Pattern of failure in anaplastic glioma patients with an IDH1/2 mutation.

PURPOSE: The current study aimed to assess patterns of failure (PoF) in anaplastic glioma (AG) patients managed with intensity-modulated radiation therapy (IMRT) and their relationship to molecular subtype. METHODS: The outcomes of AG patients managed between 2008 and 2014 and entered into a prospective database were assessed, including PoF. AG was initially defined using the WHO 2007 classification, but for analysis, patients were subsequently recategorised based on WHO 2016 as anaplastic oligodendroglioma (AOD), astrocytoma isocitrate dehydrogenase (IDH) mutant (AAmut) or astrocytoma IDH wildtype (AAwt). Management involved IMRT and temozolomide (TMZ), including from 2011 patients with an IDH mutation (IDHmut) planned with 18F-fluoroethyltyrosine (FET) and 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET). PoF was local, marginal or distant in relation to the IMRT volume. Relapse-free survival (RFS) was calculated from the start of IMRT. RESULTS: A total of 156 patients were assessed, with median follow-up of 5.1 years. Of these patients, 75% were IDHmut, 44% were managed at first or later relapse and 73% received TMZ. Relapse occurred in 68 patients, with 6­year RFS of 75.0, 48.8 and 2.5% for AOD, AAmut and AAwt, respectively (p < 0.001). There was a component of local relapse in 63%, of marginal relapse in 19% and of distant relapse in 37% of relapses. Isolated local, marginal and distant relapse was evident in 51, 9 and 22%, respectively. A distant relapse pattern was more frequent in IDHmut compared to IDHwt patients (26% vs. 45%, p = 0.005), especially within the first 2 years post-IMRT. In multivariate analysis, distant relapse remained associated with AAmut (p < 0.002) and delayed IMRT until the second relapse (p < 0.001). CONCLUSION: Although patients with IDH-mutated AG have improved outcomes, there was a higher proportion of distant relapses occurring during the 2 years after IMRT.

A multi-institutional analysis of clinical outcomes and patterns of care of 1p/19q codeleted oligodendrogliomas treated with adjuvant or salvage radiation therapy.

PURPOSE: Practice patterns vary for adjuvant treatment of 1p/19q-codeleted oligodendroglioma patients. This study evaluates the outcomes of adjuvant (aRT) versus salvage radiation therapy (sRT) in a multi-institutional cohort. METHODS: Oligodendroglioma patients with confirmed 1p/19q codeletion who were treated with RT with or without chemotherapy from 2000 to 2017 at four tertiary centers were retrospectively reviewed. Overall survival (OS), post-RT progression-free survival (PFS), freedom-from-RT (FFRT), and radiation necrosis (RN) rates were determined using Kaplan-Meier analyses. OS1/PFS1 were defined from the initial surgery. OS2/PFS2 were defined from the RT start-date. Multivariable analyses (MVAs) of prognostic factors for OS and PFS were performed with Cox regression. RESULTS: One hundred eighty-six patients were identified: 124(67%) received aRT and 62(33%) received sRT; of sRT patients, 58% were observed after surgery while 42% received chemotherapy without aRT. The median time from initial diagnosis to sRT was 61 months, and 74% had reoperations before sRT. sRT had longer OS1 than aRT (94% vs. 69% at 10 years, p = 0.03) and PFS1 (10-year PFS of 80% vs. 68%, p = 0.03), though sRT was not associated with significantly different OS1/PFS1 on MVAs. Chemotherapy did not delay sRT compared to observation and had worse PFS2 (42% vs. 79% at 5 years, p = 0.08). Higher RT dose was not associated with improved clinical outcomes but was associated with higher symptomatic RN rate (15% vs. 0% at 2 years, p = 0.003). CONCLUSIONS: Delaying RT for selected oligodendroglioma patients appears safe. Adjuvant chemotherapy does not delay sRT longer than observation and may be associated with worse PFS after RT.

Postsurgical Approaches in Low-Grade Oligodendroglioma: Is Chemotherapy Alone Still an Option?

