Differences in the Prognostic Role of Age, Extent of Resection, and Tumor Grade between Astrocytoma IDHmt and Oligodendroglioma: A Single-Center Cohort Study.

PURPOSE: IDH-mutant glioma is classified as oligodendroglioma or astrocytoma based on 1p19q-codeletion. Whether prognostic factors are similar between these tumor types is not well understood. EXPERIMENTAL DESIGN: Retrospective cohort study. Molecular characterization was performed with targeted next-generation sequencing. Tumor volumes were calculated using semiautomatic 3D segmentation on all pre- and post-operative MRI scans. Overall survival was assessed with the Cox-proportional hazards model. RESULTS: A total of 383 patients with newly diagnosed IDH-mutant glioma were followed up for a median of 7.2 years. Grades 3 and 4 patients had significantly lower Karnofsky performance, with tumors having more contrast enhancement. Patients also received more aggressive postsurgery treatment. Postoperative tumor volume is significantly and independently associated with survival (HR, per cm3 1.19; 95% CI, 1.03-1.39) in IDH-mutant glioma. A separate analysis of oligodendroglioma and astrocytoma showed a significant association of postoperative tumor volume in astrocytoma but not in oligodendroglioma. Higher age and histologic tumor grade were associated with worse survival in patients with oligodendroglioma but not with astrocytoma. CONCLUSIONS: Our data support an initial strategy of extensive resection in patients with oligodendroglioma and astrocytoma. Other important prognostic factors differ between these tumor types, urging researchers and clinicians to keep treating these tumors as separate entities.

A systematic review and meta-analysis informing the role of adjuvant radiotherapy (RT) in Grade 2 and 3 oligodendroglioma.

BACKGROUND AND PURPOSE: Evidence and clinical guidelines support the use of adjuvant RT in high-risk low-grade gliomas. However, patients with oligodendroglioma have a more indolent disease course and delaying or avoiding RT is often considered to reduce treatment-related toxicities. As the optimal adjuvant management for oligodendroglioma is unclear, we aimed to assess the effect of adjuvant RT on overall survival (OS) and progression-free survival (PFS). METHODS: MEDLINE, EMBASE, CENTRAL and CINAHL were searched from January 1990 to February 2023 for studies comparing adjuvant RT versus no adjuvant RT for patients with oligodendroglioma. RESULTS: This review found 17 eligible studies including 14 comparative retrospective studies and 3 randomized controlled trials. Using random-effects model, the results suggested that adjuvant RT improved OS by 28 % (HR 0.72, 95 % CI (0.56-0.93), I2 = 86 %), and PFS by 48 % (HR 0.52, (95 % CI 0.40-0.66), I2 = 48 %) compared to patients without adjuvant RT. Subgroup analysis showed that upfront adjuvant RT improved OS and PFS compared to salvage RT. There were no significant differences in OS and PFS between adjuvant RT versus adjuvant chemotherapy. There was improvement in PFS but not OS for adjuvant chemoradiotherapy versus adjuvant chemotherapy alone. Adjuvant RT improved OS in WHO Grade 3 but not WHO Grade 2 oligodendroglioma. CONCLUSION: Overall, adjuvant RT improved OS and PFS in patients with oligodendroglioma. In patients with low-risk features (e.g. Grade 2, gross total resection), alternative approaches and individualization of management such as adjuvant chemotherapy alone may be reasonable considering the lack of survival benefit. Future efforts should prospectively investigate these treatment regimens on molecularly-classified oligodendroglioma patients (defined by presence of IDH mutation and 1p/19q co-deletion), balancing between maximizing survival outcomes and reducing RT-related toxicities.

Higher YAP1 Levels Are Associated With Shorter Survival of Patients With Low Grade Astrocytoma.

