Functional recovery in a cohort of ECMO and non-ECMO acute respiratory distress syndrome survivors.

BACKGROUND: The mortality benefit of VV-ECMO in ARDS has been extensively studied, but the impact on long-term functional outcomes of survivors is poorly defined. We aimed to assess the association between ECMO and functional outcomes in a contemporaneous cohort of survivors of ARDS. METHODS: Multicenter retrospective cohort study of ARDS survivors who presented to follow-up clinic. The primary outcome was FVC% predicted. Univariate and multivariate regression models were used to evaluate the impact of ECMO on the primary outcome. RESULTS: This study enrolled 110 survivors of ARDS, 34 of whom were managed using ECMO. The ECMO cohort was younger (35 [28, 50] vs. 51 [44, 61] years old, p < 0.01), less likely to have COVID-19 (58% vs. 96%, p < 0.01), more severely ill based on the Sequential Organ Failure Assessment (SOFA) score (7 [5, 9] vs. 4 [3, 6], p < 0.01), dynamic lung compliance (15 mL/cmH20 [11, 20] vs. 27 mL/cmH20 [23, 35], p < 0.01), oxygenation index (26 [22, 33] vs. 9 [6, 11], p < 0.01), and their need for rescue modes of ventilation. ECMO patients had significantly longer lengths of hospitalization (46 [27, 62] vs. 16 [12, 31] days, p < 0.01) ICU stay (29 [19, 43] vs. 10 [5, 17] days, p < 0.01), and duration of mechanical ventilation (24 [14, 42] vs. 10 [7, 17] days, p < 0.01). Functional outcomes were similar in ECMO and non-ECMO patients. ECMO did not predict changes in lung function when adjusting for age, SOFA, COVID-19 status, or length of hospitalization. CONCLUSIONS: There were no significant differences in the FVC% predicted, or other markers of pulmonary, neurocognitive, or psychiatric functional recovery outcomes, when comparing a contemporaneous clinic-based cohort of survivors of ARDS managed with ECMO to those without ECMO.

Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies.

BACKGROUND: Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. METHODS AND FINDINGS: Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4-5) were infused IV with a loading RA dose of 5 µg/kg/h for 0.5 h followed by a maintenance dose of 1.44 µg/kg/h for 6 hours, Vital signs and arterial oxygen saturation were recorded, and blood samples were collected before, during and after RA infusion for analysis of CRP, D-dimer, circulating iNKT cell activation state and plasma levels of 13 proinflammatory cytokines. RA was devoid of serious side effects, and within 24 hours from the start of infusion was associated with increased oxygen saturation (93.8 ± 0.58 vs 96.6 ± 1.08%, P<0.05), decreased D-dimer (754 ± 17 vs 518 ± 98 ng/ml, P<0.05), and a trend toward decreased CRP (3.80 ± 1.40 vs 1.98 ± 0.74 mg/dL, P = 0.075). Circulating iNKT cells, but not conventional T cells, were highly activated in COVID-19 patients (65% vs 5% CD69+). RA infusion for 30 minutes reduced iNKT cell activation by 50% (P<0.01). RA infusion for 30 minutes did not influence plasma cytokines, but infusion for 4.5 or 24 hours reduced levels of 11 of 13 proinflammatory cytokines. In separate mouse studies, subcutaneous RA infusion from Alzet minipumps at 1.44 µg/kg/h increased 10-day survival of SARS-CoV-2-infected K18-hACE2 mice from 10 to 40% (P<0.001). CONCLUSIONS: Infused RA is safe and produces rapid anti-inflammatory effects mediated by A2A adenosine receptors on iNKT cells and possibly in part by A2ARs on other immune cells and platelets. We speculate that iNKT cells are activated by release of injury-induced glycolipid antigens and/or alarmins such as IL-33 derived from virally infected type II epithelial cells which in turn activate iNKT cells and secondarily other immune cells. Adenosine released from hypoxic tissues, or RA infused as an anti-inflammatory agent decrease proinflammatory cytokines and may be useful for treating cytokine storm in patients with Covid-19 or other inflammatory lung diseases or trauma.