BACKGROUND: Patients with low-grade gliomas (LGGs) with isocitrate dehydrogenase (IDH) mutation (mut) and 1p19q codeletion (codel) have a median overall survival of longer than 10 years. The aim of this study is to assess the role of postsurgical treatments. SUBJECTS, MATERIALS, AND METHODS: We evaluated patients with LGGs with IDH mut and 1p19q codel; IDH1/2 was performed by immunohistochemistry and quantitative polymerase chain reaction. In all wild-type cases, we performed next-generation sequencing. 1p19 codel analysis was performed by fluorescence in situ hybridization. RESULTS: Among the 679 patients, 93 with LGGs with IDH mutation and 1p19q codel were included. Median follow-up (FU) was 96.1 months. Eighty-four patients (90.3%) were high risk according to Radiation Therapy Oncology Group criteria. After surgery, 50 patients (53.7%) received only FU, 17 (18.3%) chemotherapy (CT), and 26 (30.1%) radiotherapy (RT) with (RT + CT, 8 patients, 8.6%) or without (RT, 18 patients, 19.4%) chemotherapy. Median progression-free survival (mPFS) was 46.3 months, 50.8 months, 103.6 months, and 120.2 months in patients with FU alone, with CT alone, with RT alone, or with RT + CT, respectively. Median PFS was significantly longer in patients who received postsurgical treatment (79.5 months, 95% confidence interval [CI]: 66.4-92.7) than patients who received FU (46.3 months, 95% CI: 36.0-56.5). Moreover, mPFS was longer in patients who received RT (alone or in combination with CT, n = 26, 113.8 months, 95% CI: 57.2-170.5) than those who did not (n = 67, 47.3 months, 95% CI: 36.4-58.2). In particular, temozolomide alone did not improve PFS with respect to FU. CONCLUSION: RT with or without chemotherapy, but not temozolomide alone, could extend PFS in IDH mut 1p19q codel LGGs. IMPLICATIONS FOR PRACTICE: Low-grade gliomas with high-risk features, defined according to Radiation Therapy Oncology Group criteria, receive radiotherapy and/or chemotherapy as postsurgical treatments. Radiotherapy, however, has serious long-term effects (cognitive impairment), which are to be taken into account in these young patients. Moreover, low-grade gliomas with isocitrate dehydrogenase mutation and 1p19q codeletion (oligodendrogliomas) have an extremely long survival and a better prognosis. This study suggests that postsurgical treatments prolong the time before tumor progression in patients with good prognosis as well as those with oligodendroglioma. Moreover, temozolomide alone might not be effective in prolonging progression-free survival.

Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma.

BACKGROUND: Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results. METHODS: We included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy. RESULTS: A total of 251 eligible patients were enrolled from 1998 through 2002. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%. A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival. CONCLUSIONS: In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375.).

Eighty percent survival rate at 15 years for 1p/19q co-deleted oligodendroglioma treated with upfront chemotherapy irrespective of tumor grade.

INTRODUCTION: Chromosomes 1p/19q co-deletion is a robust molecular marker for the diagnosis of oligodendroglial tumors, and has been included in the 2016 WHO modified classification. Although treatment for oligodendroglioma is controversial, upfront chemotherapy is regarded as one of the treatment option for low-grade tumor. We have treated all the 1p/19q co-deleted oligodendrogliomas, both grades II and III, with upfront chemotherapy without conventional radiotherapy for 20 years. The clinical experience from this trial may be suggestive for understanding of the biological features of oligodendroglioma with 1p/19q co-deletion toward precision medicine. METHODS: This is a long-term retrospective data of the non-selected patients with 1p/19q co-deleted oligodendrogliomas uniformly treated with up-front chemotherapy. Seventy consecutive patients (48 with grade II and 22 with grade III tumors) were included. RESULTS: The median follow-up period was 13 years. The 5-, 10-, and 15-year progression-free survival (PFS) rates were 85.7%, 54.8%, and 31.5%, respectively, and the median PFS was 146 months. In most cases, tumor recurrence was remained local and could be controlled by salvage surgery and/or chemotherapy. The 5-, 10-, and 15-year overall survival (OS) rates were 96.8%, 88.7%, and 80.0%, respectively, and the median OS was not reached. These survival data compared favorably with previous large clinical studies employing radiotherapy. Tumor grades based on World Health Organization classification, extent of surgery, and age affected neither PFS nor OS. Most patients were able to return to their premorbid social life. CONCLUSIONS: The long-term results drawn from 20-years of single institution experience show that the patients with 1p/19q co-deleted oligodendrogliomas can be successfully treated with up-front chemotherapy alone without compromising OS.