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is one of the most lethal types of brain cancer with a median survival of only 12 months due to its aggressiveness and lack of effective treatment options. Astrocytomas and oligodendrogliomas are classified as low-grade gliomas (LGG) and have the potential to progress into secondary GBM. YAP1 and TAZ are transcriptional co-activators of the hippo pathway and play an important role in tumorigenesis by controlling cell proliferation and differentiation. The aim of this study was to analyze whether YAP1 and TAZ influence the survival in patients with astrocytoma and oligodendroglioma. PATIENTS AND METHODS: A total of 22 patient samples of astrocytoma and 11 samples of oligodendroglioma were analyzed using real-time PCR. We utilized open-access data from The Cancer Genome Atlas (TCGA) focusing on "brain lower grade glioma". mRNA expression rates were used to validate our findings on survival analysis. RESULTS: Expression of YAP1 was twice as high in astrocytoma than in oligodendroglioma, whereas there was no difference in TAZ. In oligodendrogliomas, the expression of TAZ was higher in relapsed than in primary tumors. Patients with astrocytoma having a high YAP1 expression had a significantly shorter overall survival than patients with lower expression (median survival 161 vs. 86 months, p=0.0248). These findings were validated with survival analysis of TCGA data. CONCLUSION: High YAP1 expression shows a high correlation with poorer overall survival in LGG. YAP1 has higher levels of expression in astrocytomas than in oligodendrogliomas.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline.

PURPOSE: To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults. METHODS: ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature. RESULTS: Fifty-nine randomized trials focusing on therapeutic management were identified. RECOMMENDATIONS: Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMT promoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines.

Clinical implications of molecular analysis in diffuse glioma stratification.

The revised 4th edition of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) has introduced the integrated diagnostic classification that combines molecular and histological diagnoses for diffuse gliomas. In this study, we evaluated the molecular alterations for consecutive 300 diffuse glioma cases (grade 2, 56; grade 3, 62; grade 4, 182) based on this classification. Mutations in the isocitrate dehydrogenase (IDH) genes were common in lower grade glioma (LGG: grade2-3), and when combined with 1p/19q status, LGGs could be stratified into three groups except for four cases (Astrocytoma, IDH-mutant: 44; Oligodendroglioma, IDH-mutant and 1p/19q codeleted: 37; Astrocytoma, IDH-wildtype: 33). 1p/19q-codeleted oligodendrogliomas were clinically the most favorable subgroup even with upfront chemotherapy. In contrast, IDH-wildtype astrocytomas had a relatively worse prognosis; however, this subgroup was more heterogeneous. Of this subgroup, 11 cases had TERT promoter (pTERT) mutation with shorter overall survival than 12 pTERT-wildtype cases. Additionally, a longitudinal analysis indicated pTERT mutation as early molecular event for gliomagenesis. Therefore, pTERT mutation is critical for the diagnosis of molecular glioblastoma (WHO grade 4), regardless of histological findings, and future treatment strategy should be considered based on the precise molecular analysis.

Clinical Characteristics and Overall Survival Prognostic Nomogram for Oligodendroglioma: A Surveillance, Epidemiology, and End Results Population-Based Analysis.

OBJECTIVE: Oligodendroglioma is a rare primary malignant brain tumor that has highly variable clinical outcomes. The aim of this study was to investigate demographics, outcomes, and prognostic factors of all oligodendroglioma cases from the Surveillance, Epidemiology, and End Results database to build a clinical prognosis model to predict survival time of patients with oligodendroglioma. METHODS: Cases diagnosed between 1975 and 2016 were selected from the Surveillance, Epidemiology, and End Results database. Age, sex, race, insurance, year of diagnosis, marital status, tumor location, tumor size, summary stage, surgery method, and use of radiotherapy and chemotherapy were evaluated with respect to overall survival by univariate and multivariate analysis. A nomogram predicting 5- and 10-year survival probability for oligodendroglioma was constructed and validated. RESULTS: After data cleaning, 4568 patients with oligodendroglioma were included. At the time of last follow-up, mean survival times among grade II and grade III oligodendrogliomas were 74 and 39 months, respectively. In multivariate analysis, radiotherapy, age, tumor site, summary stage, and surgery demonstrated independent associations with survival in both cohorts. Race and radiotherapy demonstrated independent associations with survival in grade II oligodendroglioma. Sex and chemotherapy demonstrated independent associations with survival in grade III oligodendroglioma. Independent factors in either cohort were selected to build a clinical nomogram. The C-index for the nomogram was 0.738 (95% confidence interval 0.718-0.757). The calibration curves of 5- and 10-year survival rates showed good agreement between the nomogram predictions and actual observations. CONCLUSIONS: This study was the first to develop a nomogram for predicting overall survival of patients with oligodendroglioma to help clinicians predict patient prognosis accurately and conduct further treatment.