Regadenoson Reduces Soluble Receptor for Advanced Glycation End-Products in Lung Recipients.

BACKGROUND: The selective adenosine A2A receptor (A2AR) agonist regadenoson reduces inflammation due to lung ischemia-reperfusion injury (IRI). The objective of this study was to investigate molecular and cellular mechanisms by which regadenoson reduces IRI in lung transplant recipients. METHODS: Fourteen human lung transplant recipients were infused for 12 hours with regadenoson and 7 more served as untreated controls. Plasma levels of high mobility group box 1 and its soluble receptor for advanced glycation end-products (sRAGE) were measured by Luminex. Matrix metalloproteinase (MMP) 2 and 9 were measured by gelatin zymography. Tissue inhibitor of metalloproteinase 1 was measured by mass spectroscopy. A2AR expression on leukocytes was analyzed by flow cytometry. MMP-9-mediated cleavage of RAGE was evaluated using cultured macrophages in vitro. RESULTS: Regadenoson treatment during lung transplantation significantly reduced levels of MMP-9 (P < .05), but not MMP-2, and elevated levels of tissue inhibitor of metalloproteinase 1 (P < .05), an endogenous selective inhibitor of MMP-9. Regadenoson infusion significantly reduced plasma levels of sRAGE (P < .05) during lung reperfusion compared with control subjects. A2AR expression was highest on invariant natural killer T cells and higher on monocytes than other circulating immune cells (P < .05). The shedding of RAGE from cultured monocytes/macrophages was increased by MMP-9 stimulation and reduced by an MMP inhibitor or by A2AR agonists, regadenoson or ATL146e. CONCLUSIONS: In vivo and in vitro studies suggest that A2AR activation reduces sRAGE in part by inhibiting MMP-9 production by monocytes/macrophages. These results suggest a novel molecular mechanism by which A2AR agonists reduce primary graft dysfunction.

Veno-arterial extracorporeal membrane oxygenation without allogeneic blood transfusion: An observational cohort study.

INTRODUCTION: It remains unclear whether patients who will not accept allogeneic blood transfusion can be managed successfully with veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO). The objective of our study was to determine what percentage of V-A ECMO patients were managed without allogeneic blood transfusion. METHODS: This was a retrospective, observational cohort study of patients with cardiogenic shock requiring V-A ECMO between January 2016 and January 2019. The primary outcome was avoidance of any allogeneic blood transfusion. RESULTS: Of the 206 patients included, 23 (11.2%) were managed without any allogeneic blood transfusion. Fourteen (60.9%) avoided allogeneic blood transfusion during their entire hospitalization. "No-transfusion" patients were younger, more commonly men, were less likely to have a prior diagnosis of hypertension or coronary artery disease, had higher baseline hemoglobin, had higher SAVE scores, and were less likely to have received aspirin before ECMO. No patients in the "no-transfusion" group had major bleeding compared to 35% of patients in the blood transfusion group (p < 0.001). In-hospital mortality was 17.4% for those who avoided blood transfusion and 41.5% for those who received blood transfusion (p = 0.04). ECMO duration was significantly shorter in patients who avoided blood transfusion compared to those who received blood transfusion (median 3.5 vs 7 days, p < 0.001). CONCLUSIONS: Select patients can be successfully managed on V-A ECMO without allogeneic blood transfusion. Jehovah's Witnesses and other patients with objections to allogeneic transfusion might be offered V-A ECMO if its anticipated duration is short (e.g. <7 days) and baseline hemoglobin concentration is high (e.g. ≥10 mg/dL).

Mortality Risk Assessment in COVID-19 Venovenous Extracorporeal Membrane Oxygenation.

