A Randomized Trial of Intravenous Amino Acids for Kidney Protection.

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.).

Stemness and hybrid epithelial-mesenchymal profiles guide peritoneal dissemination of malignant mesothelioma and pseudomyxoma peritonei.

Intrabdominal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) is poorly characterized with respect to the stemness window which malignant cells activate during their reshaping on the epithelial-mesenchymal (E/M) axis. To gain insights into stemness properties and their prognostic significance in these rarer forms of peritoneal metastases (PM), primary tumor cultures from 55 patients selected for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were analyzed for cancer stem cells (CSC) by aldehyde dehydrogenase 1 (ALDH1) and spheroid formation assays, and for expression of a set of plasticity-related genes to measure E/M transition (EMT) score. Intratumor heterogeneity was also analyzed. Samples from PM of colorectal cancer were included for comparison. Molecular data were confirmed using principal component and cluster analyses. Associations with survival were evaluated using Kaplan-Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1bright-cells identified high-grade PMP, and discriminated solid masses from ascitic/mucin-embedded tumor cells in both forms of PM. Epithelial/early hybrid EMT scores and an early hybrid expression pattern correlated with pluripotency factors were significantly associated with early peritoneal progression (p = .0343 and p = .0339, respectively, log-rank test) in multivariable models. ASA impaired spheroid formation and increased cisplatin sensitivity in all five cultures. These data suggest that CSC subpopulations and hybrid E/M states may guide peritoneal spread of MM and PMP. Stemness could be exploited as targetable vulnerability to increase chemosensitivity and improve patient outcomes. Additional research is needed to confirm these preliminary data.

Extracorporeal Membrane Oxygenation Without Invasive Ventilation for Respiratory Failure in Adults: A Systematic Review.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) is an advanced treatment for acute severe respiratory failure. Patients on ECMO are frequently maintained sedated and immobilized until weaning from ECMO, first, and then from mechanical ventilation. Avoidance of sedation and invasive ventilation during ECMO may have potential advantages. We performed a systematic literature review to assess efficacy and safety of awake ECMO without invasive ventilation in patients with respiratory failure. DATA SOURCES: PubMed, Web of Science, and Scopus were searched for studies reporting outcome of awake ECMO for adult patients with respiratory failure. STUDY SELECTION: We included all studies reporting outcome of awake ECMO in patients with respiratory failure. Studies on ECMO for cardiovascular failure, cardiac arrest, or perioperative support and studies on pediatric patients were excluded. Two investigators independently screened and selected studies for inclusion. DATA EXTRACTION: Two investigators abstracted data on study characteristics, rate of awake ECMO failure, and mortality. Primary outcome was rate of awake ECMO failure (need for intubation). Pooled estimates with corresponding 95% CIs were calculated. Subgroup analyses by setting were performed. DATA SYNTHESIS: A total of 57 studies (28 case reports) included data from 467 awake ECMO patients. The subgroup of patients with acute respiratory distress syndrome showed a pooled estimate for awake ECMO failure of 39.3% (95% CI, 24.0-54.7%), while in patients bridged to lung transplantation, pooled estimate was 23.4% (95% CI, 13.3-33.5%). Longest follow-up mortality was 121 of 439 (pooled estimate, 28%; 95% CI, 22.3-33.6%). Mortality in patients who failed awake ECMO strategy was 43 of 74 (pooled estimate, 57.2%; 95% CI, 40.2-74.3%). Two cases of cannula self-removal were reported. CONCLUSIONS: Awake ECMO is feasible in selected patients, although the effect on outcome remains to be demonstrated. Mortality is almost 60% in patients who failed awake ECMO strategy.

Extracorporeal Blood Purification with CytoSorb in 359 Critically Ill Patients.