Molecular Signatures of Chromosomal Instability Correlate With Copy Number Variation Patterns and Patient Outcome in IDH-Mutant and IDH-Wildtype Astrocytomas.

Chromosomal instability due to mutations in genes guarding the stability of the genome is a well-known mechanism underlying tumorigenesis and malignant progression in numerous cancers. The effect of this process in gliomas is mostly unknown with relatively little research examining the effects of chromosomal instability on patient outcome and therapeutic efficacy, although studies have shown that overall/total copy number variation (CNV) is elevated in higher histologic grades and in cases with more rapid progression and shorter patient survival. Herein, we examine a 70-gene mRNA expression signature (CIN70), which has been previously shown to correlate tightly with chromosomal instability, in 2 independent cohorts of IDH-mutant astrocytomas (total n = 241), IDH-wildtype astrocytomas (n = 228), and oligodendrogliomas (n = 128). Our results show that CIN70 expression levels correlate with total CNV, as well as higher grade, progression-free survival, and overall survival in both IDH-mutant and IDH-wildtype astrocytomas. In oligodendrogliomas, these mRNA signatures correlate with total CNV but not consistently with clinical outcome. These data suggest that chromosomal instability is an underlying factor in aggressive behavior and progression of a subset of diffuse astrocytomas. In addition, chromosomal instability may in part explain the poor response of diffuse gliomas to treatment and may serve as a future therapeutic target.

Radiotherapy in adult low-grade glioma: nationwide trends in treatment and outcomes.

BACKGROUND: Management of WHO grade II gliomas (LGG) can include a combination of observation, surgery, radiotherapy (RT), and chemotherapy; however, optimal management remains unclear in regards to RT. OBJECTIVE: The current study seeks to investigate the usage of RT in LGG and its effect on survival outcomes. METHODS: Patients with diagnosis codes specific for LGG were queried from the National Cancer Database (NCDB) during the years 2004-2016. Kaplan-Meier curves with log-rank testing, univariate and multivariate Cox regression analysis, and comparisons of estimated 3- and 7-year survival were performed to investigate the effect of RT on overall survival. RESULTS: 19,382 patients with LGG were identified with histologically confirmed disease. Kaplan-Meier testing demonstrated RT impacted survival in patients undergoing biopsy or no surgery (p < 0.0001), no chemotherapy (p < 0.0001), and in regimens with early RT (p < 0.0001) and high-dose RT (p < 0.0001). Cox multivariate regression demonstrated RT and age less than 40 (HR 0.93, 95% CI 0.89-0.97, p = 0.001), no chemotherapy (HR 0.82, 95% CI 0.77-0.87, p < 0.001), and astrocytoma histology (HR 0.72, 95% CI 0.66-0.79, p < 0.001) were associated with improved survival. 3-year survival of RT versus non-RT groups showed increased survival rates for age less than 40 years (+ 5.7%, p < 0.0001), no surgery or biopsy (+ 8.1%, p < 0.0001), no chemotherapy (+ 10.3%, p < 0.0001), mixed glioma (+ 6.7%, p < 0.0001), astrocytoma (+ 7.1%, p < 0.0001), and in regimens with early RT (+ 7.6%, p < 0.0001) and high-dose RT (+ 4.7%, p < 0.0001). CONCLUSION: This nationwide analysis of LGG patients found that RT was associated with improved survival outcomes in patients less than 40 years of age, with histology subtypes of astrocytoma and mixed glioma, undergoing biopsy or no surgery, and in regimens with early RT and high-dose RT.

