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Purpose:Low-dose CT screening can reduce lung cancer–related mortality. However, CT screening has an FDR of nearly 96%. We sought to assess whether urine samples can be a source for DNA methylation–based detection of non–small cell lung cancer (NSCLC).Experimental Design:This nested case–control study of subjects with suspicious nodules on CT imaging obtained plasma and urine samples preoperatively. Cases (n = 74) had pathologic confirmation of NSCLC. Controls (n = 27) had a noncancer diagnosis. We detected promoter methylation in plasma and urine samples using methylation on beads and quantitative methylation–specific real-time PCR for cancer-specific genes (CDO1, TAC1, HOXA7, HOXA9, SOX17, and ZFP42).Results:DNA methylation at cancer-specific loci was detected in both plasma and urine, and was more frequent in patients with cancer compared with controls for all six genes in plasma and in CDO1, TAC1, HOXA9, and SOX17 in urine. Univariate and multivariate logistic regression analysis showed that methylation detection in each one of six genes in plasma and CDO1, TAC1, HOXA9, and SOX17 in urine were significantly associated with the diagnosis of NSCLC, independent of age, race, and smoking pack-years. When methylation was detected for three or more genes in both plasma and urine, the sensitivity and specificity for lung cancer diagnosis were 73% and 92%, respectively.Conclusions:DNA methylation–based biomarkers in plasma and urine could be useful as an adjunct to CT screening to guide decision-making regarding further invasive procedures in patients with pulmonary nodules.

Univariate logistic regression analysis for risk of having NSCLC.

Figure S4

Gene Methylation Detection, Sensitivity, Specificity Using Detectable vs. Non-detectable cutoff in blacks

Figure S6

Figure S5

Univariate and multivariate logistic regression analysis for risk of having NSCLC in late stages (n=53)

Figure S3

Univariate and multivariate logistic regression analysis for risk of having NSCLC in Black (n=38)

Figure S2

Univariate and multivariate logistic regression analysis for risk of having NSCLC in Early Stages (n=75)

Figure S1

Gene Methylation Detection, Sensitivity, Specificity Using Detectable vs. Non-detectable cutoff in NSCLC early stages

Gene Methylation Detection, Sensitivity, Specificity Using Detectable vs. Non-detectable cutoff in whites

Univariate and multivariate logistic regression analysis for risk of having NSCLC in Whites (n=52)

Correlation of Î"Ct methylation between Plasma and Urine

Figure S7

Gene Methylation Detection, Sensitivity, Specificity Using Detectable vs. Non-detectable cutoff in NSCLC late stages

Unicuspid aortic valve (UAV) stenosis is a rare condition accounting for 5% of non-rheumatic aortic stenosis. The diagnosis can be difficult to make prior to surgical intervention and transesophageal echocardiography has been demonstrated to be more accurate in making the diagnosis compared to transthoracic echocardiography. The presence of a posteriorly located aortic orifice on the short-axis views, with one or two visible raphe anteriorly; the absence of commissures (acommissural); or the presence of a lone commissure (unicommissural) between the left and noncoronary, or the left and right cusps suggests the diagnosis. Patients with UAV are predominantly males and present with stenosis about a decade earlier than those with the more prevalent bicuspid aortic valves (BAV). They more commonly present with aortic annular dilatation and have fewer comorbidities at presentation compared to patients with BAV. Surgical management of UAV stenosis includes aortic valve replacement through standard open heart surgery or percutaneous transcatheter aortic valve replacement (TAVR), aortic valve repair either by bicuspidization, tricuspidization or trileaflet reconstruction, or the Ross procedure. Patients with UAV stenosis require less concomitant coronary or other cardiac procedures when they need surgical intervention, but are about a decade younger at the time of their death. UAV stenosis is a distinct congenital anomaly with a different natural course than BAV. Surgical management should be individualized based on the patient's age at presentation, aortoannular anatomy, and associated cardiac conditions.

Background This study compares outcomes of conventional and less-invasive (LI) approaches for aortic valve replacement (AVR) using The Society of Thoracic Surgeons database. Methods Between 2011 and 2017, we identified 122,474 patients undergoing isolated primary AVR. Patients were categorized into 3 groups: (1) full sternotomy (FS) (n = 98,549; 78%), (2) partial sternotomy (PS) (n = 17,306; 15%), and (3) right thoracotomy (RT) (n = 6619; 7%). Results The rate of LI-AVR increased from 17% in 2011 to 23% in 2016 (P Conclusions Less-invasive AVR is associated with an operative mortality and postoperative stroke rate similar to that of FS. Less-invasive AVRs should serve as a benchmark for comparison between transcatheter aortic valve replacement and surgical AVR in low-risk patients.