INTRODUCTION: Critically ill patients with inflammatory dysregulation and organ disfunction may benefit from blood purification, although the use of this technique has not been described in large case series. We evaluated clinical outcomes and survival in high-risk intensive care unit (ICU) patients who underwent extracorporeal blood purification. METHODS: 359 consecutive ICU patients treated with CytoSorb were included. RESULTS: Main admission diagnoses were 120 (34%) refractory cardiac arrest under mechanical chest compression; 101 (28%) profound cardiogenic shock; 81 (23%) post-cardiotomy cardiogenic shock; and 37 (10%) respiratory failure. Fifteen patients (4%) were positive for SARS-CoV-2 infection. We observed 49% 30-day mortality, 57% ICU mortality, and 62% hospital mortality, all lower than the 71% mortality predicted by SAPS II and 68% predicted by SOFA score. Parameters of shock and organ failure, above all vasoactive inotropic score, reduced during CytoSorb treatment. Multivariable analysis identified SAPS II, lactate dehydrogenase, ICU stay duration, vasoactive inotropic score, lactates, intra-aortic counterpulsation on top of VA-ECMO, and total bilirubin as predictors of mortality. No CytoSorb-related complications occurred. CONCLUSION: CytoSorb treatment was effective in reducing laboratory parameters of shock and vasoactive inotropic score with possible survival implications in a large population of critically ill patients.

Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial.

Importance: Meropenem is a widely prescribed ß-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes. Objective: To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis. Design, Setting, and Participants: A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022. Interventions: Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304). Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events. Results: All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients). Conclusions and Relevance: In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. Trial Registration: ClinicalTrials.gov Identifier: NCT03452839.

Studies on the Role of Compartmentalized Profiles of Cytokines in the Risk of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is frequently diagnosed late due to the absence of symptoms during early disease, thus heavily affecting the overall survival of these patients. Soluble immunological factors persistently produced during cirrhosis have been recognized as promoters of chronic inflammation and neoplastic transformation. The aim of this pilot study was to evaluate the predictive value of the cytokine profiles for HCC development. A Luminex xMAP approach was used for the quantification of 45 proteins in plasma and ascitic fluids of 44 cirrhotic patients without or with HCC of different etiologies. The association with patient survival was also evaluated. Univariate analyses revealed that very low levels of interleukin 5 (IL-5) (<15.86 pg/mL) in ascites and IL-15 (<12.40 pg/mL) in plasma were able to predict HCC onset with an accuracy of 81.8% and a sensitivity of 95.2%. Univariate analyses also showed that HCC, hepatitis B virus/hepatitis C virus infections, low levels of IL-5 and granulocyte-macrophage colony-stimulating factor in ascitic fluids, and high levels of eotaxin-1, hepatocyte growth factor and stromal-cell-derived factor 1α in plasma samples were factors potentially associated with a poor prognosis and decreased survival. Our results suggest a potential protective role of some immune modulators that may act in the peritoneal cavity to counteract disease progression leading to HCC development.

Volatile Anesthetics versus Total Intravenous Anesthesia for Cardiac Surgery.

BACKGROUND: Volatile (inhaled) anesthetic agents have cardioprotective effects, which might improve clinical outcomes in patients undergoing coronary-artery bypass grafting (CABG). METHODS: We conducted a pragmatic, multicenter, single-blind, controlled trial at 36 centers in 13 countries. Patients scheduled to undergo elective CABG were randomly assigned to an intraoperative anesthetic regimen that included a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or to total intravenous anesthesia. The primary outcome was death from any cause at 1 year. RESULTS: A total of 5400 patients were randomly assigned: 2709 to the volatile anesthetics group and 2691 to the total intravenous anesthesia group. On-pump CABG was performed in 64% of patients, with a mean duration of cardiopulmonary bypass of 79 minutes. The two groups were similar with respect to demographic and clinical characteristics at baseline, the duration of cardiopulmonary bypass, and the number of grafts. At the time of the second interim analysis, the data and safety monitoring board advised that the trial should be stopped for futility. No significant difference between the groups with respect to deaths from any cause was seen at 1 year (2.8% in the volatile anesthetics group and 3.0% in the total intravenous anesthesia group; relative risk, 0.94; 95% confidence interval [CI], 0.69 to 1.29; P = 0.71), with data available for 5353 patients (99.1%), or at 30 days (1.4% and 1.3%, respectively; relative risk, 1.11; 95% CI, 0.70 to 1.76), with data available for 5398 patients (99.9%). There were no significant differences between the groups in any of the secondary outcomes or in the incidence of prespecified adverse events, including myocardial infarction. CONCLUSIONS: Among patients undergoing elective CABG, anesthesia with a volatile agent did not result in significantly fewer deaths at 1 year than total intravenous anesthesia. (Funded by the Italian Ministry of Health; MYRIAD ClinicalTrials.gov number, NCT02105610.).