BACKGROUND: A life-threatening complication of coronavirus disease 2019 (COVID-19) is acute respiratory distress syndrome (ARDS) refractory to conventional management. Venovenous (VV) extracorporeal membrane oxygenation (ECMO) (VV-ECMO) is used to support patients with ARDS in whom conventional management fails. Scoring systems to predict mortality in VV-ECMO remain unvalidated in COVID-19 ARDS. This report describes a large single-center experience with VV-ECMO in COVID-19 and assesses the utility of standard risk calculators. METHODS: A retrospective review of a prospective database of all patients with COVID-19 who underwent VV-ECMO cannulation between March 15 and June 27, 2020 at a single academic center was performed. Demographic, clinical, and ECMO characteristics were collected. The primary outcome was in-hospital mortality; survivor and nonsurvivor cohorts were compared by using univariate and bivariate analyses. RESULTS: Forty patients who had COVID-19 and underwent ECMO were identified. Of the 33 patients (82.5%) in whom ECMO had been discontinued at the time of analysis, 18 patients (54.5%) survived to hospital discharge, and 15 (45.5%) died during ECMO. Nonsurvivors presented with a statistically significant higher Prediction of Survival on ECMO Therapy (PRESET)-Score (mean ± SD, 8.33 ± 0.8 vs 6.17 ± 1.8; P = .001). The PRESET score demonstrated accurate mortality prediction. All patients with a PRESET-Score of 6 or lowers survived, and a score of 7 or higher was associated with a dramatic increase in mortality. CONCLUSIONS: These results suggest that favorable outcomes are possible in patients with COVID-19 who undergo ECMO at high-volume centers. This study demonstrated an association between the PRESET-Score and survival in patients with COVID-19 who underwent VV-ECMO. Standard risk calculators may aid in appropriate selection of patients with COVID-19 ARDS for ECMO.

Minimally Invasive Left Ventricular Assist Device Insertion Facilitates Subsequent Heart Transplant.

OBJECTIVE: We have observed that minimally invasive left ventricular assist device (LVAD) insertion leads to more facile re-entry and easier cardiac transplantation. We hypothesize minimally invasive LVAD implantation results in improved outcomes at the time of subsequent heart transplant. METHODS: All adults undergoing cardiac transplantation between October 2015 and March 2019 at our institution were retrospectively reviewed. Those bridged to transplantation with a HeartWare HVAD were identified and divided into 2 cohorts based upon the surgical approach: those who underwent HVAD placement by conventional sternotomy versus minimally invasive insertion via lateral thoracotomy and hemisternotomy (LTHS). Patient demographics, as well as perioperative transplant outcomes, including survival, length of stay (LOS), blood utilization, ischemic time, bypass time, and postoperative extracorporeal membrane oxygenation (ECMO) were compared between cohorts. RESULTS: Forty-two patients were bridged to heart transplant with a HVAD implanted via either sternotomy (n = 22) or LTHS technique (n = 20). Demographics were similar between groups. There was 1 predischarge death in the sternotomy group and none in the LTHS group. Body surface area, cardiopulmonary bypass time, ischemic time, ECMO utilization, and reoperation for bleeding were similar. Red blood cell units transfused were significantly lower in the LTHS cohort (3.0 [1.0-5.0] vs 6.0 [2.5-10.0] P = 0.046). The LTHS cohort had a significantly shorter hospital LOS (12.0 [11.0-28.0] vs 22.5 [15.7-41.7] P = 0.022) with a trend toward shorter intensive care unit LOS (6.0 [5.0-10.5] vs 11.0 [6.0-21.5] days P = 0.057). CONCLUSIONS: Minimally invasive HVAD implantation improves outcomes at subsequent heart transplantation, resulting in shorter LOS and less red cell transfusion. Larger multi-institutional studies are necessary to validate these findings.

A Retrospective Study of Infection in Patients Requiring Extracorporeal Membrane Oxygenation Support.