There is a growing interest in developing personalized treatment strategies for each cancer patient, especially those with non-small cell lung carcinoma (NSCLC) which annually accounts for the majority of cancer related deaths in the US. Yet identifying the optimal NSCLC treatment strategy for each cancer patient is critical due to a multitude of mutations, some of which develop following initial therapy and can result in drug resistance. A key difficulty in developing personalized therapies in NSCLC is the lack of clinically relevant assay systems that are suitable to evaluate drug sensitivity using a minuscule amount of patient-derived material available following biopsies. Herein we leverage 3D printing to demonstrate a platform based on miniature microwells in agarose to culture cancer cell spheroids. The agarose wells were shaped by 3D printing molds with 1000 microwells with a U-shaped bottom. Three NSCLC cell lines (HCC4006, H1975 and A549) were used to demonstrate size uniformity, spheroid viability, biomarker expressions and drug response in 3D agarose microwells. Results show that our approach yielded spheroids of uniform size (coefficient of variation 83% after 1 week-culture). Studies using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKIs) drugs gefitinib and osimertinib showed clinically relevant responses. Based on the physical features, cell phenotypes, and responses to therapy of our spheroid models, we conclude that our platform is suitable for in vitro culture and drug evaluation, especially in cases when tumor sample is limited.

Introduction: The limited success of pharmacological approaches to atrial fibrillation ( AF ) is due to limitations of in vitro and in vivo models and inaccessibility of human atrial tissue. Patient-specific induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are a robust platform to model the heterogeneous myocardial substrate of AF, but their immaturity limits their fidelity. Objective: We hypothesized that a combinatorial approach of biochemical (triiodothyronine [ T3 ], insulin-like growth factor-1 [ IGF-1 ], and dexamethasone; collectively TID ), bioenergetic (fatty acids [ FA ]), and electrical stimulation ( ES ) will enhance electrophysiological ( EP ), structural, and metabolic maturity of iPSC- a CMs. Methods: We assessed maturation with whole cell patch clamping, calcium transients, immunofluorescence (IF), Seahorse Analyzer, contractility assay, RT-PCR, Western Blotting, and RNA sequencing (RNAseq). Using a time series with RNAseq we identified signaling pathways and transcriptional regulation that drive EP, structural, and metabolic atrial development and compared iPSC-aCM maturity with human aCMs (haCMs) obtained from the same patient. Results: TID+FA+ES significantly improved structural organization and cell morphology ( Fig. 1a ), enhanced membrane potential stability and improved depolarization ( Fig. 1b ), improved Ca 2+ kinetics with faster and increased Ca 2+ release from sarcoplasmic reticulum ( Fig. 1c ), and increased expression of Na + , Ca 2+ , and K + channels, markers of structural maturity, FA metabolism, and oxidative phosphorylation ( Fig. 1d ). There was no difference in each parameter between TID+FA+ES iPSC-aCMs and haCMs from the same patient. Conclusion: Our optimized, combinatorial TID+FA+ES approach markedly enhanced EP, structural, and metabolic maturity of human iPSC-aCMs, which will be useful for elucidating the genetic basis of AF developing precision drug therapies.

Introduction: Increasingly, human induced pluripotent stem cells (hiPSC) faithfully recapitulate human models of arrhythmias. However, enhancing hiPSC-derived atrial cardiomyocyte (aCM) maturity is vital as modeling mature CMs will provide insights into cellular mechanisms of atrial fibrillation (AF) and signaling pathways critical to atrial development Hypothesis: Combinatorial conditioning of hiPSC-aCMs with biochemical cues (T3, IGF-1, dexamethasone; TID), fatty acids (FA; oleic/palmitic acid), and acute electrical stimulation (ES) at increasing intensity over 45 days comprehensively enhances structural, molecular, and electrophysiological (EP) maturity of hiPSC-aCMs Methods: HiPSCs generated from patient specific peripheral blood mononuclear cells were differentiated into aCMs using retinoic acid and glucose starvation. Maturity of atrial iPSC-CMs was enhanced using TID, FA, and acute ES for the final 4 weeks of culture. Structural (immunofluorescence; transmission EM), molecular (qPCR; RNAseq), and EP (patch clamping; multielectrode array; high throughput automated patch clamping) maturity is assessed and compared to untreated hiPSC-aCMs and adult human aCMs harvested from the same patient (optimal maturity) Results: We showed improved hiPSC-aCM structural maturity with TID, FA, and ES ( Fig. 1A ). EP maturity also displayed more hyperpolarized resting membrane potential (RMP; Fig. 1B ), and improved upstroke velocity, action potential duration (APD), and amplitude (not shown). Expression of ion channels, and calcium handling and structural proteins is significantly improved ( Fig. 1C ) Conclusions: Combinatorial conditioning with TID, FA, and ES markedly improved structural, molecular, and EP maturity of hiPSC-aCMs. Our findings will serve as a platform to model AF, elucidate underlying cellular mechanisms, and identify novel therapeutic targets for a personalized, mechanism based approach to treat this common condition