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

BACKGROUND: 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. OBJECTIVE: To assess the association between extent of resection (EOR) and survival for oligodendrogliomas in the general U.S. METHODS: 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. RESULTS: 3135 Cases were included in the final analysis. The 75% survival time (75ST) and 5-year survival rates were 47 months and 70.8%, respectively. Subtotal resection (STR, 75ST = 50 months) and GTR (75ST = 61 months) were associated with improved survival times compared to cases that did not undergo surgical debulking (75ST = 20 months, 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. CONCLUSION: Greater EOR is associated with improved survival in oligodendrogliomas. Our findings in this U.S. population-based cohort support national guidelines.

Semi-quantitative evaluation of brain gliomas in adults: A focus on neuropathological characteristics.

INTRODUCTION: Gliomas are neoplasms with high recurrence and mortality. Due to the difficulty to apply the World Health Organization (2016) classification, developing countries continue to use histological evaluation to diagnose and classify these neoplasms. OBJECTIVE: To develop a semi-quantitative scale to numerically grade gliomas by its morphological characteristics. METHOD: A cohort of patients with gliomas was assessed and followed for 36 months. Tumor tissue sections were analyzed and graded, including aspects such as cell line, cellularity, nuclear pleomorphism, mitosis, endothelial hyperplasia, hypoxic changes, apoptotic bodies, necrosis, hemorrhage and proliferation index. RESULTS: 58 cases were analyzed. Low-grade gliomas median score was 12 points (9 and 13.5 for percentiles 25 and 75, respectively), whereas for high-grade gliomas it was 17 points (16 and 20.5 for percentiles 25 and 75, respectively) (p < 0.0001). Thirty-six-month survival of patients with low (13/17) and high grade gliomas (6/41) was also significantly different (p < 0.0001). CONCLUSIONS: The semi-quantitative morphological scale allows an objective evaluation of gliomas, with an adequate correlation between the score, tumor grade and survival time.

Machine Learning for Better Prognostic Stratification and Driver Gene Identification Using Somatic Copy Number Variations in Anaplastic Oligodendroglioma.

BACKGROUND: 1p/19q-codeleted anaplastic gliomas have variable clinical behavior. We have recently shown that the common 9p21.3 allelic loss is an independent prognostic factor in this tumor type. The aim of this study is to identify less frequent genomic copy number variations (CNVs) with clinical importance that may shed light on molecular oncogenesis of this tumor type. MATERIALS AND METHODS: A cohort of 197 patients with anaplastic oligodendroglioma was collected as part of the French POLA network. Clinical, pathological, and molecular information was recorded. CNV analysis was performed using single-nucleotide polymorphism arrays. Computational biology and feature selection based on the random forests method were used to identify CNV events associated with overall survival and other clinical-pathological variables. RESULTS: Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. Forty-six focal amplification events and 22 focal deletion events were identified. Twenty-four focal CNV areas were associated with survival, and five of them were significantly associated with survival after multivariable analysis. Nine out of 24 CNV events were validated using an external cohort of The Cancer Genome Atlas. Five of the validated events contain a cancer-related gene or microRNA: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozygosity, FGFR3 amplification, and ARNT amplification. The CNV profile contributes to better survival prediction compared with clinical-based risk assessment. CONCLUSION: Several recurrent CNV events, detected in anaplastic oligodendroglioma, enable better survival prediction. More importantly, they help in identifying potential genes for understanding oncogenesis and for personalized therapy. IMPLICATIONS FOR PRACTICE: Genomic analysis of 197 anaplastic oligodendroglioma tumors reveals recurrent somatic copy number variation areas that may help in understanding oncogenesis and target identification for precision medicine. A machine learning multivariable model built using this genomic information enables better survival prediction.

Comparative analysis of histologically classified oligodendrogliomas reveals characteristic molecular differences between subgroups.

