ABSTRACT
Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occur through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that is dependent on Angiopoietin (Ang-2) and vascular endothelial growth factor (VEGF). In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and post-mortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcome were analyzed in BM patients. Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human brain metastases negatively correlated with survival. Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevent the outgrowth of macrometastases.
ABSTRACT
Short stature is a common phenotype in children with Schaaf-Yang syndrome (SYS). Prader-Willi syndrome (PWS) and SYS share several phenotypic features including short stature, muscular hypotonia and developmental delay/intellectual disability. Evidence exists that similar to PWS, growth hormone (GH) deficiency may also be a feature of SYS. Recombinant human GH (rhGH) therapy has been approved for PWS, but the effects of rhGH therapy in individuals with SYS have not yet been documented. This retrospective, questionnaire-based study analyzes the prevalence of rhGH therapy in children with SYS, the effects of rhGH therapy on anthropometric measures, and parental perception of the treatment. Twenty-six individuals with SYS were sent a clinical questionnaire and a request for growth charts. We found a significant increase in height z-score (p* = 0.04) as well as a significant decrease in body mass index 6 months after rhGH therapy initiation (p* = 0.04). Furthermore, height z-scores of the treated group (mean z-score = -1.00) were significantly higher than those of the untreated group (mean z-score = -3.36, p = 0.01) at time of enrollment. All parents reported an increase in muscle strength and endurance, and several families noted beneficial effects such as improved cognition and motor development.