BACKGROUND: Healthcare-associated infections (HAIs) in critically ill patients are a serious public health problem. Extracorporeal membrane oxygenation (ECMO) has been used increasingly for patients with severe cardiac or respiratory failure, but it may increase HAI risk. The goal of our study was to characterize HAIs in ECMO patients at an ECMO referral center. METHODS: This institutional review board-approved study identified all consecutive adult ECMO patients admitted to the cardiac surgery intensive care unit (CSICU) between January 1, 2015, and December 31, 2017. Demographic data, diagnosis, ECMO cannulation technique, and survival were collected. Urinary tract infection, pneumonia, and bacteremia incidence during ECMO and within 3 months of decannulation were collected. Outcomes of patients with HAIs were compared with noninfected patients, the CSICU infection incidence, and overall Extracorporeal Life Support Organization survival data. RESULTS: There were 288 ECMO patients and 3396 CSICU admissions during this period. Survival was 72.3% for venoarterial ECMO, 85.3% for venovenous ECMO, and 57.1% for multimodality or veno-arteriovenous ECMO, with discharge survival of 60.2%, 72.0%, and 28.6%, respectively. Bacteremia incidence while cannulated was 6.8% for venoarterial ECMO and 9.3% for venovenous ECMO. Bacteremia occurred in 22 of 288 (7.6%) ECMO patients, compared with 48 of 3109 (1.5%) in non-ECMO CSICU patients, which was statistically significant (P < .002). Bacteremia and pneumonia were associated with decreased VA-ECMO survival, with prolonged overall requirements for ECMO support. CONCLUSIONS: Nosocomial ECMO infections are significantly higher than in other CSICU patients. Infection risk remains significant even after decannulation. Infection is associated with increased mortality and longer duration of ECMO support. Further efforts are needed to determine HAI reduction strategies in this high-risk patient population.

Perioperative Applications of Therapeutic Plasma Exchange in Cardiac Surgery: A Narrative Review.

Therapeutic plasma exchange (TPE) has a number of applications in cardiac surgical patients and has been used increasingly in high-risk heart and lung transplant patients. In this narrative review, the authors describe TPE principles, complications, and specific indications for TPE, including thrombotic thrombocytopenic purpura, heparin-induced thrombocytopenia, induction of immunotolerance in heart and lung transplant patients, and treatment of antibody-mediated rejection in heart and lung transplant patients. The review is based on published literature and the authors' institutional experience with perioperative TPE in cardiac surgical patients.

Survey of Contemporary Cardiac Surgery Intensive Care Unit Models in the United States.

BACKGROUND: Intensive care unit (ICU) structure and intensive care physician staffing (IPS) models are thought to influence outcomes after cardiac surgery. Given limited information on staffing in the cardiothoracic ICU, The Society of Thoracic Surgeons Workforce on Critical Care undertook a survey to describe current IPS models. We hypothesized that variability would exist throughout the United States. METHODS: A survey was sent to The Society of Thoracic Surgeons centers in the United States. Center case volume, ICU census, procedure profiles, and the primary specialties of consultants were queried. Definitions of IPS models were open (managed by cardiac surgeons), closed (all decisions made by dedicated intensivists 7 days a week), or semiopen (intensivist attends 5-7 days a week with surgeons cosharing management). Experience level of bedside providers and after-hours provider coverage were also assessed. RESULTS: Of the 965 centers contacted, 148 (15.3%) completed surveys. Approximately 41% of reporting centers used a dedicated cardiothoracic ICU for immediate postoperative management. The most common IPS model was open (47%), followed by semiopen (41%) and closed (12%). The primary specialties of intensivists varied, with pulmonary medicine/critical care being predominant (67%). Physician assistants were the most common after-hours provider (44%). More than one-third of responding centers described having no house staff, other than bedside nurses, for nighttime coverage. CONCLUSIONS: Cardiothoracic ICU models vary widely in the United States, with almost half being open, often with no in-house coverage. In-house nighttime coverage was (1) not driven by case complexity and (2) most commonly provided by a physician assistant. Clinical outcomes associated with different ISPS models require further evaluation.

Thoracic Endovascular Repair of Blunt Thoracic Aortic Injury in the Setting of an Aberrant Right Subclavian Artery.

Blunt thoracic aortic injury (BTAI) in a patient with an aberrant right subclavian artery (ARSA) presents unique challenges for patient management and aortic repair. Specific considerations include the need to treat coincidental ARSA, subclavian revascularization, and ARSA exclusion. Despite the rise of endovascular repair as the primary modality for aortic repair for BTAI, reports of this technique in the setting of ARSA are limited. Here we describe 3 patients with ARSA who underwent TEVAR for BTAI, and discuss critical management and technical issues in these patients.

