Bent, M.J. van den

MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status (Article)

2012-10-01T00:00:00Z

The methylation status of the O6-methylguanine- DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg1243587 and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; Log-rank p<0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n = 50; Kappa = 0.88; Outcome, log-rank p<0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMPnegative gliomas MGMT was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor types.

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial (Article)

2012-01-16T00:00:00Z

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.

A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: A report from EORTC study 26951 (Article)

2011-11-15T00:00:00Z

Purpose: The MGMT promoter methylation status has been suggested to be predictive for outcome to temozolomide chemotherapy in patients with glioblastoma (GBM). Subsequent studies indicated that MGMT promoter methylation is a prognostic marker even in patients treated with radiotherapy alone, both in GBMs and in grade III gliomas. Experimental Design: To help determine the molecular mechanism behind this prognostic effect, we have conducted genome-wide methylation profiling and determined the MGMT promoter methylation status, 1p19q LOH, IDH1 mutation status, and expression profile on a series of oligodendroglial tumors [anaplastic oligodendrogliomas (AOD) and anaplastic oligoastrocytomas (AOA)] within EORTC study 26951. The series was expanded with tumors of the same histology and treatment from our own archive. Results: Methylation profiling identified two main subgroups of oligodendroglial brain tumors of which survival in the CpG island hypermethylation phenotype (CIMP+) subgroup was markedly better than the survival of the unmethylated (CIMP-) subgroup (5.62 vs. 1.24 years; P < 0.0001). CIMP status correlated with survival, MGMT promoter methylation, 1p19q LOH, and IDH1 mutation status. CIMP status strongly increases the predictive accuracy of survival in a model including known clinical prognostic factors such as age and performance score. We validated our results on an independent data set from the Cancer Genome Atlas (TCGA). Conclusion: The strong association between CIMP status andMGMTpromoter methylation suggests that the MGMT promoter methylation status is part of a more general, prognostically favorable genome-wide methylation profile. Methylation profiling therefore may help identify AODs and AOAs with improved prognosis.

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group (Article)

2011-09-01T00:00:00Z

Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. Patients and methods: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m2over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. Results: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1): 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. Conclusions: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Acute painful lumbosacral paresthesia after intrathecal rituximab (Article)

2011-08-10T00:00:00Z

Alpha-internexin expression predicts outcome in anaplastic oligodendroglial tumors and may positively impact the efficacy of chemotherapy (Article)

2011-07-01T00:00:00Z

BACKGROUND: Although it has been demonstrated that the neuronal intermediate filament alpha-internexin (INA) is closely related to 1p19q codeletion in gliomas, its prognostic and predictive value has not yet been confirmed in a prospective trial. The authors of this report assessed the prognostic significance of INA expression and its correlation with relevant clinical and molecular characteristics in the prospective, randomized European Organization for Research and Treatment of Cancer (EORTC) 26951 trial of adjuvant procarbazine, lomustine, and vincristine (PCV) in patients with anaplastic oligodendroglial tumors (AOTs). METHODS: INA immunohistochemistry expression in tumors from 92 patients who were included in the EORTC 26951 trial was analyzed independently by 2 observers and was correlated with relevant clinical characteristics, including progression-free survival (PFS) and overall survival (OS), and with molecular features, including 1p/19q codeletion, isocitrate dehydrogenase 1 and 2 gene (IDH1/IDH2) mutation, and O-6 methylguanine-DNA methyltransferase (MGMT) promoter methylation status. RESULTS: INA expression was observed in 33 tumors and was strongly correlated with 1p/19q codeletion, IDH1 mutations, and MGMT promoter methylation. It was associated with significantly better PFS and OS independent of the treatment received. By using Cox proportional hazard modeling for OS with stepwise selection, INA expression, patient age, and performance status were identified as independent prognostic factors. The results indicated that INA expression may have an impact on the efficacy of combined radiotherapy plus PCV. CONCLUSIONS: In a homogeneously treated group of patients with grade III AOTs, INA expression had strong favorable prognostic significance for OS and may have predictive value for sensitivity to chemotherapy. Copyright

Response assessment in neuro-oncology (a report of the RANO group): Assessment of outcome in trials of diffuse low-grade gliomas (Article)

2011-06-01T00:00:00Z

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Cytoreductive surgery of glioblastoma as the key to successful adjuvant therapies: New arguments in an old discussion (Article)

2011-06-01T00:00:00Z

Background: This article discusses data from 3 randomized phase 3 trials, supporting a role for surgery in glioblastoma. Methods: Data were reviewed by extent of resection during primary surgery from the ALA-Glioma Study (fluorescence-guided versus conventional resection), the BCNU wafer study (BCNU wafer versus placebo), and the EORTC Study 26981-22981 (radiotherapy versus chemoradiotherapy with temozolomide). Results: For glioblastoma patients in the ALA study, median survival was 16.7 and 11.8 months for complete versus partial resection, respectively (P<0.0001). Survival effects were maintained after correction for differences in age and tumor location. For glioblastoma patients who received ≥90% resection in the BCNU wafer study, median survival increased for BCNU wafer versus placebo (14.5 versus 12.4 months, respectively; P=0.02), but no survival increase was found for <90% resection (11.7 versus 10.6 months, respectively; P=0.98). In the EORTC study, absolute median gain in survival with chemoradiotherapy versus radiotherapy was greatest for complete resections (+4.1 months; P=0.0001), compared with partial resections (+1.8 months; P=0.0001), or biopsies (+1.5 months; P=0.088), suggesting surgery enhanced adjuvant treatment. Conclusion: Complete resection appears to improve survival and may increase the efficacy of adjunct/adjuvant therapies. If safely achievable, complete resection should be the surgical goal for glioblastoma.

Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951 (Article)

2011-06-01T00:00:00Z

Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify new genomic regions associated with prognosis, 60 AOTs from the EORTC trial 26951 were analyzed retrospectively using BAC-array-based comparative genomic hybridization. The data were processed using a binary tree method. Thirty-three BACs with prognostic value were identified distinguishing four genomic subgroups of AOTs with different prognosis (p < 0.0001). Type I tumors (25%) were characterized by: (1) an EGFR amplification, (2) a poor prognosis, (3) a higher rate of necrosis, and (4) an older age of patients. Type II tumors (21.7%) had: (1) loss of prognostic BACs located on 1p tightly associated with 19q deletion, (2) a longer survival, (3) an oligodendroglioma phenotype, and (4) a frontal location in brain. Type III AOTs (11.7%) exhibited: (1) a deletion of prognostic BACs located on 21q, and (2) a short survival. Finally, type IV tumors (41.7%) had different genomic patterns and prognosis than type I, II and III AOTs. Multivariate analysis showed that genomic type provides additional prognostic data to clinical, imaging and pathological features. Similar results were obtained in the cohort of 45 centrally reviewed-validated cases of AOTs. Whole genome analysis appears useful to screen the numerous genomic abnormalities observed in AOTs and to propose new biomarkers particularly in the non-1p/19q codeleted AOTs.

Reply to A.A. Brandes et al (Article)

2011-03-20T00:00:00Z

Addition of serum-containing medium to cerebrospinal fluid prevents cellular loss over time (Article)

2011-03-12T00:00:00Z

Immediately after sampling, leukocyte counts in native cerebrospinal fluid (CSF) start to decrease rapidly. As the time lapse between CSF collection to analysis is not routinely registered, the clinical significance of decreasing cell counts in native CSF is not known. Earlier data suggest that addition of serum-containing medium to CSF directly after sampling prevents this rapid decrease in leukocyte counts and, thus, may improve the accuracy of CSF cell counting and cell characterization. Here, we prospectively examined the effect of storage time after lumbar puncture on counts of leukocytes and their major subsets in both native CSF and after immediate addition of serum-containing medium, measured by flow cytometry and microscopy. We collected CSF samples of 69 patients in tubes with and tubes without serum-containing medium and determined counts of leukocytes and subsets at 30 minutes, 1 hour, and 5 hours after sampling. Compared to cell counts at 30 minutes, no significant decrease in cell number was observed in CSF with serum-containing medium 1 and 5 hours after sampling, except for the granulocytes at 1 hour. In native CSF, approximately 50% of leukocytes and all their subsets were lost after 1 hour, both in flow cytometric and microscopic counting. In 6/7 (86%) samples with mild pleocytosis (5-15 × 10(6) leukocytes/l), native CSF at 1 hour was incorrectly diagnosed as normocellular. In conclusion, addition of serum-containing medium to CSF directly after sampling prevents cell loss and allows longer preservation of CSF cells prior to analysis, both for microscopic and flow cytometric enumeration. We suggest that this protocol results in more accurate CSF cell counts and may prevent incorrect conclusions based on underestimated CSF cell counts.

Clinical trial end points for high-grade glioma: The evolving landscape (Article)

2011-03-01T00:00:00Z

To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome. Growing recognition of limitations weakening the reliability of traditional clinical trial primary end points has generated increasing uncertainty of how best to evaluate promising therapeutics for patients with HGG. The phenomena of pseudoprogression and pseudoresponse have made imaging-based end points, including overall radiographic response and progression-free survival, problematic. Although overall survival is considered the "gold-standard" end point, recently identified active salvage therapies such as bevacizumab may diminish the association between presalvage therapy and overall survival. Finally, advances in imaging as well as the assessment of patient function and well being have strengthened interest in auxiliary end points assessing these aspects of patient care and outcome. Better appreciation of the strengths and limitations of primary end points will lead to more effective clinical trial strategies. Technical advances in imaging as well as improved survival for patients with HGG support the further development of auxiliary end points evaluating novel imaging approaches as well as measures of patient function and well being.

Reply to P. Farace et al (Article)

2011-02-20T00:00:00Z

First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: Molecular characteristics in relation to response (Article)

2011-02-01T00:00:00Z

Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O6-methylguanine- methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m2/day on days 1-5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methyl-ation (P <.001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P =.01) and a methylated MGMT promoter (P =.02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.