Survival outcome and prognostic factors in anaplastic oligodendroglioma: a single-institution study of 95 cases.

The aim of this study was to evaluate prognostic factors including surgical, radiographic, and histopathologic analyses in anaplastic oligodendroglioma (AO) patients. We reviewed the electronic records of 95 patients who underwent surgery and were diagnosed with AO for 20 years. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Univariate and multivariable analyses included clinical, histopathological, and radiographic prognostic factors. Subgroup analysis was performed in isocitrate dehydrogenase (IDH1/2)-mutant and 1p/19q-codeleted patients. The median PFS and OS were 24.7 months and 50.8 months, respectively. The 1-, 3-, 5-, and 10-year PFS were 75.8%, 42.9%, 32.4%, and 16.4%, respectively. Furthermore, the 1-, 3-, 5-, and 10-year OS were 98.9%, 76.9%, 42.9%, and 29.7%, respectively. The median PFS and OS of the IDH1/2-mutant and 1p/19q-codeleted patients were 54.2 and 57.8 months, respectively. In univariate analyses, young age, frontal lobe, weak enhancement, gross total resection (GTR), low Ki-67 index, 1p/19q codeletion, and IDH1/2 mutations were associated with a favorable outcome. In multivariable analyses, IDH1/2 mutation was related to better PFS and OS. In subgroup analysis, GTR was associated with favorable outcomes.

ISL2 modulates angiogenesis through transcriptional regulation of ANGPT2 to promote cell proliferation and malignant transformation in oligodendroglioma.

Oligodendroglioma is an important type of lower-grade glioma (LGG), which is a slowly progressing brain tumor. Many LGGs eventually transform into a more aggressive or malignant type. Enhanced angiogenesis is a characteristic of malignantly transformed oligodendroglioma (m-oligodendroglioma). However, the pathogenesis and signaling pathways associated with angiogenesis and proliferation in m-oligodendroglioma are not well understood. In this study, we identified that Insulin Gene Enhancer Protein (ISL2) and its angiogenic capacity were inversely related to survival according to LGG patient data from an online database, and this was further confirmed with pathological LGG patient samples, including malignantly transformed samples, by detecting the expression of ISL2, the angiogenic markers vascular endothelial growth factor (VEGFA) and CD31 and the proliferation marker Ki-67. We then established novel oligodendroglioma patient tumor-derived orthotopic xenograft mouse models and cell lines to verify the role of ISL2 in regulating angiogenesis to promote oligodendroglioma growth and malignant transformation. Furthermore, ISL2 regulated ANGPT2 transcription by binding to the ANGPT2 promoter. Then, ANGPT2, a downstream gene, activated angiogenesis through VEGFA to promote oligodendroglioma malignant transformation. Finally, combining AAV-ISL2-shRNA with temozolomide suppressed oligodendroglioma progression more effectively than either monotherapy in vivo and in vitro. Thus, hypoxia-induced ISL2 regulated ANGPT2, which subsequently induced angiogenesis to promote oligodendroglioma growth and malignant transformation. Malignancy was accompanied by worsened hypoxia inside the tumor mass, creating a positive feedback loop. In conclusion, this study suggests that ISL2 is a biomarker for oligodendroglioma progression and that anti-ISL2 therapy may offer a potential clinical strategy for treating m-oligodendroglioma.

Extent of resection, molecular signature, and survival in 1p19q-codeleted gliomas.

