The standard of care for primary central nervous system lymphoma (PCNSL) is systemic chemotherapy with or without whole brain radiotherapy or intrathecal chemotherapy. In contrast to treatment for other brain tumors, efforts at resection are discouraged. This is a secondary analysis of the German PCNSL Study Group–1 trial, a large randomized phase III study comprising 526 patients with PCNSL. Progression-free survival (hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.10–1.74; P = .005) and overall survival (HR: 1.33; 95% CI: 1.04–1.70; P = .024) were significantly shorter in biopsied patients compared with patients with subtotal or gross total resections. This difference in outcome was not due to age or Karnofsky performance status (KPS). When controlled for the number of lesions, the HR of biopsy versus subtotal or gross total resection remained unchanged for progression-free survival (HR = 1.37; P = .009) but was smaller for overall survival (HR = 1.27; P = .085). This analysis of the largest PCNSL trial ever performed challenges the traditional view that the extent of resection has no prognostic impact on this disease. Therefore, we propose to reconsider the statement that efforts at resection should be discouraged, at least if resection seems safe, as is often the case in treatment of single PCNSL lesions.
CNS lymphoma; resection; surgery
A paucity of studies have evaluated the biopsychosocial factors contributing to quality of life (QoL) in adults with a primary brain tumor (BT). Our objective was to investigate (i) the effects of radiotherapy on the psychosocial (ie, posttraumatic stress symptoms [PTSS]) and cognitive functioning of adults with a primary BT, assessed preradiotherapy [T1] and postradiotherapy [T2], and (ii) predictors of PTSS and QoL postradiotherapy. Seventy adults with a BT were assessed at T1, and 67 patients were reassessed 3.5 months postradiotherapy. At each assessment, participants completed measures of PTSS, mood, QoL, and quality of social support and neurocognitive tests focusing on memory and executive functioning. Minimal differences in functioning were found between patients according to BT type (benign [n = 45] vs malignant [n = 25]) and tumor laterality (left vs right hemisphere), with 2 exceptions. Individuals with a left hemisphere benign BT experienced greater distress at T1, which declined at T2, whereas individuals with a left hemisphere malignant BT reported poorer social support at T2. The full sample performed poorly on tests of executive functioning, and 17% reported clinically elevated PTSS at T1, which reduced to 13% at T2. Younger age (<65 y), reduced QoL, and elevated anger symptoms at T1 predicted PTSS at T2, whilst having a benign BT, low PTSS, and depressive symptoms at T1 were predictive of improved QoL at T2. Findings highlight the importance of screening for psychosocial and cognitive disturbances in BT patients undergoing treatment to identify those at risk for acute and more prolonged problems.
brain tumor; neurocognitive; quality of life; stress
The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7–9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90–110 mg/m2) and dasatinib (100–200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2–1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.
CCNU; dasatinib; recurrent glioblastoma
World Health Organization (WHO) grade I astrocytomas include pilocytic astrocytoma (PA) and subependymal giant cell astrocytoma (SEGA). As technologies in pharmacologic neo-adjuvant therapy continue to progress and as molecular characteristics are progressively recognized as potential markers of both clinically significant tumor subtypes and response to therapy, interest in the biology of these tumors has surged. An updated review of the current knowledge of the molecular biology of these tumors is needed. We conducted a Medline search to identify published literature discussing the molecular biology of grade I astrocytomas. We then summarized this literature and discuss it in a logical framework through which the complex biology of these tumors can be clearly understood. A comprehensive review of the molecular biology of WHO grade I astrocytomas is presented. The past several years have seen rapid progress in the level of understanding of PA in particular, but the molecular literature regarding both PA and SEGA remains nebulous, ambiguous, and occasionally contradictory. In this review we provide a comprehensive discussion of the current understanding of the chromosomal, genomic, and epigenomic features of both PA and SEGA and provide a logical framework in which these data can be more readily understood.
