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PDF file - 57K, SuperArray Analysis of Oncogenes, Tumor Suppressors, and Stem Cell-Related Genes in MPM Lines Following Selective PRC2 Knockdown or 5 �M DZNep.

PDF file - 661K, TaqMan Primers, shRNA, and Antibodies.

PDF file - 102K, Effects of DZNep treatment on cultured mesothelioma cell lines relative to normal mesothelia cells. Pyrosequencing analysis of NBL2 DNA repeat in normal mesothelia (LP9) and MPM cell lines cultured in the presence or absence of DZNep.

PDf file - 63K, qRT-PCR and immunoblot analysis of EZH2 and EED levels in MPM lines following transduction with shRNA targeting EZH2, EED, or sham sequences. Effects of knock-down of EZH2 and EED on proliferation of MPM lines.

PDF file - 63K, Genes Simultaneously Modulated by DZNep in MES1 and H28.

PDF file - 661K, Photomicrographs of NMES1 and NMES2 normal pleura cultures, and MES1 through MES4 mesothelioma cell lines established at the NCI.

PDF file - 97K, Supplementary Materials and Methods.

PDF file - 62K, Demographic Data Pertaining to the Patients from whom NCI-SB-MES 1-4 lines Were Established.

PDF file - 245K, EZH2 expression in tumors correlates with cell line expression.

Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM).Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep.Results:EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment.Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy. Clin Cancer Res; 18(1); 77–90. ©2011 AACR.

PDF file - 65K, Top 20 Gene Sets Enriched in MES1 and H28 Cells following DZNep Treatment.

PDF file - 54K, Top 20 Gene Ontologies Modulated by DZNep in MES1 and H28 Cells.

PDF file - 66K, Summary of percentages of mesothelioma or normal mesothelia specimens expressing EZH2 in figure 2D.

PDF file - 52K, ABCG2 Expression in Side Populations (sp) and Non-side Populations (nsp) of A549 and Calu-6 Cells Cultured with or without CSC

PDF file - 87K, Bar graph depicting total number of differentially expressed genes, as well as relative numbers induced or repressed under various treatment conditions

PDF file - 116K, qRT-PCR analysis of ABCG2 expression in untreated NSCLC and SCLC lines relative to SAEC, and in NSCLC and SCLC lines following CSC exposure

PDF file - 111K

PDF file - 363K, Ingenuity pathway analysis demonstrating two common networks targeted by mithramycin in lung cancer cells in vitro and in vivo

PDF file - 76K, TaqMan and ChIP Primers, and Antibodies

PDF file - 346K, Ingenuity pathway analysis depicting representative intracellular networks modulated by mithramycin lung cancer xenografts

Concerns over prolonged allograft ischemia have limited the widespread adoption of long-distance organ procurement in heart transplantation (HT). We sought to assess whether donor distance from the center of transplantation independently affects mortality.We queried the United Network for Organ Sharing (UNOS) database for adults undergoing isolated HT from 2005 to 2012. Risk-adjusted Cox proportional hazards models were constructed for the primary outcomes of 30-day and 1-year mortality, and the independent impact of donor distance from transplantation center at the time of procurement was assessed.We included 14,588 heart transplant recipients. The mean distance from location of the donor heart to transplantation center was 184.4 ± 214.6 miles; 1,214 HTs (8.3%) occurred at the same location as the donor heart. Ischemic times were inversely related to the distance from the site of donor procurement to recipient transplantation. After risk adjustment, longer donor distances (in miles) were associated with a significantly lower risk of mortality at both 30 days (hazard ratio [HR] 0.9993, 95% confidence interval [CI]: 0.9988 to 0.9998, p 0.01) and 1 year (HR 0.9994, 95% CI: 0.9989 to 0.9999, p = 0.015). Risk-adjusted hazards for mortality were significantly reduced in recipients receiving hearts from more than 25 miles away. The hazard reduction was greatest in recipients receiving donor hearts from more than 500 miles away (1-year HR 0.64, p0.01; 30-day HR 0.47, p0.01).Longer distances between donor location and center of heart transplantation are associated with a reduced hazard for survival at 30 days and 1 year, despite greater ischemic times. Future studies are necessary to elucidate the protective factors surrounding long-distance heart donation.

