Much debated controversies of diffuse low-grade gliomas

Zadeh, Gelareh; Khan, Osaama H.; Vogelbaum, Michael; Schiff, David

doi:10.1093/neuonc/nou368

Cited by 8 publications

(10 citation statements)

References 37 publications

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“…Standard treatment for DLGG includes maximal safe resection whenever possible followed by routine imaging surveillance. For high-risk patients, a combination of radiation and chemotherapy is recommended [for details on clinical management of DLGG see (Duffau & Taillandier, 2015;Oberheim Bush & Chang, 2016;van den Bent et al, 2017;Zadeh, Khan, Vogelbaum, & Schiff, 2015). Recent therapeutic developments aim at targeting the mutated IDH1 enzyme with promising inhibitors (Rohle et al, 2013).…”

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confidence: 99%

Cellular and molecular characterization of IDH1‐mutated diffuse low grade gliomas reveals tumor heterogeneity and absence of EGFR/PDGFRα activation

Azar

Leventoux

Ripoll

et al. 2017

Glia

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Diffuse low grade gliomas (DLGG, grade II gliomas) are slowly-growing brain tumors that often progress into high grade gliomas. Most tumors have a missense mutation for IDH1 combined with 1p19q codeletion in oligodendrogliomas or ATRX/TP53 mutations in astrocytomas. The phenotype of tumoral cells, their environment and the pathways activated in these tumors are still ill-defined and are mainly based on genomics and transcriptomics analysis. Here we used freshly-resected tumors to accurately characterize the tumoral cell population and their environment. In oligodendrogliomas, cells express the transcription factors MYT1, Nkx2.2, Olig1, Olig2, Sox8, four receptors (EGFR, PDGFRα, LIFR, PTPRZ1) but not the co-receptor NG2 known to be expressed by oligodendrocyte progenitor cells. A variable fraction of cells also express the more mature oligodendrocytic markers NOGO-A and MAG. DLGG cells are also stained for the young-neuron marker doublecortin (Dcx) which is also observed in oligodendrocytic cells in nontumoral human brain. In astrocytomas, MYT1, PDGFRα, PTPRZ1 were less expressed whereas Sox9 was prominent over Sox8. The phenotype of DLGG cells is overall maintained in culture. Phospho-array screening showed the absence of EGFR and PDGFRα phosphorylation in DLGG but revealed the strong activation of p44/42 MAPK/ERK which was present in a fraction of tumoral cells but also in nontumoral cells. These results provide evidence for the existence of close relationships between the cellular phenotype and the mutations found in DLGG. The slow proliferation of these tumors may be associated with the absence of activation of PDGFRα/EGFR receptors.

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confidence: 99%

Cellular and molecular characterization of IDH1‐mutated diffuse low grade gliomas reveals tumor heterogeneity and absence of EGFR/PDGFRα activation

Azar

Leventoux

Ripoll

et al. 2017

Glia

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“…Prospective studies investigating the role of surgery are lacking, and the presumed benefit from extensive resection may be largely due to the patient selection process. A biopsy is performed to pathologically diagnose patients with LGGs in circumstances where the tumor location makes surgery difficult or impossible ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…Evidence over the last 2 decades, from the European and American literature, has noted that the extent of resection in patients with LGGs is an important factor affecting OS ( 12 – 15 ). However, prospective controlled studies evaluating the role of surgery are lacking ( 14 – 16 ). Observation appears to be appropriate for selected patients, and the wait-and-see approach remains widely practiced and continues to be a controversial approach ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, prospective controlled studies evaluating the role of surgery are lacking ( 14 – 16 ). Observation appears to be appropriate for selected patients, and the wait-and-see approach remains widely practiced and continues to be a controversial approach ( 16 ). Guidelines exist on the management of patients with LGGs, as outlined by the European Federation of Neurological Society and the European Association of Neuro-Oncology task force ( 17 ), however, the treatment of patients with newly diagnosed or suspected LGGs is a controversial area in neuro-oncology.…”

Section: Introductionmentioning

confidence: 99%

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Management of supratentorial recurrent low-grade glioma: A multidisciplinary experience in 35 adult patients