EBV related cerebral lymphoma in a leukemia patient treated with alemtuzumab (Article)

2010-12-10T00:00:00Z

Human chorionic gonadotropin treatment of anti-Hu-associated paraneoplastic neurological syndromes (Article)

2010-12-01T00:00:00Z

Objective: Paraneoplastic neurological syndromes associated with anti-Hu antibodies (Hu-PNS) are mediated by a T-cell immune response that is directed against the Hu antigens. In pregnancy, many Th1-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis regress. We hypothesised that this decreased disease activity during pregnancy may be related to high human chorionic gonadotropin (hCG) levels. Methods: 15 Hu-PNS patients were treated in a prospective, uncontrolled and unblinded trial with 10 000 IU daily of hCG administered by intramuscular injection during 12 weeks. Primary outcome measures were functional improvement defined as a decrease of one or more points on the modified Rankin Scale (mRS) or stabilisation in patients with mRS score ≤3 and improvement of neurological impairment assessed with the Edinburgh Functional Impairment Tests (EFIT). Secondary end points included the change in activities of daily living as evaluated using the Barthel Index. Results: Seven of 15 patients (47%) improved on the mRS or stabilised at mRS score ≤3. Four patients (27%) showed significant improvement of neurological impairment as indicated by an overall Edinburgh Functional Impairment Tests score of ≥1 point. Five patients improved on the Barthel Index (33%). Conclusion: Comparison with previous studies suggests that hCG may have immunomodulatory activity and may modify the course of Hu-PNS, although well-established confounding factors may have contributed in this uncontrolled trial.

Sitimagene ceradenovec: A gene-based drug for the treatment of operable high-grade glioma (Article)

2010-11-01T00:00:00Z

The field of gene therapy for malignant glioma has made important advances since the first gene transfer studies were performed 20 years ago. Multiple Phase I/II trials and two Phase III trials have been performed and have demonstrated the feasibility and safety of intratumoral vector delivery in the brain. Sitimagene ceradenovec is an adenoviral vector encoding the herpes simplex thymidine kinase gene, developed by Ark Therapeutics Group plc (UK and Finland) for the treatment of patients with operable high-grade glioma. In preclinical and Phase I/II clinical studies, sitimagene ceradenovec exhibited a significant increase in survival. Although the preliminary results of a Phase III clinical study demonstrated a significant positive effect of sitimagene ceradenovec treatment on time to reintervention or death when compared with standard care treatment (hazard ratio: 1.43; 95% CI: 1.06-1.93; p < 0.05), the European Committee for Medicinal Products for Human Use did not consider the data to provide sufficient evidence of clinical benefit. Further clinical evaluation, powered to demonstrate a benefit on a robust end point, is required. This article focuses on sitimagene ceradenovec and provides an overview of the developments in the field of gene therapy for malignant glioma.

Molecular diagnostics of gliomas: The clinical perspective (Article)

2010-11-01T00:00:00Z

Significant progress has been made in the molecular diagnostic subtyping of brain tumors, in particular gliomas. In contrast to the classical molecular markers in this field, p53 and epidermal growth factor receptor (EGFR) status, the clinical significance of which has remained controversial, at least three important molecular markers with clinical implications have now been identified: 1p/19q codeletion, O6-methylguanine methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase-1 (IDH1) mutations. All three are favorable prognostic markers. 1p/19q codeletion and IDH1 mutations are also useful to support and extend the histological classification of gliomas since they are strongly linked to oligodendroglial morphology and grade II/III gliomas, as opposed to glioblastoma, respectively. MGMT promoter methylation is the only potentially predictive marker, at least for alkylating agent chemotherapy in glioblastoma. Beyond these classical markers, the increasing repertoire of anti-angiogenic agents that are currently explored within registration trials for gliomas urgently calls for efforts to identify molecular markers that predict the benefit derived from these novel treatments, too.

Primary central nervous system lymphoma in the elderly: A multicentre retrospective analysis (Article)

2010-10-01T00:00:00Z

Elderly patients with primary central nervous ystem lymphoma (PCNSL) do not tolerate treatment with combined radio-chemotherapy well because of leuco-encephalopathy; they are usually treated initially with chemotherapy or radiotherapy alone. Little is known about the efficacy and toxicity of these treatments outside clinical studies. This study was a retrospective analysis of all patients aged 60 years or over who were admitted with PCNSL to one of five Dutch centers between 1998 and 2007. A total of 74 patients were identified. Twenty-nine were treated with radiotherapy only (Group A), in 36 the intended treatment was chemotherapy alone (Group B), and nine were planned to receive chemotherapy followed by radiotherapy (Group C). Median overall survival was 20 months; 4 months in patients with a Karnofsky performance status (KPS) <70, 25 months in patients with a KPS ≥ 70 (P < 0·001). Treatment modality was not an independent prognostic factor. Forty patients were treated with methotrexate 3 g/m2: there were two toxic deaths. Ten patients discontinued chemotherapy because of toxicity. Delayed encephalopathy was reported in 10 patients. In conclusion, community hospitals still frequently utilize whole brain radiotherapy in elderly PCNSL patients, though a majority tolerates chemotherapy well. Performance status was the most important variable determining prognosis. Short and long term toxicities must be weighed against possible clinical benefits of each treatment, making treatment decisions a highly individualized process.

Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician's perspective (Article)

2010-09-01T00:00:00Z

Several studies have provided ample evidence of a clinically significant interobserver variation of the histological diagnosis of glioma. This interobserver variation has an effect on both the typing and grading of glial tumors. Since treatment decisions are based on histological diagnosis and grading, this affects patient care: erroneous classification and grading may result in both over- and undertreatment. In particular, the radiotherapy dosage and the use of chemotherapy are affected by tumor grade and lineage. It also affects the conduct and interpretation of clinical trials on glioma, in particular of studies into grade II and grade III gliomas. Although trials with central pathology review prior to inclusion will result in a more homogeneous patient population, the interpretation and external validity of such trials are still affected by this, and the question whether results of such trials can be generalized to patients diagnosed and treated elsewhere remains to be answered. Although molecular classification may help in typing and grading tumors, as of today this is still in its infancy and unlikely to completely replace histological classification. Routine pathology review in everyday clinical practice should be considered. More objective histological criteria for the grade and lineage of gliomas are urgently needed.

Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas (Article)

2010-09-01T00:00:00Z

Imaging techniques are important for accurate diagnosis and follow-up of patients with gliomas. T1-weighted MRI, with or without gadolinium, is the gold standard method. However, this technique only reflects biological activity of the tumour indirectly by detecting the breakdown of the blood-brain barrier. Therefore, especially for low-grade glioma or after treatment, T1-weighted MRI enhanced with gadolinium has substantial limitations. Development of more advanced imaging methods to improve outcomes for individual patients is needed. New imaging methods based on MRI and PET can be employed in various stages of disease to target the biological activity of the tumour cells (eg, increased uptake of aminoacids or nucleoside analogues), the changes in diffusivity through the interstitial space (diffusion-weighted MRI), the tumour-induced neovascularisation (perfusion-weighted MRI or contrast-enhanced MRI, or increased uptake of aminoacids in endothelial wall), and the changes in concentrations of metabolites (magnetic resonance spectroscopy). These techniques have advantages and disadvantages, and should be used in conjunction to best help individual patients. Advanced imaging techniques need to be validated in clinical trials to ensure standardisation and evidence-based implementation in routine clinical practice.

Neurolymphomatosis: An International Primary CNS Lymphoma Collaborative Group report (Article)

2010-06-17T00:00:00Z

Neurolymphomatosis (NL) is a rare clinical entity. The International Primary CNS Lymphoma Collaborative Group retrospectively analyzed 50 patients assembled from 12 centers in 5 countries over a 16-year period. NL was related to non-Hodgkin lymphoma in 90% and to acute leukemia in 10%. It occurred as the initial manifestation of malignancy in 26% of cases. The affected neural structures included peripheral nerves (60%), spinal nerve roots (48%), cranial nerves (46%), and plexus (40%) with multiple site involvement in 58%. Imaging studies often suggested the diagnosis with 77% positive magnetic resonance imaging, and 84% (16 of 19) positive computed tomography-positron emission tomography studies. Cerebrospinal fluid cytology was positive in 40%, and nerve biopsy confirmed the diagnosis in 23 of 26 (88%). Treatment in 47 patients included systemic chemotherapy (70%), intra-cerebrospinal fluid chemotherapy (49%), and radiotherapy (34%). Response to treatment was observed in 46%. The median overall survival was 10 months, with 12- and 36-month survival proportions of 46% and 24%, respectively. NL is a challenging diagnosis, but contemporary imaging techniques frequently detect the relevant neural invasion. An aggressive multimodality therapy can prevent neurologic deterioration and is associated with a prolonged survival in a subset of patients.

Integrated genomic profiling identifies candidate genes implicated in glioma-genesis and a novel LEO1-SLC12A1 fusion gene (Article)

2010-06-01T00:00:00Z

We performed genotyping and exon-level expression profiling on 21 glioblastomas (GBMs) and 19 oligodendrogliomas (ODs) to identify genes involved in glioma initiation and/or progression. Low-copy number amplifications (2.5 < n < 7) and high-copy number amplifications (n > 7) were more frequently observed in GBMs; ODs generally have more heterozygous deletions per tumor. Four high-copy amplicons were identified in more than one sample and resulted in overexpression of the known oncogenes EGFR, MDM2, and CDK4. In the fourth amplicon, RBBP5, a member of the RB pathway, may act as a novel oncogene in GBMs. Not all hCNAs contain known genes, which may suggest that other transcriptional and/or regulatory elements are the target for amplification. Regions with most frequent allelic loss, both in ODs and GBMs, resulted in a reduced expression of known tumor suppressor genes. We identified a homozygous deletion spanning the Pragmin gene in one sample, but direct sequencing of all coding exons in 20 other glioma samples failed to detect additional genetic changes. Finally, we screened for fusion genes by identifying aberrant 5′-3′ expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. Our data show that integrated genomic profiling can identify genes involved in tumor initiation, and/or progression and can be used as an approach to identify novel fusion genes.