Previous studies have shown that diabetes mellitus (DM) is a risk factor for postoperative coronary artery bypass grafting (CABG) complications. More contemporary studies are needed to guide revascularization decisions in DM patients. We performed a single-center study of patients who underwent CABG. Patients with no DM were compared with patients with DM, subgrouped according to whether or not DM was treated with insulin before admission (Insulin and No Insulin Groups). Multivariable logistic regression was used to determine whether DM was a significant predictor of mortality, combined postoperative events, and specific postoperative complications after controlling for other predictive clinical variables. Of 11,590 consecutive patients who underwent CABG, 5,013 (43%) had DM and 6,577 (57%) had no DM. Of the patients with DM, 3,433 (68%) were not treated with insulin and 1,580 (32%) were treated with insulin before admission. Multivariable logistic regression analyses showed that DM was not significantly associated with in-hospital mortality or combined postoperative events after considering other clinical variables. The No Insulin Group was significantly associated with stroke, and the Insulin Group was significantly associated with surgical site infection and new renal failure. In conclusion, this study of consecutively treated CABG patients shows that DM is not a predictor of in-hospital mortality or combined in-hospital postoperative events after adjusting for other clinical factors. DM is a predictor of permanent stroke, surgical site infection, and new renal failure. These findings may help with case selection and management of DM patients undergoing CABG.

Renal cell carcinoma can involve the inferior vena cava and extend into the right atrium. Cure is rarely achieved in patients with concomitant metastases, but cytoreductive nephrectomy and eradication of the entire tumor thrombus can extend survival and prevent symptoms of venous congestion; however, the invasive nature of the tumor thrombus can make resection with negative margins difficult. We present a patient with aggressive renal cell carcinoma that demanded an iliac vein-to-right atrium bypass after inferior vena cava ligation during a previous attempt at curative resection with nephrectomy and caval thrombectomy.

Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell–related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies. Cancer Res; 72(16); 4178–92. ©2012 AACR.

Objective A review of all resections for recurrent or metastatic ACC was performed to identify patients who might benefit from a surgical approach, and to identify factors that might aid in prognosis among patients with metastatic disease. Summary Background Data Adrenocortical carcinoma (ACC) is a rare tumor, with frequent recurrences and metastases even after complete resection. Chemotherapy has limited efficacy, and surgical resection of metastatic ACC remains controversial. Methods A retrospective review was performed of all patients who underwent surgical intervention for metastatic ACC in a single tertiary center from 1977 to 2009. All available clinicopathologic data were analyzed to determine potential factors associated with response to treatment and survival. Results Fifty-seven patients underwent 116 procedures for recurrent or metastatic disease. Twenty-three resections were for liver metastases, 48 for pulmonary metastases, 22 for abdominal disease including local recurrences, and 13 were for metastases at other sites. Median and 5-year survivals from time of first metastasectomy were 2.5 years, and 41%, respectively. The median survival of patients with DFI 12 months (P = 0.015). Median survival for right versus left-sided primaries was 1.9 years versus 3.8 years (P = 0.03). Liver metastases were more common with right-sided primaries (67% vs. 41%, P = 0.05). Chemotherapy had no impact on survival. Conclusions Resection of recurrent or metastatic ACC is safe, and may result in prolongation of survival in selected patients with DFI greater than 1 year. J. Surg. Oncol. 2012; 105:709–713. © 2011 Wiley Periodicals, Inc.

Background Adrenocortical carcinoma (ACC) is a rare neoplasm with a high propensity for locoregional recurrences and distant metastases for which there are no effective systemic therapies. This study was undertaken to determine outcomes of patients undergoing pulmonary metastasectomy for ACC. Methods A single-institution retrospective review was performed of patients undergoing pulmonary metastasectomy for ACC from 1979 to 2010. Results Twenty-six patients underwent 60 pulmonary metastasectomies. Fifteen patients (58%) underwent unilateral thoracotomy, 6 (23%) had staged thoracotomies, and 5 (19%) underwent median sternotomy as the initial thoracic procedure. Median number and size of lesions were 6 and 2 cm, respectively. Twenty-three patients (88%) were rendered free of disease in the lung, and 14 (54%) were rendered completely free of disease. Median overall and 5-year actuarial survivals from initial pulmonary metastasectomy were 40 months and 41%, respectively, with a median potential follow-up of 120 months. Median recurrence-free survival (RFS) and 5-year RFS for ipsilateral thoracic recurrences were 6 months, and 25%, respectively. The median RFS in the contralateral thorax was 5 months. Time to first recurrence after adrenalectomy and T stage of the primary tumor, but not adjuvant or neoadjuvant chemotherapy, were associated with increased overall survival after pulmonary metastasectomy. Conclusions This study represents the most comprehensive review of outcomes of patients undergoing pulmonary metastasectomy for ACC. Given the lack of effective systemic therapies, pulmonary metastasectomy may be beneficial in properly selected patients.

