Timing of Complete Revascularization Stratified by Index Presentation During On- and Off-Hours

Recent trials suggested immediate complete revascularization (ICR) as a safe alternative to staged complete revascularization (SCR), but the impact of the respective percutaneous coronary intervention strategies between on- versus off-hours is unclear. On-hours was defined as an index revascularization performed between 8:00 A.M. and 6:00 P.M., Monday to Friday, or else the procedure was defined as performed during off-hours. The primary end point consisted of a composite of all-cause mortality, myocardial infarction, unplanned ischemia-driven revascularization, and cerebrovascular events at 1-year follow-up. We used Cox regression models to relate randomized treatment with study end points. We evaluated multiplicative and additive interactions between on- versus off-hours and randomized treatment. The BIOVASC (Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndromes and Multivessel Disease) trial enrolled 1,097 and 428 patients during on- and off-hours, respectively. Patients randomized during off-hours were more likely to present with ST-segment elevation myocardial infarction (66.4% vs 29.5%, p &lt;0.001). The composite primary outcome occurred in 8.4% and 10.1% of patients randomized to ICR and SCR, respectively, during on-hours (hazard ratio 0.80, 95% confidence interval 0.54 to 1.19). During off-hours, the primary composite outcome occurred in 5.4% and 7.7% in ICR and SCR (0.69, 95% confidence interval 0.32 to 1.46) with no evidence of a differential effect (interaction pmultiplicative = 0.70, padditive = 0.56). No differential effect was found between treatment allocation and on- versus off-hours in any of the secondary outcomes. In conclusion, no differential treatment effect was found when comparing ICR versus SCR in patients presenting with acute coronary syndrome and multivessel disease during on- or off-hours.</p

Timing of Complete Revascularization Stratified by Index Presentation During On- and Off-Hours

Recent trials suggested immediate complete revascularization (ICR) as a safe alternative to staged complete revascularization (SCR), but the impact of the respective percutaneous coronary intervention strategies between on- versus off-hours is unclear. On-hours was defined as an index revascularization performed between 8:00 A.M. and 6:00 P.M., Monday to Friday, or else the procedure was defined as performed during off-hours. The primary end point consisted of a composite of all-cause mortality, myocardial infarction, unplanned ischemia-driven revascularization, and cerebrovascular events at 1-year follow-up. We used Cox regression models to relate randomized treatment with study end points. We evaluated multiplicative and additive interactions between on- versus off-hours and randomized treatment. The BIOVASC (Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndromes and Multivessel Disease) trial enrolled 1,097 and 428 patients during on- and off-hours, respectively. Patients randomized during off-hours were more likely to present with ST-segment elevation myocardial infarction (66.4% vs 29.5%, p &lt;0.001). The composite primary outcome occurred in 8.4% and 10.1% of patients randomized to ICR and SCR, respectively, during on-hours (hazard ratio 0.80, 95% confidence interval 0.54 to 1.19). During off-hours, the primary composite outcome occurred in 5.4% and 7.7% in ICR and SCR (0.69, 95% confidence interval 0.32 to 1.46) with no evidence of a differential effect (interaction pmultiplicative = 0.70, padditive = 0.56). No differential effect was found between treatment allocation and on- versus off-hours in any of the secondary outcomes. In conclusion, no differential treatment effect was found when comparing ICR versus SCR in patients presenting with acute coronary syndrome and multivessel disease during on- or off-hours.</p

Propensity Matched Comparison of Clinical Outcome After Immediate Versus Staged Complete Revascularization in Patients With Acute Coronary Syndrome and Multivessel Disease

Complete revascularization (CR) in patients with acute coronary syndromes (ACS) and multivessel disease (MVD) improves clinical outcomes compared with culprit-only revascularization, but the optimal timing for non–culprit lesions treatment remains unclear. This study evaluated patients presenting with ACS and MVD admitted between January 2015 and September 2021 at the Erasmus University Medical Center. Clinical outcomes were compared between immediate and staged CR in terms of major adverse cardiac and cerebrovascular events (MACCEs), a composite of all-cause mortality, myocardial infarction, stroke, and any unplanned revascularization. A total of 1,400 patients presenting with ACS and MVD who underwent immediate or staged CR were included in this study. Using 1/many propensity score matching without replacement, 299 patients in the staged CR group were matched to 598 patients in the immediate CR group (mean 1:2 ratio), rendering a total of 897 patients for analysis. The median follow-up period was 648 days. MACCE rate was significantly higher in the staged CR group than in the immediate CR group (adjusted hazard ratio [95% confidence interval] 1.60 [1.05 to 2.45], p = 0.03). Furthermore, number of stents, stent length, and contrast usage were significantly greater in the staged revascularization group. Immediate CR was associated with less risk of MACCE than was staged CR. Staged CR required overall more contrast and stent material.</p

Improving tumor budding reporting in colorectal cancer : a Delphi consensus study

Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.Peer reviewe

Complete Revascularization Strategies in Women and Men With Acute Coronary Syndrome and Multivessel Disease

This prespecified substudy of the randomized Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndromes and Multivessel Disease (BIOVASC) trial aimed to compare immediate complete revascularization (ICR) and staged complete revascularization (SCR) in patients with acute coronary syndrome and multivessel disease, stratified by gender. The primary end point consisted of a composite of all-cause mortality, myocardial infarction, unplanned ischemia-driven revascularization, and cerebrovascular events at 1-year follow-up. The secondary end points included the individual components of the primary composite and major bleedings. We used Cox regression models to relate randomized treatment with study end points. We evaluated the multiplicative and additive interactions between gender and randomized treatment. The BIOVASC trial enrolled 338 women and 1,187 men. Women were older than men (median age 71.6 vs 63.7 years, p &lt;0.001) and had a higher prevalence of chronic obstructive pulmonary disease (10.1% vs 5.6%, p = 0.003), renal insufficiency (7.7% vs 4.4%, p = 0.015), and hypertension (60.4% vs 51.7%, p = 0.005). In women, the composite primary outcome occurred in 7.3% versus 12.9% (hazard ratio 0.53, 95% confidence interval 0.26 to 1.08) in patients randomly allocated to ICR and SCR, respectively, and in men in 7.7% versus 8.4% (hazard ratio 0.89, 95% confidence interval 0.60 to 1.34), with no evidence of a differential effect (interaction pmultiplicative = 0.20, padditive = 0.87). No evidence of heterogeneity between women and men was found when comparing ICR with SCR in terms of the secondary outcomes. In conclusion, no differential treatment effect was found when comparing ICR versus SCR in women or men presenting with acute coronary syndrome and multivessel disease.</p

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 protein

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

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