Spatial heterogeneity in medulloblastoma

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation

Focal ischemia due to traumatic contusions documented by stable xenon-CT and ultrastructural studies

✓ A traumatic cerebral contusion causes a zone of perifocal neuronal necrosis, the cause of which is not known; the surgical management of these lesions remains controversial. To determine the pathophysiological mechanisms responsible for brain damage after contusions, the authors performed cerebral blood flow (CBF) mapping studies and related these to change in local cerebral blood volume (CBV) and ultrastructure. In 11 severely head injured patients with contusion, CBF and CBV were measured in pericontusional areas using stable xenon-computerized tomography (CT). These studies demonstrated a profound reduction in perilesional CBF (mean 17.5 ± 4 ml/100 g/min), which was always accompanied by a zone of edema defined by CT density measurements. Mean CBV in these regions was 2.3 ± 0.4 ml/100 g, a reduction to approximately one-half the value of 4.8 ml/100 g found in the nonedematous regions, and to approximately 35% of the value of 6.0 ml/100 g found in normal volunteers. Ultrastructural analysis of the pericontusional tissue, taken at surgery in four patients with high intracranial pressure showed glial swelling with narrowing of the microvascular lumina due to massive podocytic process swelling. Additionally, some suggestion of vascular occlusion due to erythrocyte and leukocyte stasis was seen. These data support the conclusion that microvascular compromise by compression and/or occlusion is a major event associated with profound perilesional hypoperfusion, which is a uniform finding within edematous pericontusional tissue