Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system.

Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy.

Malignant astrocytoma in elderly patients: where do we stand?

Purpose Of Review: Age is inversely correlated with clinical outcome and a strong prognostic factor for the course of most primary brain tumors including malignant astrocytoma, i.e. anaplastic astrocytoma and glioblastoma.

Infiltrative patterns of glioblastoma: Identification of tumor progress using apparent diffusion coefficient histograms.

Purpose: To investigate whether apparent diffusion coefficient (ADC) histogram analysis can differentiate between patients presenting T2-progress and patients presenting stable T2-signal in glioblastoma.

Materials And Methods: Fourteen patients presenting an isolated T2-progress and a matched control group exhibiting stable disease were included. Relative ADC value distribution within tumoral and peritumoral FLAIR hyperintensities were evaluated using ADC-histogram analysis.

Quantitative and qualitative analysis of study-related patient information sheets in randomised neuro-oncology phase III-trials.

Introduction: In randomised controlled trials (RCTs), patient informed consent documents are an essential cornerstone of the study flow. However, these documents are often oversized in format and content. Clinical experience suggests that study information sheets are often not used as an aid to decision-making due to their complexity.

Immature mesenchymal stem cell-like pericytes as mediators of immunosuppression in human malignant glioma.

Malignant gliomas are primary brain tumors characterized by profound local immunosuppression. While the remarkable plasticity of perivascular cells - resembling mesenchymal stem cells (MSC) - in malignant gliomas and their contribution to angiogenesis is increasingly recognized, their role as potential mediators of immunosuppression is unknown. Here we demonstrate that FACS-sorted malignant glioma-derived pericytes (HMGP) were characterized by the expression of CD90, CD248, and platelet-derived growth factor receptor-β (PDGFR-β).

Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation.

Objective: To explore whether the isocitrate dehydrogenase 1 (IDH1) or 1p/19q status determines the prognostic vs predictive role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in the Neuro-Oncology Working Group of the German Cancer Society (NOA)-04 trial anaplastic glioma biomarker cohort.

Methods: Patients (n = 183) of the NOA-04 trial with known MGMT and IDH1 status were analyzed for interdependency of the prognostic vs predictive role of MGMT promoter methylation from IDH1 or 1p/19q status and treatment, using progression-free survival (PFS) as an endpoint. An independent validation cohort of the German Glioma Network (n = 75) and the NOA-08 trial (n = 34) served as a confirmation cohort.

Differential expression of the tumor suppressor A-kinase anchor protein 12 in human diffuse and pilocytic astrocytomas is regulated by promoter methylation.

The scaffold protein A-kinase anchor protein 12 (AKAP12) exerts tumor suppressor activity and is downregulated in several tumor entities. We characterized AKAP12 expression and regulation in astrocytomas, including pilocytic and diffusely infiltrating astrocytomas. We examined 194 human gliomas and 23 normal brain white matter samples by immunohistochemistry or immunoblotting for AKAP12 expression.

Malignant melanoma S3-guideline "diagnosis, therapy and follow-up of melanoma".

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma.

Protein kinase Cβ as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis.

Disruption of the blood-brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins.

Enzastaurin before and concomitant with radiation therapy, followed by enzastaurin maintenance therapy, in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation.

Background: This study's primary objective was evaluation of the progression-free survival rate at 6 months (PFS-6) in patients with newly diagnosed glioblastoma without O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation postsurgically treated with enzastaurin before and concomitantly with radiation therapy, followed by enzastaurin maintenance therapy. PFS-6 of at least 55% was set to be relevant compared with the data of the EORTC 26981/22981 NCIC CE.3 trial.

Anaplastic oligodendroglioma: a new treatment paradigm and current controversies.

Anaplastic oligodendroglial tumors have gained increasing interest with the emerging role of molecular markers and systemic chemotherapy during the past years. The long-term results of two landmark trials, RTOG 9402 and EORTC 26961, have resulted in a reconsideration of the appropriate therapeutic approaches for patients with these tumors. Both trials indicate that patients whose tumors harbor a 1p/19q co-deletion benefit particularly from the addition of procarbazine/lomustine (CCNU)/vincristine (PCV) chemotherapy to radiation therapy (RT).

ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis.

Mutation/loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression has been described in anaplastic gliomas. The present study explored the role of ATRX status in the molecular classification of anaplastic gliomas and its impact on survival in the biomarker cohort of the NOA-04 anaplastic glioma trial. Patients (n = 133) of the NOA-04 trial were analyzed for ATRX expression using immunohistochemistry.

Molecular neuro-oncology in clinical practice: a new horizon.