Trend and Pattern of 100 Acute Respiratory Distress Syndrome Patients Referred for Venovenous Extracorporeal Membrane Oxygenation Treatment in a National Referral Center in North Italy During the Last Decade.

OBJECTIVE: Current evidence supports centralization of patients with refractory acute respiratory distress syndrome (ARDS) to institutions with a high level of expertise and with extracorporeal membrane oxygenation (ECMO) capabilities. The aim of this study was to analyze and report the data of transferred refractory ARDS patients managed with venovenous (VV) ECMO at a national referral center over the last 11 years. DESIGN: Observational study. SETTING: Referral center in Italy. PARTICIPANTS: The study comprised 100 patients treated from May 2009-November 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean age was 54 ± 14 years, and 65% of patients were male. Patients were treated throughout the year, with seasonal peaks in the winter months. The majority of patients were referred from hospitals within the Lombardia region (81%), mainly from the city of Milan and surrounding area (36% of the total). The most common etiology of refractory ARDS was H1N1 influenza A (42 patients [42%]), followed by bacterial pneumonia (35 patients [35%]), and severe acute respiratory syndrome due to Sars-CoV-2 infection (five patients [5%]). All patients were severely hypoxic at the time of VV ECMO treatment. No transport-related complication was recorded. The most common configuration used in the authors' clinical practice was a bicaval dual-lumen configuration (61 patients [61%]), followed by a femoro-jugular configuration (38 patients [38%]). The intensive care unit survival rate was 55%. CONCLUSIONS: Referral to a specialized center for VV ECMO treatment should be considered expeditiously in case of refractory ARDS, which often is lethal. Transport of patients with an unstable condition, although challenging, is feasible, and centralization of patient care is associated with good outcomes.

Eleven Years of Venovenous Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: From H1N1 to SARS-CoV-2. Experience and Perspectives of a National Referral Center.

OBJECTIVE: Despite growing expertise and wide application of venovenous extracorporeal membrane oxygenation (VV ECMO) treatment for acute respiratory distress syndrome (ARDS) of different origin and during pandemics (H1N1 Influenza A virus and SARS-CoV-2), large reports are few and pertain mostly to multicenter registries, and randomized trials are difficult to perform. The aim of this study was to report outcomes, trends, and innovations of VV ECMO treatment over the last 11 years. DESIGN, SETTING, AND PARTICIPANTS: Observational study on 142 patients treated at the IRCCS San Raffaele Hospital in Milan from June 2009 (year of the H1N1 pandemic) to May 2020 (SARS-CoV-2 pandemic). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main causes of ARDS were H1N1 pneumonia in 36% of patients, bacterial pneumonia in 17%, and SARS-CoV-2 in 9%. Seventy-two percent of patients were centralized from remote hospitals, of whom 33% had implanted VV ECMO before transport. The most common cannulation strategy was the dual-lumen catheter cannulation system (55%), and anticoagulation was performed with bivalirudin in most patients (79%). Refractory hypoxia was treated with intravenous beta-blockers (64%), nitric oxide (20%), and pronation (8%). Almost one-third of patients (32%) were extubated while on ECMO. Forty-nine percent of patients were discharged from the intensive care unit, and hospital discharge was 46%; survival was lower in patients requiring VV ECMO for more than three weeks compared with shorter support duration (23% v 56%, p = 0.007). Anticoagulation with bivalirudin was associated with higher survival, compared with heparin (55% v 31%, p = 0.03), and lower thrombocytopenia incidence (69% v 35%, p = 0.003). CONCLUSION: VV ECMO is the pivotal rescue treatment for refractory ARDS-timely treatment and optimal care are needed to optimize therapy, as duration of support is associated with outcome. Anticoagulation with bivalirudin may improve outcome.

Anticoagulation Strategies in Critically Ill Patients With SARS-CoV-2 Infection: The Role of Direct Thrombin Inhibitors.