astrocytoma; brain tumor; giant cell; pilocytic; subependymal
The arginine 132 (R132) mutation of isocitrate dehydrogenase –1 (IDH1R132) results in production of 2-hydroxyglutarate (2-HG) and is associated with a better prognosis compared with wild-type (WT) in glioma patients. The majority of lower-grade gliomas express IDH1R132, whereas this mutation is rare in grade IV gliomas. The aim of this study was to noninvasively investigate metabolic and physiologic changes associated with the IDH1 mutation in a mouse glioma model. Using a 7T magnet, we compared MRI and proton magnetic resonance spectroscopy (MRS) in U87 glioma cells overexpressing either the mutated IDH1R132 or IDH1 wild-type (IDH1WT) gene in a mouse flank xenograft model. Flank tumors overexpressing IDH1R132 showed a resonance at 2.25 ppm corresponding to the 2-HG peak described for human IDH1R132 gliomas. WT tumors lacked this peak in all cases. IDH1 mutant tumors demonstrated significantly reduced glutamate by in vivo MRS. There were no significant differences in T2, apparent diffusion coefficient (ADC), or perfusion values between the mutant and IDH1WT tumors. The IDH1R132 mutation results in 2-HG resonance at 2.25 ppm and a reduction of glutamate levels as determined by MRS. Our results establish a model system where 2-HG can be monitored noninvasively, which should be helpful in validating 2-HG levels as a prognostic and/or predictive biomarker in glioma.
animal models; glioblastoma; glioma; isocitrate dehydrogenase 1 (IDH1); MRI; MRS
Oligodendroglial components (OC) and loss of heterozygosity on chromosomes 1p and 19q (LOH 1p/19q) are associated with better outcome in patients with glioma. We aimed to assess the fitness of [18F]fluoroethyltyrosine positron-emission-tomography (FET-PET) for noninvasively identifying these important prognostic/predictive factors. One hundred forty-four patients with MRI-suspected WHO grade II and III glioma underwent FET-PET scans prior to histological diagnosis. FET-PET analyses included maximal tumoral uptake (SUVmax/BG), biological tumor volume (BTV), mean tumoral uptake (SUVmean/BG), total tumoral uptake (SUVtotal/BG), and kinetic analysis. Suspicion of OC was based on static and dynamic FET-uptake parameters. PET results were correlated with histology and 1p/19q status. OC tumors exhibited significantly higher uptake values, compared with astrocytomas (AC) (SUVmax/BG 3.1 vs 2.3, BTV 15.5 mL vs 7.2 mL, SUVtotal/BG 38.5 vs 17.4, P < .01 each; SUVmean/BG 2.2 vs 2.1, P < .05). These differences were more pronounced in WHO grade II gliomas. Comparable results were found with respect to 1p/19q status. Kinetic analysis misclassified 18 of 34 low-grade OC tumors as high-grade glioma but misclassified only 5 of 45 of the low-grade ACs. FET-based suspicion of OC resulted in concordance rates of both 76% for the prediction of OC and LOH 1p/19q. FET-uptake was significantly higher in gliomas with OC, compared with AC, and likewise in 1p/19q codeleted, compared with noncodeleted tumors. However, FET-PET analysis did not reliably predict the presence of OC/LOH 1p/19q in the individual patient, mostly because of an overlap in PET characteristics of OC tumors and high-grade AC. Histological examination is still required for an accurate diagnosis.
FET-PET; FET uptake; glioma; kinetic analysis; LOH1p/19q; oligodendroglial tumor components
Defining glioma subtypes based on objective genetic and molecular signatures may allow for a more rational, patient-specific approach to molecularly targeted therapy. However, prior studies attempting to classify glioma subtypes have given conflicting results. We aim to complement and validate the existing molecular classification system on a large number of samples from an East Asian population. A total of 225 samples from Chinese patients was selected for whole genome gene expression profiling. Consensus clustering was applied. Three major groups of gliomas were identified (referred to as G1, G2, and G3). The G1 subgroup correlates with a good clinical outcome, young age, and extremely high frequency of IDH1 mutations. Relative to the G1 subgroup, the G3 subgroup is correlated with a poorer clinical outcome, older age, and a very low rate of mutations in the IDH1 gene. Correlations of the G2 subgroup with respect to clinical outcome, age, and IDH1 mutation fall between the G1 and G3 subgroups. In addition, the G2 subtype was associated with a higher percentage of loss of 1p/19q when compared with G1 and G3 subtypes. Furthermore, our classification scheme was validated on 2 independent datasets derived from the cancer genome atlas (TCGA) and Rembrandt. With use of the TCGA classification system, proneural, neural, and mesenchymal, but not classical subtype, associated gene signatures were clearly defined. In summary, our results reveal that 3 main subtypes stably exist in Chinese patients with glioma. Our classification scheme may reflect the clinical and genetic alterations more clearly. Classical subtype–associated gene signature was not found in our dataset.