Unicuspid aortic valve (UAV) stenosis is a rare condition accounting for 5% of non-rheumatic aortic stenosis. The diagnosis can be difficult to make prior to surgical intervention and transesophageal echocardiography has been demonstrated to be more accurate in making the diagnosis compared to transthoracic echocardiography. The presence of a posteriorly located aortic orifice on the short-axis views, with one or two visible raphe anteriorly; the absence of commissures (acommissural); or the presence of a lone commissure (unicommissural) between the left and noncoronary, or the left and right cusps suggests the diagnosis. Patients with UAV are predominantly males and present with stenosis about a decade earlier than those with the more prevalent bicuspid aortic valves (BAV). They more commonly present with aortic annular dilatation and have fewer comorbidities at presentation compared to patients with BAV. Surgical management of UAV stenosis includes aortic valve replacement through standard open heart surgery or percutaneous transcatheter aortic valve replacement (TAVR), aortic valve repair either by bicuspidization, tricuspidization or trileaflet reconstruction, or the Ross procedure. Patients with UAV stenosis require less concomitant coronary or other cardiac procedures when they need surgical intervention, but are about a decade younger at the time of their death. UAV stenosis is a distinct congenital anomaly with a different natural course than BAV. Surgical management should be individualized based on the patient's age at presentation, aortoannular anatomy, and associated cardiac conditions.

Background: Atrial fibrillation (AF), the most common arrhythmia, is associated with significant morbidity and increased mortality. Although antiarrhythmic drugs are still commonly used to treat symptomatic AF, membrane-active drugs are incompletely and unpredictably effective, failing to target the underlying mechanisms of AF. Our pilot data shows atrial iPSC-CMs generated from a familial AF kindred recapitulated the electrophysiologic (EP) phenotype of an AF-linked SCN5A mutation, serving as a novel platform to target underlying cellular AF mechanisms. However, structural, molecular, and EP immaturity as compared to adult atrial CMs has hindered successful mechanistic evaluation. Objective: We aim to determine optimal condition(s) to enhance the maturity of atrial iPSC-CMs, establishing them as a novel platform to model AF, elucidate the cellular mechanisms, and identify/assess novel, mechanism based therapies. Methods: Maturity of atrial iPSC-CMs was enhanced using TID (T3, IGF-1, dexamethasone), fatty acids (FA), acute electrical stimulation (ES), and extracellular matrix (ECM) modulation. We examined for improvements in structural maturity (immunofluorescence, transmission electron microscopy), molecular (qPCR, RNA seq) and EP (patch clamping, multi-electrode array, high-throughput automated patch clamping). The maturity of atrial iPSC-CMs was compared with adult atrial CMs obtained from the same patient during cardiac surgery. Results and Conclusion: Fig. 1 demonstrates that acute ES, combined with TID and FA supplementation, significantly improves structural and in part EP maturity of atrial iPSC-CMs.

Purpose: Low-dose CT screening can reduce lung cancer–related mortality. However, CT screening has an FDR of nearly 96%. We sought to assess whether urine samples can be a source for DNA methylation–based detection of non–small cell lung cancer (NSCLC). Experimental Design: This nested case–control study of subjects with suspicious nodules on CT imaging obtained plasma and urine samples preoperatively. Cases (n = 74) had pathologic confirmation of NSCLC. Controls (n = 27) had a noncancer diagnosis. We detected promoter methylation in plasma and urine samples using methylation on beads and quantitative methylation–specific real-time PCR for cancer-specific genes (CDO1, TAC1, HOXA7, HOXA9, SOX17, and ZFP42). Results: DNA methylation at cancer-specific loci was detected in both plasma and urine, and was more frequent in patients with cancer compared with controls for all six genes in plasma and in CDO1, TAC1, HOXA9, and SOX17 in urine. Univariate and multivariate logistic regression analysis showed that methylation detection in each one of six genes in plasma and CDO1, TAC1, HOXA9, and SOX17 in urine were significantly associated with the diagnosis of NSCLC, independent of age, race, and smoking pack-years. When methylation was detected for three or more genes in both plasma and urine, the sensitivity and specificity for lung cancer diagnosis were 73% and 92%, respectively. Conclusions: DNA methylation–based biomarkers in plasma and urine could be useful as an adjunct to CT screening to guide decision-making regarding further invasive procedures in patients with pulmonary nodules.

The technique for successful surgical correction of an anomalous origin of the right coronary artery from the opposite aortic cusp with an aberrant course between the aorta and pulmonary artery is illustrated in a symptomatic 62-year-old woman. The intramural course of the right coronary artery traversed the tip of the commissure between the anterior and posterior leaflets, and its repair entailed unroofing of the intramural segment from inside the aortic intima. This technique required resuspension of the overlying commissure to maintain optimal aortic valve leaflet coaptation and prevent aortic insufficiency. Modifications of this technique have been utilized by us whenever the intramural segment traversed behind the commissure. In these cases, partial or subtotal unroofing of the intramural segment was performed to preserve the integrity of the intima behind the overlying commissure. More recently, we have performed the surgical correction by probing the intramural segment within the aortic wall to its most anterior location and then performing a wide anterior unroofing in the aortic intima, and marsupializing the aortic and coronary intima to avoid dissection or intimal flap development. We favor utilizing these techniques of anatomic correction of the anomalous coronary to other techniques involving coronary artery bypass grafting of the anomalous coronary, especially in adult patients, as unroofing provides more lasting results.

