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.

No abstract

Amyloidogenic processing of the amyloid precursor protein (APP) results in the generation of ␤-amyloid, the main constituent of Alzheimer plaques, and the APP intracellular domain (AICD).Recently, it has been demonstrated that AICD has transactivation potential; however, the targets of AICD-dependent gene regulation and hence the physiological role of AICD remain largely unknown. We analyzed transcriptome changes during AICD-dependent gene regulation by using a human neural cell culture system inducible for expression of AICD, its coactivator FE65, or the combination of both. Induction of AICD was associated with increased expression of genes with known function in the organization and dynamics of the actin cytoskeleton, including ␣2-Actin and Transgelin (SM22). AICD target genes were also found to be differentially regulated in the frontal cortex of Alzheimer's disease patients compared with controls as well as in AICD/FE65 transiently transfected murine cortical neurons. Confocal image analysis of neural cells and cortical neurons expressing both AICD and FE65 confirmed pronounced changes in the organization of the actin cytoskeleton, including the destabilization of actin fibers and clumping of actin at the sites of cellular outgrowth. Our data point to a role of AICD in developmental and injury-related cytoskeletal dynamics in the nervous system. INTRODUCTIONThe amyloid precursor protein (APP) is a type-1 transmembrane protein composed of a large extracellular and a small intracellular domain and has been widely implicated in the pathogenesis of Alzheimer's disease (AD). APP can undergo proteolytic cleavage by ␤-and ␥-secretase activities, resulting in the production of ␤-amyloid (A␤) (Selkoe, 1994). A␤ is the main constituent of amyloid plaques and is thought to be neurotoxic by inducing oxidative stress, inflammation, and neurodegeneration (Mattson, 2004). The intraneuronal accumulation of A␤ protofibrils is thought to cause progressive neurotoxicity in cortical neurons (Hartley et al., 1999). In addition, the secretion of soluble A␤ oligomers inhibits hippocampal long-term potentiation and alters the memory of complex learned behavior (Walsh et al., 2005).The APP intracellular domain (AICD), a small 6-kDa protein, originates from APP cleavage mediated by ␥-secretase activity (Octave et al., 2000). This cleavage can occur after Val636 (AICD59), Ala638 (AICD57), or Leu645 (AICD50) corresponding to the ␥-or -cleavage site ( Figure 1A) of the ␥-secretase complex (Sastre et al., 2001;Yu et al., 2001). More recently, AICD was shown to have transactivation potential (Cao and Sudhof, 2001). AICD levels are detectable in membrane fractions of murine total brain homogenates, and they increase significantly in mice overexpressing the Swedish mutation of human APP (Ryan and Pimplikar, 2005). Moreover, Hirano bodies found in the degenerating neurons of Alzheimer's patients stain positive with antisera raised against the cytoplasmic domain of APP (Munoz et al., 1993), suggesting an accumulation of AICD during Alzheimer...

Intra-tumoural PpIX concentrations exhibited pronounced inter- and intra-tumoural variations in glioblastoma, which are directly linked to variable degrees of fluorescence intensity. High intra-tumoural PpIX concentrations with strong fluorescence intensity and complete photobleaching after iPDT seem to be associated with favourable outcome. Real-time monitoring of PpIX fluorescence intensity and photobleaching turned out to be feasible and safe and might be employed for early treatment prognosis of iPDT.