Adrenocortical carcinoma (ACC) is a rare disease without effective chemotherapy treated most appropriately with resection. The aim of this study was to evaluate our experience with liver resection for metastatic ACC.This study is a retrospective review of patients who underwent liver resection or radiofrequency ablation (RFA) for ACC from 1979 to 2009.A total of 27 patients were identified. Of the 27, 19 underwent liver resection. Of the 19, 10 had a single liver lesion, and 18 of 19 were rendered free of disease in the liver, although only 11 of 19 were rendered completely free of disease because of extrahepatic disease (EHD). Of the 19, 13 had synchronous EHD. Also, 6 of 17 remained disease free in the liver at a median follow-up of 6.2 years (status of 2 of 19 was unknown). Of the 27 patients, 8 underwent RFA, 7 of 8 became free of disease in the liver, and 5 of 7 had EHD. No patients responded to prior chemotherapy. Median overall survival and survival of patients who underwent liver resection or RFA were both 1.9 years (0.2-12 + years); 5-year actuarial survivals were 29% and 29%, respectively. Disease-free interval (DFI) greater than 9 months from primary resection was associated with longer survival (median 4.1 vs 0.9 years; P = .013).This study is a tertiary institution series of liver resection and RFA for ACC. Given the lack of effective systemic treatment options and the safety of resection and ablation, liver resection or RFA may be considered in selected patients with ACC metastatic to the liver especially with a long DFI.

Objectives Although refractory to chemotherapy, metastatic melanoma may respond to adoptive immunotherapy. As novel treatments evolve, surgeons may be asked to perform metastasectomy not only for palliation or potential cure but also for isolation of tumor-infiltrating lymphocytes. This study was undertaken to examine outcomes of patients with melanoma undergoing thoracic metastasectomy in preparation for investigational immunotherapy. Methods A retrospective review identified 107 consecutive patients who underwent 116 thoracic metastasectomy procedures from April 1998 to July 2009. Indications for surgical intervention included procurement of tumor-infiltrating lymphocytes, rendering of patients to no evaluable disease status, palliation, and diagnosis. Response Evaluation Criteria in Solid Tumors criteria were used to assess tumor response. Results Thoracotomy, lobectomy, and video-assisted thoracoscopic surgery with nonanatomic resection were the most common procedures. Major complications included 1 death and 1 coagulopathy-induced hemothorax. Seventeen patients were rendered to no evaluable disease status. Virtually all patients with residual disease had tumor specimens cultured for tumor-infiltrating lymphocytes; approximately 70% of tumor-infiltrating lymphocyte cultures exhibited antitumor reactivity. Of the 91 patients with residual or recurrent disease, 24 (26%) underwent adoptive cell transfer of tumor-infiltrating lymphocytes, of whom 7 exhibited objective responses (29% response rate and 8% based on intent to treat). Rapid disease progression precluded tumor-infiltrating lymphocyte therapy in most cases. Actuarial 1- and 5-year survival rates for patients rendered to no evaluable disease status or receiving or not receiving tumor-infiltrating lymphocytes were 93% and 76%, 64% and 33%, and 43% and 0%, respectively. Conclusions Relatively few patients currently having thoracic metastasectomy undergo adoptive cell transfer. Continued refinement of tumor-infiltrating lymphocyte expansion protocols and improved patient selection might increase the number of patients with melanoma benefiting from these interventions.