OBJECTIVES: To compare heparin-based anticoagulation and bivalirudin-based anticoagulation within the context of critically ill patients with a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN: An observational study. SETTING: At the intensive care unit of a university hospital. PARTICIPANTS AND INTERVENTIONS: Critically ill patients with a SARS-CoV-2 infection receiving full anticoagulation with heparin or bivalirudin. MEASUREMENTS AND MAIN RESULTS: Twenty-three patients received full anticoagulation with bivalirudin and 60 with heparin. Despite patients in the bivalirudin group having higher mortality risk scores (SAPS II 60 ± 16 v 39 ±7, p < 0.001) and a higher need for extracorporeal support compared to the heparin group, hospital mortality was comparable (57% v 45, p = 0.3). No difference in thromboembolic complications was observed, and bleeding events were more frequent in patients treated with bivalirudin (65% v 40%, p = 0.01). Similar results were confirmed in the subgroup analysis of patients undergoing intravenous anticoagulation; in addition to comparable thrombotic complications occurrence and thrombocytopenia rate, however, no difference in the bleeding rate was observed (65% v 35%, p = 0.08). CONCLUSIONS: Although heparin is the most used anticoagulant in the intensive care setting, bivalirudin-based anticoagulation was safe and effective in a cohort of critically ill patients with SARS-CoV-2. Bivalirudin may be given full consideration as an anticoagulation strategy for critically ill patients with SARS-CoV-2, especially in those with thrombocytopenia and on extracorporeal support.

Impact of CytoSorb on kinetics of vancomycin and bivalirudin in critically ill patients.

CytoSorb is a promising tool to treat severe inflammatory status with multiple mechanisms in the acute care setting. Its effect on drugs is, however, poorly documented in vivo, although removal of small molecules might translate into decreased blood levels of life-saving medications. The aim of this study was to assess the impact of CytoSorb on vancomycin and bivalirudin clearance in a large population of critically ill patients. We performed a single-center analysis of CytoSorb treatments performed between January 2018 and March 2019 in critically ill patients admitted to our intensive care unit. A total of 109 CytoSorb treatments were performed in 89 patients. A decrease in lactate dehydrogenase (P = .007), troponin T (P = .022), and creatine phosphokinase (P = .013) was reported during treatment. Vancomycin dose required significant adjustments during treatment (P < .001), but no significant change was necessary after the first 3 days. Similarly, the requirements of bivalirudin significantly changed over days (P < .001), but no dose adjustment was needed after the first 3 days of treatment. No differences in terms of vancomycin and bivalirudin dose need was observed between patients on extracorporeal membrane oxygenation and those who were not (P = .6 and P = .6, respectively), between patients with and without continuous veno-venous hemofiltration (P = .9 and P = .9, respectively), and between CytoSorb responders or not (P = .4 and P = .7, respectively). CytoSorb is effective in mitigating the systemic inflammatory response and safe with respect to vancomycin and bivalirudin administration. These preliminary data further support the use of CytoSorb as adjunct therapy in critically ill patients.

Prevalence, Characteristics, Risk Factors, and Outcomes of Invasively Ventilated COVID-19 Patients with Acute Kidney Injury and Renal Replacement Therapy.

BACKGROUND: There is no information on acute kidney injury (AKI) and continuous renal replacement therapy (CRRT) among invasively ventilated coronavirus disease 2019 (COVID-19) patients in Western healthcare systems. OBJECTIVE: To study the prevalence, characteristics, risk factors and outcome of AKI and CRRT among invasively ventilated COVID-19 patients. METHODS: Observational study in a tertiary care hospital in Milan, Italy. RESULTS: Among 99 patients, 72 (75.0%) developed AKI and 17 (17.7%) received CRRT. Most of the patients developed stage 1 AKI (33 [45.8%]), while 15 (20.8%) developed stage 2 AKI and 24 (33.4%) a stage 3 AKI. Patients who developed AKI or needed CRRT at latest follow-up were older, and among CRRT treated patients a greater proportion had preexisting CKD. Hospital mortality was 38.9% for AKI and 52.9% for CRRT patients. CONCLUSIONS: Among invasively ventilated COVID-19 patients, AKI is very common and CRRT use is common. Both carry a high risk of in-hospital mortality.