We report a rare case of left atrial paraganglioma with a synchronous carotid body paraganglioma in a 30-year-old man with succinate dehydrogenase B gene mutation. The patient initially presented with a neck mass and palpitations. Laboratory test results showed elevated catecholamine levels. A cardiac paraganglioma was identified by computed tomography, meta-iodobenzylguanidine scintigraphy, and magnetic resonance imaging. Surgical resection of both paragangliomas were performed on two separate occasions. Serum and urine catecholamine levels returned to normal range. On follow-up, there was no recurrence of the cardiac paraganglioma. Radiotherapy was subsequently initiated for recurrence in the carotid body paraganglioma.

Leiomyosarcoma (LMS) is a mesenchymal tumor originating from the smooth muscle cells. LMS of the great vessels accounts for 60% of cases, with inferior vena cava being the most common site. Pulmonary vein LMS is an extremely rare subset that was first reported in 1939. LMS is an aggressive tumor, making surgical resection the treatment of choice. Herein, we present a rare case of pulmonary vein LMS extending into the left atrium, which was resected.

Background Studies reporting on penetrating thoracic trauma in the pediatric population have been limited by small numbers and implied differences with the adult population. Our objectives were to report on a large cohort of pediatric patients presenting with penetrating thoracic trauma and to determine age-related impacts on management and outcome through comparison with an adult cohort. Methods A Level I trauma center registry was queried between 2006 and 2012. All patients presenting with penetrating thoracic trauma were identified. Patient demographics, injury mechanism, injury severity, admission physiology, and outcome were recorded. Patients were compared, and outcomes were analyzed based on age at presentation, with patients 17 years or younger defining our pediatric cohort. Results A total of 1,423 patients with penetrating thoracic trauma were admitted during the study period. Two hundred twenty patients (15.5%) were pediatric, with 205 being adolescents (13-17 years) and 15 being children (≤ 12 years). In terms of management for the pediatric population, tube thoracostomy alone was needed in 32.7% (72 of 220), whereas operative thoracic exploration was performed in 20.0% (44 of 220). Overall mortality was 13.6% (30 of 220). There was no significant difference between the pediatric and adult population with regard to injury mechanism or severity, need for therapeutic intervention, operative approach, use of emergency department thoracotomy, or outcome. Stepwise logistic regression failed to identify age as a predictor for the need for either therapeutic intervention or mortality between the two age groups as a whole. However, subgroup analysis revealed that being 12 years or younger (odds ratio, 3.84; 95% confidence interval, 1.29-11.4) was an independent predictor of mortality. Conclusion Management of traumatic penetrating thoracic injuries in terms of the need for therapeutic intervention and operative approach was similar between the adult and pediatric populations. Mortality from penetrating thoracic trauma can be predicted based on injury severity, the use of emergency department thoracotomy, and admission physiology for adolescents and adults. Children may be at increased risk for poor outcome independent of injury severity. Level of evidence Epidemiologic study, level III.

Background Large series reporting outcomes for penetrating thoracic trauma have identified injury pattern and injury severity scoring as predictors of poor outcome. However, the impact of surgical expertise on patient outcomes has not been previously investigated. We sought to determine how often board-certified cardiothoracic surgeons are utilized for operative thoracic trauma and whether this has an effect on patient outcomes. Methods A level I trauma center registry was queried between 2003 and 2011. Records of patients undergoing surgery as a result of penetrating thoracic trauma were retrospectively reviewed. Patient demographics, injuries, injury severity, utilization of a cardiothoracic surgical operative consult and outcomes were recorded. Patients operated on by cardiothoracic surgeons were compared with patients operated on by trauma surgeons using stepwise multivariate analyses to determine the factors associated with utilization of cardiothoracic surgeons for operative thoracic trauma and survival. Results Cardiothoracic surgeons were used in 73.0% of cases (162 of 222) over the study period. The use of cardiothoracic surgeons increased incrementally both overall (38.5% to 73.9%), and for emergent/urgent cases (31.8% to 73.3%). When comparing patients undergoing operation on an emergent/urgent basis by cardiothoracic versus trauma surgeons, there was no significant difference with regard to demographics, mechanism of injury, injury severity scoring, or surgical morbidity. Stepwise logistic regression showed the presence of a cardiothoracic surgeon to be independently associated with survival (odds ratio 4.70; p = 0.019). Conclusions Use of cardiothoracic surgeons for operative thoracic trauma increased over the study period. Outcomes for severely injured patients with elevated chest injury scores or decreased revised trauma scores may be improved with appropriate operative consultation with a board-certified cardiothoracic surgeon.

Diagnosis and management of blood culture-negative endocarditis constitute a formidable clinical challenge and a systemic approach is necessary for a successful outcome. Blood cultures are negative in endocarditis due mainly to preceding antibiotic administration or to fastidious slow-growing organisms. Less so, non-infective endocarditis is a paraneoplastic manifestation or may occur in association with autoimmune diseases. When the clinical diagnosis is contemplated and cultures and serologies are negative, histologic and molecular examination of the removed valve tissue may confirm the diagnosis. Treatment with antibiotics is often warranted and valve replacement remains appropriate for patients with heart failure or irreversible structural damage.