BackgroundThe 5-year survival of patients receiving standard-of-care chemotherapy for metastatic gastric cancer (MGC) to the liver is 5 years.ResultsNineteen studies reported on 436 patients. Median 5-year survival was 26.5% (range: 0–60%). Overall, 13.4% (48/358) of patients were alive at 5 years and studies with extended follow-up reported that 4.0% (7/174) of patients survived for >10 years. Overall in-hospital mortality was 3.5% (12/340 patients); however, the median mortality rate across the studies was 0%. No prognostic factor was found to be consistently statistically significant across these small studies.ConclusionsDespite the limitations of any analysis of retrospective data for highly selected groups of patients, it would appear that liver resections combined with systemic therapy for MGC can result in prolonged survival.

Introduction: Sixteen percent of patients with gastric cancer will develop pulmonary metastases. Standard of care for these patients is systemic chemotherapy with a median survival of 6 months and a 5-year survival of only 2%. Our aim was to critically evaluate the published data on pulmonary resection for metastatic gastric cancer (MGC) and to analyze the potential rationale for surgical management to determine which patients may benefit from this approach. Methods: The Pubmed and SCOPUS databases were queried for all studies reporting on pulmonary resections for MGC. All available clinicopathologic data were analyzed. Results: Twenty-one studies from 1975 to 2008 reported 48 pulmonary resections in 43 patients including five repeat resections and four extrapulmonary metastasectomies. Eighty-two percent (34/43) of patients had solitary lesions with a median size of 24 mm (4–90 mm). Median time from gastrectomy to pulmonary resection was 35 months (0–120 months). At a median follow-up of 23 months, 15 of 43 (35%) patients were alive without disease, and two patients died without disease. Median survival was 29 months (3–84 months) after pulmonary metastasectomy and 65 months (5–180 months) after gastrectomy. Fifty-six percent (24/43) of patients had another recurrence at a median of 12 months (range: 6–48 months) after resection including 30% (13/43) of patients with pulmonary recurrences. Overall 5-year survival was 33%. Conclusions: Pulmonary metastasectomy for MGC can potentially result in long-term survival in a highly selected group of patients and should be considered for those who present with small, isolated lesions after a prolonged disease-free interval.

Purpose Surgery followed by chemotherapy and radiation (CRT) offers patients with pancreatic adenocarcinoma a chance for extended survival. In some patients, however, resection is difficult because of vascular involvement by the carcinoma, necessitating resection and grafting of the mesenterico-portal vessels. The purpose of this study was to compare outcomes between pancreaticoduodenectomy (PD) with and without mesenterico-portal vein resection (VR) in patients receiving adjuvant CRT for pancreatic adenocarcinoma. Methods and Materials Between 1993 and 2005, 160 patients underwent PD with 5-FU–based adjuvant CRT followed by maintenance chemotherapy at the Johns Hopkins Hospital; 20 (12.5%) of the 160 underwent VR. Clinical outcomes, including median survival, overall survival, and complication rates were assessed for both groups. Results Patients who underwent VR had significantly longer operative times ( p = 0.009), greater intraoperative blood loss ( p = 0.01), and longer postoperative lengths of stay ( p = 0.03). However, postoperative morbidity, median survival, and overall survival rates were similar between the two groups. Most patients (70%) from both groups were able to complete CRT, and a subgroup analysis demonstrated no appreciable differences in terms of complications. None of the VR patients who received adjuvant CRT developed veno-oclusive disease or graft failure/leakage. Conclusion In a cohort of patients treated with adjuvant 5-FU–based CRT at the Johns Hopkins Hospital, having a VR at the time of PD resulted in similar complication rates and survival. These data support the feasibility and safety of adjuvant CRT in patients undergoing VR at the time of PD.