Chinese Glioma Genome Atlas; glioma; microarray; molecular classification
The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor–β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.
anaplastic glioma; glioblastoma; malignant glioma; sorafenib; temsirolimus
Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor–2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma.
angiogenesis; EGFR; glioma; vandetanib; VEGFR
Putative cancer stem cells have been identified in glioblastoma (GBM), associated with resistance to conventional therapies. Overcoming this resistance is a major challenge to manage this deadly brain tumor. Epidermal growth factor receptor (EGFR) is commonly amplified, over-expressed, and/or mutated in GBM, making it a compelling target for therapy. This study investigates the behavior of 3 primary neurosphere (NS) cell lines and their adherent counterparts originated from human GBM resections, when treated with EGFR–tyrosine kinase inhibitor erlotinib, associated or not with cyclopamine, a hedgehog pathway inhibitor. Adherent cells cultured in the presence of serum expressed the glial fibrillary acidic protein, whereas NS-forming cells cultured in serum-free medium expressed CD133, nestin, and Oct-4, markers of neural stem and progenitor cells. For the 3 adherent cell lines, erlotinib has a moderate effect (50% inhibitory concentration [IC50], >10 µM). Conversely, erlotinib induced a strong cell growth inhibition (IC50, <1 µM) on NS-forming cells, related to the EGFR gene amplification and EGFR protein expression. A short exposure to erlotinib reduced nestin-positive cell proliferation, but NS-initiating activity and self-renewal were not altered. EGFR pathway seems essential for GBM progenitor cell proliferation but dispensable for cancer stem-like cell self-renewal. Inhibition of hedgehog pathway with cyclopamine was evaluated in association with erlotinib on NS growth. Although each drug separately had no effect on sphere initiation, their combination significantly decreased the sphere number (P < .001). Our findings show synergic efficiency for erlotinib-cyclopamine association and provide a suitable in vitro model to explore drug combinations on GBM cells.
cancer stem cells; cyclopamine; epidermal growth factor receptor; glioblastoma; tyrosine kinase inhibitor
Implementation of chemotherapy with the drug temozolomide increased the overall survival of patients with glioblastoma multiforme (GBM; WHO grade IV), in particular when the O6-methylguanine DNA methyltransferase (MGMT) promoter is epigenetically silenced. Nevertheless, the prognosis remains poor, and relapse in GBM occurs regularly. This clinical behavior seems to be due to the existence of a therapy-resistant subpopulation of cells that induce tumor regrowth. The objective of this work was to analyze the role of aldehyde dehydrogenase (ALDH) 1A1 in mediating temozolomide resistance and its value as a predictor of clinical outcome in GBM patients. Nine GBM cell lines were treated with temozolomide alone or in combination with 4-diethylaminobenzaldehyde (DEAB), an inhibitor of ALDH1A1, or with ALDH1A1 short hairpin (sh)RNA. ALDH1A1 expression and MGMT status of 70 primary GBM patients were correlated with median survival. ALDH1A1 overexpression predicted temozolomide resistance in vitro. Sensitivity of ALDH1A1 positive/MGMT-positive cells to temozolomide could be restored by inhibition of ALDH1A1 by DEAB or by knockdown with shRNA, as indicated by increased cytotoxicity, reduced clonogenicity, and accumulation in the G2/M cell-cycle phase. The prognosis of patients with a high level of ALDH1A1 expression was poor compared with that of patients with low levels (P < .0001). ALDH1A1 is a new mediator for resistance of GBM to temozolomide and a reliable predictor of clinical outcome and may serve as a potential target to improve treatment of human GBM.
ALDH1A1; clonogenicity; G2/M arrest; glioblastoma; temozolomide resistance