Primary brain tumours are heterogeneous in histology, genetics, and outcome. Although WHO's classification of tumours of the CNS has greatly helped to standardise diagnostic criteria worldwide, it does not consider the substantial progress that has been made in the molecular classification of many brain tumours. Recent practice-changing clinical trials have defined a role for routine assessment of MGMT promoter methylation in glioblastomas in elderly people, and 1p and 19q codeletions in anaplastic oligodendroglial tumours.

[Personalized neurooncology].

The treatment of patients with intrinsic brain tumors is radically changing. This change is currently not (yet) signified by the use of targeted therapy in clinical practice but more by the definition of molecular markers as predictors for response to therapy which have been used for a long time. While in the past the choice of treatment has been based solely on the tumor entity and its degree of malignancy derived from histological analyses, large randomized trials have now provided a solid basis for personalized molecular-guided treatment decisions.

Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective.

Background: The number of patients age >65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients.

Quantitative susceptibility mapping differentiates between blood depositions and calcifications in patients with glioblastoma.

Objectives: The application of susceptibility weighted imaging (SWI) in brain tumor imaging is mainly used to assess tumor-related "susceptibility based signals" (SBS). The origin of SBS in glioblastoma is still unknown, potentially representing calcifications or blood depositions. Reliable differentiation between both entities may be important to evaluate treatment response and to identify glioblastoma with oligodendroglial components that are supposed to present calcifications.

The endogenous tryptophan metabolite and NAD+ precursor quinolinic acid confers resistance of gliomas to oxidative stress.

Quinolinic acid is a product of tryptophan degradation and may serve as a precursor for NAD(+), an important enzymatic cofactor for enzymes such as the DNA repair protein PARP. Pathologic accumulation of quinolinic acid has been found in neurodegenerative disorders including Alzheimer and Huntington disease, where it is thought to be toxic for neurons by activating the N-methyl-D-aspartate (NMDA) receptor and inducing excitotoxicity. Although many tumors including gliomas constitutively catabolize tryptophan, it is unclear whether quinolinic acid is produced in gliomas and whether it is involved in tumor progression.

Deciphering the systems biology of mTOR inhibition by integrative transcriptome analysis.

The mTOR signaling plays an integral role in cellular homeostasis controlling the transition between the catabolic and anabolic states. Originally approved as immunosuppressive agents preventing allograft rejection, inhibitors of mTOR signaling have recently entered the arena of cancer therapy. Using rapamycin derivative (RAD001) as a prototype inhibitor, we aimed to systematically analyze the molecular mechanisms underlying the pleiotropic effects of mTOR signaling.

Differentiation of glioblastoma and primary CNS lymphomas using susceptibility weighted imaging.

Introduction: Reliable differentiation between glioblastoma and primary CNS lymphoma (PCNSL) using conventional MR imaging is challenging, since both entities may show similar appearance on structural MR imaging. Here we analyzed if the appearance of intratumoural susceptibility signals (ITSS) on susceptibility weighted imaging (SWI) may differentiate between both entities.

Methods And Materials: SWI and contrast enhanced T1-weighted images were acquired from 15 patients with newly diagnosed PCNSL (14 B-cell PCNSL, 1 T-cell PCNSL) and 117 patients with newly diagnosed glioblastoma with a 3 Tesla MR.

Bevacizumab alone or in combination with irinotecan in recurrent WHO grade II and grade III gliomas.

Background: The repertoire of salvage regimens for patients with WHO grade II and III gliomas recurring or progressing after surgery, radiotherapy and temozolomide chemotherapy is limited. Based on promising response and progression-free survival (PFS) data in recurrent glioblastoma, the use of bevacizumab (BEV) has been extended to recurrent grade II/III gliomas.

Methods: We retrospectively assessed the safety and efficacy of BEV alone or combined with irinotecan in 39 patients with recurrent grade II/III gliomas.

Molecular predictors of outcome in low-grade glioma.

Purpose Of Review: Recent and ongoing translational studies in neurooncology have investigated the role of molecular markers as potential predictors of outcome in patients with WHO grade I and II gliomas, commonly summarized as low-grade gliomas (LGGs). Here, we seek to highlight the most relevant molecular aberrations associated with these tumour types and update on recent findings on their potential prognostic and predictive value.

Recent Findings: So far, no biomarker discussed has any relevance for the postoperative course of disease without genotoxic treatment.

Standards of care for treatment of recurrent glioblastoma--are we there yet?

Newly diagnosed glioblastoma is now commonly treated with surgery, if feasible, or biopsy, followed by radiation plus concomitant and adjuvant temozolomide. The treatment of recurrent glioblastoma continues to be a moving target as new therapeutic principles enrich the standards of care for newly diagnosed disease. We reviewed PubMed and American Society of Clinical Oncology abstracts from January 2006 to January 2012 to identify clinical trials investigating the treatment of recurrent or progressive glioblastoma with nitrosoureas, temozolomide, bevacizumab, and/or combinations of these agents.