Faculty Bibliography

Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein (LDL) cholesterol. Although ANGPTL3 modulates the metabolism of circulating lipoproteins, its role in triglyceride-rich lipoprotein assembly and secretion remains unknown. CRISPR-associated protein 9 (CRISPR/Cas9) was used to target ANGPTL3 in HepG2 cells (ANGPTL3^-/-) whereupon we observed ∼50% reduction of apolipoprotein B100 (ApoB100) secretion, accompanied by an increase in ApoB100 early presecretory degradation via a predominantly lysosomal mechanism. Despite defective particle secretion in ANGPTL3^-/- cells, targeted lipidomic analysis did not reveal neutral lipid accumulation in ANGPTL3^-/- cells; rather ANGPTL3^-/- cells demonstrated decreased secretion of newly synthesized triglycerides and increased fatty acid oxidation. Furthermore, RNA sequencing demonstrated significantly altered expression of key lipid metabolism genes, including targets of peroxisome proliferator-activated receptor α, consistent with decreased lipid anabolism and increased lipid catabolism. In contrast, CRISPR/Cas9 LDL receptor (LDLR) deletion in ANGPTL3^-/- cells did not result in a secretion defect at baseline, but proteasomal inhibition strongly induced compensatory late presecretory degradation of ApoB100 and impaired its secretion. Additionally, these ANGPTL3^-/-;LDLR^-/- cells rescued the deficient LDL clearance of LDLR^-/- cells. In summary, ANGPTL3 deficiency in the presence of functional LDLR leads to the production of fewer lipoprotein particles due to early presecretory defects in particle assembly that are associated with adaptive changes in intrahepatic lipid metabolism. In contrast, when LDLR is absent, ANGPTL3 deficiency is associated with late presecretory regulation of ApoB100 degradation without impaired secretion. Our findings therefore suggest an unanticipated intrahepatic role for ANGPTL3, whose function varies with LDLR status.

Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

BACKGROUND:Recent years have seen a trend towards utilizing a video-assisted thoracic surgery (VATS) approach for treatment of thymoma. Although increasing in practice, intermediate- and long-term oncologic outcome data is lacking for the VATS approach. There is no oncologic data for the uniportal VATS approach. We sought to evaluate the feasibility and impact on patient survival of uniportal VATS thymectomy for early-stage thymoma. METHOD/METHODS:The clinical outcomes for 17 patients with Masaoka stage I to II thymomas treated between January of 2009 and July of 2014 at a single institution were collected retrospectively. Primary endpoint was overall survival (OS) and secondary endpoint was recurrence-free survival (RFS). RESULTS:Ten women and seven men underwent uniportal VATS thymectomy; eleven had stage I thymoma and six had stage II thymoma. There were no conversions to open surgery. Operative mortality was zero. Mean tumor size was 3.8±1.0 centimeters, with a range of 1.9 to 6.0 centimeters. All patients underwent a R0 resection. Five-year survival was 100%, and the estimated RFS was 100%. CONCLUSIONS:Our findings suggest that uniportal VATS thymectomy for early-stage thymoma is feasible, and the intermediate-term oncologic outcomes are comparable to historic standards for open and multi-incision VATS thymectomy. However, additional follow-up is required to evaluate for long-term oncologic outcomes.

PURPOSE/OBJECTIVE:The primary objective of this study was to determine the rate of pathological response after preoperative celecoxib and concurrent taxane-based chemotherapy in patients with cancer of the esophagus and gastroesophageal junction. METHODS:Thirty-nine patients were enrolled in this single-arm, phase II clinical trial. Patients were administered daily celecoxib in combination with two to three cycles of carboplatin and paclitaxel with preoperative intent. Levels of cyclooxygenase (COX)-2 expression in resected tumors were analyzed by immunohistochemistry and correlated with clinical outcome measures. Postoperatively, patients were administered daily celecoxib for 1 year or until documented tumor recurrence. RESULTS:All patients received two to three cycles of chemotherapy plus celecoxib 800 mg/d. Toxicities were as expected. A major clinical response (complete response + partial response) was noted in 22 patients (56%); six patients (15%) had a complete clinical response. Thirty-seven patients underwent esophagectomy. Five patients had a major pathological response (12.8%). Four-year overall and disease-free survivals were 40.9% and 30.3%, respectively. Patients with tumors expressing COX-2 demonstrated a higher likelihood of a major clinical response response (62% versus 50%) and an improved overall survival, compared with patients with COX-2-negative tumors. CONCLUSIONS:Preoperative celecoxib with concurrent chemotherapy demonstrated sufficient effect on pathologic response to warrant further study. Patients with tumors expressing COX-2 demonstrated trends toward improved response to preoperative therapy and improved overall survival compared with nonexpressors.