BACKGROUND: Molecular data of histologically classified oligodendrogliomas are available offering the possibility to stratify these human brain tumors into clinically relevant molecular subtypes. METHODS: Gene copy number, mutation, and expression data of 193 histologically classified oligodendrogliomas from The Cancer Genome Atlas (TCGA) were analyzed by well-established computational approaches (unsupervised clustering, statistical testing, network inference). RESULTS: We applied hierarchical clustering to tumor gene copy number profiles and revealed three molecular subgroups within histologically classified oligodendrogliomas. We further screened these subgroups for molecular glioma markers (1p/19q co-deletion, IDH mutation, gain of chromosome 7 and loss of chromosome 10) and found that our subgroups largely resemble known molecular glioma subtypes. We excluded glioblastoma-like tumors (7a10d subgroup) and derived a gene expression signature distinguishing histologically classified oligodendrogliomas with concurrent 1p/19q co-deletion and IDH mutation (1p/19q subgroup) from those with predominant IDH mutation alone (IDHme subgroup). Interestingly, many signature genes were part of signaling pathways involved in the regulation of cell proliferation, differentiation, migration, and cell-cell contacts. We further learned a gene regulatory network associated with the gene expression signature revealing novel putative major regulators with functions in cytoskeleton remodeling (e.g. APBB1IP, VAV1, ARPC1B), apoptosis (CCNL2, CREB3L1), and neural development (e.g. MYTIL, SCRT1, MEF2C) potentially contributing to the manifestation of differences between both subgroups. Moreover, we revealed characteristic expression differences of several HOX and SOX transcription factors suggesting the activity of different glioma stemness programs in both subgroups. CONCLUSIONS: We show that gene copy number profiles alone are sufficient to derive molecular subgroups of histologically classified oligodendrogliomas that are well-embedded into general glioma classification schemes. Moreover, our revealed novel putative major regulators and characteristic stemness signatures indicate that different developmental programs might be active in these subgroups, providing a basis for future studies.

Regional specificity of 1p/19q co-deletion combined with radiological features for predicting the survival outcomes of anaplastic oligodendroglial tumor patients.

In this study we aimed to identify the anatomic features of 1p/19q co-deletion and investigate the predictive values of tumor location and radiological characteristics for the survival of anaplastic oligodendroglial (AO) glioma patients. Voxel-based lesion-symptom mapping (VLSM) analysis was applied to define the brain regions associated with occurrence of 1p/19q co-deletion in a cohort of 206 AO tumor patients (discovery set) treated between May 2009 and September 2013. Retrospectively, the acquired clusters and radiological features were subjected to Kaplan-Meier survival analysis using data from the Chinese Glioma Genome Atlas (validation set) to evaluate their prognostic role in AO patients. The institutional review board approved this study. The right frontal lobe and right anterior insular lobe were specifically associated with high occurrence of 1p/19q co-deletion. For AO tumors not involving these areas, the absence of contrast enhancement predicted longer progression-free (p = 0.018) and overall survival (p = 0.020); moreover, in patients with contrast enhancement, edema could stratify the survival outcome (p = 0.013 for progression-free survival, p = 0.016 for overall survival). For AO tumors located in the VLSM-identified regions, edema was also able to stratify the survival outcome of patients without contrast enhancement (p = 0.025 for progression-free survival, p = 0.028 for overall survival). The 1p/19q co-deletion showed predilection for specific brain regions. According to the tumor involvement of VLSM-identified regions associated with 1p/19q co-deletion, radiological features were predictive for AO patient survival outcomes.

Oligodendrogliomas in pediatric and teenage patients only rarely exhibit molecular markers and patients have excellent survivals.

Although oligodendrogliomas appear histologically similar in adult and pediatric patients, the latter have only been rarely studied and most of those studies did not have long follow-up. We examined 55 oligodendroglial tumors from pediatric and teenage patients for their biomarkers with formalin-fixed paraffin-embedded tissues and studied their survival status. None of the tumors harbored 1p/19q codeletion or IDH mutation. Mutations in TERTp (4%), BRAF (11%), FGFR1 (3%) and H3F3A (5%), fusions of BRAF (8%) and FGFR1 (8%) were found sparingly and almost all in a mutually exclusive manner. Molecular events were exclusively found in tumors with classic oligodendroglial histology. Survival analysis showed remarkably excellent prognosis compared to the adult counterparts. 5-year overall survival was 95% in our cohort with median follow-up of 8.1 years and in nine patients with follow-up more than 10 years, the 10-year overall survival was 100%. The 5-year and 10-year progression-free survivals of our cohort were 89 and 77%, respectively. FGFR1 fusion seemed to confer a poor prognosis in pediatric oligodendrogliomas. Patients receiving adjuvant chemotherapy (p = 0.046) or harboring Grade II histology (p < 0.001) had longer interval to recurrence. Our study demonstrated the distinct indolent clinical course of pediatric and teenage oligodendrogliomas compared to the adult tumors. Molecular markers commonly seen in adult oligodendrogliomas and other pediatric low-grade gliomas were only rarely seen. Since there is no clinical or molecular evidence suggesting that pediatric "oligodendrogliomas" are the same as adult oligodendrogliomas albeit histologic similarity, a case can be made for their separation from adult oligodendrogliomas in the next WHO classification.

