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.

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.

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.

Appropriate use of emergency department thoracotomy: implications for the thoracic surgeon.

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.

Current outcomes of simultaneous carotid endarterectomy and coronary artery bypass graft surgery in North America.

OBJECTIVE: Management of patients with concomitant carotid and coronary artery disease has been controversial. Divergent strategies have been employed, including simultaneous carotid endarterectomy and coronary bypass (SCC) versus various staged procedures. Although no strict comparison group is available, this study defines current outcomes of SCC, compared qualitatively to two reference categories. METHODS: Utilizing the STS database from 2003 to 2007, patients who had SCC were compared with patients with cerebrovascular disease who had coronary bypass (CABG) with prior carotid endarterectomy (CEA), and those with carotid Doppler stenosis >75% and no carotid intervention. Logistic regression analysis adjusted for differences in baseline characteristics and operative mortality (OM), and a composite of neurological complications (NC) was assessed. RESULTS: Of 745,769 patients who underwent isolated CABG with/without CEA, 108,212 (14%) had cerebrovascular disease. Of this group, 5,732 (5%) underwent SCC. The SCC group had more males and lower preoperative risk factors. After statistical adjustment for all baseline differences, SCC had clinically and statistically higher OM and NC compared with any of the reference groups, with 20-40% higher event risk. CONCLUSIONS: Although no quantitative control group exists for comparison, SCC as recently performed in North America has a high risk compared with any of the reference groups. Suboptimal results associated with the SCC strategy suggest a need for quality improvement and research on the optimal management of patients with simultaneous carotid and coronary disease.

Current and future therapy for pulmonary hypertension in patients with right and left heart failure.

Pulmonary hypertension (PH) is a devastating condition that without proper management can deteriorate progressively. Elevated pulmonary artery pressure without an identifiable etiology is called IPAH. PH resulting from a specific disease is referred to as secondary PH; left-sided cardiac disease can lead to an increase in pulmonary artery pressure resulting in increased vascular resistance and subsequent structural remodeling. If left-sided failure progresses to right-sided failure with high pulmonary artery pressure, the outcome is ominous. It has been clearly proven that early diagnosis and effective medical therapy can markedly decrease morbidity and mortality. In this review, we discuss the current treatment modalities and their limitations for PH secondary to heart failure. Conventional therapy in patients with pulmonary arterial hypertension as well as recent advances in the medical management of PH in general, are also described. Last, the surgical management of these patients and other promising interventional modalities are reviewed.