BACKGROUND:Several single-institution series have demonstrated that compared with open thoracotomy, video-assisted thoracoscopic lobectomy may be associated with fewer postoperative complications. In the absence of randomized trials, we queried the Society of Thoracic Surgeons database to compare postoperative mortality and morbidity following open and video-assisted thoracoscopic lobectomy. A propensity-matched analysis using a large national database may enable a more comprehensive comparison of postoperative outcomes. METHODS:All patients having lobectomy as the primary procedure via thoracoscopy or thoracotomy were identified in the Society of Thoracic Surgeons database from 2002 to 2007. After exclusions, 6323 patients were identified: 5042 having thoracotomy, 1281 having thoracoscopy. A propensity analysis was performed, incorporating preoperative variables, and the incidence of postoperative complications was compared. RESULTS:Matching based on propensity scores produced 1281 patients in each group for analysis of postoperative outcomes. After video-assisted thoracoscopic lobectomy, 945 patients (73.8%) had no complications, compared with 847 patients (65.3%) who had lobectomy via thoracotomy (P < .0001). Compared with open lobectomy, video-assisted thoracoscopic lobectomy was associated with a lower incidence of arrhythmias [n = 93 (7.3%) vs 147 (11.5%); P = .0004], reintubation [n = 18 (1.4%) vs 40 (3.1%); P = .0046], and blood transfusion [n = 31 (2.4%) vs n = 60 (4.7%); P = .0028], as well as a shorter length of stay (4.0 vs 6.0 days; P < .0001) and chest tube duration (3.0 vs 4.0 days; P < .0001). There was no difference in operative mortality between the 2 groups. CONCLUSIONS:Video-assisted thoracoscopic lobectomy is associated with a lower incidence of complications compared with lobectomy via thoracotomy. For appropriate candidates, video-assisted thoracoscopic lobectomy may be the preferred strategy for appropriately selected patients with lung cancer.

OBJECTIVES/OBJECTIVE:The 2009 outbreak of novel influenza A H1N1 reached a pandemic status on June 11, 2009. Early detection is a key factor for management and infection-control practices. Recent studies have suggested a difference in performance of rapid influenza kits for influenza A H1N1. Our goal was to evaluate the performance of the QuickVue influenza A+B test (Quidel Corp., San Diego, CA) in an emergency department setting and determine the most current epidemiologic trends in our community. METHODS:Results from 1137 samples for influenza A collected between April 8, 2009 and June 30, 2009 were retrospectively reviewed. Results of QuickVue influenza A+B test were compared with R-Mix viral culture and DFA results. Age distribution and hospitalization rates by age group were analyzed to further delineate the epidemiology of influenza A in a suburban hospital. RESULTS:The sensitivity of the rapid test was 77%, the specificity was 85%, the positive predictive value was 74%, and the negative predictive value was 87%. We found a similar age distribution for positive influenza tests and admissions when compared with the national Centers for Disease Control and Prevention data. CONCLUSIONS:The QuickVue influenza A+B test is a sensitive assay for the novel H1N1 strain of influenza. In our hospital, the group with highest risk of hospital admission was patients aged < 25 years.

BACKGROUND:Chylothorax remains an uncommon but challenging clinical problem. Thoracic duct ligation is the treatment of choice for postsurgical patients. However, the optimal treatment for traumatic patients is unclear. We wanted to examine the outcomes of patients with high output or recurrent chylothorax who were treated by surgical means. METHODS:From December 1992 to April 2008, 29 patients underwent surgical procedures for high output (> 1 L/day) (16) or recurrent chylothorax (13). We analyzed these patients to determine the surgical approach, perioperative complications, and outcomes of the treatment approach. RESULTS:Of the 29 patients, 12 patients developed chylothorax following esophagectomy, in 5 patients it resulted from lymphoproliferative disorders, in 2 patients following ascending aneurysm repair, in 2 after trauma, in 3 following lung resection, and in 1 patient respectively from coronary artery bypass grafting (CABG), thymectomy for thymoma, vasculitis, and metastatic lung cancer, while 1 patient had no clear etiology. The median age of patients was 61 (range 20-79) years. 22 patients initially underwent thoracic duct ligation, 6 had talc pleurodesis, and one underwent bilateral pleuroperitoneal shunt placement. Approaches for thoracic duct ligation included: right thoracotomy (16), left thoracotomy (3), VATS (2), and right thoracotomy together with laparotomy (1). There were no intraoperative complications or deaths within 30 days or during postoperative hospitalization. The success rate after initial thoracic duct ligation was 95 % (21/22). One patient needed re-exploration after ligation with resolution of chylothorax after the second operation. The success rate after pleurodesis was 83 % (5/6). One patient after pleurodesis needed subsequent thoracic duct ligation for resolution of bilateral chylothoraces. All patients in this series had resolution of chylothorax. CONCLUSIONS:Thoracic duct ligation is the treatment of choice for high output or recurrent chylothorax with a 96 % success rate. Surgical pleurodesis is effective in some cases and may be an option for marginal patients.

BACKGROUND:As the US population ages, clinicians are increasingly confronted with octogenarians with resectable non-small cell lung cancer. Earlier reports documented substantial risk for surgical resection in this age group. METHODS:We reviewed our surgical experience in octogenarians who underwent curative resection from 1990 to 2003. RESULTS:Sixty-one patients underwent resection: 46 lobectomies, 6 segmentectomies, 5 wedge resections, and 4 pneumonectomies. There was one perioperative death (1.6%). The overall complication rate was 38% with a major complication rate of 13%. The average postoperative length of stay was 7 days. Overall 5-year survival was 38%, and 82% for stage IA patients. Patients with more advanced disease had a significantly worse survival. CONCLUSIONS:Appropriately selected octogenarians with early stage disease should be offered anatomic surgical resection for cure. These patients can anticipate a long-term survival, and should not be denied an operation on the basis of age alone.