Immediate or staged complete revascularisation in patients presenting with acute coronary syndrome by number of diseased vessels: a substudy of the BIOVASC randomised trial.

BACKGROUND: In patients presenting with acute coronary syndrome (ACS), the number of diseased vessels may affect the efficacy of a complete revascularisation strategy. AIMS: The authors sought to evaluate the safety and efficacy of immediate complete revascularisation (ICR) and staged complete revascularisation (SCR) in patients presenting with ACS stratified by the number of diseased vessels. METHODS: In this prespecified analysis of the BIOVASC trial, ICR was compared with SCR in patients with two-vessel disease (2VD) or three-vessel disease (3VD). The primary endpoint was a composite of all-cause mortality, myocardial infarction (MI), any unplanned ischaemia-driven revascularisation or cerebrovascular events at 1 year after the index procedure. Comparisons were performed using Cox regression. RESULTS: A total of 1,525 patients were enrolled in the BIOVASC trial, of whom 1,177 presented with 2VD and 265 with 3VD. In the 2VD group, 613 patients were assigned to ICR and 564 to SCR. In the 3VD group, 117 patients were assigned to ICR and 148 to SCR. ICR and SCR led to similar results in both the 2VD (hazard ratio [HR] 0.76, 95% confidence interval [CI]: 0.50-1.13; p=0.18) and 3VD groups (HR 0.79, 95% CI: 0.39-1.59; p=0.51) (pinteraction=0.91) in terms of the primary endpoint. ICR was associated with a lower rate of MI in patients with 3VD (HR 0.21, 95% CI: 0.046-0.93; p=0.04) (pinteraction=0.30). CONCLUSIONS: ICR might be an option in patients presenting with extensive 3VD and might be associated with a lower rate of myocardial infarction compared with SCR.

Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Non-ST-Elevation Coronary Syndromes and Multivessel Disease: A Systematic Review and Meta-Analysis.

There is lack of evidence regarding the optimal revascularization strategy in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and multivessel disease (MVD). This systematic review and meta-analysis compares the clinical impact of percutaneous coronary intervention (PCI) with that of coronary artery bypass graft surgery (CABG) in this subset of patients. EMBASE, MEDLINE, and Web of Knowledge were searched for studies including patients with NSTE-ACS and MVD who underwent PCI or CABG up to September 1, 2021. The primary end point of the meta-analysis was all-cause mortality at 1 year. The secondary end points were myocardial infarction (MI), stroke, or repeat revascularization at 1 year. The analysis was conducted using the Mantel-Haenszel random-effects model to calculate the odds ratio (OR) with 95% confidence interval (CI). Four prospective observational studies met the inclusion criteria, including 1,542 patients who underwent CABG and 1,630 patients who underwent PCI. No significant differences were found in terms of all-cause mortality (OR 0.91, 95% CI 0.68 to 1.21, p = 0.51), MI (OR 0.78, 95% CI 0.40 to 1.51, p = 0.46), or stroke (OR 1.54, 95% CI 0.55 to 4.35, p = 0.42) between PCI and CABG. Repeat revascularization was significantly lower in the CABG group (OR 0.21, 95% CI 0.13 to 0.34, p <0.00001). In patients presenting with NSTE-ACS and MVD, 1-year mortality, MI, and stroke were similar between patients treated with either PCI or CABG, but the repeat revascularization rate was higher after PCI.

Periarteriolar Glioblastoma Stem Cell Niches Express Bone Marrow Hematopoietic Stem Cell Niche Proteins.

In glioblastoma, a fraction of malignant cells consists of therapy-resistant glioblastoma stem cells (GSCs) residing in protective niches that recapitulate hematopoietic stem cell (HSC) niches in bone marrow. We have previously shown that HSC niche proteins stromal cell-derived factor-1α (SDF-1α), C-X-C chemokine receptor type 4 (CXCR4), osteopontin (OPN), and cathepsin K (CatK) are expressed in hypoxic GSC niches around arterioles in five human glioblastoma samples. In HSC niches, HSCs are retained by binding of SDF-1α and OPN to their receptors CXCR4 and CD44, respectively. Protease CatK cleaves SDF-1α to release HSCs out of niches. The aim of the present study was to reproduce the immunohistochemical localization of these GSC markers in 16 human glioblastoma samples with the addition of three novel markers. Furthermore, we assessed the type of blood vessels associated with GSC niches. In total, we found seven GSC niches containing CD133-positive and nestin-positive GSCs as a single-cell layer exclusively around the tunica adventitia of 2% of the CD31-positive and SMA-positive arterioles and not around capillaries and venules. Niches expressed SDF-1α, CXCR4, CatK, OPN, CD44, hypoxia-inducible factor-1α, and vascular endothelial growth factor. In conclusion, we show that GSC niches are present around arterioles and express bone marrow HSC niche proteins.

Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells.

Glioblastoma (GBM) is the most aggressive primary brain tumor with poor patient survival that is at least partly caused by malignant and therapy-resistant glioma stem-like cells (GSLCs) that are protected in GSLC niches. Previously, we have shown that the chemo-attractant stromal-derived factor-1α (SDF-1α), its C-X-C receptor type 4 (CXCR4) and the cysteine protease cathepsin K (CatK) are localized in GSLC niches in glioblastoma. Here, we investigated whether SDF-1α is a niche factor that through its interactions with CXCR4 and/or its second receptor CXCR7 on GSLCs facilitates their homing to niches. Furthermore, we aimed to prove that SDF-1α cleavage by CatK inactivates SDF-1α and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1α after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1α at 3 sites in the N-terminus, which is the region of SDF-1α that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1α and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1α had chemotactic activity whereas CatK cleavage products of SDF-1α did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1α. This implies that CatK activity facilitates migration of GSLCs out of niches. We propose that activation of CatK may be a promising strategy to prevent homing of GSLCs in niches and thus render these cells sensitive to chemotherapy and radiation.