Scalp block for glioblastoma surgery is associated with lower inflammatory scores and improved survival.

BACKGROUND: Regional anesthesia has anti-inflammatory effects. Recent studies suggest that regional anesthesia might improve the survival of patients with cancer. We hypothesized that the use of a scalp block (SB) during craniotomy for glioblastoma (GB) decreases the postoperative systemic and local inflammatory response and extend their survival. METHODS: This retrospective study included 119 patients with GB who underwent tumor resection. We divided patients into 2 groups based on the use of SB during surgery. Preoperative and postoperative neutrophil-to-lymphocyte (NLR) ratio and platelet-to-lymphocyte (PLR) ratios were calculated as well as the percentage change in postoperative T2/FLAIR (FLuid-Attenuated Inversion Recovery) volume. Both markers of the inflammatory response were compared between patients with and without an SB. Progression-free survival (PFS) was also compared in both groups of patients. Univariate and multivariate analysis were used to test the association between SB and patients' survival. RESULTS: On day 3 after surgery, patients who had an SB showed statistically significant lower NLRs and PLRs than those without an SB. There was also a significant larger reduction in postoperative T2/FLAIR signal in patients with SB than in those without SB. The median PFS (progression-free survival) was longer in patients with SB (16.7 months) than those without an SB (6.5 months, P<0.001). The multivariate analysis indicated that the use of SB was an independent factor for longer PFS (hazard ratio: 0.31 95% confidence interval: 0.07-0.21, P<0.001). CONCLUSIONS: This retrospective study supports the hypothesis that in patients with GB undergoing craniotomy, the use of SB is associated with lower levels of systemic and local inflammation, and longer survival.

Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer.

Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions. Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify 'synthetic-essential' genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency. We also posited that such synthetic-essential genes would be therapeutic targets in cancers that harbour specific tumour-suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3ß-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the ß-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF-NF-κB gene network. This study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of 'trackable' targets in cancers that harbour specific tumour-suppressor deficiencies.

Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis.

Intratumoral hypoxia, a frequent finding in metastatic cancer, results in the activation of hypoxia-inducible factors (HIFs). HIFs are implicated in many steps of breast cancer metastasis, including metastatic niche formation through increased expression of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) proteins, enzymes that remodel collagen at the metastatic site and recruit bone marrow-derived cells (BMDCs) to the metastatic niche. We investigated the effect of two chemically and mechanistically distinct HIF inhibitors, digoxin and acriflavine, on breast cancer metastatic niche formation. Both drugs blocked the hypoxia-induced expression of LOX and LOXL proteins, collagen cross-linking, CD11b⁺ BMDC recruitment, and lung metastasis in an orthotopic breast cancer model. Patients with HIF-1 α-overexpressing breast cancers are at increased risk of metastasis and mortality and our results suggest that such patients may benefit from aggressive therapy that includes a HIF inhibitor.

Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation.

Primary tumors facilitate metastasis by directing bone marrow-derived cells (BMDCs) to colonize the lungs before the arrival of cancer cells. Here, we demonstrate that hypoxia-inducible factor 1 (HIF-1) is a critical regulator of breast cancer metastatic niche formation through induction of multiple members of the lysyl oxidase (LOX) family, including LOX, LOX-like 2, and LOX-like 4, which catalyze collagen cross-linking in the lungs before BMDC recruitment. Only a subset of LOX family members was expressed in any individual breast cancer, but HIF-1 was required for expression in each case. Knockdown of HIF-1 or hypoxia-induced LOX family members reduced collagen cross-linking, CD11b(+) BMDC recruitment, and metastasis formation in the lungs of mice after orthotopic transplantation of human breast cancer cells. Metastatic niche formation is an HIF-1-dependent event during breast cancer progression.