This study was performed to assess the efficacy of GKS in patients with ten or more brain metastases. From Aug 2002 to Dec 2007, twenty-six patients (13 men and 13 women) with ten or more cerebral metastatic lesions underwent GKS. The mean age was 55 years (32-80). All patients had Karnofsky performance status (KPS) score of 70 or better. According to recursive partitioning analysis (RPA) classification, 3 patients belonged to class I and 23 to class II. The location of primary tumor was lung (21), breast (3) and unknown (2). The mean number of the lesions per patient was 16.6 (10-37). The mean cumulated volume was 10.9 cc (1.0-42.2). The median marginal dose was 15 Gy (9-23). Overall survival and the prognostic factors for the survival were retrospectively analyzed by using Kaplan Meier method and univariate analysis. Overall median survival from GKS was 34 weeks (8-199). Local control was possible for 79.5% of the lesions and control of all the lesions was possible in at least 14 patients (53.8%) until 6 months after GKS. New lesions appeared in 7 (26.9%) patients during the same period. At the last follow-up, 18 patients died; 6 (33.3%) from systemic causes, 10 (55.6%) from neurological causes, and 2 (11.1%) from unknown causes. Synchronous onset in non-small cell lung cancer (p=0.007), high KPS score (>/=80, p=0.029), and controlled primary disease (p=0.020) were favorable prognostic factors in univariate analysis. In carefully selected patients, GKS may be a treatment option for ten or more brain metastases.

Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs) would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases.

We aimed to evaluate the potential of radiomics as an imaging biomarker for glioblastoma (GBM) patients and explore the molecular rationale behind radiomics using a radio-genomics approach. A total of 144 primary GBM patients were included in this study (training cohort). Using multi-parametric MR images, radiomics features were extracted from multi-habitats of the tumor. We applied Cox-LASSO algorithm to build a survival prediction model, which we validated using an independent validation cohort. GBM patients were consensus clustered to reveal inherent phenotypic subtypes. GBM patients were successfully stratified by the radiomics risk score, a weighted sum of radiomics features, corroborating the potential of radiomics as a prognostic biomarker. Using consensus clustering, we identified three distinct subtypes which significantly differed in the prognosis (“heterogenous enhancing”, “rim-enhancing necrotic”, and “cystic” subtypes). Transcriptomic traits enriched in individual subtypes were in accordance with imaging phenotypes summarized by radiomics. For example, rim-enhancing necrotic subtype was well described by radiomics profiling (T2 autocorrelation and flat shape) and highlighted by the inflammatory genomic signatures, which well correlated to its phenotypic peculiarity (necrosis). This study showed that imaging subtypes derived from radiomics successfully recapitulated the genomic underpinnings of GBMs and thereby confirmed the feasibility of radiomics as an imaging biomarker for GBM patients with comprehensible biologic annotation.