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Background: Acute kidney injury (AKI) is a serious and common complication of cardiac surgery, for which reduced kidney perfusion is a key contributing factor. Intravenous amino acids increase kidney perfusion and recruit renal functional reserve. However, the efficacy of amino acids in reducing the occurrence of AKI after cardiac surgery is uncertain. Methods: In a multinational, double-blind trial, we randomly assigned adult patients who were scheduled to undergo cardiac surgery with cardiopulmonary bypass to receive an intravenous infusion of either a balanced mixture of amino acids, at a dose of 2 g per kilogram of ideal body weight per day, or placebo (Ringer's solution) for up to 3 days. The primary outcome was the occurrence of AKI, defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria. Secondary outcomes included the severity of AKI, the use and duration of kidney-replacement therapy, and all-cause 30-day mortality. Results: We recruited 3511 patients at 22 centers in three countries and assigned 1759 patients to the amino acid group and 1752 to the placebo group. AKI occurred in 474 patients (26.9%) in the amino acid group and in 555 (31.7%) in the placebo group (relative risk, 0.85; 95% confidence interval [CI], 0.77 to 0.94; P = 0.002). Stage 3 AKI occurred in 29 patients (1.6%) and 52 patients (3.0%), respectively (relative risk, 0.56; 95% CI, 0.35 to 0.87). Kidney-replacement therapy was used in 24 patients (1.4%) in the amino acid group and in 33 patients (1.9%) in the placebo group. There were no substantial differences between the two groups in other secondary outcomes or in adverse events. Conclusions: Among adult patients undergoing cardiac surgery, infusion of amino acids reduced the occurrence of AKI. (Funded by the Italian Ministry of Health; PROTECTION ClinicalTrials.gov number, NCT03709264.). [ABSTRACT FROM AUTHOR]