Left Ventricular Unloading With an IABP in Patients Undergoing Ventricular Tachycardia Ablation With ECMO Support.

OBJECTIVE: The authors investigated the preprocedural predictors of postprocedural intra-aortic balloon pump (IABP) need in patients undergoing transcatheter ventricular tachycardia (VT) ablation on venoarterial (VA) extracorporeal membrane oxygenation (ECMO). DESIGN: Observational study. SETTING: Hybrid operating room and intensive care unit of a teaching hospital. PATIENTS: Participants were 121 consecutive patients with unstable VT undergoing transcatheter ablation with VA-ECMO. INTERVENTIONS: In patients with postprocedural echocardiographic, radiographic, or hemodynamic signs of increased left ventricle afterload, an IABP was positioned. MEASUREMENTS AND MAIN RESULTS: Patients in the IABP group were more frequently on angiotensin-converting enzyme inhibitors (58% v 37%; p = 0.03) and had lower median baseline ejection fraction (25% v 28% p = 0.05), larger end-diastolic diameter (69.7 mm ± 13.0 v 65.7 mm ± 11.3; p = 0.03), and more frequent ischemic etiology as the reason for dilated cardiomyopathy (76% v 47%; p = 0.04,) when compared with patients not requiring IABP. Postoperatively, the IABP group required longer mechanical ventilation (24 hours [20-56.5] v 23 hours [15-28]; p = 0.003), intensive care unit stay (78 hours [46-174] v 48 hours [24-72]; p < 0.001), and continuous renal replacement therapy (13.3% v 1.3%; p = 0.006). By multivariate analysis, end-diastolic diameter (odds ratio [OR]:1.08; confidence interval [CI]: 1.00-1.16; p = 0.049), ischemic dilated cardiomyopathy (OR: 8.40; CI: 2.15-32.88; p = 0.002), and more-than-moderate mitral regurgitation (OR: 4.83; CI: 1.22-19.22; p = 0.025) were independent predictors of need for IABP. CONCLUSIONS: The need for an IABP to unload the left ventricle can be predicted by ventricular size, medium-severe mitral valvular defect, and ischemic etiology of the dilated cardiomyopathy.

Pulmonary Vascular Thrombosis in COVID-19 Pneumonia.

OBJECTIVES: During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, dramatic endothelial cell damage with pulmonary microvascular thrombosis have been was hypothesized to occur. The aim was to assess whether pulmonary vascular thrombosis (PVT) is due to recurrent thromboembolism from peripheral deep vein thrombosis or to local inflammatory endothelial damage, with a superimposed thrombotic late complication. DESIGN: Observational study. SETTING: Medical and intensive care unit wards of a teaching hospital. PARTICIPANTS: The authors report a subset of patients included in a prospective institutional study (CovidBiob study) with clinical suspicion of pulmonary vascular thromboembolism. INTERVENTIONS: Computed tomography pulmonary angiography and evaluation of laboratory markers and coagulation profile. MEASUREMENTS AND MAIN RESULTS: Twenty-eight of 55 (50.9%) patients showed PVT, with a median time interval from symptom onset of 17.5 days. Simultaneous multiple PVTs were identified in 22 patients, with bilateral involvement in 16, mostly affecting segmental/subsegmental pulmonary artery branches (67.8% and 96.4%). Patients with PVT had significantly higher ground glass opacity areas (31.7% [22.9-41] v 17.8% [10.8-22.1], p < 0.001) compared with those without PVT. Remarkably, in all 28 patients, ground glass opacities areas and PVT had an almost perfect spatial overlap. D-dimer level at hospital admission was predictive of PVT. CONCLUSIONS: The findings identified a specific radiologic pattern of coronavirus disease 2019 (COVID-19) pneumonia with a unique spatial distribution of PVT overlapping areas of ground-glass opacities. These findings supported the hypothesis of a pathogenetic relationship between COVID-19 lung inflammation and PVT and challenged the previous definition of pulmonary embolism associated with COVID-19 pneumonia.

Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era.

