Background: Diffuse infiltrative low-grade gliomas of the cerebral hemispheres in the adult are a group of tumors with distinct clinical, histological and molecular characteristics, and there are still controversies in management. Methods: The scientific evidence of papers collected from the literature was evaluated and graded according to EFNS guidelines, and recommendations were given accordingly. Results and conclusions: WHO classification recognizes grade II astrocytomas, oligodendrogliomas and oligoastrocytomas. Conventional MRI is used for differential diagnosis, guiding surgery, planning radiotherapy and monitoring treatment response. Advanced imaging techniques can increase the diagnostic accuracy. Younger age, normal neurological examination, oligodendroglial histology and 1p loss are favorable prognostic factors. Prophylactic antiepileptic drugs are not useful, whilst there is no evidence that one drug is better than the others. Total/near total resection can improve seizure control, progression-free and overall survival, whilst reducing the risk of malignant transformation. Early post-operative radiotherapy improves progressionfree but not overall survival. Low doses of radiation are as effective as high doses and better tolerated. Modern radiotherapy techniques reduce the risk of late cognitive deficits. Chemotherapy can be useful both at recurrence after radiotherapy and as initial treatment after surgery to delay the risk of late neurotoxicity from large-field radiotherapy. Neurocognitive deficits are frequent and can be caused by the tumor itself, tumor-related epilepsy, treatments and psychological distress.

Gliomas are primary brain tumors mainly affecting adults. The cellular origin is unknown. The recent identification of tumor-initiating cells in glioma, which share many similarities with normal neural stem cells, has suggested the cell of origin to be a transformed neural stem cell. In previous studies, using the RCAS/tv-a mouse model, platelet-derived growth factor B (PDGF-B)-induced gliomas have been generated from nestin or glial fibrillary acidic protein-expressing cells, markers of neural stem cells. To investigate if committed glial progenitor cells could be the cell of origin for glioma, we generated the Ctv-a mouse where tumor induction would be restricted to myelinating oligodendrocyte progenitor cells (OPCs) expressing 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase. We showed that PDGF-B transfer to OPCs could induce gliomas with an incidence of 33%. The majority of tumors resembled human WHO grade II oligodendroglioma based on close similarities in histopathology and expression of cellular markers. Thus, with the Ctv-a mouse we have showed that the cell of origin for glioma may be a committed glial progenitor cell.

PDGF receptors have recently been found to be expressed in microvascular endothelium in vivo under circumstances of endothelial cell activation and angiogenesis suggesting that PDGF may have a direct effect on endothelial cells. We have tested the angiogenic activity of PDGF-AA and -BB homodimers in the chick chorioallantoic membrane in vivo. PDGF-BB was found to consistently induce an angiogenic response whereas PDGF-AA was less active. Morphological analyses revealed that there was little inflammation associated with this response but an increase in vessel density suggested a direct effect of PDGF on embryonic chorioallantoic endothelial cells. In vitro, PDGF-BB was found to be more potent than PDGF-AA in stimulating the chemotaxis of rat brain capillary endothelial cells. This is consistent with a direct effect of PDGF on endothelial cells. Thus, this novel angiogenic activity of PDGF has implications for several developmental and pathological events in which PDGF, particularly the B-chain, is expressed.

The homeobox gene PROX1 is critical for organ development during embryogenesis. The Drosophila homologue, known as prospero has been shown to act as a tumor suppressor by controlling asymmetric cell division of neuroblasts. Likewise, alterations in PROX1 expression and function are associated with a number of human cancers including hematological malignancies, carcinomas of the pancreas, liver and the biliary system, sporadic breast cancer, Kaposiform hemangioendothelioma, colon cancer, and brain tumors. PROX1 is involved in cancer development and progression and has been ascribed both tumor suppressive and oncogenic properties in a variety of different cancer types. However, the exact mechanisms through which PROX1 regulates proliferation, migration, and invasion of cancer cells are by large unknown. This review provides an update on the role of PROX1 in organ development and on its emerging functions in cancer, with special emphasis on the central nervous system and glial brain tumors.

Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is upregulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates β1 integrin signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytic cleavage. The CD93-MMRN2 complex was required for activation of β1 integrin, phosphorylation of focal adhesion kinase (FAK), and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of β1 integrin and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

The The in vivo function ofPDGF is not well known. It has been suggested that the factor has a role in early development (11) and in wound healing (12). PDGF has also been found to have a role in the development of glial cells in the central nervous system (reviewed in ref. 13). PDGF-AA is produced by type 1 astrocytes, and it stimulates division and motility and prevents premature differentiation of the 0-2A progenitor cells (14-16), which possess PDGF a receptors but no ( receptors (17).We have further explored the possibility that PDGF has a functional role in the brain. We show by immunohistochemistry, receptor binding and functional assays that ( receptors are present on neurons in the brains of young rats. MATERIALS AND METHODSImmunohistochemistry of Rat Brain Sections. The brains of rats aged 1 day, 3 days, 1 week, 3 weeks, and 6 weeks (one rat of each age) were immediately frozen and sectioned coronally at three different levels. The brains oftwo newborn rats were cut coronally into -500 sections. Sections were fixed for 10 min in cold 100%6 acetone and stored at -20TC. PDGFR-3, a rabbit antiserum raised against a synthetic peptide corresponding to amino acids 981-994 in the murine ( receptor (18), was affinity-purified using a column of immobilized peptide. The affinity-purified antiserum was used for immunoperoxidase staining (Vectastain ABC Elite kit, Vector Laboratories), as described (19) Neuronal Cell Cultures. Neuron-enriched cultures were obtained from 1-to 2-day-old Sprague-Dawley rats (21), with two rats for each experiment. The brains were dissected and the cells were dispersed by treatment with trypsin and DNase I and washed free of enzymes. Cultures were incubated for 3 days at 370C in humidified 5% C02/95% air. The cells were then treated with 10 ,uM 1-3-D-arabinofuranosylcytosine (araC) in Dulbecco's modified Eagle's medium (DMEM) containing 5% fetal bovine serum and 10o horse serum. This treatment was repeated after 3 and 6 days. For comparison, untreated cells were kept in DMEM with 10%o fetal bovine serum in parallel cultures.To determine the percentage of neuronal cells, we combined bisbenzimide (Sigma) staining of nuclei with immunofluorescence staining using the anti-NF antibody. Cells grown on chamber slides were washed with prewarmed medium containing 1% fetal bovine serum and then were Abbreviations: araC, 1-f-D-arabinofuranosylcytosine; FITC, fluorescein isothiocyanate; GFAP, glial fibrillary acidic protein; NF, neurofilament; NGF, nerve growth factor; PDGF, platelet-derived growth factor.tTo whom reprint requests should be addressed. 8159The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Spasticity according to the modified Ashworth Scale usually occurs within 1 month and disabling spasticity later in a subgroup. Severe paresis of the arm is a risk factor for spasticity.

Direct costs for 12-month stroke survivors are 4 times higher than direct costs for patients with stroke without spasticity during the first year after the event.