Background: Hybrid-convergent radiofrequency (RF) ablation targeting pulmonary veins (PVs) and left atrial posterior wall (LAPW) has shown better arrhythmic outcomes than an endocardial-only RF strategy, despite higher rates of complications. Comparisons with extensive pulsed field ablation (PFA) are currently lacking., Objectives: This study aimed to compare the efficacy and safety of the hybrid-convergent RF vs PFA of PVs and LAPW in long-standing persistent atrial fibrillation (LSPAF)., Methods: Ninety-three consecutive LSPAF patients, treated with 2-step hybrid-convergent RF ablation (hybrid group, n = 49) or with PFA of PVs and LAPW (PFA group, n = 44) were enrolled. Primary efficacy endpoint was defined as any atrial tachyarrhythmias (ATA) recurrence after the 3-month blanking period, over a follow-up time of 12 months. Periprocedural adverse events and late complications during follow-up were deemed primary safety outcomes., Results: The hybrid and PFA groups had similar baseline characteristics; mean age was hybrid 63.8 ± 10.6 years vs PFA 66.0 ± 7.4 years; P = 0.105. PV and LAPW ablation were acutely successful in all patients. Step 1 hybrid-epicardial procedures were longer than PFA (166 [Q1-Q3: 140-205] minutes vs 107.5 [Q1-Q3: 82.5-12] minutes; P < 0.01). At 12-month follow-up, there was no difference in ATA recurrences between groups (hybrid 36.7% vs PFA 40.9%; P = 0.680; log-rank at survival analysis P = 0.539). After adjusting for confounders, a larger left atrial volume and recurrences during the blanking-period were predictors of ATA recurrences after ablation, regardless of procedural technique employed. PFA showed a better safety profile with a lower rate of major periprocedural complications compared with hybrid ablation (12% vs 0%; P = 0.028)., Conclusions: Hybrid-convergent and PFA share comparable arrhythmic outcomes in LSPAF, but hybrid-convergent ablation carries higher periprocedural risks., Competing Interests: Funding Support and Author Disclosures Dr Tondo serves a member of scientific advisory boards for Medtronic Inc and Boston Scientific; and receives lecture/proctoring fees from Abbott Medical, AtriCure, Boston Scientific, and Medtronic Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative acute kidney injury (AKI) is frequent in cardiac surgery patients. Its pathophysiology is complex and involves decreased renal perfusion. Preliminary clinical evidence in critically ill patients shows that amino acids infusion increases renal blood flow and may decrease the incidence and severity of AKI. We designed a study to evaluate the effectiveness of perioperative continuous infusion of amino acids in decreasing AKI., Methods: This is a phase III, multi-center, randomized, double-blind, placebo-controlled trial. Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) are included. Patients are randomly assigned to receive either continuous infusion of a balanced mixture of amino acids in a dose of 2 g/kg ideal body weight/day or placebo (balanced crystalloid solution) from the operating room up to start of renal replacement therapy (RRT), or ICU discharge, or 72 h after the first dose. The primary outcome is the incidence of AKI during hospital stay defined by KDIGO (Kidney Disease: Improving Global Outcomes). Secondary outcomes include the need for, and duration of, RRT, mechanical ventilation; ICU and hospital length of stay; all-cause mortality at ICU, hospital discharge, 30, 90, and 180 days after randomization; quality of life at 180 days. Data will be analyzed in 3500 patients on an intention-to-treat basis., Discussion: The trial is ongoing and currently recruiting. It will be one of the first randomized controlled studies to assess the relationship between amino acids use and kidney injury in cardiac surgery. If our hypothesis is confirmed, this practice could reduce morbidity in the studied population., Study Registration: This trial was registered on ClinicalTrials.gov with the trial identification NCT03709264 in October 2018., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The majority of BRCA1-mutant breast cancers are characterized by a triple-negative phenotype and a basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options are limited, highlighting the need for the development of novel targeted therapies for this tumor subtype., Methods: Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient breast tumors and blocking EZH2 enzymatic activity could be a potent treatment strategy. To validate the role of EZH2 as a therapeutic target and to identify new synergistic drug combinations, we performed a high-throughput drug combination screen in various cell lines derived from BRCA1-deficient and -proficient mouse mammary tumors., Results: We identified the combined inhibition of EZH2 and the proximal DNA damage response kinase ATM as a novel synthetic lethality-based therapy for the treatment of BRCA1-deficient breast tumors. We show that the combined treatment with the EZH2 inhibitor GSK126 and the ATM inhibitor AZD1390 led to reduced colony formation, increased genotoxic stress, and apoptosis-mediated cell death in BRCA1-deficient mammary tumor cells in vitro. These findings were corroborated by in vivo experiments showing that simultaneous inhibition of EZH2 and ATM significantly increased anti-tumor activity in mice bearing BRCA1-deficient mammary tumors., Conclusion: Taken together, we identified a synthetic lethal interaction between EZH2 and ATM and propose this synergistic interaction as a novel molecular combination for the treatment of BRCA1-mutant breast cancer., (© 2022. The Author(s).)

Purpose: BRCA1-deficient breast cancers carry a specific DNA copy-number signature (" BRCA1-like ") and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human BRCA1 -deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in Brca1 -deficient murine mammary tumors., Experimental Design: EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing. We classified 370 tumors by copy-number profiles as BRCA1 -like or non- BRCA1 -like and examined its association with EZH2 expression. Additionally, we assessed BRCA1 loss through mutation or promoter methylation status and investigated the predictive value of EZH2 expression in a study population of breast cancer patients treated with adjuvant high-dose platinum-based chemotherapy compared with standard anthracycline-based chemotherapy. To explore whether EZH2 inhibition by GSK126 enhances sensitivity to platinum drugs in EZH2-overexpressing breast cancers we used a Brca1 -deficient mouse model., Results: The highest EZH2 expression was found in BRCA1-associated tumors harboring a BRCA1 mutation, BRCA1 -promoter methylation or were classified as BRCA1 like. We observed a greater benefit from high-dose platinum-based chemotherapy in BRCA1 -like and non- BRCA1 -like patients with high EZH2 expression. Combined treatment with the EZH2 inhibitor GSK126 and cisplatin decreased cell proliferation and improved survival in Brca1 -deficient mice in comparison with single agents., Conclusions: Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1 -deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who benefit significantly from intensified DSB-inducing platinum-based chemotherapy independent of BRCA1 -like status. EZH2 inhibition improves the antitumor effect of platinum drugs in Brca1 -deficient breast tumors in vivo ., (©2019 American Association for Cancer Research.)

