[Show abstract][Hide abstract] ABSTRACT: Introduction:
Recent advances in molecular diagnostics allow diffuse gliomas to be classified based on their genetic changes into distinct prognostic subtypes. However, a systematic analysis of all molecular markers has thus far not been performed; most classification schemes use a predefined and select set of genes/molecular markers. Here, we have analysed the TCGA dataset (combined glioblastoma (GBM) and lower grade glioma (LGG) datasets) to identify all prognostic genetic markers in diffuse gliomas in order to generate a comprehensive classification scheme.
Of the molecular markers investigated (all genes mutated at a population frequency >1.7 % and frequent chromosomal imbalances) in the entire glioma dataset, 57 were significantly associated with overall survival. Of these, IDH1 or IDH2 mutations are associated with lowest hazard ratio, which confirms IDH as the most important prognostic marker in diffuse gliomas. Subsequent subgroup analysis largely confirms many of the currently used molecular classification schemes for diffuse gliomas (ATRX or TP53 mutations, 1p19q codeletion). Our analysis also identified PI3-kinase mutations as markers of poor prognosis in IDH-mutated + ATRX/TP53 mutated diffuse gliomas, median survival 3.7 v. 6.3 years (P = 0.02, Hazard rate (HR) 2.93, 95 % confidence interval (CI) 1.16 - 7.38). PI3-kinase mutations were also prognostic in two independent datasets. In our analysis, no additional molecular markers were identified that further refine the molecular classification of diffuse gliomas. Interestingly, these molecular classifiers do not fully explain the variability in survival observed for diffuse glioma patients. We demonstrate that tumor grade remains an important prognostic factor for overall survival in diffuse gliomas, even within molecular glioma subtypes. Tumor grade was correlated with the mutational load (the number of non-silent mutations) of the tumor: grade II diffuse gliomas harbour fewer genetic changes than grade III or IV, even within defined molecular subtypes (e.g. ATRX mutated diffuse gliomas).
We have identified PI3K mutations as novel prognostic markers in gliomas. We also demonstrate that the mutational load is associated with tumor grade. The increase in mutational load may partially explain the increased aggressiveness of higher grade diffuse gliomas when a subset of the affected genes actively contributes to gliomagenesis and/or progression.
[Show abstract][Hide abstract] ABSTRACT: The introduction of antiangiogenic therapies for the treatment of malignant glioma and the effect of these agents on standard
imaging studies were the stimuli for forming a small group of investigators to critically evaluate the limitations of the
Macdonald criteria in assessing response to treatment. The initial goal of this group was to highlight the challenges in accurately
determining the efficacy of therapeutic interventions for malignant glioma and to develop new criteria that could be implemented
in clinical care as well as in the design and conduct of clinical trials. This initial Response Assessment in Neuro-Oncology
(RANO) effort started in 2008 and over the last 7 years, it has expanded to include a critical review of response assessment
across several tumor types as well as endpoint selection and trial design to improve outcome criteria for neuro-oncological
trials. In this paper, we review the overarching principles of the RANO initiative and the efforts to date. We also highlight
the diverse and expanding efforts of the multidisciplinary groups of investigators who have volunteered their time as part
of this endeavor.
[Show abstract][Hide abstract] ABSTRACT: Purpose of review:
The role of chemotherapy in low-grade glioma has been redefined with the long-term follow-up of the RTOG 9802, which investigated adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy in addition to radiotherapy, and the results of EORTC trial 22033 in a similar patient population that compared temozolomide to radiotherapy.
RTOG 9802 trial showed an increase in overall survival after adjuvant chemotherapy. Median overall survival increased from 7.8 to 13.3 years, with a hazard ratio of death of 0.59 (log rank: P = 0.002), and despite a 77% cross-over rate to chemotherapy in patients progressing after radiotherapy. The EORTC trial 22033 did not reveal differences in progression-free survival between patients treated initially with radiotherapy or with temozolomide.
With these results and similar results of trials in anaplastic glioma, radiotheraphy with PCV is now to be considered standard of care for low-grade glioma requiring postsurgical adjuvant treatment. The optimal parameter for selecting patients for adjuvant PCV has not yet been fully elucidated. It is still unclear if temozolomide can replace PCV, but temozolomide is better tolerated than nitrosoureas. The current evidence supports treating patients with grade II and III glioma based on their molecular characteristics.
No preview · Article · Sep 2015 · Current opinion in neurology
[Show abstract][Hide abstract] ABSTRACT: Background:
Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in the EORTC phase III trial 26951 on procarbazine/lomustine/vincristine (PCV) chemotherapy to explore the diagnostic, prognostic, and predictive value of targeted next-generation sequencing (NGS) in diffuse glioma and to assess the prognostic impact of FUBP1 and CIC mutations.
Mostly formalin-fixed paraffin-embedded samples were tested with targeted NGS for mutations in ATRX, TP53, IDH1, IDH2, CIC, FUBP1, PI3KC, TERT, EGFR, H3F3A, BRAF, PTEN, and NOTCH and for copy number alterations of chromosomes 1p, 19q, 10q, and 7. TERT mutations were also assessed, with PCR.
Material was available from 139 cases, in 6 of which results were uninformative. One hundred twenty-six tumors could be classified: 20 as type II (IDH mutation [mut], "astrocytoma"), 49 as type I (1p/19q codeletion, "oligodendroglioma"), 55 as type III (7+/10q- or TERTmut and 1p/19q intact, "glioblastoma"), and 2 as childhood glioblastoma (H3F3Amut), leaving 7 unclassified (total 91% classified). Molecular classification was of clear prognostic significance and correlated better with outcome than did classical histopathology. In 1p/19q codeleted tumors, outcome was not affected by CIC and FUBP1 mutations. MGMT promoter methylation remained the most predictive factor for survival benefit of PCV chemotherapy.
Targeted NGS allows a clinically relevant classification of diffuse glioma into groups with very different outcomes. The diagnosis of diffuse glioma should be primarily based on a molecular classification, with the histopathological grade added to it. Future discussion should primarily aim at establishing the minimum requirements for molecular classification of diffuse glioma.
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma.
In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated.
The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS.
CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.British Journal of Cancer advance online publication, 4 June 2015; doi:10.1038/bjc.2015.191 www.bjcancer.com.
No preview · Article · Jun 2015 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Treatment of older patients with glioblastoma must take into account reduced treatment benefits and increased treatment-related toxicity, as this group of frail patients has a particularly poor prognosis. A new systematic review provides guidance for treating elderly patients, but decision-making in clinical practice faces many challenges.
No preview · Article · May 2015 · Nature Reviews Neurology