Primary effusion lymphoma (PEL) is an uncommon non-Hodgkin lymphoma associated with human herpes virus-8 (HHV-8) that grows mainly in serous body cavities. The most common presentation of PEL is that of a young immunocompromised male with shortness of breath, as the pleural cavity is most commonly affected. Diagnosis is primarily based on fluid cytology in which PEL cells display variable morphology and a null lymphocyte immunophenotype; however, evidence of HHV-8 infection within the neoplastic cell is essential. Patients have commonly been treated with systemic multidrug chemotherapy and antiretroviral therapy if they were HIV positive or were immunocompromised for other reasons. In the immunocompetent patient, there have been no agreed-upon pathways for management of this condition. Progression of disease is common and median survival is approximately 6 months. Novel intrapleural treatments with antiviral agents such as intracavity cidofovir have shown to be effective in controlling local disease, and ongoing clinical trials may provide some promise in the treatment for this condition.

Background Chest computed tomography (CCT) is a method of screening for intrathoracic injuries in hemodynamically stable patients with penetrating thoracic trauma. The objective of this study was to examine the changes in utilization of CCT over time and evaluate its contribution to guiding therapeutic intervention. Methods A level 1 trauma center registry was queried between 2006 and 2011. Patients undergoing CCT in the emergency department after penetrating thoracic trauma as well as patients undergoing thoracic operations for penetrating thoracic trauma were identified. Patient demographics, operative indications, use of CCT, injuries, and hospital admissions were analyzed. Results In all, 617 patients had CCTs performed, of whom 61.1% (371 of 617) had a normal screening plain chest radiograph (CXR). In 14.0% (51 of 371) of these cases, the CCT revealed findings not detected on screening CXR. The majority of these injuries were occult pneumothoraces or hemothoraces (84.3%; 43 of 51), of which 27 (62.8%) underwent tube thoracostomy. In only 0.5% (2 of 371), did the results of CCT alone lead to an operative indication: exploration for hemopericardium. The use of CCT in our patients significantly increased overall (28.8% to 71.4%) as well as after a normal screening CXR (23.3% to 74.6%) over the study period. Conclusions The use of CCT for penetrating thoracic trauma increased 3.5-fold during the study period with a concurrent increase in findings of uncertain clinical significance. Patients with a normal screening CXR should be triaged with 3-hour delayed CXR, serial physical examinations, and focused assessment with sonography for trauma; and CCT should only be used selectively as a diagnostic modality.

Background Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm of endothelial origin with clinical behavior intermediate between hemangioma and angiosarcoma. The natural history of EHE is highly variable. This study uses an Internet registry to identify clinical patterns with prognostic significance in EHE. Methods Cases from the International Hemangioendothioma, Epithelioid Hemangioendothelioma, and Related Vascular Disorders (HEARD) Support Group were evaluated based on demographics, organ involvement, disease progression, presence or absence of pleural effusion, and treatment. Survival among various cohorts was compared using log-rank analysis of Kaplan-Meier plots. Results Two hundred sixty-four patients were identified from April 2004 to November 2009. Fifty-eight cases were excluded because of inadequate information or wrong diagnosis. EHE was more common in female patients (61%). Male gender and age ≥ 55 years were associated with decreased survival. The most commonly affected organs were liver, lung, and bone. No specific organ or combination of organ involvement differentially affected survival, and survival was no different between patients with multiple vs single organ involvement. However, pattern B, defined as lesions without distinct borders (eg, pulmonary infiltrates, pleural effusion, ascites), hemoptysis, or involvement of more than two bones adversely affected survival in all cohorts. Conclusion A novel staging system with prognostic value for EHE is proposed. Pleural effusion or other signs of uncontained tumor growth, hemoptysis, and osseous involvement of more than two bones implied worse survival than did localized and discrete tumors, regardless of number of organs involved. A lay registry can provide useful insights into the clinical behavior of a rare cancer.

Background Practice guidelines for the appropriate use of emergency department thoracotomy (EDT) according to current national resuscitative guidelines have been developed by the American College of Surgeons Committee on Trauma (ACS-COT) and published. At an urban level I trauma center we analyzed how closely these guidelines were followed and their ability to predict mortality. Methods Between January 2003 and July 2010, 120 patients with penetrating thoracic trauma underwent EDT at Mount Sinai Hospital (MSH). Patients were separated based on adherence (group 1, n=70) and nonadherence (group 2, n=50) to current resuscitative guidelines, and group survival rates were determined. These 2 groups were analyzed based on outcome to determine the effect of a strict policy of adherence on survival. Results Of EDTs performed during the study period, 41.7% (50/120) were considered outside current guidelines. Patients in group 2 were less likely to have traditional predictors of survival. There were 6 survivors in group 1 (8.7%), all of whom were neurologically intact; there were no neurologically intact survivors in group 2 ( p = 0.04). The presence of a thoracic surgeon in the operating room (OR) was associated with increased survival (p = 0.039). Conclusions A policy of strict adherence to EDT guidelines based on current national guidelines would have accounted for all potential survivors while avoiding the harmful exposure of health care personnel to blood-borne pathogens and the futile use of resources for trauma victims unable to benefit from them. Cardiothoracic surgeons should be familiar with current EDT guidelines because they are often asked to contribute their operative skills for those patients who survive to reach the OR.