AIMS: To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs). METHODS AND RESULTS: We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019. We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P < 0.001). The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7-32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3-70.3; P < 0.001). Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191). A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%). The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7-6.6; P < 0.001]. A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1-2.8; P = 0.009). CONCLUSION: Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates. This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies.

Mechanisms Involved in the Promoting Activity of Fibroblasts in HTLV-1-Mediated Lymphomagenesis: Insights into the Plasticity of Lymphomatous Cells.

Among the mechanisms leading to progression to Adult T-cell Leukaemia/Lymphoma in Human T-cell Leukaemia Virus type 1 (HTLV-1)-infected subjects, the contribution of stromal components remains poorly understood. To dissect the role of fibroblasts in HTLV-1-mediated lymphomagenesis, transcriptome studies, cytofluorimetric and qRT-PCR analyses of surface and intracellular markers linked to plasticity and stemness in coculture, and in vivo experiments were performed. A transcriptomic comparison between a more lymphomagenic (C91/III) and the parental (C91/PL) cell line evidenced hyperactivation of the PI3K/Akt pathway, confirmed by phospho-ELISA and 2-DE and WB analyses. C91/III cells also showed higher expression of mesenchymal and stemness genes. Short-term coculture with human foreskin fibroblasts (HFF) induced these features in C91/PL cells, and significantly increased not only the cancer stem cells (CSCs)-supporting CD10+GPR77+ HFF subpopulation, but also the percentage of ALDH1bright C91/PL cells. A non-cytotoxic acetylsalicylic acid treatment decreased HFF-induced ALDH1bright C91/PL cells, downregulated mesenchymal and stemness genes in cocultured cells, and delayed lymphoma growth in immunosuppressed mice, thus hindering the supportive activity of HFF on CSCs. These data suggest that crosstalk with HFF significantly intensifies the aggressiveness and plasticity of C91/PL cells, leading to the enrichment in lymphoma-initiating cells. Additional research is needed to better characterize these preliminary findings.

Levosimendan for Hemodynamic Support after Cardiac Surgery.

BACKGROUND: Acute left ventricular dysfunction is a major complication of cardiac surgery and is associated with increased mortality. Meta-analyses of small trials suggest that levosimendan may result in a higher rate of survival among patients undergoing cardiac surgery. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving patients in whom perioperative hemodynamic support was indicated after cardiac surgery, according to prespecified criteria. Patients were randomly assigned to receive levosimendan (in a continuous infusion at a dose of 0.025 to 0.2 µg per kilogram of body weight per minute) or placebo, for up to 48 hours or until discharge from the intensive care unit (ICU), in addition to standard care. The primary outcome was 30-day mortality. RESULTS: The trial was stopped for futility after 506 patients were enrolled. A total of 248 patients were assigned to receive levosimendan and 258 to receive placebo. There was no significant difference in 30-day mortality between the levosimendan group and the placebo group (32 patients [12.9%] and 33 patients [12.8%], respectively; absolute risk difference, 0.1 percentage points; 95% confidence interval [CI], -5.7 to 5.9; P=0.97). There were no significant differences between the levosimendan group and the placebo group in the durations of mechanical ventilation (median, 19 hours and 21 hours, respectively; median difference, -2 hours; 95% CI, -5 to 1; P=0.48), ICU stay (median, 72 hours and 84 hours, respectively; median difference, -12 hours; 95% CI, -21 to 2; P=0.09), and hospital stay (median, 14 days and 14 days, respectively; median difference, 0 days; 95% CI, -1 to 2; P=0.39). There was no significant difference between the levosimendan group and the placebo group in rates of hypotension or cardiac arrhythmias. CONCLUSIONS: In patients who required perioperative hemodynamic support after cardiac surgery, low-dose levosimendan in addition to standard care did not result in lower 30-day mortality than placebo. (Funded by the Italian Ministry of Health; CHEETAH ClinicalTrials.gov number, NCT00994825 .).

Role of Epithelial-Mesenchymal Plasticity in Pseudomyxoma Peritonei: Implications for Locoregional Treatments.