According to the cancer stem cell (CSC) theory, therapies that do not target the CSC compartment have limited, if any, chances to eradicate established tumors. While cytotoxic T lymphocytes (CTLs) have the potential to recognize and kill single neoplastic cells within a tissue, whether CSCs can be targeted by the immune system during spontaneous or vaccination-elicited responses is poorly defined. Here, we provide experimental evidence showing that CSC lines established from the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice expressed prostate cancer-associated antigens, MHC Class I and II molecules as well as ligands for natural killer (NK) cell receptors. Indeed, CSC were targets for both NK cell- and CTL-mediated cytotoxicity, both in vitro and in vivo. The administration of dendritic cells pulsed with irradiated CSCs induced a tumor-specific immune response that was more robust than that induced by dendritic cells pulsed with differentiated tumor cells, delayed tumor growth in mice challenged with prostate CSCs and caused tumor regression in TRAMP mice. Thus, CSC are targeted by both innate and adaptive immune responses and might be exploited for the design of novel immunotherapeutic approaches against cancer.

Surfactant derived protein B (SPB) and plasma receptor for advanced glycation end products (RAGE) have been proposed as markers of lung injury. The former is produced specifically by pneumocytes while RAGE production is present in several body tissues. Cardiopulmonary bypass (CPB) generates a transient lung injury. We measured SPB and RAGE in plasma before surgery and after CPB, as well as 24 h and 48 h later. We analysed plasma samples from 20 subjects scheduled for elective coronary artery bypass grafting. We performed a quantitative analysis of plasma levels of RAGE and SPB mature form (8 kDa) by ELISA and a semi-quantitative analysis of SPB immature form (~ 40 kDa) by Western blotting. Surgery procedures were uneventful. After CPB RAGE median (75th-25th interquartile difference) increased from 633 (539) pg·mL⁻¹ to 1,362 (557) pg·mL⁻¹ (p < 0.01), while mature SPB increased from 5,587 (3,089) ng·mL⁻¹ to 20,307 (19,873) ng·mL⁻¹ (p < 0.01). RAGE and mature SPB returned to normal values within 48 h. This behaviour was confirmed when RAGE and SPB were normalised for protein content. Parallel changes were observed for immature SPB. Plasma RAGE and SPBs are sensitive and rapid markers of lung distress.

Aims: To assess EuroSCORE performance in predicting in-hospital mortality in on-pump coronary artery bypass grafting (CABG) and off-pump coronary artery bypass grafting (OPCAB)., Methods and Results: Additive and logistic EuroSCORE were computed for consecutive patients undergoing CABG (n = 3440, 75%) or OPCAB (n = 1140, 25%) at our hospital from 1999 to September 2007. The areas under the receiver operating characteristic (ROC) curves (AUCs) were used to describe performance and accuracy. No difference in performance between CABG and OPCAB and between additive and logistic EuroSCORE (additive EuroSCORE AUCs of 0.808 and 0.779 for CABG and OPCAB, respectively; logistic EuroSCORE AUCs of 0.813 and of 0.773 for CABG and OPCAB, respectively) was found, although a marked tendency to overpredict mortality by both models was evident. A meta-analysis of previously published data was done, and a total of eight studies representing 19 212 and 5461 patients undergoing CABG and OPCAB, respectively, met inclusion criteria. Meta-analysis confirmed similar performance of EuroSCORE in CABG and OPCAB: estimated AUCs were 0.767 and 0.766 for CABG and OPCAB, respectively, with an estimated difference of 0.001 (95% CI -0.061 to 0.063)., Conclusion: Additive and logistic EuroSCORE algorithms performed similarly, and cumulative evidence suggests comparable performance in CABG and OPCAB procedures; both risk models, however, significantly overestimated mortality.