Restricted Albumin Utilization Is Safe and Cost Effective in a Cardiac Surgery Intensive Care Unit.

BACKGROUND: Volume expansion is often necessary after cardiac surgery, and albumin is often administered. Albumin's high cost motivated an attempt to reduce its utilization. This study analyzes the impact limiting albumin infusion in a cardiac surgery intensive care unit. METHODS: This retrospective study analyzed albumin use between April 2014 and April 2015 in patients admitted to a cardiac surgery intensive care unit. During the first 9 months, there were no restrictions. In January 2015, institutional guidelines limited albumin use to patients requiring more than 3 L crystalloid in the early postoperative period, hypoalbuminemic patients, and to patients considered fluid overloaded. Albumin utilization was obtained from pharmacy records and compared with outcome quality metrics. RESULTS: In all, 1,401 patients were admitted over 13 months. Albumin use, mortality, ventilator days, patients receiving transfusions, and length of stay were compared for 961 patients before and 440 patients after guidelines were initiated. After restrictive guidelines were instituted, albumin utilization was reduced from a mean of 280 monthly doses to a mean of 101 monthly doses (p < 0.001). There was also a trend toward reduced ventilator days. Mortality, length of stay, and transfusion requirements demonstrated no significant change. Based on an average wholesale price and an average monthly reduction of 180 albumin doses, the cardiac surgery intensive care unit demonstrated more than $45,000 of wholesale savings per month after restrictions were implemented. CONCLUSIONS: Albumin restriction in the cardiac surgery intensive care unit was feasible and safe. Significant reductions in utilization and cost with no changes in morbidity or mortality were demonstrated. These findings may provide a strategy for reducing cost while maintaining quality of care.

Nonoperative Management of Traumatic Aortic Pseudoaneurysms.

BACKGROUND: Current blunt thoracic aortic injury (BTAI) guidelines recommend early repair of traumatic pseudoaneurysms (PSAs) due to risk for subsequent aortic rupture. Recent analyses indicate that early repair is required only in the setting of high-risk features, while delayed repair is safe and associated with lower morbidity and mortality in appropriately selected patients. To evaluate the appropriate indications for nonoperative management (NOM) of traumatic PSAs, we performed a systematic review of studies reporting outcomes for this management strategy. We hypothesized that NOM is safe in appropriately selected patients with traumatic aortic PSAs. METHODS: English language single- and multi-institutional series reporting NOM of traumatic thoracic aortic PSAs were identified by systematic literature search and review. A descriptive analysis was performed of NOM, with stratification by lesion size and patient follow-up. The primary outcomes were late aortic intervention, aortic-related death, and all-cause mortality. RESULTS: Eighteen studies, which included 937 patients with traumatic PSAs, were analyzed. One hundred ninety-one patients were managed nonoperatively. The primary indication for NOM was prohibitive risk for aortic repair due to severe comorbidities or concurrent injuries. Where reported, PSAs with <50% circumferential involvement accounted for 88% of lesions selected for NOM. Late interventions were required in 4% of patients. Inpatient aortic-related mortality was 2%, and all-cause inpatient mortality was 32%. Although survival at up to 4-7 years was reported, postdischarge follow-up after PSA NOM was limited to <1 year in most studies. CONCLUSIONS: NOM of traumatic aortic PSAs is a common practice in BTAI series reporting lesion-specific management, and is associated with low rates of treatment failure. These findings suggest that routine early repair may not be required for traumatic PSAs, particularly for lesions limited to <50% of the aortic circumference. Definitive repair can be delayed until patient stability and repair timing can be guided by assessment of lesion stability on follow-up imaging.

A Statewide Analysis of the Incidence and Outcomes of Acute Mesenteric Ischemia in Maryland from 2009 to 2013.

