The number of methylated CpG sites within the MGMT promoter region linearly correlates with outcome in glioblastoma receiving alkylating agents.

MGMT-promoter methylation is associated with favorable outcome in glioblastoma. The aim of this study was to determine whether the absolute number of methylated Cytosine-Guanine-dinucleotide-(CpG-)sites within the DMR-2 island of the MGMT-promoter may correlate with outcome in a qualitative or quantitative fashion. In a cohort of newly diagnosed glioblastoma patients treated with stereotactic biopsy or open tumor resection plus concomitant chemoradiotherapy, we assessed MGMT-promoter methylation by methylation-specific polymerase-chain-reaction (MSP).

MGMT promoter methylation is not correlated with integrin expression in malignant gliomas: clarifying recent clinical trial results.

Integrin alpha-v-beta-3 (αβ) is important for invasive tumor growth and angiogenesis in glioblastomas (GBM). However, recent clinical trials on inhibition of this integrin led to ambiguous results whether patients with methylated or unmethylated O-methylguanine methyltransferase (MGMT) promoter might profit from this kind of therapy. Therefore, we addressed the still unanswered question about a possible correlation between integrin αβ expression and MGMT promoter methylation in GBM.

Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice.

Prion diseases have been linked to impaired copper homeostasis and copper induced-oxidative damage to the brain. Divalent metal ions, such as Cu2+ and Zn2+, bind to cellular prion protein (PrPC) at octapeptide repeat (OR) and non-OR sites within the N-terminal half of the protein but information on the impact of such binding on conversion to the misfolded isoform often derives from studies using either OR and non-OR peptides or bacterially-expressed recombinant PrP. Here we created new transgenic mouse lines expressing PrP with disrupted copper binding sites within all four histidine-containing OR's (sites 1-4, H60G, H68G, H76G, H84G, "TetraH>G" allele) or at site 5 (composed of residues His-95 and His-110; "H95G" allele) and monitored the formation of misfolded PrP in vivo.

Overexpression of cytosolic, plasma membrane bound and extracellular heat shock protein 70 (Hsp70) in primary glioblastomas.

A unique feature in several non-CNS-tumors is the overexpression of heat shock protein 70 (Hsp70, HSPA1A) in the cytosol, but also its unusual plasma membrane expression and release. Although in gliomas, cytosolic Hsp70 levels are not associated with histological grading, the role of membrane bound and released Hsp70 is still completely unknown. Membrane bound as well as cytosolic Hsp70 can be detected in viable tumor cells with the monoclonal antibody (mAb) cmHsp70.

Outcome in unresectable glioblastoma: MGMT promoter methylation makes the difference.

In 2011, we reported a predominant prognostic/predictive role of MGMT promoter methylation status on progression-free survival (PFS) in unresectable glioblastoma patients undergoing upfront radiotherapy plus concomitant and maintenance temozolomide (RTX/TMZ → TMZ). We, here, present the final results of this prospective study focussing on the prognostic/predictive value of MGMT promoter methylation status for death risk stratification. Overall, 56 adult patients with unresectable, biopsy proven glioblastoma were prospectively assigned to upfront RTX/TMZ → TMZ treatment between March 2006 and August 2008.

Quantifying prion disease penetrance using large population control cohorts.

More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence.

Biological tumor volume in 18FET-PET before radiochemotherapy correlates with survival in GBM.

Objective: The aim of this prospective longitudinal study was to identify static and dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine PET ((18)FET-PET)-derived imaging biomarkers in patients with glioblastoma (GBM).

Methods: Seventy-nine patients with newly diagnosed GBM were included; 42 patients underwent stereotactic biopsy (unresectable tumors) and 37 patients microsurgical tumor resection. All patients were scheduled to receive radiotherapy plus concomitant and adjuvant temozolomide (RCx/TMZ).

Prognostic significance of dynamic 18F-FET PET in newly diagnosed astrocytic high-grade glioma.

Unlabelled: Despite advances in diagnosis and the use of different therapeutic regimens in astrocytic high-grade glioma (HGG), the prognosis for patients remains grim. Additional pretherapeutic information is needed to tailor management. To gain additional prognostic information at primary diagnosis, we investigated the value of dynamic O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET.

Dynamic 18F-FET PET in suspected WHO grade II gliomas defines distinct biological subgroups with different clinical courses.

