HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Bio-carrier and operating temperature effect on ammonia removal from secondary wastewater effluents using moving bed biofilm reactor (MBBR)

This study investigates the impact of bio-carriers' surface area and shape, wastewater chemistry and operating temperature on ammonia removal from real wastewater effluents using Moving bed biofilm reactors (MBBRs) operated with three different AnoxKaldness bio-carriers (K3, K5, and M). The study concludes the surface area loading rate, specific surface area, and shape of bio-carrier affect ammonia removal under real conditions. MBBR kinetics and sensitivity for temperature changes were affected by bio-carrier type. High surface area bio-carriers resulted in low ammonia removal and bio-carrier clogging. Significant ammonia removals of 1.420 ± 0.06 and 1.103 ± 0.06 g − N/m2. d were achieved by K3(As = 500 m2/m3) at 35 and 20 °C, respectively. Lower removals were obtained by high surface area bio-carrier K5 (1.123 ± 0.06 and 0.920 ± 0.06 g − N/m2. d) and M (0.456 ± 0.05 and 0.295 ± 0.05 g − N/m2. d) at 35 and 20 °C, respectively. Theta model successfully represents ammonia removal kinetics with θ values of 1.12, 1.06 and 1.13 for bio-carrier K3, K5 and M respectively. MBBR technology is a feasible choice for treatment of real wastewater effluents containing high ammonia concentrations.The authors gratefully acknowledge the financial support provided by the Qatar University Internal Grant ( QUUG-CENG-CHE-14\15-11 ).Scopu

Conventional versus minimally invasive extracorporeal circulation in patients undergoing cardiac surgery: protocol for a randomised controlled trial (COMICS)

Introduction: Despite low mortality, cardiac surgery patients may experience serious life-threatening post-operative complications, often due to extracorporeal circulation and reperfusion. Miniaturised cardiopulmonary bypass (minimally invasive extracorporeal circulation) has been developed aiming to reduce the risk of post-operative complications arising with conventional extracorporeal circulation. Methods: The COMICS trial is a multi-centre, international, two-group parallel randomised controlled trial testing whether type II, III or IV minimally invasive extracorporeal circulation is effective and cost-effective compared to conventional extracorporeal circulation in patients undergoing elective or urgent coronary artery bypass grafting, aortic valve replacement or coronary artery bypass grafting + aortic valve replacement. Randomisation (1:1 ratio) is concealed and stratified by centre and surgical procedure. The primary outcome is a composite of 12 serious complications, objectively defined or adjudicated, 30 days after surgery. Secondary outcomes (at 30 days) include other serious adverse events (primary safety outcome), use of blood products, length of intensive care and hospital stay and generic health status (also at 90 days). Status of the trial: Two centres started recruiting on 08 May 2018; 10 are currently recruiting and 603 patients have been randomised (11 May 2020). The recruitment rate from 01 April 2019 to 31 March 2020 was 40-50 patients/month. About 80% have had coronary artery bypass grafting only. Adherence to allocation is good. Conclusions: The trial is feasible but criteria for progressing to a full trial were not met on time. The Trial Steering and Data Monitoring Committees have recommended that the trial should currently continue