Bevacizumab and recurrent malignant gliomas: A European perspective (Article)

2010-04-20T00:00:00Z

An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients (Article)

2010-04-01T00:00:00Z

Aims: The psychometric properties of the EORTC QLQ-BN20, a brain cancer-specific HRQOL questionnaire, have been previously determined in an English-speaking sample of patients. This study examined the validity and reliability of the questionnaire in a multi-national, multi-lingual study. Methods: QLQ-BN20 data were selected from two completed phase III EORTC/NCIC clinical trials in brain cancer (N = 891), including 12 languages. Experimental treatments were surgery followed by radiotherapy (RT) and adjuvant PCV chemotherapy or surgery followed by concomitant RT plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy. Standard treatment consisted of surgery and postoperative RT alone. The psychometrics of the QLQ-BN20 were examined by means of multi-trait scaling analyses, reliability estimation, known groups validity testing, and responsiveness analysis. Results: All QLQ-BN20 items correlated more strongly with their own scale (r > 0.70) than with other QLQ-BN20 scales. Internal consistency reliability coefficients were high (all α ≥ 0.70). Known-groups comparisons yielded positive results, with the QLQ-BN20 distinguishing between patients with differing levels of performance status and mental functioning. Responsiveness of the questionnaire to changes over time was acceptable. Conclusion: The QLQ-BN20 demonstrates adequate psychometric properties and can be recommended for use in conjunction with the QLQ-C30 in assessing the HRQOL of brain cancer patients in international studies.

IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: A report of the European Organization for Research and Treatment of Cancer Brain Tumor Group (Article)

2010-03-01T00:00:00Z

Purpose: Recent studies have shown the prognostic significance of IDH1 mutations in glioma. It is yet unclear if IDH1 mutations are predictive for outcome to chemotherapy. We determined the effect of IDH1 mutations on progression-free survival and overall survival (OS), and its correlation with other clinical and molecular features in the prospective randomized European Organization for Research and Treatment of Cancer study 26951 on adjuvant procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-L-nitrosourea, and vincristine (PCV) in anaplastic oligodendroglioma. Experimental Design: IDH1 and IDH2 alterations of the mutational hotspot codons R132 and R172 were assessed by the bidirectional cycle sequencing of PCR-amplified fragments. MGMT promoter methylation was assessed using methylation-specific multiplex ligation-dependant probe amplification based on methylation-sensitive restriction analysis. Loss of chromosomes 1p, 19q, 10, and 10q and the gain of 7 and the EGFR gene were assessed with fluorescence in situ hybridization. Results: From 159 patients, sufficient material was available for IDH1 analysis. In 151 and 118 of these patients, respectively, the 1p/19q status and the MGMT promoter methylation status were known. In 73 cases (46%), an IDH1 mutation was found and only one IDH2 mutation was identified. The presence of IDH1 mutations correlated with 1p/19q codeletion and MGMT promoter methylation, and inversely correlated with loss of chromosome 10, EGFR amplification, polysomy of chromosome 7, and the presence of necrosis. IDH1 mutations were found to be prognostic in the radiotherapy- and the radiotherapy/PCV-treated patients, for both progression-free survival and OS. With Cox proportional hazard modeling for OS with stepwise selection, IDH1 mutations and 1p/19q codeletion but not MGMT promoter methylation were independent prognostic factors. Conclusion: In this homogeneously treated group of anaplastic oligodendroglioma patients, the presence of IDH1 mutations was found to carry a very strong prognostic significance for OS but without evidence of a predictive significance for outcome to PCV chemotherapy. IDH1 mutations were strongly associated with 1p/ 19q codeletion and MGMT promoter methylation. ©2010 AACR.

Segregation of non-p.R132H mutations in IDH1 in distinct molecular subtypes of glioma (Article)

2010-03-01T00:00:00Z

Mutations in the gene encoding the isocitrate dehydrogenase 1 gene (IDH1) occur at a high frequency (up to 80%) in many different subtypes of glioma. In this study, we have screened for IDH1 mutations in a cohort of 496 gliomas. IDH1 mutations were most frequently observed in low grade gliomas with c.395G>A (p.R132H) representing >90% of all IDH1 mutations. Interestingly, non-p.R132H mutations segregate in distinct histological and molecular subtypes of glioma. Histologically, they occur sporadically in classic oligodendrogliomas and at significantly higher frequency in other grade II and III gliomas. Genetically, non-p.R132H mutations occur in tumors with TP53 mutation, are virtually absent in tumors with loss of heterozygosity on 1p and 19q and accumulate in distinct (gene-expression profiling based) intrinsic molecular subtypes. The IDH1 mutation type does not affect patient survival. Our results were validated on an independent sample cohort, indicating that the IDH1 mutation spectrum may aid glioma subtype classification. Functional differences between p.R132H and non-p.R132H mutated IDH1 may explain the segregation in distinct glioma subtypes.

Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma? (Article)

2010-01-01T00:00:00Z

The discovery of somatic mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) in glioblastomas was remarkable because the enzyme was not previously identified with any known oncogenic pathway. IDH1 is mutated in up to 75% of grade II and grade III diffuse gliomas. Apart from acute myeloid leukaemia, other tumour types do not carry IDH1 mutations. Mutations in a homologous gene, IDH2, have also been identified, although they are much rarer. Although TP53 mutations and 1p/19q codeletions are mutually exclusive in gliomas, in both of these genotypes IDH1 mutations are common. IDH1 and IDH2 mutations are early events in the development of gliomas. Moreover, IDH1 and IDH2 mutations are a major prognostic marker for overall and progression-free survival in grade II-IV gliomas. Mutated IDH1 has an altered catalytic activity that results in the accumulation of 2-hydroxyglutarate. Molecularly, IDH1 and IDH2 mutations are heterozygous, affect only a single codon, and rarely occur together. Because IDH1 does not belong to a traditional oncogenic pathway and is specifically and commonly mutated in gliomas, the altered enzymatic activity of IDH1 may provide a fundamentally new understanding of diffuse glioma.

MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation (Article)

2010-01-01T00:00:00Z

Hypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII) to anaplastic astrocytoma (AIII) and secondary glioblastoma (sGB). In this study biopsy specimens from 51 patients with astrocytic tumors with radiologically proved progression from low to high-grade malignancy were investigated for the presence and consistency of MGMT promoter hypermethylation and TP53 mutations. For 27 patients biopsy samples both of primary tumors and their recurrences were available. For the other 24 patients histology of either the low-grade lesion or the high-grade recurrence was available. It was found that MGMT promoter hypermethylation and TP53 mutations are both frequent and early events in the progression of astrocytomas and that their status is consistent over time. No correlation was found between MGMT methylation status and the presence of TP53 mutations. In addition, no correlation was found between MGMT promoter hypermethylation and the type of TP53 mutations. These results argue against the putative TP53 G:C>A:T transition mutations suggested to occur preferentially in MGMT hypermethylated tumors.

MGMT promoter methylation in malignant gliomas: Ready for personalized medicine? (Article)

2010-01-01T00:00:00Z

The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile. Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either upfront or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

EORTC study 26041-22041: Phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma (Article)

2010-01-01T00:00:00Z

Background: Glioblastoma is a highly vascularised tumour with a high expression of both vascular endothelial growth factor (VEGF) and VEGFR. PTK787/ZK222584 (PTK/ZK, vatalanib), a multiple VEGF receptor inhibitor, blocks the intracellular tyrosine kinase activity of all known VEGF receptors and is therefore suitable for long-term therapy of pathologic tumour neovascularisation. Patients and methods: The study was designed as an open-label, phase I/II study. A classic 3 + 3 design was selected. PTK/ZK was added to standard concomitant and adjuvant treatment, beginning in the morning of day 1 of radiotherapy (RT), and given continuously until disease progression or toxicity. PTK/ZK doses started from 500 mg with subsequent escalations to 1000 and 1250 mg/d. Adjuvant or maintenance PTK after the end of radiochemotherapy was given at a previously established dose of 750 mg twice daily continuously with TMZ at the standard adjuvant dose. Results: Twenty patients were enrolled. Dose-limiting toxicities at a once daily dose of 1250 mg were grade 3 diarrhoea (n = 1), grade 3 ALT increase (n = 2), and myelosuppression with grade 4 thrombocytopenia and neutropenia (n = 1). The recommended dose of PTK/ZK in combination with radiotherapy and temozolomide (TMZ) is 1000 mg once a day. This treatment is safe and well tolerated. Conclusion: In our phase I study once daily administration of up to 1000 mg of PTK/ZK in conjunction with concomitant temozolomide and radiotherapy was feasible and safe. Prolonged administration of this oral agent is manageable. The planned randomised phase II trial was discontinued right at its onset due to industry decision not to further develop this agent.