Outcomes and Prognostic Factors in Pediatric Oligodendroglioma: A Population-Based Study.

BACKGROUND/AIMS: Pediatric oligodendroglioma (pODG) is a rare primary brain tumor that remains poorly understood. Demographics, outcomes, and prognostic factors were analyzed in 346 pODG cases from the Surveillance, Epidemiology, and End Results database. METHODS: Gender, race, age, tumor location, tumor size, tumor grade, extent of resection, and use of radiotherapy were evaluated with respect to overall survival (OS) by univariate and multivariate analysis. These factors were assessed in the pediatric cohort and 5,753 adult oligodendroglioma cases for comparison. RESULTS: The mean OS in pODG was 199.6 months. Five- and 10-year survival rates were 85 and 81%. pODG arose less frequently in the frontal lobe than adult tumors (53 vs. 22%) but was more common in the temporal lobe (32 vs. 18%) and extracortical regions (19 vs. 5%, p < 0.0001). pODG presented with smaller size (55 vs. 24%, p < 0.0001) and lower grade (72 vs. 54%, p < 0.0001) than adult tumors. Tumor location, size, grade, use of radiotherapy, and extent of resection were significant prognostic factors. Size and grade were much stronger prognostic factors in children than adults. While children with oligodendroglioma survive much longer than adults on the whole, there was no difference in outcome between children with high-grade tumors and adults with high-grade tumors. CONCLUSION: pODG differs significantly from adult oligodendroglioma along a number of demographic and tumor factors at a population level, and key prognostic factors influence survival differently in pODG than in adult disease.

[Prognostic significance of combined TERT and IDH gene mutation analysis in diffusely infiltrating gliomas].

Objective: To investigate the status and prognostic significance of TERT and IDH1/2 genes mutations in diffusely infiltrating gliomas. Methods: Hot spot mutations of TERT and IDH1/2 genes were detected by DNA sequencing in 236 cases of gliomas at West China Hospital from 2012 to 2016, including pilocytic astrocytoma (WHO grade Ⅰ, 16 cases), diffuse astrocytoma and oligodendroglioma (WHO grade Ⅱ, 89 cases), anaplastic astrocytoma and oligodendroglioma (WHO grade Ⅲ, 72 cases) and glioblastoma (WHO grade Ⅳ, 59 cases). The prognostic significance of TERT and IDH1/2 hot spot mutations was evaluated. Results: No IDH or TERT mutations were detected in pilocytic gliomas. TERT promoter mutation frequency was higher in patients aged ≥40 years(60.8%, 93/153) than in patients aged <40 years (32.8%, 22/67; P<0.01). TERT promoter mutation rate was also significantly higher in oligodendroglioma (87.5% , 56/64) than that in astrocytoma(37.8%, 59/156; P<0.01). Young age (<40 years), oligodendroglioma and IDH1 mutation were favorable prognostic factors for diffusely infiltrating astrocytic and oligodendroglial tumors. TERT mutation alone was not of prognostic significance. Diffusely infiltrating astrocytic and oligodendroglial tumors were divided into four molecular subtypes according to TERT and IDH1 mutation status: IDH(+ )/TERT(+ ), IDH(+ )/TERT(-), IDH(-)/TERT(-) and IDH(-)/TERT(+ ). There was significant prognostic difference among the 4 subtypes. Conclusions: Combined IDH and TERT gene mutation analysis may be useful for prognostic subgrouping. Notably, IDH1 wild-type cases can be further subdivided into TERT(+ ) or (-) subgroups with significant prognostic difference.

