Pervasive structural heterogeneity rewires glioblastoma chromosomes to sustain patient-specific transcriptional programs.

Glioblastoma multiforme (GBM) encompasses brain malignancies marked by phenotypic and transcriptional heterogeneity thought to render these tumors aggressive, resistant to therapy, and inevitably recurrent. However, little is known about how the spatial organization of GBM genomes underlies this heterogeneity and its effects. Here, we compile a cohort of 28 patient-derived glioblastoma stem cell-like lines (GSCs) known to reflect the properties of their tumor-of-origin; six of these were primary-relapse tumor pairs from the same patient. We generate and analyze 5 kbp-resolution chromosome conformation capture (Hi-C) data from all GSCs to systematically map thousands of standalone and complex structural variants (SVs) and the multitude of neoloops arising as a result. By combining Hi-C, histone modification, and gene expression data with chromatin folding simulations, we explain how the pervasive, uneven, and idiosyncratic occurrence of neoloops sustains tumor-specific transcriptional programs via the formation of new enhancer-promoter contacts. We also show how even moderately recurrent neoloops can relate to patient-specific vulnerabilities. Together, our data provide a resource for dissecting GBM biology and heterogeneity, as well as for informing therapeutic approaches.

Impact of 4K ultra-high-definition endoscope in pituitary surgery: analysis of a comparative institutional case series.

BACKGROUND: Trans-sphenoidal endoscopic surgery has drawn huge benefits from advances in surgical visualization. The Ultra-HD "4K" endoscope has improved 4-fold image resolution compared with HD, but its actual advantages are unclear. Aim of the present study was to assess its usefulness in the early outcome of trans-sphenoidal surgery. METHODS: We analyzed a series of 199 trans-sphenoidal pituitary adenoma procedures performed by an experienced team using alternatively HD (N.=102) or 4K (N.=97) endoscopes. We evaluated extent of resection both subjectively, based on intraoperative surgeon's impression, and objectively based on postoperative MR scan. RESULTS: Baseline patients' characteristics were balanced. Objective near-total and total resection rates were comparable between 4K and HD groups (91.5% vs. 86.3% and 64.9% vs. 56.9%, respectively). 4K endoscope slightly improved resection rate in recurrent adenoma. At multivariate analysis, the only independent prognosticator of total resection was cavernous sinus invasion. Importantly, 4K endoscope enhanced the reliability of intraoperative judgement on extent of resection, significantly reducing unexpected residuals (12.8% vs. 33.3% for HD). Operative features and clinical outcomes were similar. CONCLUSIONS: The HD endoscope remains the standard-of-care for pituitary surgery. The 4K enhanced, "immersive" visualization significantly improved the reliability of surgeon's judgment on resection and might be useful in surgically difficult cases.

Decompressive craniectomy for the treatment of traumatic brain injury: does an age limit exist?

OBJECT: It is generally believed that the outcome of traumatic brain injury is not improved by decompressive craniectomy in patients older than 30-50 years. A literature search was performed to assess the level of evidence with respect to the effect of age on outcome in these cases. METHODS: References were identified by PubMed searches of journal articles published between 1995 and December 2008. The inclusion criteria were as follows: 1) clinical series including adults; and 2) focus on age as a prognostic factor. Technical notes and laboratory investigations were excluded. RESULTS: Fourteen English-language articles were finally selected. In 5 of the 14 studies, the authors performed no statistical analysis. In 6 studies they concluded that age was not significantly related to outcome (with 1 of these studies showing a correlation between age and outcome only after 65 years). Three studies showed a correlation between age and outcome. CONCLUSIONS: With respect to age and effectiveness of decompressive craniectomy, there are no robust data to establish any degree of core evidence and the referred age thresholds are arbitrary.