The mechanisms by which neoplastic cells disseminate from the primary tumor to metastatic sites, so-called metastatic organotropism, remain poorly understood. Epithelial-mesenchymal transition (EMT) plays a role in cancer development and progression by converting static epithelial cells into the migratory and microenvironment-interacting mesenchymal cells, and by the modulation of chemoresistance and stemness of tumor cells. Several findings highlight that pathways involved in EMT and its reverse process (mesenchymal-epithelial transition, MET), now collectively called epithelial-mesenchymal plasticity (EMP), play a role in peritoneal metastases. So far, the relevance of factors linked to EMP in a unique peritoneal malignancy such as pseudomyxoma peritonei (PMP) has not been fully elucidated. In this review, we focus on the role of epithelial-mesenchymal dynamics in the metastatic process involving mucinous neoplastic dissemination in the peritoneum. In particular, we discuss the role of expression profiles and phenotypic transitions found in PMP in light of the recent concept of EMP. A better understanding of EMP-associated mechanisms driving peritoneal metastasis will help to provide a more targeted approach for PMP patients selected for locoregional interventions involving cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Circulating miRNA-375 as a potential novel biomarker for active Kaposi's sarcoma in AIDS patients.

The aim of this study was to identify circulating microRNAs (miRNAs) that could be used as biomarkers in patients at risk for or affected by AIDS-Kaposi's sarcoma (KS). Screening of 377 miRNAs was performed using low-density arrays in pooled plasma samples of 10 HIV/human herpesvirus 8 (HHV8)-infected asymptomatic and 10 AIDS-KS patients before and after successful combined antiretroviral therapy (cART). MiR-375 was identified as a potential marker of active KS, being the most down-regulated in AIDS-KS patients after cART and the most up-regulated in naïve AIDS-KS patients compared to naïve asymptomatic subjects. Validation on individual plasma samples confirmed that miR-375 levels were higher in AIDS-KS compared to asymptomatic patients, decreased after cART-induced remission in most AIDS-KS patients and increased in patients with active KS. In asymptomatic patients miR-375 was up-regulated after cART in both screening and validation. Statistical analyses revealed an association between miR-375 changes and CD4 cell counts, which could explain the discordant cases and the opposite trend between asymptomatic and AIDS-KS patients. These data suggest that circulating miR-375 might be a good indicator of active AIDS-KS. Moreover, changes in miR-375 levels may have a prognostic value in HIV/HHV8-infected patients undergoing treatment. Further large-scale validation is needed.

Prevention, Monitoring, and Management of Cardiac Dysfunction in Patients with Metastatic Breast Cancer.

Cardiac monitoring is becoming an important part of breast cancer care. Breast cancer and cardiovascular disease (CVD) share many common risk factors, and it is estimated that by the median age of diagnosis, many patients with breast cancer will have established or subclinical CVD. In addition, a number of treatments for metastatic breast cancer are known to have cardiac effects. As such, there is a clear need to prevent, identify, and effectively manage cardiovascular events in patients with breast cancer. Current clinical practice for patients with metastatic breast cancer involves a comprehensive set of assessments to ensure efficacy and safety of treatment. Adding cardiac monitoring to the assessments already required for patients with breast cancer may improve survival and quality of life. Currently, cardiac monitoring is recommended for several breast cancer treatments, and guidelines related to cardiac monitoring are available. Here, we review the risk of CVD in patients with breast cancer, providing an overview of the cardiac events associated with standard therapies for metastatic breast cancer. We also assess the current clinical recommendations relating to cardiac monitoring, and practical management strategies for oncologists. Cardio-oncology is a growing medical subspecialty that promotes the need for effective cancer therapy while minimizing cardiac effects. Integrating cardiac monitoring into routine clinical practice may safeguard patients with metastatic breast cancer against adverse cardiac effects. IMPLICATIONS FOR PRACTICE: This review details the common risk factors associated with cardiovascular disease that are frequently observed in patients with metastatic breast cancer, as well as the adverse cardiac effects of many therapies that are commonly prescribed. The review also provides a rationale for routine and comprehensive cardiovascular assessment of all patients at baseline, and during and after therapy depending on the treatment and presence of risk factors for cardiovascular disease. The medical discipline of cardio-oncology is increasingly being recognized as an important part of clinical practice to ensure effective cancer therapy while maintaining cardiac health.