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma (Article)

2009-12-01T00:00:00Z

Background: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). Methods: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). Results: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). Conclusions: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology (Article)

2009-12-01T00:00:00Z

Gliomas are the most common primary brain tumors with heterogeneous morphology and variable prognosis. Treatment decisions in patients rely mainly on histologic classification and clinical parameters. However, differences between histologic subclasses and grades are subtle, and classifying gliomas is subject to a large interobserver variability. To improve current classification standards, we have performed gene expression profiling on a large cohort of glioma samples of all histologic subtypes and grades. We identified seven distinct molecular subgroups that correlate with survival. These include two favorable prognostic subgroups (median survival, >4.7 years), two with intermediate prognosis (median survival, 1-4 years), two with poor prognosis (median survival, <1 year), and one control group. The intrinsic molecular subtypes of glioma are different from histologic subgroups and correlate better to patient survival. The prognostic value of molecular subgroups was validated on five independent sample cohorts (The Cancer Genome Atlas, Repository for Molecular Brain Neoplasia Data, GSE12907, GSE4271, and Li and colleagues). The power of intrinsic subtyping is shown by its ability to identify a subset of prognostically favorable tumors within an external data set that contains only histologically confirmed glioblastomas (GBM). Specific genetic changes (epidermal growth factor receptor amplification, IDH1 mutation, and 1p/19q loss of heterozygosity) segregate in distinct molecular subgroups. We identified a subgroup with molecular features associated with secondary GBM, suggesting that different genetic changes drive gene expression profiles. Finally, we assessed response to treatment in molecular subgroups. Our data provide compelling evidence that expression profiling is a more accurate and objective method to classify gliomas than histologic classification. Molecular classification therefore may aid diagnosis and can guide clinical decision making.

Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951 (Article)

2009-12-01T00:00:00Z

Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFRamp), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1ploss19qloss) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFRamp were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients with AOA with only endothelial proliferation had better overall survival. In univariate analyses, all molecular factors except loss of 10q were of prognostic significance, but on multivariate analysis a histopathological diagnosis of AOA, necrosis, and 1ploss19qloss remained independent prognostic factors. AOA tumors with necrosis are to be considered WHO grade IV tumors (GBM). Of all molecular markers analyzed in this study, especially loss of 1p/19q carried prognostic significance, while the others contributed little prognostic value to classical histology. Copyright 2009 by the Society for Neuro-Oncology.

Pseudoprogression and pseudoresponse in the treatment of gliomas (Article)

2009-11-01T00:00:00Z

PURPOSE OF REVIEW: Treatment response of brain tumours is typically evaluated with gadolinium-enhanced MRI using the Macdonald criteria. These criteria depend on changes in the area of enhancement. However, gadolinium enhancement of brain tumours primarily reflects impairment of the blood-brain barrier. RECENT FINDINGS: Combined chemo-irradiation with temozolomide may induce in 20-30% of cases pseudoprogression, defined as an increase of contrast-enhancement and/or oedema on MRI without true tumour progression. Also, full-blown radiation necrosis may be more frequent after combined chemo-irradiation. After treatment with vascular endothelial growth factor receptor signalling pathway inhibitors pseudoresponse is frequent: a decrease in contrast-enhancement of brain tumours on MRI without a decrease of tumour activity. This to some extent explains the high response rate without a major increase in survival after treatment with these agents for recurrent glioblastoma. SUMMARY: Both pseudo-phenomenona confuse the assessment of outcome of brain tumours in clinical practice and in clinical trials. To overcome these issues, alternative endpoints and response criteria are being developed by an international working party [response assessment in neuro-oncology (RANO)]. It is as yet unclear to what extent alternative imaging tools (positron emission tomography and MRI techniques) provide more reliable indicators of outcome.

Neurological adverse effects caused by cytotoxic and targeted therapies (Article)

2009-08-26T00:00:00Z

Historically, body tissues with a high rate of cell turnover, such as the bone marrow, have been most susceptible to chemotherapy-induced damage. The widespread use of hematopoietic colony-stimulating factors, as well as the development of new agents, has led to improved outcomes in many types of cancer. As a consequence, neurotoxicity has become increasingly important as a cause of dose-limiting chemotherapy toxicity. An understanding of the neurologic complications of these new agents is crucial in order to prevent irreversible neurologic injury. Moreover, chemotherapy complications that require discontinuation of a potentially effective drug need to be distinguished from other causes of neurotoxicity including the tumor itself, paraneoplasia, radiation and surgery, which may require a different therapeutic strategy. We review the prevalence, prevention, and management of important and unusual neurotoxicities related to chemotherapy and targeted agents approved by the FDA since January 1999. These agents include DNA-damaging agents such as oxaliplatin and temozolomide, microtubule poisons like ixabepilone, proteasome inhibitors (bortezomib), and signal transduction inhibitors such as imatinib, sunitinib and bevacizumab.

End point assessment in gliomas: Novel treatments limit usefulness of classical Macdonald's criteria (Article)

2009-06-20T00:00:00Z

Cost-effectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme (Article)

2009-06-01T00:00:00Z

Aim: To perform a systematic review on the costs and cost-effectiveness of concomitant and adjuvant temozolomide with radiotherapy for the treatment of newly diagnosed glioblastoma compared with initial radiotherapy alone. Methods: Electronic databases were searched for relevant publications on costs and cost-effectiveness until October 2008. Results: We found four relevant clinical trials, one cost study and two economic models. The mean survival benefit in the radiotherapy plus temozolomide group varied between 0.21 and 0.25 life-years. Treatment costs were between €27,365 and €39,092. The costs of temozolomide amounted to approximately 40% of the total treatment costs. The incremental cost-effectiveness ratios found in the literature were €37,361 per life-year gained and €42,912 per quality-adjusted life-year gained. However, the models are not comparable because different outcomes are used (i.e., life-years and quality-adjusted life-years). Conclusion: Although the models are not comparable according to outcome, the incremental cost-effectiveness ratios found are within acceptable ranges. We concluded that despite the high temozolomide acquisition costs, the costs per life-year gained and the costs per quality-adjusted life-year gained are comparable with other accepted first-line treatments with chemotherapy in patients with cancer.

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial (Article)

2009-05-01T00:00:00Z

Background: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Methods: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. Findings: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27·2% (95% CI 22·2-32·5) at 2 years, 16·0% (12·0-20·6) at 3 years, 12·1% (8·5-16·4) at 4 years, and 9·8% (6·4-14·0) at 5 years with temozolomide, versus 10·9% (7·6-14·8), 4·4% (2·4-7·2), 3·0% (1·4-5·7), and 1·9% (0·6-4·4) with radiotherapy alone (hazard ratio 0·6, 95% CI 0·5-0·7; p<0·0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Interpretation: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. Funding: EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.

Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034 (Article)

2009-03-10T00:00:00Z

Purpose Approximately 50% of glioblastomas (GBMs) are characterized by overexpression of the epidermal growth factor receptor (EGFR) and EGFR gene amplification. In approximately 25% of instances, constitutively activated EGFR mutants are present. These observations make EGFR-inhibiting drugs a logical approach for trials in recurrent GBM. Patients and Methods In a randomized, controlled, phase II trial, 110 patients with progressive GBM after prior radiotherapy were randomly assigned to either erlotinib or a control arm that received treatment with either temozolomide or carmustine (BCNU). The primary end point was 6-month progression-free survival (PFS). Tumor specimens obtained at first surgery were investigated for EGFR expression; EGFRvlll mutants; EGFR amplification; EGFR mutations in exons 18, 19, and 21; and pAkt. These results were correlated with outcome. Pharmacokinetic analysis was part of the study. Results Treatment was well tolerated in general; skin toxicity was the most frequent adverse effect of erlotinib. The 6-month PFS rate in the erlotinib arm was 11.4% (95% CI, 4.6% to 21.5%), and it was 24% in the control arm. Of all explored biomarkers, only low pAkt expression appeared to be of borderline significance to an improved outcome. None of the eight patients who had tumors with EGFRvlll mutant presence and PTEN expression had 6-month PFS. The use of enzyme-inducing anticonvulsants significantly increased erlotinib clearance, but pharmacokinetic findings were not related to outcome. Conclusion Erlotinib has insufficient single-agent activity in unselected GBM. No clear biomarker associated with improved outcome to erlotinib was identified. Copyright

Oligodendrogliomas: Molecular biology and treatment (Article)

2009-02-01T00:00:00Z

Oligodendroglial tumors continue to receive much attention because of their relative sensitivity to chemotherapy. The histological diagnosis of oligodendroglial tumors is subject to considerable interobserver variation. The revised 2007 World Health Organization classification of brain tumors no longer accepts the diagnosis "mixed anaplastic oligoastrocytoma" if necrosis is present; these tumors should be considered glioblastomas (perhaps with oligodendroglial features). The 1p/19q codeletion that is associated with sensitivity to chemotherapy is mediated by an unbalanced translocation of 19p to 1q. Randomized studies have shown that patients with 1p/19q codeleted tumors also have a better outcome with radiotherapy.Histologically more atypical tumors are less likely to have this 1p/19q codeletion; here, other alterations usually associated with astrocytic tumors are often found. Some patients with tumors with classic histological features but no 1p/19q codeletion still have a very favorable prognosis. Currently, the best approach for newly diagnosed anaplastic oligodendroglial tumors is unclear. Early adjuvant chemotherapy does not provide a better outcome than chemotherapy at the time of progression. The value of combined chemoirradiation with temozolomide has not been proven in these tumors, and could at least theoretically be associated with greater neurotoxicity. Tumors with 1p and 19q loss can also be managed with early chemotherapy, while deferring radiotherapy to the time of further progression. The presently available second-line chemotherapy results are modest, and better salvage treatments are necessary. The molecular explanation for the greater sensitivity of 1p/19q codeleted tumors is still unclear, and this could, in part, be explained by more frequent MGMT promoter gene methylation.