Objectives: To assess if 2 different anesthesia strategies, high-thoracic epidural anesthesia (HTEA) plus inhalation anesthesia and total intravenous anesthesia (TIVA) with sufentanil/propofol had different influence on outcomes of coronary artery bypass graft (CABG) surgery patients., Design: Retrospective comparison of outcomes between HTEA and TIVA patients using propensity score pair-wise matching of patients., Setting: A university teaching hospital., Participants: A study of 1,473 consecutive patients undergoing elective CABG surgery; of these, 476 (32%) received HTEA combined with inhalation anesthesia, whereas 997 (68%) underwent TIVA alone., Interventions: The patients undergoing CABG surgery were offered the epidural-inhalation anesthetic approach., Measurements and Main Results: Propensity matching yielded 389 pairs of patients. Patients were well matched in preoperative and operative features. Postoperative mortality, myocardial infarction, stroke, acute renal failure rates, and intensive care unit (ICU) stay were not statistically different in HTEA and TIVA groups. On the other hand, patients treated with HTEA had shorter ventilation times (5.8 +/- 3.11 v 6.9 +/- 5.0 hours, HTEA and TIVA, respectively, p < 0.001); in addition, vasoconstrictors were more frequently used in cases of HTEA, whereas vasodilators were mainly used with TIVA both intra- and postoperatively. No neurologic complications related to the use of HTEA were observed., Conclusions: HTEA and TIVA provided similar early outcomes after CABG surgery, and there were no major differences between these 2 strategies in the average risk CABG patient populations. Although HTEA did not cause neurologic problems and yielded a significant reduction in time to extubation, a consistent benefit over standard techniques could not be shown.

Objective: To assess the feasibility of high thoracic epidural anesthesia combined with sevoflurane for off-pump coronary artery bypass surgery and to evaluate the postoperative pain control, side effects, and perioperative hemodynamics., Design: Retrospective review of prospectively collected data., Setting: A university teaching hospital., Participants: One hundred six consecutive patients receiving thoracic epidural combined with sevoflurane., Intervention: From November 1999, the patients undergoing off-pump coronary artery bypass grafting were offered the epidural-inhalation anesthetic approach., Measurements and Main Results: Insertion of the epidural catheter was successful in all but 2 patients; 1 bloody tap occurred and the dura was never punctured, although 1 patient presented with postoperative paraplegia. An emergency spinal cord nuclear magnetic resonance excluded signs of medullary compression caused by epidural or spinal hematoma. Visual analog scale scores for pain during the first 24-hour period were < 2 in all patients. Mean time to extubation was 4.6 +/- 2.9 hours. The average intensive care unit stay was 1.5 +/- 0.8 days. Incidences of perioperative myocardial infarction, myocardial ischemia, and atrial fibrillation were 2.8%, 7.5%, and 10.6%, respectively. Two patients died: 1 from multiorgan failure and the other from myocardial infarction. Heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were not affected by thoracic epidural alone. Mean arterial pressure and cardiac index decreased (p < 0.05) when general anesthesia was induced and remained stable thereafter. Neither heart rate nor systemic vascular resistance changed from baseline during operation., Conclusions: Thoracic epidural as an adjunct to general anesthesia is a feasible technique in off-pump coronary artery bypass surgery. It induces intense postoperative analgesia and does not compromise central hemodynamics.

