefore, it might be warranted to replace PCV by temozolomide, which displays a more favorable side effect profile. Data from the NOA-04 study suggest that PCV and temozolomide have similar effects. However, long-term data on the benefit from temozolomide are lacking, making a definite answer on the equivalence of temozolomide and PCV in anaplastic oligodendroglioma (AO) impossible. The current evidence precludes RT alone for AO patients. Neither the RTOG nor the EORTC trial defined the role of chemotherapy alone. A comparison of combined modality treatment with chemotherapy alone followed by RT at progression is pending. Long-term follow-up of NOA-04 patients and results from future trials may help to clarify these questions. With more and more AO patients living 10 years or more, particular attention must be paid to late side effects, such as neurotoxicity, and careful monitoring is required for all treated patients.