OBJECTIVE: Genomic analysis in neurooncology has underscored the importance of understanding the patterns of survival in different molecular subtypes within gliomas and their responses to treatment. In particular, diffuse gliomas are now principally characterized by their mutation status (IDH1 and 1p/19q codeletion), yet there remains a paucity of information regarding the prognostic value of molecular markers and extent of resection (EOR) on survival. Furthermore, given the modern emphasis on molecular rather than histological diagnosis, it is important to examine the effect of maximal resection on survival in all gliomas with 1p/q19 codeletions, as these will now be classified as oligodendrogliomas under the new WHO guidelines. The objectives of the present study were twofold: 1) to assess the association between EOR and survival for patients with oligodendrogliomas in the National Cancer Database (NCDB), which includes information on mutation status, and 2) to demonstrate the same effect for all patients with 1p/19q codeleted gliomas in the NCDB. METHODS: The NCDB was queried for all cases of oligodendroglioma between 2004 and 2014, with follow-up dates through 2016. The authors found 2514 cases of histologically confirmed oligodendrogliomas for the final analysis of the effect of EOR on survival. Upon further query, 1067 1p/19q-codeleted tumors were identified in the NCDB. Patients who received subtotal resection (STR) or gross-total resection (GTR) were compared to those who received no tumor debulking surgery. Univariable and multivariable analyses of both overall survival and cause-specific survival were performed. RESULTS: EOR was associated with increased overall survival for both histologically confirmed oligodendrogliomas and all 1p/19q-codeleted-defined tumors (p < 0.001 and p = 0.002, respectively). Tumor grade, location, and size covaried predictably with EOR. When evaluating tumors by each classification system for predictors of overall survival, facility setting, age, comorbidity index, grade, location, chemotherapy, and radiation therapy were all shown to be significantly associated with overall survival. STR and GTR were independent predictors of improved survival in historically classified oligodendrogliomas (HR 0.83, p = 0.18; HR 0.69, p = 0.01, respectively) and in 1p/19q-codeleted tumors (HR 0.49, p < 0.01; HR 0.43, p < 0.01, respectively). CONCLUSIONS: By using the NCDB, the authors have demonstrated a side-by-side comparison of the survival benefits of greater EOR in 1p/19q-codeleted gliomas.

Survival, Prognostic Factors, and Volumetric Analysis of Extent of Resection for Anaplastic Gliomas.

PURPOSE: The aim of this study is to evaluate the survival rate and prognostic factors of anaplastic gliomas according to the 2016 World Health Organization classification, including extent of resection (EOR) as measured by contrast-enhanced T1-weighted magnetic resonance imaging (MRI) and the T2-weighted MRI. MATERIALS AND METHODS: The records of 113 patients with anaplastic glioma who were newly diagnosed at our institute between 2000 and 2013 were retrospectively reviewed. There were 62 cases (54.9%) of anaplastic astrocytoma, isocitrate dehydrogenase (IDH) wild-type (AAw), 18 cases (16.0%) of anaplastic astrocytoma, IDH-mutant, and 33 cases (29.2%) of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted. RESULTS: The median overall survival (OS) was 48.4 months in the whole anaplastic glioma group and 21.5 months in AAw group. In multivariate analysis, age, preoperative Karnofsky Performance Scale score, O6-methylguanine-DNA methyltransferase (MGMT) methylation status, postoperative tumor volume, and EOR measured from the T2 MRI sequence were significant prognostic factors. The EOR cut-off point for OS measured in contrast-enhanced T1-weighted MRI and T2-weighted MRI were 99.96% and 85.64%, respectively. CONCLUSION: We found that complete resection of the contrast-enhanced portion (99.96%) and more than 85.64% resection of the non-enhanced portion of the tumor have prognostic impacts on patient survival from anaplastic glioma.

All-cause and tumor-specific mortality trends in geriatric oligodendroglioma (OG) patients: A surveillance, epidemiology, and end results (SEER) analysis.