et al. 2017

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The management of recurrent diffuse low-grade gliomas (LGGs) is controversial. In the present study, the multidisciplinary management of 35 patients with recurrent LGGs was retrospectively analyzed. Tumor progression or recurrence was defined by clinical, radiological and/or metabolic pejorative evolution. All patients were regularly followed up by a multidisciplinary neuro-oncological group at Hôpital Erasme. Patients with histologically confirmed supratentorial LGGs (7 astrocytoma, 22 oligodendrogliomas and 6 oligoastrocytomas) who had undergone surgery between August 2004 and November 2010 were included. A total of 3 patients exhibited no tumor progression (median follow-up (FU), 81 months; range, 68–108 months). Tumor recurrence occurred in the 32 remaining patients [progression-free survival (PFS), 26 months; range, 2–104 months]. In addition, 25/29 (86%) patients who received surgery alone underwent reoperation at the time of tumor recurrence, and high-grade transformation occurred in 6 of these patients (24%). Furthermore, 4/29 (14%) patients were treated with adjuvant therapy alone (3 chemotherapy and 1 radiotherapy). In the 19 patients with no high-grade transformation at reintervention, 3 received adjuvant therapy and 16 were regularly followed up through multimodal imaging. The PFS time of the patients who underwent reoperation with close FU (n=16) and for the patients receiving adjuvant therapy with or without surgery (n=7) at first recurrence was 10 and 24 months (P=0.005), respectively. However, no significant difference was observed for overall survival (P=0.403). At the time of this study, 22 of the 35 patients included were alive following a median FU time of 109 months (range, 55–136). The results of the present study could change the multidisciplinary approach used into a more aggressive approach with adjuvant therapy, with or without surgery, for the treatment of a select subpopulation of patients with LGGs at the first instance of tumor recurrence.

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“…[23] Such variation in the disease evolution of lower grade diffuse gliomas (LGGs) creates significant challenges for prognostication and management. [45] The ability to accurately predict OS outcome would facilitate the design of appropriate surveillance and/or treatment strategies to assess disease aggressiveness. [267] Toward the construction of such models, it is essential to first identify tumor-derived factors that have previously been associated with the likely course of the disease.…”

Section: Introductionmentioning

confidence: 99%

Identification of Histological Correlates of Overall Survival in Lower Grade Gliomas Using a Bag-of-words Paradigm: A Preliminary Analysis Based on Hematoxylin & Eosin Stained Slides from the Lower Grade Glioma Cohort of The Cancer Genome Atlas

Powell¹,

Olar

Narang

et al. 2017

Journal of Pathology Informatics

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Background:Glioma, the most common primary brain neoplasm, describes a heterogeneous tumor of multiple histologic subtypes and cellular origins. At clinical presentation, gliomas are graded according to the World Health Organization guidelines (WHO), which reflect the malignant characteristics of the tumor based on histopathological and molecular features. Lower grade diffuse gliomas (LGGs) (WHO Grade II–III) have fewer malignant characteristics than high-grade gliomas (WHO Grade IV), and a better clinical prognosis, however, accurate discrimination of overall survival (OS) remains a challenge. In this study, we aimed to identify tissue-derived image features using a machine learning approach to predict OS in a mixed histology and grade cohort of lower grade glioma patients. To achieve this aim, we used H and E stained slides from the public LGG cohort of The Cancer Genome Atlas (TCGA) to create a machine learned dictionary of “image-derived visual words” associated with OS. We then evaluated the combined efficacy of using these visual words in predicting short versus long OS by training a generalized machine learning model. Finally, we mapped these predictive visual words back to molecular signaling cascades to infer potential drivers of the machine learned survival-associated phenotypes.Methods:We analyzed digitized histological sections downloaded from the LGG cohort of TCGA using a bag-of-words approach. This method identified a diverse set of histological patterns that were further correlated with OS, histology, and molecular signaling activity using Cox regression, analysis of variance, and Spearman correlation, respectively. A support vector machine (SVM) model was constructed to discriminate patients into short and long OS groups dichotomized at 24-month.Results:This method identified disease-relevant phenotypes associated with OS, some of which are correlated with disease-associated molecular pathways. From these image-derived phenotypes, a generalized SVM model which could discriminate 24-month OS (area under the curve, 0.76) was obtained.Conclusion:Here, we demonstrated one potential strategy to incorporate image features derived from H and E stained slides into predictive models of OS. In addition, we showed how these image-derived phenotypic characteristics correlate with molecular signaling activity underlying the etiology or behavior of LGG.

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Much debated controversies of diffuse low-grade gliomas

Cited by 8 publications

References 37 publications

Cellular and molecular characterization of IDH1‐mutated diffuse low grade gliomas reveals tumor heterogeneity and absence of EGFR/PDGFRα activation

Cellular and molecular characterization of IDH1‐mutated diffuse low grade gliomas reveals tumor heterogeneity and absence of EGFR/PDGFRα activation

Management of supratentorial recurrent low-grade glioma: A multidisciplinary experience in 35 adult patients

Identification of Histological Correlates of Overall Survival in Lower Grade Gliomas Using a Bag-of-words Paradigm: A Preliminary Analysis Based on Hematoxylin & Eosin Stained Slides from the Lower Grade Glioma Cohort of The Cancer Genome Atlas

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