Treatment Outcomes in 1p19q Co-deleted/Partially Deleted Gliomas.

BACKGROUND: Radiotherapy with procarbazine, lomustine, and vincristine improves overall survival (OS) in patients with 1p19q co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma. METHODS: This retrospective analysis investigated outcomes in patients with 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma. OS and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and prognostic factors using the Cox proportional hazard model. RESULTS: A total of 106 patients (between December 1997 and December 2013) were included. Median age was 40 years (19-66), 58 were male (55%), Eastern Cooperative Oncology Group performance status was 0 in 80 patients (75%). 1p19q status was co-deleted in 66 (62%), incompletely co-deleted in 27 (25%), and 1p or 19q loss alone in four (4%) and nine (8%) patients, respectively. Isocitrate dehydrogenase-1 R132H mutation was found in 67 of 85 patients with sufficient material. Upfront treatment was given in 72 (68%) patients and temozolomide alone in 52 (49%). Median time to radiotherapy in 47 patients (44%) was 34.7 months and 41.2 months in 9 patients with co-deleted/incompletely co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma who received upfront temozolomide alone. Median OS was not reached and 5-year OS was 91% for all groups (median follow-up, 5.1 years). On multivariable analysis for all patients, receipt of therapy upfront versus none (p=0.04), PS 1 versus 0 (p<0.001) and 1p19q co-deletion/incomplete deletion versus 1p or 19q loss alone (p=0.005) were prognostic for PFS. Isocitrate dehydrogenase-1 status was not prognostic for PFS. CONCLUSIONS: With similar survival patterns in low-grade/anaplastic gliomas, molecular characteristics may be more important than histological grade. Longer follow-up and results of prospective trials are needed for definitive guidance on treatment of these patients.

[Diagnostic and prognostic roles of loss of CIC protein expression in oligodendroglial tumors].

Objective: To investigate the usefulness of loss of CIC expression as the prescreening detection of 1p/19q co-deletion in the diagnosis of oligodendroglial tumors and its prognostic implication. Methods: The retrospective study included 113 oligodendroglial tumors diagnosed in the Department of Pathology, Xuanwu Hospital, Capital Medical University. Expression of CIC protein was detected by immunohistochemistry, and the 1p/19q co-deletion by fluorescence in situ hybridization in all the tumors; and the correlation of the loss of protein and 1p/19q co-deletion with prognosis was assessed. Results: The rate of negative CIC protein expression was 59.3% (67/113) in 113 oligodendroglial tumors. CIC protein expression was differentially lost in various gliomas, 85.7% (42/49) in pure oligodendrogliomas and 39.1% (25/64) in mixed oligodendroglial tumors (P<0.01). The loss of CIC protein expression showed a sensitivity of 76.1% (54/71), specificity 71.1% (27/38), false positive rate of 16.9% (11/65), and a false negative rate of 38.6% (17/44). In 63 cases integrated diagnosis as oligodendroglial tumors with mutant IDH and 1p/19q co-deletion, the loss of CIC protein expression was 81.0% (51/63); the sensitivity and specificity were increased to 81.0% (51/63) and 76.9% (20/26), and the false positive rate and false negative rate decreased to 10.5% (6/57) and 37.5% (12/32), respectively. By using Kaplan-Meier analysis, the CIC negative group showed a trend towards better outcome than the CIC positive group, but there was no statistical difference (overall survival: P=0.218; progression free survival: P=0.249). Conclusions: Detection of the lost CIC protein expression can predict the chromosome 1p/19q co-deletion. In oligodendroglial tumors with IDH mutant and 1p/19q co-deletion, there is no relation between prognosis and CIC protein expression.

Utilization and impact of adjuvant therapy in anaplastic oligodendroglioma: an analysis on 1692 patients.