Recent efforts have been made to identify mortality risk factors in Oligodendroglioma (OG) patients, however, efforts have fallen short within the geriatric population. The purpose of this study was to identify mortality trends and risk factors within a geriatric cohort of patients with OGs. 762 cases (1973-2012, age at diagnosis 65+ years) within the Surveillance, Epidemiology, and End Results (SEER) database were included. Variables were age at diagnosis, decade of diagnosis, sex, race and whether or not surgery was performed. All-cause mortality was identified prior to stratification, while tumor-specific mortality was identified after stratification of data by the SEER cause of death "Dead (attributable to this cancer dx)". Before stratification, decade 4 and patients aged 65-74 years at diagnosis had the lowest mortality, while 85+ years had the highest. Furthermore, women had lower mortality than men and surgery performed resulted in lower mortality in the univariate, but not the multivariate analysis. Following stratification, however, multivariate analysis showed less mortality with surgery performed, but differences between decades and sex were no longer detected. Similarly, patients aged 65-74 years at diagnosis continued to have the lowest mortality, while 85+ years continued to have the highest. Although all-cause mortality decreased over time, tumor-specific mortality remained unchanged since 1973 for geriatric patients with OGs. This highlights the need for further research into new therapeutic strategies for this rapidly growing population.

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.

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.

Ki-67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1-mutant and 1p/19q-codeleted: a multicenter study from the French POLA network.

Anaplastic oligodendroglioma (AO), IDH-mutant and 1p/19q codeleted (IDHmut+/1p19qcodel), is a high-grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki-67, in a large series of IDHmut+/1p19qcodel AO included in the POLA ("Prise en charge des Oligodendrogliomes Anaplasiques") French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labeling indices (LI) of MCM6 and Ki-67 were obtained via computer-assisted color image analyses on immunostained AO tissues of the cohort (n = 220). Furthermore, a subgroup of AO (n = 68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki-67 (≥15%) correlated with shorter overall survival, both in univariate (P = 0.013 and P = 0.004, respectively) and multivariate analyses (P = 0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki-67). MCM6 and Ki-67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro-neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta-amyloid binding and postsynaptic specialization. In conclusion, the overexpression of MCM6 and/or Ki-67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy-to-use and cost-effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down-regulated immune response and lower microglial cells activation, and bears pro-neural phenotype.

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.

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.

Multiparametric and multiregional diffusion features help predict molecule information, grade and survival in lower-grade gliomas: a feasibility study.

OBJECTIVE: This study was to investigate the relationship of diffusion features with molecule information, and then predict grade and survival in lower-grade gliomas. METHODS: 65 patients with primary lower-grade gliomas (WHO Grade II & III) who underwent conventional MRI and diffusion tensor imaging were retrospectively studied. The tumor region was automatically segmented into contrast-enhancing tumor, non-enhancing tumor, edematous and necrotic volumes. Diffusion features, including fractional anisotropy (FA), axial diffusivity, radial diffusivity and apparent diffusion coefficient (ADC), were extracted from each volume using histogram analysis. To estimate molecule biomarkers and predict clinical characteristics of grade and survival, support vector machine, generalized linear model, logistic regression and Cox regression were performed on the related features. RESULTS: The diffusion features in non-enhancing tumor volume showed differences between isocitrate dehydrogenase mutant and wild-type gliomas. And the mean accuracy of support vector machine classifiers was 0.79. Ki-67 labeling index was correlated with these features, which were combined to significantly estimate Ki-67 expression level (r = 0.657, p < 0.001). These features also showed differences between Grade II and III gliomas. A combination of them for grade classification resulted in an area under the curve of 0.914 (0.857-0.971). Mean FA and fifth percentile of ADC were independently associated with overall survival, with lower FA and higher ADC showing better survival outcome. CONCLUSION: In lower-grade gliomas, multiparametric and multiregional diffusion features could help predict molecule information, histological grade and survival. ADVANCES IN KNOWLEDGE: The multi parametric diffusion features in non-enhancing tumor were associated with molecule information, grade and survival in lower-grade gliomas.