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BACKGROUND: The long-term safety and performance of magnesium-based bioresorbable scaffolds (MgBRS) in ST-segment-elevation myocardial infarction (STEMI) patients are uncertain. AIMS: The aim of this study was to report the 3-year clinical outcomes of the MAGSTEMI trial. METHODS: This investigator-driven, multicentre, randomised, single-blind, controlled trial randomised STEMI patients 1:1 to MgBRS or to permanent metallic sirolimus-eluting stents (SES) at 11 academic centres. The main secondary endpoints included device-oriented composite endpoints (DoCE) and patient-oriented composite endpoints (PoCE), their individual components, any bleeding, and device thrombosis rate. All endpoints were defined according to the Academic Research Consortium. Events were adjudicated by an independent committee. RESULTS: Three-year clinical follow-up was obtained in 142 (90.0%) patients. At 3-year follow-up, MgBRS were associated with a higher rate of DoCE than SES (13 [17.6%] vs 5 [6.6%], diff -11.0 [95% CI: -21.3 to -0.7]; p=0.038). This difference was driven by an increased incidence of DoCE within the first year of follow-up. In the landmark analysis, there was no difference between 1 and 3 years (0 [0.0%] vs 1 [1.4%]; p=1.000). The difference in the rate of DoCE was driven by a higher incidence of target lesion revascularisation (TLR) in the MgBRS group compared to SES (12 [16.2%] vs 4 [5.3%]; diff -10.9% [95% CI: -20.7 to -1.2]; p=0.030). The difference in TLR was observed during the first year, with no further differences observed between 1 and 3 years (0 [0.0%] vs 1 [1.4%]; p=1.000). CONCLUSIONS: At 3-year follow-up, MgBRS were associated with a higher rate of TLR, which was clustered within the first year, compared to SES.

Aim Use of a Bioresorbable Scaffolds (BRS) either in clinical practice or in the setting of an acute myocardial infarction (MI) is controversial. Despite an overall high rate of thrombosis, vascular healing response following BRS implantation tend to superiority as compared to metallic drug-eluting stent in ST-segment elevation myocardial infarction (STEMI) patients. We sought to compare the in-stent/scaffold vasomotion between metallic BRS and sirolimus eluting stent (SES) at 12-month angiographic follow-up in the setting of patients with STEMI treated by primary PCI. Study design This is an investigator-driven, prospective, multicenter, randomized, single blind, two-arm, controlled trial ( number: NCT03234348). This trial will randomize similar to 148 patients 1:1 to SES or BRS. Primary end-point is the in-stent/scaffold change in mean lumen diameter after nitroglycerin administration at 12-month angiographic follow-up. Besides, patient-oriented combined endpoint of all-cause death, any MI, and any revascularization, together with scaffold/stent thrombosis rate and device-oriented endpoint of cardiac death, target vessel (TV)-MI and TVR at 1 year will be also evaluated. Clinical follow-up will be scheduled yearly up to 5 years. Conclusion This trial will shed light on the vascular vasomotion following BRS implantation in the complex scenario of STEMI.

Cancer patients often show an imbalance condition between coagulation system and fibrinolysis which causes a prothrombotic state. Different molecular factors like von Willebrand factor (vWf), presenting higher plasmatic rates in these patients, play an important role in this situation. During active angiogenesis taking place in tumor growth, the vascular endothelial growth factor (VEGF) and the fibroblast growth factor (FGF-2) contribute to the proliferation and differentiation of endothelial tissue, the main vWf producer, promoting increased rates of vWf in the serum of neoplastic patients. Recently vWf's contribution to tumor cells and platelet adhesion has been described. In this process, the discovery of platelet, endothelial and tumor cell membrane integrins and their implication in cellular adhesion has represented a major step in demonstrating how blood clotting and platelet aggregation are mediated by tumor cell and platelet linkage. Migration properties acquired by tumor cells as a result of this binding have been also pointed out. Clinical trials show higher rates of plasmatic vWf in cancer patients the more advanced clinical and radiological stage they present (metastasic versus localized). Moreover, higher pre-surgical serum vWf rates in patients can be used to predict poorer survival after resection surgery. vWf high molecular weight multimers have been also related to a cleavage protease deficiency in the serum of the oncologic population. The promising results of antiaggregation/anticoagulation therapies in these patients permit us to envisage new therapeutic targets.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Final overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711 ), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2–positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2–positive breast cancer with different CD16A allelic variants are warranted.