Background Lipid emulsion infusion reverses local anesthetic-induced cardiac toxicity, but the effect of adding epinephrine has not been studied. We compared escalating doses of epinephrine on recovery with lipid infusion in a rat model of bupivacaine overdose. Methods Rats anesthetized with isoflurane received an IV bolus of 20 mg/kg bupivacaine, producing asystole (zero time) in all animals. Ventilation (100% oxygen) and chest compressions were started immediately, and at 3 min the rats received one of six IV treatments (n = 5 for all groups): 5 ml/kg saline followed by infusion for 2 min at 1.0 ml x kg x min, and a second 5 ml/kg bolus at 5 min; or the same bolus and infusion treatment using 30% lipid emulsion plus a single injection of epinephrine at one of five doses: 0 (lipid control), 1, 2.5, 10, or 25 mcg/kg. An electrocardiogram and arterial pressure were monitored continuously, and arterial blood gas was measured at 7.5 and 15 min. Results Epinephrine improved initial return of spontaneous circulation (rate-pressure product > 30% baseline) but only 3 of 5 rats at 10 mcg/kg and 1 of 5 rats at 25 mcg/kg sustained return of spontaneous circulation by 15 min. Lipid alone resulted in slower but more sustained recovery. Epinephrine doses above a threshold near 10 mcg/kg increased lactate, worsened acidosis, and resulted in poor recovery at 15 min, as compared with lipid controls. There was tight correlation of epinephrine dose to serum lactate at 15 min. Conclusions Epinephrine over a threshold dose near 10 mcg/kg impairs lipid resuscitation from bupivacaine overdose, possibly by inducing hyperlactatemia.

BACKGROUND Unroofing of anomalous coronary artery originating from the opposite sinus of Valsalva has become the procedure of choice for this congenital lesion, with surgery performed in children as young as two years old. An increasing number of this anomaly is diagnosed in infancy with no clear indication whether surgical repair should be done in this age group. This paper reviews our experience with this anomaly, and focuses on its surgical management in infants. METHODS Between April 2002 and February 2007, eight patients underwent surgical repair of anomalous coronary artery arising from the opposite sinus of Valsalva and coursing between the aorta and pulmonary artery. Patients' age varied from two months to 28 years with a mean of 11.7 +/- 11.1 years. SURGICAL TECHNIQUE Surgical repair involved unroofing the intramural segment of the anomalous coronary artery using cardiopulmonary bypass. RESULTS Two patients were younger than one year (Group A), and six patients were older than one year (group B). The mean intensive care unit stay was 2.5 +/- 0.7 days for Group A and 2.8 +/- 1.9 for Group B. The mean hospital stay was 4 +/- 1.4 days for Group A and 4.3 +/- 2.4 days for Group B. There was no mortality and no complications. The mean follow-up period is 14 +/- 15.7 months with a range of one to 39 months. At the time of the last follow-up, all patients were asymptomatic in New York Heart Association class I and follow-up echocardiography on six of eight patients showed wide open coronary ostium. CONCLUSION Unroofing the anomalous coronary artery arising from the opposite sinus of valsalva can be done in infants with minimal morbidity and mortality. Longer follow-up is needed to assess long-term results.

Background Lipid emulsion infusion reverses cardiovascular compromise due to local anesthetic overdose in laboratory and clinical settings. The authors compared resuscitation with lipid, epinephrine, and saline control in a rat model of bupivacaine-induced cardiac toxicity to determine whether lipid provides a benefit over epinephrine. Methods Bupivacaine, 20 mg/kg, was infused in rats anesthetized with isoflurane, producing asystole in all subjects. Ventilation with 100% oxygen and chest compressions were begun immediately, along with intravenous treatment with 30% lipid emulsion or saline (5-ml/kg bolus plus continuous infusion at 0.5 ml . kg . min) or epinephrine (30 microg/kg). Chest compressions were continued and boluses were repeated at 2.5 and 5 min until the native rate-pressure product was greater than 20% baseline. Electrocardiogram and arterial pressure were monitored continuously and at 10 min, arterial blood gas, central venous oxygen saturation, and blood lactate were measured. Effect size (Cohen d) was determined for comparisons at 10 min. Results Lipid infusion resulted in higher rate-pressure product (P < 0.001, d = 3.84), pH (P < 0.01, d = 3.78), arterial oxygen tension (P < 0.05, d = 2.8), and central venous oxygen saturation (P < 0.001, d = 4.9) at 10 min than did epinephrine. Epinephrine treatment caused higher lactate (P < 0.01, d = 1.48), persistent ventricular ectopy in all subjects, pulmonary edema in four of five rats, hypoxemia, and a mixed metabolic and respiratory acidosis by 10 min. Conclusions Hemodynamic and metabolic metrics during resuscitation with lipid surpassed those with epinephrine, which were no better than those seen in the saline control group. Further studies are required to optimize the clinical management of systemic local anesthetic toxicity.