No evidence for the presence of HuD-specific T cells in the cerebrospinal fluid of patients with Huassociated paraneoplastic neurological syndromes (Letter To Editor)

2009-02-01T00:00:00Z

A novel tool to analyze MRI recurrence patterns in glioblastoma (Article)

2008-12-01T00:00:00Z

At least 10% of glioblastoma relapses occur at distant and even contralateral locations. This disseminated growth limits surgical intervention and contributes to neurological morbidity. Preclinical data pointed toward a role for temozolomide (TMZ) in reducing radiotherapy-induced glioma cell invasiveness. Our objective was to develop and validate a new analysis tool of MRI data to examine the clinical recurrence pattern of glioblastomas. MRI-cro software was used to map the location and extent of initial preoperative and recurrent tumors on MRI of 63 patients in the European Organisation for Research and Treatment of Cancer (EORTC) 26981/22981/National Cancer Institute of Canada (NCIC) CE.3 study into the same stereotaxic space. This allowed us to examine changes of site and distance between the initial and the recurrent tumor on the group level. Thirty of the 63 patients were treated using radiotherapy, while the other patients completed a radiotherapy-plus-TMZ treatment. Baseline characteristics (median age, KPS) and outcome data (progression-free survival, overall survival) of the patients included in this analysis resemble those of the general study cohort. The patient groups did not differ in the promoter methylation status of methyl guanine methyltransferase (MGMT). Overall frequency of distant recurrences was 20%. Analysis of recurrence patterns revealed no difference between the groups in the size of the recurrent tumor or in the differential effect on the distance of the recurrences from the pre-operative tumor location. The data show the feasibility of groupwise recurrence pattern analysis. An effect of TMZ treatment on the recurrence pattern in the EORTC 26981/22981/NCIC CE.3 study could not be demonstrated. Copyright 2008 by the Society for Neuro-Oncology.

Phase II study of imatinib in patients with recurrent gliomas of various histologies: A European organisation for research and treatment of cancer brain tumor group study (Article)

2008-10-01T00:00:00Z

Purpose: To evaluate the safety and the efficacy of imatinib in recurrent malignant gliomas. Patients and Methods: This was a single-arm, phase II study. Eligible patients had recurrent glioma after prior radiotherapy with an enhancing lesion on magnetic resonance imaging. Three different histologic groups were studied: glioblastomas (GBM), pure/mixed (anaplastic) oligodendrogliomas (OD), and low-grade or anaplastic astrocytomas (A). Imatinib was started at a dose of 600 mg/d with dose escalation to 800 mg in case of no toxicity; during the trial this dose was increased to 800 mg/d with escalation to 1,000 mg/d. Trial design was one-stage Fleming; both an objective response and 6 months of progression-free survival (PFS) were considered a successful outcome to treatment. Results: A total of 112 patients (51 patients with GBM, 25 patients with A, and 36 patients with OD) were enrolled. Imatinib was in general well tolerated. The median number of cycles was 2.0 (range, 1 to 43 cycles). Five patients had an objective partial response, including three patients with GBM; all had 6 months of PFS. The 6-month PFS rate was 16% (95% CI, 8.0% to 34.0%) in GBM, 4.0% (95% CI, 0.3% to 15.0%) in OD, and 9% (95% CI, 2.0% to 25.0%) in A. The exposure to imatinib was significantly lower in patients using enzyme-inducing antiepileptic drugs. The presence of ABCG2 point mutations were not correlated with pharmacokinetic findings. No somatic activating mutations of KIT or platelet-derived growth factor receptor-A or -B were found. Conclusion: In the dose range of 600 to 1,000 mg/d, single-agent imatinib is well tolerated but has limited antitumor activity in patients with recurrent gliomas.

In reply (Article)

2008-09-15T00:00:00Z

Frequently asked questions in the medical management of high-grade glioma: A short guide with practical answers (Article)

2008-09-01T00:00:00Z

Chromosome 1p loss evaluation in anaplastic oligodendrogliomas (Article)

2008-08-01T00:00:00Z

The chromosome (chr) 1p deletion is a favorable biomarker in oligodendroglial tumors and is even more powerful a marker when combined with chr 19q loss. As a result, the 1p deletion is taken into account more and more in clinical trials and the management of patients. However, the laboratory technique implemented for detection of this biomarker has been a topic of debate. To illustrate the usefulness of evaluating multiple loci, we here report two anaplastic oligodendrogliomas that were investigated using fluorescent in situ hybridization (FISH) and bacterial artificial chromosome (BAC)-array-based comparative genomic hybridization (aCGH). Indeed, segmental analysis using FISH, limited to chr 1p36 was unable to discriminate between complete and partial deletions of chrs 1p. However, complete and partial deletions of 1p are reported to have distinct clinical outcomes. Our results illustrate that aCGH (or other multiple loci technologies) provide complementary information to single locus technologies such as FISH because multiple loci technologies can evaluate the extent of the chr 1p deletion.

The management of cerebral metastasis from germ cell cancer; walking the tightrope (Article)

2008-08-01T00:00:00Z

Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide (Article)

2008-07-15T00:00:00Z

BACKGROUND. Radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ) is now the standard of care for patients with newly diagnosed glioblastoma. The occurrence of pseudo-progression directly after RT is a recognized phenomenon, but to the authors' knowledge its incidence after combined RT/TMZ is unknown. The occurrence of early pseudo-progression was retrospectively assessed in a cohort of malignant glioma patients treated with RT/TMZ. METHODS. The pre-RT and post-RT brain scans from patients treated with RT/TMZ for a malignant glioma were reviewed. Scans were made before the start of RT, 4 weeks after the end of RT, and every 3 months thereafter. In addition, information was collected regarding clinical signs and symptoms, dexamethasone dose, histology, and survival. RESULTS. Eighty-five patients were identified. In 36 patients (42%) the first followup scan 4 weeks after the end of RT indicated disease progression. Of these 36 patients, 18 (50%) were diagnosed with pseudo-progression. None of the patients received additional treatment other than TMZ. Six of 18 patients with pseudo-progression and 12 of the 18 patients with real tumor progression developed new clinical signs and symptoms during RT or in the first 4 weeks thereafter. CONCLUSIONS. Up to 50% of malignant glioma patients treated with RT/TMZ and progression immediately after RT develop pseudo-progression. The current study data support the idea to continue TMZ in the case of progressive lesions immediately after RT/TMZ. Surgery should be considered in symptomatic cases. The inclusion of patients with progressive lesions developing direcdy after chemoradiation in studies regarding recurrent gliomas will lead to an overestimation of the results.

Incidence of central nervous system involvement in chronic lymphocytic leukemia and outcome to treatment (Article)

2008-06-01T00:00:00Z

Leptomeningeal involvement in patients with CLL is relatively rare and the prognosis is usually considered to be poor. The authors reviewed all CLL patients treated in a tertiary referral center to assess the incidence and outcome of leptomeningeal involvement (LI) in CLL. They found an incidence of 1-2% of LI. Most of the patients with LI had a longterm survival, despite failure to clear the cerebrospinal fluid from tumor cells.

Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: Results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882) (Article)

2008-06-01T00:00:00Z

Background: In a previous randomised EORTC study on adjuvant dibromodulcitol (DBD) and bichloroethylnitrosourea (BCNU) in adults with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), a clinically significant trend towards a longer overall survival (OS) and a progression-free survival (PFS) was observed in the subgroup of AA. The aim of the present study was to test this adjuvant regimen in a larger number of AA patients. Methods: Continuation of the previous phase III trial for newly diagnosed AA according to the local pathologist. Patients were randomised to either radiotherapy only or to radiotherapy in combination with BCNU on day 2 and weekly DBD, followed by adjuvant DBD and BCNU in cycles of six weeks for a maximum total treatment duration of one year. OS was the primary end-point. Results: Patients (193 ) with newly diagnosed AA according to local pathological assessment were randomised to radiotherapy (RT) alone (n = 99), or to RT plus DBD/BCNU (n = 94); 12 patients were considered not eligible. At central pathology review, over half (53%) of the locally diagnosed AA cases could not be confirmed. On intent-to-treat analysis, no statistically significant differences in OS (p = 0.111) and PFS (p = 0.087) were observed, median OS after RT was only 23.9 months 95% confidence interval (CI), [18.4-34.0] after RT plus DBD/BCNU 27.3 months 95% CI [21.4-46.8]. Conclusion: No statistically significant improvement in survival was observed after BCNU/DBD adjuvant chemotherapy in AA patients. The trend towards improved survival is consistent with previous reports. Central pathology review of grade 3 tumours remains crucial.

Oligodendroglioma (Article)

2008-06-01T00:00:00Z

Oligodendrogliomas (OD) are rare, diffusely infiltrating tumors, arising in the white matter of cerebral hemispheres, and displaying better sensitivity to treatment and prognosis than other gliomas. Favorable prognostic factors are low-grade, combined loss of 1p/19q, younger age, good performance status, and frontal localization. Low-grade OD usually present with seizures, whereas high-grade tumors often present with focal deficits, increased intracranial pressure or cognitive deficits. Treatment may be deferred until progression in young patients with low-grade OD presenting with seizures only. Patients with enhancing lesions, mass effect, focal deficits or increased intracranial pressure should be treated without delay. Treatment consists of resection as extensive and as safe possible. Postoperative radiotherapy is indicated for large, unresectable, or incompletely resected tumors; focal deficits; anaplastic tumors; or enhancing lesions. Adjuvant PCV chemotherapy increased progression-free survival but does not improve survival as compared to PCV given at recurrence. Chemotherapy with either PCV or temozolomide constitutes a standard for recurrent/progressive disease.

Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas (Article)

2008-05-01T00:00:00Z

Since the introduction of chemoradiotherapy with temozolomide as the new standard of care for patients with glioblastoma, there has been an increasing awareness of progressive and enhancing lesions on MRI, noted immediately after the end of treatment, which are not related to tumour progression, but which are a treatment effect. This so-called pseudoprogression can occur in up to 20% of patients who have been treated with temozolomide chemoradiotherapy, and can explain about half of all cases of increasing lesions after the end of this treatment. These lesions decrease in size or stabilise without additional treatments and often remain clinically asymptomatic. Additionally, there is evidence that treatment-related necrosis occurs more frequently and earlier after temozolomide chemotherapy than after radiotherapy alone. The mechanisms behind these events have not yet been fully elucidated, but the likelihood is that chemoradiotherapy causes a higher degree of (desired) tumour-cell and endothelial-cell killing. This increased cell kill might lead to secondary reactions, such as oedema and abnormal vessel permeability in the tumour area, mimicking tumour progression, in addition to subsequent early treatment-related necrosis in some patients and milder subacute radiotherapy reactions in others. In patients managed with temozolomide chemoradiotherapy who have clinically asymptomatic progressive lesions at the end of treatment, adjuvant temozolomide should be continued; in clinically symptomatic patients, surgery should be considered. If mainly necrosis is noted during surgery, continuation of adjuvant temozolomide is logical. Trials on the treatment of recurrent malignant glioma should exclude patients with progression within the first 3 months after temozolomide chemoradiotherapy unless histological confirmation of tumour recurrence is available. Further research is needed to establish reliable imaging parameters that distinguish between true tumour progression and pseudoprogression or treatment-related necrosis.