In suspected grade II gliomas, three distinct patterns of time-activity curves (TAC) on O-(2-[(18)F]fluoroethyl)-1-tyrosine ((18)F-FET) positron emission tomography (PET) have been delineated (i) increasing TAC homogeneously throughout the tumor, and decreasing TAC, (ii) either homogeneously throughout the tumor or (iii) only focally within otherwise increasing TAC patterns. Increasing TAC was associated with low-grade histology and decreasing TAC with high-grade histology. This prospective study analyzed whether these patterns correlate with distinct biological tumor subtypes and differential outcome.

Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients.

Background: In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection. We developed and validated prospectively (6/10-12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies.

Male sex as a risk factor for the clinical course of skull base chordomas.

Object: Chordomas of the skull base are rare and locally invasive and have a poor prognosis. The aim of this retrospective multicenter study was to evaluate the current pattern of care and clinical course and to identify prognostic factors.

Methods: A total of 47 patients (26 men; mean age 48.

Dynamic 18F-FET PET in newly diagnosed astrocytic low-grade glioma identifies high-risk patients.

Unlabelled: Because the clinical course of low-grade gliomas in the individual adult patient varies considerably and is unpredictable, we investigated the prognostic value of dynamic (18)F-fluorethyltyrosine ((18)F-FET) PET in the early diagnosis of astrocytic low-grade glioma (World Health Organization grade II).

Methods: Fifty-nine patients with newly diagnosed low-grade glioma and dynamic (18)F-FET PET before histopathologic assessment were retrospectively investigated. (18)F-FET PET analysis comprised a qualitative visual classification of lesions; assessment of the semiquantitative parameters maximal, mean, and total standardized uptake value as ratio to background and biologic tumor volume; and dynamic analysis of intratumoral (18)F-FET uptake over time (increasing vs.

[18F]fluoroethyltyrosine-positron emission tomography-based therapy monitoring after stereotactic iodine-125 brachytherapy in patients with recurrent high-grade glioma.

Therapy monitoring of glioma after stereotactic iodine-125 brachytherapy (SBT) remains challenging because posttherapeutic changes in magnetic resonance imaging can mimic tumor progression. We evaluated the prognostic value of serial [18F]fluoroethyltyrosine (FET)-positron emission tomographic (PET) scans for therapy monitoring of high-grade glioma (HGG) after SBT. Thirty-three patients with recurrent HGG were included.

Report about four novel mutations in the prion protein gene.

Background/aims: Since detection of the prion protein gene (PRNP) more than 30 mutations have been discovered. Some have only been found in single case reports without known intrafamilial accumulation or neuropathological proof so that the causal connection between mutation and disease could not be proved. Those patients often present atypical clinical phenotypes, and it is not unusual that they are classified as diseases other than Creutzfeldt-Jakob disease (CJD).

Atypical parkinsonism due to a D202N Gerstmann-Sträussler-Scheinker prion protein mutation: first in vivo diagnosed case.

Background: Parkinsonism with dopa-sensitivity and a correlating DaTSCAN turned out to be due to a D202N mutation which is associated with the Gerstmann-Sträussler-Scheinker (GSS) disease.

Methods/results: We report a 51-year old female who presented with left-dominant parkinsonism and a positive DaTSCAN. She was diagnosed with idiopathic Parkinson's syndrome.

Optical needle endoscope for safe and precise stereotactically guided biopsy sampling in neurosurgery.

Proper treatment of deep seated brain tumors requires correct histological diagnosis which unambiguously necessitates biopsy sampling. Stereotactically guided sampling of biopsies is widely used but bears the danger of incorrect sampling locations and damage to intracerebral blood vessels. Here, we present a minimally invasive contact endoscopic probe that can be inserted into the tissue inside a standard biopsy needle and allows for fluorescence detection of both tumorous tissue and intracerebral blood vessels.

Isolation and characterization of bone marrow-derived progenitor cells from malignant gliomas.

Background: Malignant gliomas are highly-vascularised tumours. Neoangiogenesis is a crucial factor in the malignant behaviour of tumour and prognosis of patients. Several mechanisms are suspected to lead to neoangiogenesis, one of them is the recruitment of multipotent progenitor cells towards the tumour.

Prediction of oligodendroglial histology and LOH 1p/19q using dynamic [(18)F]FET-PET imaging in intracranial WHO grade II and III gliomas.