Background: Cardiopulmonary bypass (CPB) has been reported to increase oxygen metabolism and to influence the relation between oxygen consumption (VO(2)) and delivery (DO(2)) in the early hours after cardiac surgery. To investigate the role of CPB, we studied oxygen metabolism in coronary artery bypass procedures performed on-pump (CABG) and off-pump (OPCAB)., Methods: Twenty-five patients were randomized to undergo CABG (n = 14) or OPCAB (n = 11). All patients received the same anesthetic management. Oxygen metabolism variables were assessed before induction of anesthesia and up to 18-hours after surgery., Results: At baseline, before induction of anesthesia, there were no differences between CABG and OPCAB in oxygen consumption (VO(2)), delivery (DO(2)), or extraction (ExO(2)). After surgery VO(2) and ExO(2) increased in both groups, while DO(2) decreased. No significant differences between CABG and OPCAB were detected in postoperative VO(2), DO(2), and ExO(2) levels. The relation between VO(2) and DO(2) was very similar in CABG and OPCAB patients throughout the study, and no significant differences were detected in slopes and intercepts of the regression lines between CABG and OPCAB at all time points. There was, however, a significant effect of time on the relation between VO(2) and DO(2): this relation was stronger in the postoperative period, and the slope of this relation increased over time as well., Conclusions: A hypermetabolic state and progressive and significant increases in the strength of the relationship between VO(2) and DO(2) and in the slope of this relationship occur after both CABG and OPCAB. Cardiopulmonary bypass is not responsible for these changes in oxygen metabolism.

Allopurinol reduces formation of cytotoxic free radicals during myocardial ischemia/reperfusion in animals. To evaluate the effect of allopurinol on cardiac performance and metabolism after coronary bypass in humans, we divided 33 patients into two groups: 15 patients (controls) received no allopurinol and 18 patients received 200 mg allopurinol intravenously (i.v.) 1 h preoperatively. Hemodynamic measurements were made with a triple-lumen thermodilution pulmonary artery catheter before cardiopulmonary bypass (CPB), 30 min after completion of CPB and 6 h later in the intensive care unit (ICU). A catheter placed into the coronary sinus was used for blood sampling for measurement of lactate and creatine phosphokinase MB. Peripheral blood was obtained for measurement of xanthine oxidase activity (XO), uric acid, and thiol groups. A myocardial biopsy was taken for measurement of thiol group content and XO before CPB and after heparin neutralization with protamin (a few minutes after CPB). Treated patients had better recovery of cardiac output (CO) and left ventricular stroke work (LVSW) 30 min and 6 h after completion of CPB than did controls. Allopurinol significantly reduced plasma XO. Plasma concentrations of uric acid increased significantly in both groups 30 min after completion of CPB, but the increase in controls was greater (p < 0.02) than with allopurinol. Thiol group levels increased (p < 0.05) only in controls. Our results demonstrate improvement of cardiac function in coronary artery bypass surgery with allopurinol that is related to its metabolic effects consistent with protection against XO catalyzed free radical-mediated injury.

The course of respiratory exchange through arterial blood gas analysis after coronary bypass-grafting and valvular replacement has been investigated in a cohort of 62 patients. Arterial blood gases were measured at baseline (the day before surgery), and then 1, 2, 3 and 9 days after surgery; in a subset of 18 patients, randomly selected from the same population, pulmonary function tests were also performed at baseline and repeated on day 9. Arterial blood gases showed a remarkable prevalence of hypoxaemia (as defined as arterial PaO2 less than 60 mmHg): 31% on the first, 50% on the second, and 40% on the third post-operative day; anemia and desaturated mixed venous blood were also prominent findings during the first two days. Arterial PO2 resulted higher afterward, although its mean value then was significantly lower than baseline (81.5 +/- 8.8 vs 93.1 +/- 9 mmHg, p less than 0.005). Pulmonary function tests evidenced widespread restrictive changes, with alterated thoraco-pulmonary mechanics (loss of more than 40% of vital capacity and one second forced expiratory flow) and parenchimal lung damage (residual volume and CO diffusion capacity decrease). Some differences in PaO2 course between coronary patients and valvular patients have been releaved; the mean basal PaO2 value of valvular was significantly lower then the other one (86.7 +/- 10.8 vs 94.7 +/- 10.9, p less than 0.05).