INTRODUCTION: Acute mesenteric ischemia is a surgical emergency that entails complex, multi-modal management, but its epidemiology and outcomes remain poorly defined. The aim of this study was to perform a population analysis of the contemporary incidence and outcomes of mesenteric ischemia. METHODS: This was a retrospective analysis of acute mesenteric ischemia in the state of Maryland during 2009-2013 using a comprehensive statewide hospital admission database. Demographics, illness severity, comorbidities, and outcomes were studied. The primary outcome was inpatient mortality. Survivors and non-survivors were compared using univariate analyses, and multivariable logistic regression analysis was performed to evaluate risk factors for mortality. RESULTS: During the 5-year study period, there were 3,157,499 adult hospital admissions in Maryland. A total of 2,255 patients (0.07%) had acute mesenteric ischemia, yielding an annual admission rate of 10/100,000. Increasing age, hypercoagulability, cardiac dysrhythmia, renal insufficiency, increasing illness severity, and tertiary hospital admission were associated with development of mesenteric ischemia. Inpatient mortality was high (24%). After multivariate analysis, independent risk factors for death were age >65 years, critical illness severity, mechanical ventilation, tertiary hospital admission, hypercoagulability, renal insufficiency, and dysrhythmia. CONCLUSION: Acute mesenteric ischemia occurs in approximately 1/1,000 admissions in Maryland. Patients with mesenteric ischemia have significant illness severity, substantial rates of organ dysfunction, and high mortality. Patients with chronic comorbidities and acute organ dysfunction are at increased risk of death, and recognition of these risk factors may enable prevention or earlier control of mesenteric ischemia in high-risk patients.

Evolution of lesion-specific management of blunt thoracic aortic injury.

Developments in diagnosis and treatment have transformed the management of blunt thoracic aortic injuries (BTAIs). For patients in stable condition, treatment practice has shifted from early open repair to nonoperative management for low-grade lesions and routine delayed endovascular repair for more significant injuries. However, effective therapy depends on accurate staging of injury grade and stability to select patients for appropriate management. Recent developments in BTAI risk stratification enable lesion-specific management tailored to the patient and aortic lesion. This review summarizes advances in lesion assessment and treatment and proposes an integrated scheme for the modern management of BTAI.

Venovenous extracorporeal membrane oxygenation as a bridge to lung transplantation: successful transplantation after 155 days of support.

We present a case of a woman with acute respiratory distress syndrome and irrecoverable lung function that was successfully bridged to lung transplantation after 155 consecutive days of venovenous extracorporeal membrane oxygenation.

A new aortic injury score predicts early rupture more accurately than clinical assessment.

OBJECTIVE: The optimal timing for repair of a high-grade blunt thoracic aortic injury (BTAI) is uncertain. Delayed repair is common and associated with improved outcomes, but some lesions may rupture during observation. To determine optimal patient selection for appropriate management, we developed a pilot clinical risk score to evaluate aortic stability and predict rupture. METHODS: Patients presenting in stable condition with Society for Vascular Surgery grade III or IV BTAI diagnosed on computed tomography (CT) were retrospectively reviewed. To determine clinical and radiographic factors associated with aortic rupture, patients progressing to aortic rupture (defined by contrast extravasation on CT or on operative or autopsy findings) were compared with those who had no intervention ≤48 hours of admission. A model targeting 100% sensitivity for rupture was generated and internally validated by bootstrap analysis. Clinical utility was tested by comparison with clinical assessment by surgeons experienced in BTAI management who were provided with CT images and clinical data but were blinded to outcome. RESULTS: The derivation cohort included 18 patients whose aorta ruptured and 31 with stable BTAI. There was no difference in age, gender, injury mechanism, nonchest injury severity, blood pressure, or Glasgow Coma Scale on admission between patient groups. As dichotomous factors, admission lactate >4 mM, posterior mediastinal hematoma >10 mm, and lesion/normal aortic diameter ratio >1.4 on the admission CT were independently associated with aortic rupture. The model had an area under the receiver operator curve of .97, and in the presence of any two factors, was 100% sensitive and 84% specific for predicting aortic rupture. No aortic lesions ruptured in patients with fewer than two factors. In contrast, clinical assessment had lower accuracy (65% vs 90% total accuracy, P < .01). CONCLUSIONS: This novel risk score can be applied on admission using clinically relevant factors that incorporate patient physiology, size of the aortic lesion, and extent of the mediastinal hematoma. The model reliably identifies and distinguishes patients with high-grade BTAI who are at risk for early rupture from those with stable lesions. Although preliminary, because it is more accurate than clinical assessment alone, the score may improve patient selection for emergency or delayed intervention.

Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase.

Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5' untranslated region (UTR). Oncogenes with complex 5'UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5'UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G(+) splenic B cells, from which most DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM(+) B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas.

Early aortic repair worsens concurrent traumatic brain injury.

BACKGROUND: Blunt thoracic aortic injury (BTAI) and traumatic brain injury (TBI) are the leading causes of death after blunt trauma, and TBI is common among patients with BTAI. Although aspects of aortic management, such as repair timing and procedural anticoagulation therapy, may complicate TBI, the optimal management of these patients is undefined. METHODS: Adults with BTAI and moderate to severe TBI admitted to a level I trauma center over 12 years were retrospectively analyzed; patients presenting in extremis were excluded. The primary outcome was neurologic progression within 48 hours of aortic repair. Patients undergoing nonoperative aortic management served as controls for baseline TBI progression. Secondary outcomes were aortic morbidity and mortality and overall inpatient survival. RESULTS: Of 309 patients with BTAI, 138 had concurrent TBI, and 75 were included for analysis. Twenty-two (29%) were treated nonoperatively, 29 (39%) had early aortic repair (17 open, 12 endovascular), and 24 (32%) had delayed repair (3 open, 21 endovascular). The severity of TBI was similar between groups. Early aortic repair within 24 hours of admission was independently associated with worsening TBI, regardless of repair modality or anticoagulation use. In contrast, patients undergoing delayed repair had no perioperative neurologic progression despite procedural anticoagulation therapy. Early aortic repair was also associated with increased aortic morbidity and mortality. CONCLUSIONS: For patients with BTAI and TBI, early aortic intervention is associated with progressive TBI regardless of repair modality, as well as increased aortic morbidity and mortality. Patients not requiring emergent intervention can undergo delayed repair with full anticoagulation therapy.

Parameters for successful nonoperative management of traumatic aortic injury.

OBJECTIVE: Blunt traumatic aortic injury is associated with significant mortality, and increased computed tomography use identifies injuries not previously detected. This study sought to define parameters identifying patients who can benefit from medical management. METHODS: We reviewed 4.5 years of blunt traumatic aortic injuries. Injury was classified as grade I (intimal flap or intramural hematoma), II (small pseudoaneurysm <50% circumference), III (large pseudoaneurysm >50% circumference), and IV (rupture/transection). Secondary signs of injury included pseudocoarctation, extensive mediastinal hematoma, and large left hemothorax. Follow-up, including computed tomography, was reviewed. RESULTS: We identified 97 patients: 31 grade I, 35 grade II, 24 grade III, and 7 grade IV; 67(69%) male; mean age 47 ± 18.8 years, mean Injury Severity Score 38.8 ± 14.6; overall survival 76 (78.4%). Secondary signs of injury were found in 30 patients. Overall, 52 (53.6%) underwent repair, 45 undergoing thoracic endovascular aortic repair, with 2 (2.22%) procedure-related deaths, and 7 undergoing open repair. Five patients undergoing thoracic endovascular aortic repair required 7 additional procedures. In 45 medically managed patients, there were 14 deaths (31%), all secondary to associated injuries. Injury Severity Scores of survivors and nonsurvivors were 33 ± 10.8 and 48.6 ± 12.8, respectively (P < .001). Follow-up showed resolution or no change in 21 (91%) and a small increase in 2 grade I injuries. CONCLUSIONS: All blunt traumatic aortic injury does not necessitate repair. Stratification by injury grade and secondary signs of injury identifies patients appropriate for medical management. Grade IV injury necessitates emergency procedures and carries high mortality. Grade III injury with secondary signs of injury should be urgently repaired; patients without secondary signs of injury may undergo delayed repair. Grade I and II injuries are amenable to medical management.