Oligodendroglial components (OC) and loss of heterozygosity on chromosomes 1p and 19q (LOH 1p/19q) are associated with better outcome in patients with glioma. We aimed to assess the fitness of [(18)F]fluoroethyltyrosine positron-emission-tomography (FET-PET) for noninvasively identifying these important prognostic/predictive factors. One hundred forty-four patients with MRI-suspected WHO grade II and III glioma underwent FET-PET scans prior to histological diagnosis.

Re-irradiation in recurrent malignant glioma: prognostic value of [18F]FET-PET.

The aim of the present study is to determine new positron emission tomography (PET) imaging-related factors predictive of progression-free survival as well as survival in patients with recurrent malignant glioma (MG) prior to and after re-irradiation. Fifty-six patients with recurrent MG who underwent re-irradiation treatment and pretherapeutic dynamic [(18)F]-fluoroethyl-L-tyrosine (FET)-PET scan were retrospectively analyzed. The prognostic value of different parameters, such as biological tumor volume, maximal tumor uptake (SUV(max)/BG), mean tumor uptake (SUV(mean)/BG), as well as uptake kinetics, was evaluated.

Intramedullary pilomyxoid astrocytoma with intracerebral metastasis exhibiting oligoden-droglioma-like features.

Intramedullary glioma are rare and their biological behaviour can differ from their cerebral counterparts. Pilomyxoid astrocytoma (PMA, WHO grade II), predominantly occur in the hypothalamic/chiasmatic region of infants and children. The few reported cases of pediatric intramedullary PMA displayed a particularly aggressive behavior.

FET-PET assessed recurrence pattern after radio-chemotherapy in newly diagnosed patients with glioblastoma is influenced by MGMT methylation status.

Background And Purpose: The aim of the present study was to evaluate factors predicting the recurrence pattern determined by [(18)F]FET-PET imaging in patients with newly diagnosed glioblastoma after combined radio-chemotherapy treated according to the EORTC/NCIC trial.

Material And Methods: Seventy-nine patients with newly diagnosed GBM treated with radiotherapy plus temozolomide (75 mg/m(2)/d) followed by adjuvant cyclic (5/28 days) temozolomide (150-200 mg/m(2)) were retrospectively analysed. Recurrence patterns were assessed by means of positron-emission-tomography with [(18)F]FET and additional MRI; in 54 patients MGMT methylation status was evaluated.

MRI-suspected low-grade glioma: is there a need to perform dynamic FET PET?

Purpose: Since differentiation between low-grade glioma (LGG) and high-grade glioma (HGG) remains challenging according to MRI criteria alone, we investigated the discriminative value of additional dynamic FET PET in patients with MRI-suspected LGG.

Methods: Included in this retrospective study were 127 patients with newly diagnosed MRI-suspected LGG and dynamic FET PET prior to histopathological assessment. FET PET lesions were visually classified as having reduced, normal, or increased tracer uptake.

ALDH1A1 is a marker of astrocytic differentiation during brain development and correlates with better survival in glioblastoma patients.

Glioblastoma is the most common malignant brain tumor and patients usually succumb to their disease within 2 years. Aldehyde dehydrogenase 1A1 (ALDH1A1) has been suggested as a marker for cancer stem cells that is associated with poor prognosis in human gliomas. However, little is known about the expression and the function of ALDH1A1 in early stages of brain development.

Magnetic resonance imaging in E200K and V210I mutations of the prion protein gene.

Magnetic resonance imaging (MRI), with diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR), is a useful diagnostic investigation for Creutzfeldt-Jakob disease (CJD). Amendment of the diagnostic criteria for sporadic CJD (sCJD) to include defined MRI alterations has just recently been proposed. We analyzed MRI scans with FLAIR and/or DWI available of 29 patients with the E200K or the V210I mutation, and a control group of 29 sCJD patients to compare the MRI lesion profile and evaluate the applicability of new MRI criteria to genetic CJD patients.

Krüppel-like factor 8 (KLF8) is expressed in gliomas of different WHO grades and is essential for tumor cell proliferation.

Krüppel-like factor 8 (KLF8) has only recently been identified to be involved in tumor cell proliferation and invasion of several different tumor entities like renal cell carcinoma, hepatocellular carcinoma and breast cancer. In the present study, we show for the first time the expression of KLF8 in gliomas of different WHO grades and its functional impact on glioma cell proliferation. In order to get information about KLF8-mRNA regulation qPCR was performed and did not reveal any significant difference in samples (n = 10 each) of non-neoplastic brain (NNB), low-grade gliomas (LGG, WHO°II) and glioblastomas (GBM, WHO°IV).