A. von Deimling

Hot spots in dynamic18FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas

Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.

Diagnostic value of immunohistochemistry for the detection of the BRAFV600E mutation in primary lung adenocarcinoma Caucasian patients

BACKGROUNDnNon-small-cell lung carcinoma (NSCLC) patients with a BRAF(V600E) mutation benefit from targeted therapy. The usefulness of immunohistochemistry (IHC) as an alternative approach for the detection of BRAF(V600E) in NSCLC patients has not been evaluated until now. This study compared the specificity and sensitivity of IHC with other methods for the detection of BRAF(V600E) in primary lung adenocarcinoma.nnnPATIENTS AND METHODSnBRAF mutations were analysed by DNA sequencing of a Caucasian subpopulation of selected 450 of 1509 (30%) EGFR, KRAS, PI3KA, Her2 and EML4-ALK wild-type (wt) primary lung adenocarcinomas. Detection of the BRAF(V600E) mutation was carried out by IHC using the VE1 clone antibody and compared with the results of other molecular methodologies.nnnRESULTSnOf 450 (9%) of tumours, 40 harboured a BRAF mutation, which corresponded to either a BRAF(V600E) or a non-BRAF(V600E) mutation in 21 of 450 (5%) and 19 of 450 (4%) cases, respectively. The IHC VE1 assay was positive in 19 of 21 (90%) BRAF(V600E)-mutated tumours and negative in all BRAF(nonV600E)-mutated tumours.nnnCONCLUSIONnIHC using the VE1 clone is a specific and sensitive method for the detection of BRAF(V600E) and may be an alternative to molecular biology for the detection of mutations in NSCLC.

NDRG1 prognosticates the natural course of disease in WHO grade II glioma

There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O6-methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2xa0years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (Pxa0=xa00.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial

BackgroundnThe addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RTxa0→xa0TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population.nnnPatients and methodsnARTE was a 2xa0:xa01 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40u2009Gy in 15 fractions) with bevacizumab (10u2009mg/kg×14u2009days) (arm A, Nu2009=u200950) or without bevacizumab (arm B, Nu2009=u200925) in patients with newly diagnosed glioblastoma agedu2009≥65u2009years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses.nnnResultsnMedian PFS was longer in arm A than in arm B (7.6 and 4.8u2009months, Pu2009=u20090.003), but OS was similar (12.1 and 12.2u2009months, Pu2009=u20090.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, Pu2009=u20090.014) and proneural gene expression (HR 0.29, Pu2009=u20090.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for ageu2009<70u2009years (HR 0.52, Pu2009=u20090.018) and Karnofsky performance score 90%-100% (HR 0.51, Pu2009=u20090.026). Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS (HR 1.73, Pu2009=u20090.076).nnnConclusionnEfficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients. Molecular biomarkers may identify patients with preferential benefit from bevacizumab.nnnClinical trial registration numbernNCT01443676.

Biomarkers for malignant peripheral nerve sheath tumours

BACKGROUNDnMalignant peripheral nerve sheath tumour (MPNST) is a highly aggressive soft tissue sarcoma affecting predominantly patients with neurofibromatosis type I. The appearance of MPNST varies considerably and discrimination from other high-grade soft tissue tumours as well as cellular variants of benign nerve sheath tumours may be difficult. Therefore, there is great interest in defining biological markers for MPNST.nnnOBJECTIVEnThis review summarises research on the pathogenesis and progress in diagnostics of MPNST.nnnMETHODSnThe literature on MPNST focusing on pathogenesis and potential biomarkers was reviewed.nnnCONCLUSIONnRecent molecular analyses contributed significantly to our understanding of MPNST. Candidate markers and expression signatures await further validation for their feasibility in guiding diagnostic and therapeutic decisions.