Antibody–drug conjugates (ADC) are antineoplastic agents recently introduced into the antitumor arsenal. T-DM1, a trastuzumab-based ADC that relies on lysosomal processing to release the payload, is approved for HER2-positive breast cancer. Next-generation ADCs targeting HER2, such as [vic-]trastuzumab duocarmazine (SYD985), bear linkers cleavable by lysosomal proteases and membrane-permeable drugs, mediating a bystander effect by which neighboring antigen-negative cells are eliminated. Many antitumor therapies, like DNA-damaging agents or CDK4/6 inhibitors, can induce senescence, a cellular state characterized by stable cell-cycle arrest. Another hallmark of cellular senescence is the enlargement of the lysosomal compartment. Given the relevance of the lysosome to the mechanism of action of ADCs, we hypothesized that therapies that induce senescence would potentiate the efficacy of HER2-targeting ADCs. Treatment with the DNA-damaging agent doxorubicin and CDK4/6 inhibitor induced lysosomal enlargement and senescence in several breast cancer cell lines. While senescence-inducing drugs did not increase the cytotoxic effect of ADCs on target cells, the bystander effect was enhanced when HER2-negative cells were cocultured with HER2-low cells. Knockdown experiments demonstrated the importance of cathepsin B in the enhanced bystander effect, suggesting that cathepsin B mediates linker cleavage. In breast cancer patient-derived xenografts, a combination treatment of CDK4/6 inhibitor and SYD985 showed improved antitumor effects over either treatment alone. These data support the strategy of combining next-generation ADCs targeting HER2 with senescence-inducing therapies for tumors with heterogenous and low HER2 expression., This work was supported by Breast Cancer Research Foundation (BCRF-20-008), Instituto de Salud Carlos III (project reference numbers AC15/00062, CB16/12/00449 and PI19/01181), the EC under the framework of the ERA-NET TRANSCAN-2 initiative co-financed by FEDER, Fundacion Mutua Madrilena and Asociación ~ Española Contra el Cáncer. S. Duro-Sanchez is supported by the Spanish Ministerio de Universidades by the grant Formacion de Profesorado Universitario (FPU20/05388). A. Esteve-Codina is funded by ISCIII /MINECO (PT17/0009/0019) and co-funded by FEDER.

Breast cancer; Liquid biopsy; Neoadjuvant therapy Càncer de mama; Biòpsia líquida; Teràpia neoadjuvant Cáncer de mama; Biopsia líquida; Terapia neoadyuvante Background: Although the standard of care is to perform surgery of primary breast cancer (BC) after neoadjuvant chemotherapy (NAC), for certain patients achieving clinical complete response (cCR) and pathologic complete response (pCR), omission of surgical treatment may be an option. Levels of circulating tumor DNA (ctDNA) during and after therapy could identify patients achieving minimal residual disease. In this study, we evaluated whether ctDNA clearance during NAC could be a correlate to effective response in human epidermal growth factor receptor 2 positive (HER2+) and triple-negative (TN) BC patients. Methods: A prospective study was conducted to identify patient-specific PIK3CA and TP53 mutations in tissue using next-generation sequencing, which could then be used to track the presence/absence of mutations prior to, during, and following NAC using Sysmex SafeSEQ technology. All patients underwent a surgical excision after NAC, and pCR was assessed. Results: A total of 29 TN and HER2+ BC patients were examined and 20 that carried mutations in the PIK3CA and/or TP53 genes were recruited. Overall, 19 of these 20 patients harbored at least one tumor-specific mutation in their plasma at baseline. After NAC, 15 patients (75.0%) achieved pCR according to the histopathologic evaluation of the surgical specimen, and 15 patients (75.0%) had a cCR; 18 of 20 patients (90.0%) had concordant pCR and cCR. The status of ‘no mutation detected’ (NMD) following NAC in cCR patients correctly identified the pCR in 14 of 15 patients (93.33%), as well as correctly ruled out pCR in three patients, with an accuracy of 89.47%. During the 12-month follow-up after surgery, 40 plasma samples collected from 15 patients all showed no detectable ctDNA (NMD), and no patient recurred. Conclusion: These findings prompt further research of the value of ctDNA for non-invasive prediction of clinical/pathological response, raising the possibility of sparing surgery following NAC in selected BC patients. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a grant from Sysmex Inostics, Inc. The sponsor coordinated data collection from study centers, and funded the statistical analysis and medical writing assistance.