Tissue engineering is a prerequisite for cell replacement as therapeutic strategy for degenerative diseases, such as Parkinson's disease. In the present study, we investigated regional identity of mesencephalic neural progenitors and characterized their development toward ventral mesencephalic dopaminergic neurons. We show that neural progenitors from ventral and dorsal mouse embryonic day 12 mesencephalon exhibit regional identity in vitro. Treatment of ventral midbrain dissociated neurospheres with transforming growth factor ␤ (TGF-␤) increased the number of Nurr1-and tyrosine hydroxylase (TH)-immunoreactive cells, which can be further increased when the spheres are treated with TGF-␤ in combination with sonic hedgehog (Shh) and fibroblast growth factor 8 (FGF8). TGF-␤ differentiation signaling is TGF-␤ receptor-mediated, involving the Smad pathway, as well as the p38 mitogen-activated protein kinase pathway. In vivo, TGF-␤2/TGF-␤3 doubleknockout mouse embryos revealed significantly reduced numbers of TH labeled cells in ventral mesencephalon but not in locus coeruleus. TH reduction in Tgf␤2 ؊/؊ /Tgf␤3 ؉/؊ was higher than in Tgf-␤2 ϩ/Ϫ /Tgf-␤3 Ϫ/Ϫ . Most importantly, TGF-␤ may ectopically induce TH-immunopositive cells in dorsal mesencephalon in vitro, in a Shh-and FGF8-independent manner. Together, the results clearly demonstrate that TGF-␤2 and TGF-␤3 are essential signals for differentiation of midbrain progenitors toward neuronal fate and dopaminergic phenotype. STEM CELLS 2006;24:2120 -2129

HA-WBRT (simultaneous integrated protection, SIP) with SIB to metastases is a safe and tolerable regime that shows favorable LTC for patients with multiple brain metastases, while it has the potential to minimize the side-effect of cognitive deterioration.

BackgroundMany patients with brain metastases from non-small cell lung cancer have limited survival, while others survive for several years, depending on patterns of spread, EGFR and ALK alterations, among others. The purpose of this study was to validate a new prognostic model (Lung-molGPA) originally derived from a North American database.Patients and methodsThis retrospective study included 269 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status, histology, EGFR and ALK alterations was collected. The Lung-molGPA score was calculated as described by Sperduto et al.ResultsMedian survival was 5.4 months. The score predicted survival in patients with adenocarcinoma histology and those with other types. For example, median survival was 3.0, 6.2, 14.7 and 25.0 months in the 4 different prognostic strata for adenocarcinoma. The corresponding figures were 2.4, 5.5 and 12.5 months in the 3 different prognostic strata for non-adenocarcinoma.ConclusionsThese results confirm the validity of the Lung-molGPA in an independent dataset from a different geographical region. However, median survival was shorter in 6 of 7 prognostic strata. Potential explanations include lead time bias and differences in treatment selection, both brain metastases-directed and systemically.

BackgroundThe higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone.MethodsThis protocol describes a prospective, open label, randomized, multi-center phase II trial designed to test if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS) in patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based on T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary endpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious of progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression or death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRI- or PET-derived target volumes, rate of long term survivors (>1 year), localization of necrosis after re-irradiation, quality of life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET imaging and toxicity of re-irradiation.DiscussionThis is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target volume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a standardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning.Trial registrationThe GLIAA trial is registered with ClinicalTrials.gov (NCT01252459, registration date 02.12.2010), German Clinical Trials Registry (DRKS00000634, registration date 10.10.2014), and European Clinical Trials Database (EudraCT-No. 2012-001121-27, registration date 27.02.2012).