Cost-effectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme: A report from the EORTC 26981/22981 NCI-C CE3 intergroup study (Article)

2008-03-15T00:00:00Z

BACKGROUND. The study aimed to compare the cost-effectiveness of concomitant and adjuvant temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma multiforme versus initial radiotherapy alone from a public health care perspective. METHODS. The economic evaluation was performed alongside a randomized, multicenter, phase 3 trial. The primary endpoint of the trial was overall survival. Costs included all direct medical costs. Economic data were collected prospectively for a subgroup of 219 patients (38%). Unit costs for drugs, procedures, laboratory and imaging, radiotherapy, and hospital costs per day were collected from the official national reimbursement lists based on 2004. For the cost-effectiveness analysis, survival was expressed as 2.5 years restricted mean estimates. The incremental cost-effectiveness ratio (ICER) was constructed. Confidence intervals for the ICER were calculated using the Fieller method and bootstrapping. RESULTS. The difference in 2.5 years restricted mean survival between the treatment arms was 0.25 life-years and the ICER was €37,361 per life-year gained with a 95% confidence interval (CI) ranging from €19,544 to €123,616. The area between the survival curves of the treatment arms suggests an increase of the overall survival gain for a longer follow-up. An extrapolation of the overall survival per treatment arm and imputation of costs for the extrapolated survival showed a substantial reduction in ICER. CONCLUSIONS. The ICER of €37,361 per life-year gained is a conservative estimate. We concluded that despite the high TMZ acquisition costs, the costs per life-year gained are comparable to accepted first-line treatment with chemotherapy in patients with cancer.

B and T cell imbalances in CSF of patients with Hu-antibody associated PNS (Article)

2008-03-01T00:00:00Z

In paraneoplastic neurological syndromes associated with Hu-antibodies (Hu-PNS) an important role for cellular immunity is hypothesized. We characterized the cerebrospinal fluid (CSF) pleocytosis in Hu-PNS patients by assessing the major lymphocyte subsets by flow cytometry. The B cell subset in the CSF of Hu-PNS patients showed a significant absolute (~ 20×) and relative (~ 3×) expansion, while the numbers of CD4+ T cells, CD8+ T cells and NK cells only showed an absolute expansion (~ 4-7×) compared to the controls. On the other hand, the NKT cell subset showed a significant relative reduction in CSF and in blood of Hu-PNS patients. The relative B cell expansion is consistent with the intrathecal synthesis of Hu-antibodies, while the increased number of T and NK cells supports an additional role for cellular immunity in the pathogenesis of Hu-PNS. In addition, the autoimmune hypothesis of Hu-PNS is supported by the relative NKT cell deficiency.

A 40-year-old woman with a progressive periventricular white matter lesion (Article)

2008-01-01T00:00:00Z

A 40-year-old woman presented with blurred vision and diplopia, followed by slowly progressive left-sided motor and sensory disturbances. She also suffered from memory loss and had mild spatial and temporal disorientation. A T2-weighted MRI showed a large area of high signal intensity in the periventricular white matter of the right more than the left occipital region and the corpus callosum, without enhancement on T1-weighted images after gadolinium administration and without mass effect. A stereotacticbiopsy of the intracerebral lesion showed blast-like neoplastic cells within a mononuclear infiltrate. No diagnosis could be made based on morphology and immunohistochemistry using a large series of markers. However, based on positive OCT3/4 nuclear staining, the tumor was diagnosed as a germinoma (seminoma of the brain). The patient was treated accordingly and her condition improved, although focal deficits remained.

Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3 (Article)

2008-01-01T00:00:00Z

Background: A randomised trial published by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group (trial 26981-22981/CE.3) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival. We aimed to undertake an exploratory subanalysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma, derive nomograms that predict an individual patient's prognosis, and suggest stratification factors for future trials. Methods: Data from 573 patients with newly diagnosed glioblastoma who were randomly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this subanalysis. Survival modelling was done in three patient populations: intention-to-treat population of all randomised patients (population 1); patients assigned temozolomide and radiotherapy (population 2, n=287); and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection (population 3, n=103). Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Nomograms were developed to predict an individual patient's median and 2-year survival probabilities. No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new standard of care. Findings: Independent of the MGMT promoter methylation status, analysis in all randomised patients (population 1) identified combined treatment with temozolomide, more extensive tumour resection, younger age, Mini-Mental State Examination (MMSE) score of 27 or higher, and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome. In patients assigned temozolomide and radiotherapy (population 2), younger age, better performance status, more extensive tumour resection, and MMSE score of 27 or higher were associated with better survival. In patients who had tumours resected, who were assigned temozolomide and radiotherapy, and who had available MGMT promoter methylation status (population 3), methylated MGMT, better performance status, and MMSE score of 27 or higher were associated with improved survival. Nomograms were developed and are available at http://www.eortc.be/tools/gbmcalculator. Interpretation: MGMT promoter methylation status, age, performance status, extent of resection, and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma. Stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy. Nomograms can be used to predict an individual patient's prognosis, and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management.

Intratumoral distribution of 1p loss in oligodendroglial tumors (Article)

2007-12-01T00:00:00Z

The favorable response of oligodendrogliomas correlates well with characteristic chromosomal losses, of which loss of the short arm of chromosome 1 is most predictive. Oligodendrogliomas are histopathologically heterogeneous tumors and, in addition to the classic honeycomb histology, fields of nonclassic histology are often encountered. Information about the distribution of 1p loss in various regions of oligodendroglioma is, therefore, important to interpret findings in tumor biopsies. In this study we investigated the distribution of 1p loss in multiple fields in 24 biopsy specimens of oligodendroglioma consisting of classic and nonclassic histology by fluorescent in situ hybridization and loss of heterozygosity analysis. By fluorescent in situ hybridization analysis, loss of 1p was found in all fields examined in 37% of the tumor samples, and no loss was detected in 46%. In fields of classic oligodendroglial and polar spongioblastoma-like histology, significantly more loss for 1p was found (p < 0.001 and p < 0.01, respectively). Although fluorescent in situ hybridization analysis indicated heterogeneity for 1p loss in the other 17% of tumors, loss of heterozygosity analysis of these samples pointed to homogeneity of 1p status in all fields. The 1p status of the fields with classic histology significantly correlated with the status of the other fields in the same tumors (Spearman's rho 0.918, p < 0.001). These results point to genotypic homogeneity for 1p in oligodendroglial tumors.

Predictive and prognostic markers in neuro-oncology (Article)

2007-12-01T00:00:00Z

Over the past few years molecular assays have been introduced to aid in typing and grading of gliomas. This is the result of improved understanding of these tumors at the molecular level. In particular, the presence or absence of combined 1p/19 loss in oligodendroglial tumors, epidermal growth factor receptor amplification, epidermal growth factor receptor vIII mutations in grade III tumors and glioblastoma multiforme, and MGMT promoter gene methylation in glioblastoma multiforme are now being used to tailor treatment decisions in patients. However, the application of these tests is far from straightforward, and certain standards are required before any test can be introduced in the daily management of patients. Some of these requirements concern inter- and intratest variability, including whether a test gives the same results if repeated in the same or in another laboratory or when different methodologies are used (e.g. loss of heterozygosity vs fluorescence in situ hybridization and a polymerase chain reaction-based test vs immunohistochemistry). The sensitivity and specificity of a test (or negative and positive predictive value) indicate the likelihood that the test results are positive if the disease is present and the likelihood that the disease is present if the test results are positive. Studies on these test characteristics usually require the presence of a gold standard to which new tests should be compared. Last but not least there is the question of what added value the test has; this criterion determines the clinical usefulness of the assay and why some recently introduced molecular assays need to be scrutinized.

Molecular targeted therapies and chemotherapy in malignant gliomas (Article)

2007-11-01T00:00:00Z

PURPOSE OF REVIEW: To review current developments in the field of chemotherapy and targeted treatment of high-grade glioma. RECENT FINDINGS: Two independent large phase III trials on adjuvant procarbazine, lomustine and vincristine chemotherapy in anaplastic oligodendroglial tumors have shown this improves progression-free survival, but not overall survival, regardless of 1p/19q status. If given sequentially, the timing of procarbazine, lomustine and vincristine chemotherapy has no clear effect on the survival of anaplastic oligodendroglioma. Virtually none of the many new targeted agents directed against pathways that are upregulated in high-grade gliomas has shown significant clinical activity as single agent in phase II studies. The exception are trials with the vascular endothelial growth factor signaling system inhibiting agents bevacizumab and AZD2171 (cediranib) that showed high response rates (which might be due to vessel normalization similar to the effects of steroid treatment) and promising 6-month progression-free survival rates in glioblastoma multiforme. SUMMARY: Further research to define the role of vascular endothelial growth factor inhibition in the management is indicated. For the many other targeted agents, a critical review of the pathological role of their targets in glioblastoma multiforme is required, especially if combination regimens are investigated. The role of combined chemo-irradiation for non-glioblastoma multiforme high-grade glioma remains to be identified.