The aim of this study was to determine the utilization rates and impact of adjuvant therapy on overall survival (OS) for anaplastic oligodendroglioma (AO). Data were extracted from the National Cancer Data Base (NCDB). Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 1692 patients with AO who underwent surgery were identified. 945 (55.9 %) received adjuvant radiotherapy with concomitant chemotherapy (chemoRT), 102 (6.0 %) adjuvant radiotherapy (RT) sequentially followed by chemotherapy, 244 (14.4 %) adjuvant RT alone, and 401 (23.7 %) received no adjuvant therapy. Patients were more likely to receive adjuvant chemoRT if they were diagnosed in 2009-2013 vs. 2004-2008 (p < 0.001), had Karnofsky Performance Status >70 vs. <70 (p = 0.018), had private insurance vs. Medicaid vs. no insurance (p < 0.001), or had median income ≥$63,000 vs. <$63,000 (p = 0.014). Those who received adjuvant chemoRT (concomitant or sequential) had significantly better 5-year OS than those who received adjuvant RT alone or no adjuvant therapy (59.8 % vs. 65.0 % vs. 44.9 % vs. 45.6 %, p < 0.001). This significant 5-year OS benefit was also observed regardless of age. There was no difference in OS when comparing concomitant chemoRT to sequential RT and chemotherapy (p = 0.481). On multivariate analysis, receipt of adjuvant chemoRT (concomitant or sequential) remained an independent prognostic factor for improved OS. Adjuvant chemoRT (concomitant or sequential) is an independent prognostic factor for improved OS in anaplastic oligodendroglioma and should be considered for all clinically suitable patients who have undergone surgery for the disease.

Oligodendrogliomas in Children: Clinical Experiences With 20 Patients.

Oligodendrogliomas occurring rarely in children are incompletely characterized. The purpose of this study was to identify prognostic factors affecting the local control and survival in the management of children with oligodendrogliomas. We retrospectively analyzed clinical data on 20 pediatric patients with oligodendrogliomas treated at Chang Gung Children's Hospital between 1994 and 2014. There were 12 males and 8 females with a median age of 9.2 years at diagnosis (range, 3 mo to 18 y). Eighteen (90%) tumors were located in the cerebral hemispheres, 10 cases were located on the right, 8 on the left. One was located in the third ventricle and 1 in the thoracic spine. Presenting symptoms included seizures (n=7), headache (n=5), visual field defects (n=3), limb weakness (n=2), vomiting (n =1), back pain (n=1), and increased head circumference (n=1). All patients underwent craniotomy: 8 gross total resections, 8 subtotal resections, and 4 biopsies. Nine of the patients had pure oligodendroglioma and 11 had anaplastic oligodendroglioma (WHO grade III or IV). Ten children had adjuvant therapy including radiation (n=7), chemotherapy (n=1) or both (n=2). With the median follow-up of 5.3 years (range, 1.2 to 14.7 y), the 5-year overall survival and disease-free survival rates were 78.9% with 65.0%, respectively. Total tumor resection offers better overall survival regardless of the histologic grading. Our data demonstrate that patients with less than gross total resections are at increased risk for progression and may benefit from more aggressive therapy.

Stereotactic interstitial brachytherapy for the treatment of oligodendroglial brain tumors.

PURPOSE: We evaluated the treatment of oligodendroglial brain tumors with interstitial brachytherapy (IBT) using (125)iodine seeds ((125)I) and analyzed prognostic factors. PATIENTS AND METHODS: Between January 1991 and December 2010, 63 patients (median age 43.3 years, range 20.8-63.4 years) suffering from oligodendroglial brain tumors were treated with (125)I IBT either as primary, adjuvantly after incomplete resection, or as salvage therapy after tumor recurrence. Possible prognostic factors influencing disease progression and survival were retrospectively investigated. RESULTS: The actuarial 2-, 5-, and 10-year overall and progression-free survival rates after IBT for WHO II tumors were 96.9, 96.9, 89.8 % and 96.9, 93.8, 47.3 %; for WHO III tumors 90.3, 77, 54.9 % and 80.6, 58.4, 45.9 %, respectively. Magnetic resonance imaging demonstrated complete remission in 2 patients, partial remission in 13 patients, stable disease in 17 patients and tumor progression in 31 patients. Median time to progression for WHO II tumors was 87.6 months and for WHO III tumors 27.8 months. Neurological status improved in 10 patients and remained stable in 20 patients, while 9 patients deteriorated. There was no treatment-related mortality. Treatment-related morbidity was transient in 11 patients. WHO II, KPS ≥ 90 %, frontal location, and tumor surface dose > 50 Gy were associated with increased overall survival (p ≤ 0.05). Oligodendroglioma and frontal location were associated with a prolonged progression-free survival (p ≤ 0.05). CONCLUSION: Our study indicates that IBT achieves local control rates comparable to surgery and radio-/chemotherapy treatment, is minimally invasive, and safe. Due to the low rate of side effects, IBT may represent an attractive option as part of a multimodal treatment schedule, being supplementary to microsurgery or as a salvage therapy after chemotherapy and conventional irradiation.

