Myo1e overexpression in lung adenocarcinoma is associated with increased risk of mortality.

This study aims to perform a comprehensive genomic analysis to assess the influence of overexpression of MYO1E in non-small cell lung carcinoma (NSCLC) and whether there are differences in survival and mortality risk in NSCLC patients depending on both DNA methylation and RNA expression of MYO1E. The DNA methylation probe cg13887966 was inversely correlated with MYO1E RNA expression in both LUAD and LUSC subpopulations showing that lower MYO1E RNA expression was associated with higher MYO1E DNA methylation. Late stages of lung cancer showed significantly lower MYO1E DNA methylation and significantly higher MYO1E RNA expression for LUAD but not for LUSC. Low DNA methylation as well as high RNA expression of MYO1E are associated with a shorter median survival time and an increased risk of mortality for LUAD, but not for LUSC. This study suggests that changes in MYO1E methylation and expression in LUAD patients may have an essential role in lung cancer's pathogenesis. It shows the utility of MYO1E DNA methylation and RNA expression in predicting survival for LUAD patients. Also, given the low normal expression of MYO1E in blood cells MYO1E DNA methylation has the potential to be used as circulating tumor marker in liquid biopsies.

Non-small cell lung carcinoma spheroid models in agarose microwells for drug response studies.

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 <22%) and high viability (>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.

Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC-derived atrial fibrillation model.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can model heritable arrhythmias to personalize therapies for individual patients. Although atrial fibrillation (AF) is a leading cause of cardiovascular morbidity and mortality, current platforms to generate iPSC-atrial (a) CMs are inadequate for modeling AF. We applied a combinatorial engineering approach, which integrated multiple physiological cues, including metabolic conditioning and electrical stimulation, to generate mature iPSC-aCMs. Using the patient's own atrial tissue as a gold standard benchmark, we assessed the electrophysiological, structural, metabolic, and molecular maturation of iPSC-aCMs. Unbiased transcriptomic analysis and inference from gene regulatory networks identified key gene expression pathways and transcription factors mediating atrial development and maturation. Only mature iPSC-aCMs generated from patients with heritable AF carrying the non-ion channel gene (NPPA) mutation showed enhanced expression and function of a cardiac potassium channel and revealed mitochondrial electron transport chain dysfunction. Collectively, we propose that ion channel remodeling in conjunction with metabolic defects created an electrophysiological substrate for AF. Overall, our electro-metabolic approach generated mature human iPSC-aCMs that unmasked the underlying mechanism of the first non-ion channel gene, NPPA, that causes AF. Our maturation approach will allow for the investigation of the molecular underpinnings of heritable AF and the development of personalized therapies.

Surgical Transcatheter Aortic Valve Replacement Explantation Technique.

As transcatheter aortic valve replacement (TAVR) indications expand, cardiac surgeons need to be prepared to manage heretofore rare TAVR complications requiring explantation, such as acute type A dissection, in these typically high-risk patients. This report describes the successful use of an explantation technique that is ready to hand, efficient, and effective at avoiding further injury to the aortic root and coronary ostia.

Considerations in the Surgical Management of Unicuspid Aortic Stenosis.

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.

Less-Invasive Aortic Valve Replacement: Trends and Outcomes From The Society of Thoracic Surgeons Database.

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 < .001). Femoral cannulation was used in 1.5% of FS, 5.4% of PS, and 71% of RT patients (P < .001). Full sternotomy patients were older and had higher rates of preoperative renal failure, atrial fibrillation, and stroke, and had a higher NYHA function class, lower ejection fraction, and higher STS risk score. Total operative, cardiopulmonary bypass, and cross-clamp time were longest in RT-AVR patients and shortest in those who had FS-AVR. Overall, unadjusted operative mortality was 1.9% (1.05% among low-risk patients) and was not different among the 3 groups (1.97% FS, 1.77% PS, and 1.90% RT; P = .4). The rate of postoperative stroke was 1.2% and was not different among the 3 groups (1.2% FS, 1.3% PS, and 1.1% RT; P = .3). After risk adjustment, these differences remained nonsignificant. After risk adjustment, prolonged ventilation and atrial fibrillation were less common in PS-AVR patients. The adjusted risk for blood transfusion was lower in RT-AVR patients, as was the incidence of renal failure. Femoral cannulation was not associated with increased risk for stroke or mortality after LI-AVR. 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.

Detection of Promoter DNA Methylation in Urine and Plasma Aids the Detection of Non-Small Cell Lung Cancer.

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.

Primary Pulmonary Vein Leiomyosarcoma With Left Atrial Extension.

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.

Left Atrial and Carotid Body Paraganglioma.

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.

Surgical Correction of Aberrant Right Coronary Anomalies Stranding an Aortic Commissure with and Without Unroofing.

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.

Age-associated impact on presentation and outcome for penetrating thoracic trauma in the adult and pediatric patient populations.

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.

Utilization of cardiothoracic surgeons for operative penetrating thoracic trauma and its impact on clinical outcomes.

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.

Current issues in the diagnosis and management of blood culture-negative infective and non-infective endocarditis.

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.

Diagnosis and management of primary effusion lymphoma in the immunocompetent and immunocompromised hosts.

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.

Chest computed tomography for penetrating thoracic trauma after normal screening chest roentgenogram.

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.

Occult infiltrating bi-ventricular papillary renal cell carcinoma metastasis found during coronary artery bypass graft surgery.

Metastatic papillary renal cell carcinoma (RCC) to the heart has never been reported. We report the case of a 73-year-old patient with papillary RCC metastatic to the left and right ventricles, found during a triple vessel coronary artery bypass graft surgery.