Case-referent comparison of cognitive functions in patients receiving haematopoietic stem-cell transplantation for haematological malignancies: Two-year follow-up results (Article)

2007-09-01T00:00:00Z

During bone marrow or haematopoietic stem-cell transplantation (HSCT), potentially neurotoxic treatments are used. Previous studies identified cognitive disturbances in patients treated with HSCT, but prospective studies with longitudinal assessment are sparse. We examined cognitive functions up to 20 months after a first baseline assessment in 101 patients undergoing HSCT and in 82 reference patients with a haematological malignancy treated with non-myeloablative cancer therapies. Baseline findings revealed no between-group differences and demonstrated mild cognitive impairments in both groups. Follow-up analyses showed no significant changes over time, though poorer performance in attention and executive function, and psychomotor function was found in HSCT patients. Our results suggest limited HSCT-related cognitive dysfunctions. Additional follow-up is necessary to assess long-term effects.

Chairperson's Introduction (Article)

2007-09-01T00:00:00Z

Treatment of newly diagnosed anaplastic gliomas (Article)

2007-09-01T00:00:00Z

The prognostic value of health-related quality-of-life data in predicting survival in glioblastoma cancer patients: Results from an international randomised phase III EORTC Brain Tumour and Radiation Oncology Groups, and NCIC Clinical Trials Group study (Article)

2007-07-31T00:00:00Z

This is one of the few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in brain cancer patients. Baseline HRQOL scores (from the EORTC QLQ-C30 and the Brain Cancer Module (BN 20)) were examined in 490 newly diagnosed glioblastoma cancer patients for the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap re-sampling procedure and the computation of C-indexes and R2- coefficients were used to try and validate the model. Classical analysis controlled for major clinical prognostic factors selected cognitive functioning (P=0.0001), global health status (P=0.0055) and social functioning (P<0.0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings. C-indexes and R2-coefficients, which are measures of the predictive ability of the models, did not exhibit major improvements when adding selected or all HRQOL scores to clinical factors. While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor in cancer patients.

Identification of differentially regulated splice variants and novel exons in glial brain tumors using exon expression arrays (Article)

2007-06-15T00:00:00Z

Aberrant splice variants are involved in the initiation and/or progression of glial brain tumors. We therefore set out to identify splice variants that are differentially expressed between histologic subgroups of gliomas. Splice variants were identified using a novel platform that profiles the expression of virtually all known and predicted exons present in the human genome. Exon-level expression profiling was done on 26 glioblas tomas, 22 oligodendrogliomas, and 6 control brain samples. Our results show that Human Exon arrays can identify subgroups of gliomas based on their histologic appearance and genetic aberrations. We next used our expression data to identify differentially expressed splice variants. In two independent approaches, we identified 49 and up to 459 exons that are differentially spliced between glioblastomas and oligodendrogliomas, a subset of which (47% and 33%) were confirmed by reverse transcription-PCR (RT-PCR). In addition, exon level expression profiling also identified >700 novel exons. Expression of ∼67% of these candidate novel exons was confirmed by RT-PCR. Our results indicate that exon level expression profiling can be used to molecularly classify brain tumor subgroups, can identify differentially regulated splice variants, and can identify novel exons. The splice variants identified by exon level expression profiling may help to detect the genetic changes that cause or maintain gliomas and may serve as novel treatment targets.

Panel review of anaplastic oligodendroglioma from European organization for research and treatment of cancer trial 26951: Assessment of consensus in diagnosis, influence of 1p/19q loss, and correlations with outcome (Article)

2007-06-01T00:00:00Z

The diagnosis of anaplastic oligodendroglioma (AOD) or anaplastic oligoastrocytoma (AOA) is subject to interobserver variation. The aim of this study was to estimate consensus in typing and grading of these tumors using tumor material collected in a large prospective randomized phase III study and to correlate the consensus diagnosis with the 1p/19q status of the tumors and the clinical outcome. The available pathology material of the first 150 patients, randomized into the European Organization for Research and Treatment of Cancer Trial 26951, was reviewed by an independent panel of 9 neuropathologists. The presence of deletions of 1p and 19q was assessed by fluorescence in situ hybridization with locus-specific probes. The panel reached consensus on the diagnosis of AOD in 52% of the tumors that had been diagnosed as AOD by the local pathologists, whereas only 8% of the local diagnosis of AOA was confirmed with consensus. The concordance on the panel diagnosis of AOD was high (intraclass correlation = 86%). The survival curves for AOD with 1p/19q loss, AOD without these losses, and AOA without 1p/19q loss ran separately in this order. The absence of necrosis and the presence of endothelial abnormalities were correlated with better outcomes. In multivariate analysis, patients' age, 1p/19q loss, and necrosis were identified as independent prognostic factors.

Hemangioblastomatosis in a patient with von Hippel-Lindau disease (Article)

2007-04-01T00:00:00Z

Winst en verlies: een balans van 15 jaar neuro-oncologie in Rotterdam (Inaugural Lecture)

2007-01-19T00:00:00Z

Rede, in verkorte vorm uitgesproken ter gelegenheid van het aanvaarden van het ambt van bijzonder hoogleraar in de Neuro-Oncologie aan het Erasmus MC, faculteit van de Erasmus Universiteit Rotterdam op 19 januari 2007

An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes (Article)

2006-01-01T00:00:00Z

Abstract Anti-CD20 monoclonal antibody (rituximab) is effectively used in the treatment of B-cell lymphomas. Recent reports in the literature suggest that antibody associated autoimmune disorders may respond to rituximab. We therefore treated nine patients with anti-Hu or anti-Yo associated paraneoplastic neurological syndromes (PNS) with a maximum of four monthly IV infusions of rituximab (375mg/m(2)). In this uncontrolled, unblinded trial of rituximab, three patients improved > or =1 point on the Rankin Scale (RS). One patient with limbic encephalitis improved dramatically (RS from 5 to 1). Further studies of rituximab in autoantibody associated PNS are warranted.

Low-molecular weight caldesmon as a potential serum marker for glioma. (Article)

2005-06-15T00:00:00Z

PURPOSE: Testing the feasibility of using the serum low-molecular weight caldesmon (l-CaD) level as a serum marker for the presence of glioma. EXPERIMENTAL DESIGN: Within a total of 230 serum samples, the l-CaD level was measured in healthy volunteers (30), patients with gliomas (57), nonglial intracranial tumors (107), and nontumor neurologic diseases (36) by ELISA. The specificity of the assay was monitored by combination of immunoprecipitation and immunoblotting. RESULTS: The serum level of l-CaD is significantly higher in the group of glioma patients as compared with any of the other groups (P < 0.001). The cutoff value of 45 yields optimal sensitivity and specificity of the assay (91% and 84%, respectively; area under the curve score = 0.91). The specificity of ELISA was confirmed by the immunoprecipitation/immunoblotting control experiments. There were no significant differences in serum l-CaD levels between patients with low- or high-grade gliomas. CONCLUSIONS: The serum l-CaD level as determined by ELISA is a good discriminator between glioma patients versus patients with other intracranial tumors, other neurologic diseases, and healthy people. Prospective studies are required to test the contribution of the assay in making the diagnosis of glioma, or its feasibility for monitoring the tumor during treatment.

Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972 (Article)

2003-01-01T00:00:00Z

BACKGROUND: Oligodendroglial tumors are chemosensitive, with two-thirds of patients responding to PCV combination chemotherapy with procarbazine, lomustine (CCNU) and vincristine. Temozolomide (TMZ), a new alkylating and methylating agent has shown high response rates in recurrent anaplastic astrocytoma. We investigated this drug in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after prior PCV chemotherapy and radiation therapy. PATIENTS AND METHODS: In a prospective non-randomized multicenter phase II trial patients were treated with TMZ 150 mg/m(2) on days 1-5 in cycles of 28 days for 12 cycles. Eligible patients had a recurrence after prior PCV chemotherapy, with measurable and enhancing disease as shown by magnetic resonance imaging. Pathology and all responses were centrally reviewed. RESULTS: Thirty-two eligible patients were included. In four patients the pathology review did not confirm the presence of an OD or OA. Twelve of 24 patients [50%, 95% confidence interval (CI) 29% to 71%] evaluable for response to first-line PCV chemotherapy had responded to PCV. Temozolomide was in general well tolerated; the most frequent side-effects were hematological. One patient discontinued treatment due to toxicity. In seven of 28 patients (25%, 95% CI 11% to 45%) with histologically confirmed OD an objective response to TMZ was observed. Median time to progression for responding patients was 8.0 months. After 6 and 12 months from the start of treatment, 29% and 11% of patients, respectively, were still free from progression. CONCLUSIONS: TMZ may be regarded as the preferred second-line treatment in OD after failure of PCV chemotherapy. Further studies on TMZ in OD are indicated.

Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients (Article)

2003-01-01T00:00:00Z

Paraneoplastic cerebellar degeneration (PCD) is a heterogeneous group of disorders characterized by subacute cerebellar ataxia, specific tumour types and (often) associated antineuronal antibodies. Nine specific antineuronal antibodies are associated with PCD. We examined the relative frequency of the antineuronal antibodies associated with PCD and compared the neurological symptoms and signs, associated tumours, disability and survival between groups of PCD with different antibodies. Also, we attempted to identify patient-, tumour- and treatment-related characteristics associated with functional outcome and survival. In a 12-year period, we examined >5000 samples for the presence of antineuronal antibodies. A total of 137 patients were identified with a paraneoplastic neurological syndrome and high titre (> or =400) antineuronal antibodies. Fifty (36%) of these patients had antibody-associated PCD, including 19 anti-Yo, 16 anti-Hu, seven anti-Tr, six anti-Ri and two anti-mGluR1. Because of the low number, the anti-mGluR1 patients were excluded from the statistical analysis. While 100% of patients with anti-Yo, anti-Tr and anti-mGluR1 antibodies suffered PCD, 86% of anti-Ri and only 18% of anti-Hu patients had PCD. All patients presented with subacute cerebellar ataxia progressive over weeks to months and stabilized within 6 months. The majority of patients in all antibody groups had both truncal and appendicular ataxia. The frequency of nystagmus and dysarthria was lower in anti-Ri patients (33 and 0%). Later in the course of the disease, involvement of non-cerebellar structures occurred most frequently in anti-Hu patients (94%). In 42 patients (84%), a tumour was detected. The most commonly associated tumours were gynaecological and breast cancer (anti-Yo and anti-Ri), lung cancer (anti-Hu) and Hodgkin's lymphoma (anti-Tr and anti-mGluR1). In one anti-Hu patient, a suspect lung lesion on CT scan disappeared while the PCD evolved. Seven patients improved by at least 1 point on the Rankin scale, while 16 remained stable and 27 deteriorated. All seven patients that improved received antitumour treatment for their underlying cancer, resulting in complete remission. The functional outcome was best in the anti-Ri patients, with three out of six improving neurologically and five were able to walk at the time of last follow-up or death. Only four out of 19 anti-Yo and four out of 16 anti-Hu patients remained ambulatory. Also, survival from time of diagnosis was significantly worse in the anti-Yo (median 13 months) and anti-Hu (median 7 months) patients compared with anti-Tr (median >113 months) and anti-Ri (median >69 months). Patients receiving antitumour treatment (with or without immunosuppressive therapy) lived significantly longer [hazard ratio (HR) 0.3; 95% confidence interval (CI) 0.1-0.6; P = 0.004]. Patients > or =60 years old lived somewhat shorter from time of diagnosis, although statistically not significant (HR 2.9; CI 1.0-8.5; P = 0.06).

European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme (Article)

2003-01-01T00:00:00Z

BACKGROUND: Glufosfamide is a new alkylating agent in which the active metabolite of isophosphoramide mustard is covalently linked to beta-D-glucose to target the glucose transporter system and increase intracellular uptake in tumor cells. We investigated this drug in a multicenter prospective phase II trial in recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Eligible patients had recurrent GBM following surgery, radiotherapy and no more than one prior line of chemotherapy. Patients were treated with glufosfamide 5000 mg/m(2) administered as a 1-h intravenous infusion. Treatment success was defined as patients with either an objective response according to Macdonald's criteria or 6 months progression-free survival. Toxicity was assessed with the Common Toxicity Criteria (CTC) version 2.0. RESULTS: Thirty-one eligible patients were included. Toxicity was modest, the main clinically relevant toxicities being leukopenia (CTC grade >3 in five patients) and hepatotoxicity (in three patients). No responses were observed; one patient (3%; 95% confidence interval 0 to 17%) was free from progression at 6 months. Pharmacokinetic analysis showed a 15% decrease in area under the curve and glufosfamide clearance in patients treated with enzyme-inducing antiepileptic drugs, but no effect of these drugs on maximum concentration and plasma half-life. CONCLUSION: Glufosfamide did not show significant clinical antitumor activity in patients with recurrent GBM.

Involvement of the peripheral nervous system in primary Sjogren's syndrome (Article)

2001-01-01T00:00:00Z

BACKGROUND: Involvement of the peripheral nervous system in patients with primary Sjogren's syndrome (SS) has been reported, but its prevalence in neurologically asymptomatic patients is not well known. OBJECTIVE: To assess clinical and neurophysiological features of the peripheral nervous system in patients with primary SS. PATIENTS AND METHODS: 39 (38 female) consecutive patients with primary SS, aged 20-81 years (mean 50), with a disease duration of 1-30 years (mean 8) were studied. The peripheral nervous system was evaluated by a questionnaire, physical examination, quantified sensory neurological examination, and neurophysiological measurements (nerve conduction studies). To assess autonomic cardiovascular function an orthostatic challenge test, a Valsalva manoeuvre, a forced respiration test, and pupillography were done. RESULTS: Abnormalities as indicated in the questionnaire were found in 8/39 (21%) patients, while an abnormal neurological examination was found in 7/39 (18%) patients. Abnormalities in quantified sensory neurological examination were found in 22/38 (58%) patients. In 9/39 (23%) patients, neurophysiological signs compatible with a sensory polyneuropathy were found. No differences were found in the autonomic test results, disease duration, serological parameters, or erythrocyte sedimentation rate between the patients with primary SS with and those without evidence of peripheral nervous involvement. CONCLUSION: Subclinical abnormalities of the peripheral nervous system may occur in patients with primary SS selected from a department of rheumatology, but clinically relevant involvement of the peripheral nervous system in this patient group is rare.

Increased incidence of neurological complications in patients receiving an allogenic bone marrow transplantation from alternative donors (Article)

2000-01-01T00:00:00Z

OBJECTIVE: To compare the frequency and type of neurological complications after bone marrow transplantation (BMT) with an HLA identical unrelated donor or a mismatched related donor (alternative donors) to the neurological complications after matched sibling BMT for standard and high risk leukaemia or myelodysplastic syndromes. METHODS: Retrospective analysis of consecutively treated patients with (a) BMT from alternative donors (n=39), (b) treated with matched sibling BMT for standard risk leukaemia, myelodysplastic syndromes, or aplastic anaemia (n=53), and (c) treated with matched sibling BMT for high risk leukaemia, myelodysplastic syndromes, or aplastic anaemia (n=49). RESULTS: A total of 72 neurological complications were found. Most of these occurred within the first 6 months after transplant. Thirty six patients developed a severe neurological complication: 17 Alternative donor patients (44%) by contrast with six standard risk patients (11%) and 13 high risk patients (27%; p<0.005). The most frequent complication was a metabolic encephalopathy occurring in 18% of patients. Most of the encephalopathies were caused by either the transplant procedure, cyclosporin, systemic infections, microangiopathic thrombopathy, or by complications induced by graft versus host disease. Infections of the CNS developed in 9% of patients, cerebrovascular lesions in 3%. CONCLUSIONS: Severe neurological complications are more frequent after BMT from alternative donors. This is mainly due to increased treatment related morbidity and to more profound immunosuppression after BMT from alternative donors.

Leptomeningeal metastasis after surgical resection of brain metastases (Article)

1999-01-01T00:00:00Z

OBJECTIVE: To determine the incidence and risk factors for leptomeningeal metastasis after surgery for brain metastasis of solid tumors. METHODS: Review of the records of all patients operated on for brain metastasis between January 1990 and August 1995. RESULTS: In this period 28 patients underwent surgery for brain metastasis, of whom 27 were available for evaluation in this study. Median survival after craniotomy was 11 months. Nine patients (33%) developed leptomeningeal metastasis 2-13 months after surgery, which included six of the nine patients operated on for posterior fossa metastasis (p=0.05). In five patients, leptomeningeal metastasis was the only site of recurrence. Three patients developed the leptomeningeal metastasis as bulky tumour along the spinal cord, which is a rare presentation. No other risk factors for the development of leptomeningeal metastasis other than surgery for posterior fossa metastasis were identified. CONCLUSIONS: There is an increased risk of leptomeningeal metastasis after surgery for posterior fossa metastasis. Future trials should consider the value of an active approach to this complication in these patients.

Het gebruik van polymethylmethacrylaat bĳ de cervicale anterieure discectomie (Doctoral Thesis)

1994-03-31T00:00:00Z

In veel klinieken worden patienten die veor operatie veor een cervicaal radiculair syndroom door discuspathologie in aanmerking komen behandeld met een of andere variant van de anterieure cervicale discectomie. In het Sint Lucas Ziekenhuis te Amsterdam gebeurde dit tot eind 1984 door anterieure discectomie gevolgd door fusie met autoloog bot. Daarbij wordt na het uitruimen van de discus een bottransplantaat, verkregen uit de bekkenkam van tussenwervelruimte gebracht zodat een benige vergroeiing tussen wervellichamen ontstaat. de patient, in de de aangrenzende Vanaf 1985 werd in plaats van bot 'botcement' of weI polymethylmethacrylaat (PMMA) in de uitgeruimde tussenwervelruimte ingebracht. Het doe! van deze wijziging was: - het vermijden van postoperatieve pijnklachten ter plaatse van de bekkenkam doordat uitname van een transplantaat niet meer plaatsvond - het verkrijgen van een snelle immobilisering van het geopereerde segment, zodat het niet langer noodzakelijk zou zijn de cervica1e wervelkolom van de patienten tijdelijk te immobiliseren met een gipskraag. Dit werd na het inbrengen van een bottransplantaat weI wenselijk geacht, teneinde een goede fusie te verkrijgen. Besloten werd deze wijziging te evalueren. Hiervoor is in eerste instantie een retrospectief onderzoek verricht naar de resultaten van de anterieure discectomie met fusie met autoloog bot. (8) Daarna is een prospectief onderzoek gestart naar de resultaten van anterieure discectomie gevolgd door interpositie van PMMA. Omdat uit een aantal studies was gebleken cIat resultaten van discectomie zonder fusie gelijkwaardig waren aan die van discectomie met fusie (87.91. 116), is besloten het effect van discectomie met het inbrengen van PMMA te vergelijken met een controlegroep die met alleen discectomie was behandeld. Daarbij is gekozen voor een gerandomiseerde opzet, met beoordeling van het resultaat door een onafhankelijke beoordelaar. Het onderzoek moet een antwoord geven op de volgende vragen: 1) Verbetert het klinisch resultaat van de anterieure discectomie als behandeling van een cervicaal radiculair syndroom door een discusprolaps of door osteofyten indien hierna PMMA wordt ingebracht in de uitgeruimde tussenwervelschijf? Maakt het inbrengen van PMMA verschil voor wat betreft het persisteren of ontstaan van nekklachten na de ingreep? 2) Is er bij radiologisch naonderzoek een verschil zichtbaar tussen beide groepen in het optreden of de progressie van degeneratieve afwijkingen in de aangrenzende segmenten? Voldoet PMMA vanuit radiologisch perspectief aan de doelstellingen van het inbrengen van een implantaat?