Quantitative proteomic analysis shows differentially expressed HSPB1 in glioblastoma as a discriminating short from long survival factor and NOVA1 as a differentiation factor between low-grade astrocytoma and oligodendroglioma.

BACKGROUND: Gliomas account for more than 60 % of all primary central nervous system neoplasms. Low-grade gliomas display a tendency to progress to more malignant phenotypes and the most frequent and malignant gliomas are glioblastomas (GBM). Another type of glioma, oligodendroglioma originates from oligodendrocytes and glial precursor cells and represents 2-5 % of gliomas. The discrimination between these two types of glioma is actually controversial, thus, a molecular distinction is necessary for better diagnosis. METHODS: iTRAQ-based quantitative proteomic analysis was performed on non-neoplastic brain tissue, on astrocytoma grade II, glioblastoma with short and long survival and oligodendrogliomas. RESULTS: We found that expression of nucleophosmin (NPM1), glucose regulated protein 78 kDa (GRP78), nucleolin (NCL) and heat shock protein 90 kDa (HSP90B1) were increased, Raf kinase inhibitor protein (RKIP/PEBP1) was decreased in glioblastoma and they were associated with a network related to tumor progression. Expression level of heat shock protein 27 (HSPB1/HSP27) discriminated glioblastoma presenting short (6 ± 4 months, n = 4) and long survival (43 ± 15 months, n = 4) (p = 0.00045). Expression level of RNA binding protein nova 1 (NOVA1) differentiated low-grade oligodendroglioma and astrocytoma grade II (p = 0.0082). Validation were done by Western blot, qRT-PCR and immunohistochemistry in a larger casuistry. CONCLUSION: Taken together, our quantitative proteomic analysis detected the molecular triad, NPM1, GRP78 and RKIP participating together with NCL and HSP27/HSPB1 in a network related to tumor progression. Additionally, two new important targets were uncovered: NOVA1 useful for diagnostic refinement differentiating astrocytoma from oligodendroglioma, and HSPB1/HSP27, as a predictive factor of poor prognosis for GBM.

Efficacy and patient-reported outcomes with dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma: a phase II multicenter study.

Standard initial therapy for patients with pure and mixed anaplastic oligodendrogliomas (AO/MAO) includes chemotherapy and radiation therapy. Anaplastic oligodendrogliomas with 1p/19q co-deletion are more responsive to chemotherapy. There is concern for potential long-term CNS toxicity of radiation. Hence an approach using chemotherapy initially and reserving radiation for progressive disease is attractive. This multicenter phase II trial included patients with newly diagnosed AO/MAO with central pathology review and 1p/19q assay. Temozolomide was given 150 mg/m(2) days 1-7 and 15-21, every 28 days for 8 cycles. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate, overall survival (OS), treatment toxicity and health-related quality of life (HRQL). Data from 62 patients enrolled between December 2001 and April 2007 at seven centers were analyzed. Among patients with measurable disease, 8 % achieved complete remission, 56 % had stable disease and 36 % had progression. The median PFS and OS were 27.2 months (95 % CI 11.9-36.3) and 105.8 months (95 % CI 51.5-N/A), respectively. Both 1p loss and 1p/19q co-deletion were positive prognostic factors for PFS (p < 0.001) and OS (p < 0.001); and there was some suggestion that 1p/19q co-deletion also predicted better response to chemotherapy (p = 0.007). Grade 3/4 toxicities were mainly hematological. Significantly improved HRQL in the future uncertainty domain of the brain cancer module was seen after cycle 4 (p < 0.001). This trial achieved outcomes similar to those reported previously. Toxicities from dose-intense temozolomide were manageable. Improvement in at least one HRQL domain increased over time. This trial supports the further study of first-line temozolomide monotherapy as an alternative to radiation therapy for patients with newly diagnosed AO/MAO with 1p 19q co-deleted tumors.