It is clearly established that morbidity and mortality from congestive heart failure (CHF) is related to the irreversible progression of left ventricular (LV) dysfunction. Regardless of the etiology of CHF, the associated deterioration in LV diastolic compliance and systolic function results in impaired ventricular filling and decreased tissue perfusion leading to the progression of the symptoms of fatigue, dyspnea on exertion and peripheral edema [1]. The management options for CHF range from medical therapy, to conventional surgical procedures aimed at alleviating the cause of CHF, to cardiac augmentation procedures and total cardiac transplantation [1]. With the introduction of more effective antiarrhythmic agents and afterload reducing agents to the drug armamentarium, the currently available pharmacologic therapy for CHF is of proven, but limited, efficacy in reducing symptoms and long-term mortality [2]. A Survival Trial of Amiodarone Therapy in Congestive Heart Failure (STAT-CHF trial) found no difference in survival among heart failure patients with asymptomatic ventricular arrhythmias who received amiodarone therapy or placebo [3]. The conventional surgical options for the management of CHF are directed at the underlying pathophysiology of the disease; Coronary artery bypass grafting (CABG), mitral valve repair or replacement and LV aneurysm resection or remodeling are all attempts to reverse or slow down the progressive LV dilatation and failure. The Duke Cardiovascular Disease Databank followed more than 1400 patients with CHF and compared CABG to medical therapy [4]. The study reported favorable event-free survival for CABG over medical therapy after 30 days to over 10 years. The 10-year adjusted survival in the CABG cohort was 42 compared with only 13% for nonsurgically treated patients [4]. In patients with ischemic or nonischemic CHF, the associated or functional mitral regurgitation (MR) worsens both symptoms and prognosis. In these instances, surgical approaches including mitral valve repair with an annuloplasty ring and valve replacement with preservation of the subvalvular apparatus may alleviate these symptoms or delay their progression.

Warfarin and heparin have formed the mainstay in the prophylaxis of deep vein thrombosis (DVT), stroke prevention in atrial fibrillation, and treatment of thromboembolic disease (TED). However, these choices are hampered by difficult administration, interactions with other medications, side effect profile, and limited indications for treatment. Anti-factor Xa (anti-Xa) inhibitors have already entered the drug market with the drug Fondaparinux being the first anti- Xa inhibitor to be approved for use in the U.S. by the Food and Drug Administration (FDA), and other drugs such as idraparinux being currently in development. A new class of medications, known as direct thrombin inhibitors (DTI), includes the parental agents lepirudin, argatroban and bivalirudin which have been approved by the FDA and the oral agents ximelagatran, melagatran and dabigatran. The latter three drugs which are oral DTIs may soon replace warfarin and heparin as the preferred medications for DVT prophylaxis and for reducing the relative risk of stroke. These drugs do not rely on blocking serine proteases nor do they require a co-factor (antithrombin III) like unfractionated heparin (UFH) or low molecular weight heparin (LMWH). DTIs are rapid in onset, easy to administer, do not interact with other medications or foods, have limited side effects, and can be administered in a fixed dose. The DTI ximelagatran has already been approved in several European and Asian countries, and over a dozen randomized clinical trials have been conducted demonstrating its performance to be on par with warfarin. However, approval by the FDA in the U.S. remains pending in view of reported incidences of elevations in hepatic enzymes that are currently under evaluation. This review examines the role of DTIs in the prevention and treatment of TED and the recent patents reported in the literature.

Patients with pulmonary insufficiency due to scleroderma have long been considered suboptimal candidates for lung transplantation. This has been supported by small single-center experiences that did not reflect the entire U.S. experience. We sought to evaluate the outcome of patients with scleroderma who underwent lung transplantation. We conducted a retrospective review of 47 patients with scleroderma who underwent lung transplantation at 23 U.S. centers between 1987 and 2004 and were reported to the United Network for Organ Sharing. Women constituted 57% of the patients. The mean age was 46 years. Twenty-seven patients received single lung transplants (57%), and the remaining received double lung transplants. The mean cold ischemia time was 4.1 hours. There were 7 early deaths (or =30 days) and 17 late deaths (30 days). The causes of early death were primary graft failure and a cardiac event in two patients each and bacterial infection and stroke in one patient each. Late mortality was due to infection in seven patients, respiratory failure in three, malignancy in two, and multisystem organ failure, rejection, pulmonary hypertension, and a cardiac event in one patient each. The causes of early and late death were not recorded for two patients. One patient received a second transplant owing to graft failure of the first. Twenty-three patients (49%) were alive at a mean follow-up of 24 months. The Kaplan-Meier 1- and 3-year survival rates were 67.6% and 45.9% respectively, which are not significantly different from those of 10,070 patients given transplants for other lung conditions during the same period (75.5% and 58.8% respectively, P = 0.25). Donor gender, recipient's age, and type of transplant did not affect survival. In carefully selected patients with scleroderma who have end-stage lung disease, lung transplantation is a valid life-saving therapeutic option. Available data suggest acceptable short-term morbidity and mortality and a long-term survival similar to that of patients given transplants for other lung conditions.

Sirolimus is a potent immunosuppressive agent used with increasing frequency in solid organ transplantation (SOT). However, it has been associated with rare but devastating pulmonary toxicity. We describe a case of pulmonary toxicity associated with the use of sirolimus in a 64-yr-old heart transplant recipient. We also review all reported cases of sirolimus-associated lung toxicity among SOT recipients in an effort to better understand the pathophysiology, risk factors, and outcomes of this rare but serious complication. A total of 64 cases have been reported since January 2000 including the present case. These consisted of 52 kidney, four lung, three liver, three heart, one heart-lung and one islet cell transplants. In most cases, patients presented with a constellation of symptoms consisting of fever, dyspnea, fatigue, cough, and occasionally hemoptysis. Although the risk factors for this association have not been clearly established, high dose, late exposure to the drug and male gender have been noticed among most. In almost all of the reported cases, sirolimus was added later in the course of immunosuppressive therapy, usually in an effort to attenuate the nephrotoxic effects of a previous regimen containing a calcineurin inhibitor. There were three deaths (4.8%) among 62 patients with known status at follow up; all deaths were among heart transplant recipients. Most patients (95%) resolved their clinical and radiographic findings with discontinuation or dose-reduction of the drug. Sirolimus-induced pulmonary toxicity is a rare but serious entity that should be considered in the differential diagnosis of a transplant recipient presenting with respiratory compromise. Dose-reduction or discontinuation of the drug can be life saving.

Purpose Lung transplantation has been increasingly used as a treatment modality for patients with pulmonary lymphangioleiomyomatosis (LAM). In this study, we evaluated the outcome of patients with LAM who underwent lung transplantation with the aim of making some recommendations regarding patient management. Methods We conducted a retrospective review of 79 patients who underwent primary lung transplantation for end-stage pulmonary LAM at 31 US transplant centers between January 1987 and December 2002 and were reported to the United Network for Organ Sharing (UNOS). Results All patients were women with a mean age of 41.1 years (range, 24–65 years). Thirty-four patients (43%) received single-lung transplants. Bilateral lung transplantation was performed in 45 patients (57%). The mean cold ischemia time was 4.7 hours. There were 2 intra-operative deaths. The 30-day mortality was 5% (4 patients). The causes of early death were primary graft failure in 2 patients, hyperacute rejection in 1 patient, and a cardiac event in 1 patient. Twenty late deaths (>30 days post-transplant) occurred. Of those, 5 were from multisystem organ failure, 5 from pulmonary complications, and 2 from fungal infection. Rejection and bronchiolitis obliterans accounted for 2 deaths each. The cause of death was a cardiac event in 1 patient and was not recorded in the remaining 3. Four patients were re-transplanted. Fifty-five patients (70%) were alive at a mean follow-up of 37 months (range 0–128 months). The actuarial Kaplan-Meier survival was 85.75% at 1 year, 76.35% at 3 years, and 64.91% at 5-years. Log-rank analysis showed a statistically significant difference in the survival rate of LAM patients compared with a historical group of patients who had transplantation for all lung conditions during the same period (45.12%, p = 0.0012). Transplant era, type of transplant, donor gender, ischemia time of more than 4 hours, age more than 40 years, and donor/recipient cytomegalovirus did not impact survival. Conclusions Lung transplantation is a valuable therapeutic option for patients with end-stage pulmonary LAM. Transplantation offers survival rates that are equivalent to or better than those of patients who received a lung transplant for other indications.

Postoperative bleeding is a common complication following cardiothoracic surgical procedures requiring cardiopulmonary bypass (CPB). Serious bleeding complications requiring the administration of blood products, hemostatic drugs, and even repeat surgery are associated with considerable morbidity, mortality, and resource consumption. Therapy with recombinant activated factor VII (rFVIIa) may be an effective treatment strategy for patients with refractory bleeding. We report the successful use of rFVIIa for the treatment of intractable postoperative bleeding following aortic aneurysm repair in two patients with Marfan syndrome. In both patients, surgical reexploration was avoided, and the patients' clinical status was stabilized after the administration of rFVIIa. In one patient, hemostasis was rapidly achieved within minutes, whereas hemostasis occurred gradually over several hours in the second patient. Including our personal experience with the two cases, the use of rFVIIa has been reported in 20 patients who required CPB for cardiothoracic surgical procedures. Hemostasis was achieved in all patients. In 14 patients (70%), rapid hemostasis was achieved following a single dose of rFVIIa (mean dose, 57 microg/kg). In the remaining six patients, gradual hemostasis was achieved after a mean of 3.4 doses (mean cumulative dose, 225 microg/kg). Two patients (10%) were believed to have experienced thromboembolic complications after the administration of rFVIIa (one was fatal), and, in another patient, intracoronary thrombosis was suspected but was not confirmed. In patients experiencing postoperative bleeding complications that are refractory to treatment with blood products, hemostatic agents, and/or repeat surgery, the use of rFVIIa may be considered.