The optimal timing of chemotherapy relative to resection of synchronous colorectal liver metastases (SCRLM) is not known. The objective of this retrospective multi-institutional study was to assess the influence of chemotherapy administered before and after hepatic resection on long-term outcomes among patients with initially resectable SCRLM treated from 1995 to 2005. Clinicopathologic data, treatments, and long-term outcomes from patients with initially resectable SCRLM who underwent partial hepatectomy at three hepatobiliary centers were reviewed. Four hundred ninety-nine consecutive patients underwent resection; 297 (59.5%) and 264 (52.9%) were treated with chemotherapy before and after resection. Chemotherapy strategies included pre-hepatectomy alone (n = 148, 24.7%), post-hepatectomy alone (n = 115, 23.0%), perioperative (n = 149, 29.0%), and no chemotherapy (n = 87, 17.4%). Male gender (p = 0.0029, HR = 1.41 [1.12-1.77]), node-positive primary tumor (p = 0.0046, HR = 1.40 [1.11-1.77]), four or more SCRLM (p = 0.0005, HR = 1.65 [1.24-2.18]), and post-hepatectomy chemotherapy treatment for 6 months or longer (p = 0.039, HR = 0.75 [0.57-0.99]) were associated with recurrence-free survival after discovery of SCRLM. Carcinoembryonic antigen >200 ng/ml (p = 0.0003, HR = 2.33 [1.48-3.69]), extrahepatic metastatic disease (p = 0.0025, HR = 2.34 [1.35-4.05]), four or more SCRLM (p = 0.033, HR = 1.43 [1.03-2.00]), and post-hepatectomy chemotherapy treatment for 2 months or longer (p < 0.0001, HR = 0.59 [0.45-0.76]) were associated with overall survival. Pre-hepatectomy chemotherapy was not associated with recurrence-free or overall survival. Patients treated with perioperative chemotherapy had similar outcomes as patients treated with post-hepatectomy chemotherapy only. We conclude that chemotherapy administered after but not before resection of SCRLM was associated with improved recurrence-free and overall survival. However, prospective randomized trials are needed to determine the optimal timing of chemotherapy.

Although nonneurologic organ dysfunction (NNOD) has been shown to significantly affect mortality in subarachnoid hemorrhage, the contribution of NNOD to mortality after severe traumatic brain injury (TBI) has yet to be defined. We hypothesized that NNOD has a significant impact on mortality after severe TBI. The trauma registry was queried for all patients admitted between January 2004 and December 2004 who died during their initial hospitalization after severe TBI (head Abbreviated Injury Score 3 or greater). Cause of death and contributing factors to mortality were determined by an attending trauma surgeon from the medical record. The data were analyzed using both Fisher's exact and Wilcoxon rank sum. One hundred thirty-five patients met inclusion criteria. Sixty-seven per cent were males, 83 per cent were white, and the mean age was 38.5 years. Mean length of stay was 2.9 days. Fifty-four patients (40%) had isolated TBI (chest Abbreviated Injury Score = 0, abdominal Abbreviated Injury Score = 0). Of the 81 deaths attributed to a single cause, 48 (60%) patients died from nonsurvivable TBI or brain death, whereas 33 (40%) died of a nonneurologic cause. Cardiovascular and respiratory dysfunction (excluding pneumonia) contributed to mortality in 51.1 per cent and 34.1 per cent of patients, respectively. NNOD contributes to approximately two-thirds of all deaths after severe TBI. These complications occur early and are seen even among those with isolated head injuries. These findings demonstrate the impact of the extracranial manifestations of severe TBI on overall mortality and highlight potential areas for future intervention and research.

Primary small bowel neoplasms (PSBN) are uncommon, accounting for less than 15 per cent of all gastrointestinal tumors. Benign duodenal neoplasms (BDN) are rare, comprising only 10 to 20 per cent of all PSBN. The treatment is generally surgical resection ranging from local excision to pancreaticoduodenectomy depending on size, location, and number of lesions. Patients undergoing surgical treatment for BDN at Vanderbilt University Medical Center from July 1984 to April 2006, were identified and reviewed retrospectively. Medical records were examined for demographics, operative details, results, and complications. Twenty-six patients were identified of which 56 per cent were male and the mean age was 56 ± 14 years. Lesions were found throughout the duodenum, but the majority (62%) were ampullary. Nearly 75 per cent were adenomas, including over half with dysplasia. Operative interventions and complication rates were: duodenal resection with primary anastomosis (n = 3, 0%), local excision (n = 6, 50%), ampullary resection (n = 10, 30%), and pancreaticoduodenectomy (n = 7, 86%). There were no reoperations or mortalities. Mean followup was 14 months. BDN are an increasingly common problem in an era of frequent use of upper endoscopy. The surgical management of these lesions must be tailored to their size, number, location, and malignant potential. A wide variety of surgical procedures can be performed with acceptable morbidity.

Fibrous dysplasia causing thoracic outlet syndrome is rare. A 41-year-old woman presented with neurogenic thoracic outlet syndrome with imaging that demonstrated a large tumor of her proximal left first rib. Transaxillary excision was unsuccessful due to involvement of the subclavian vasculature and brachial plexus. Subsequent posterolateral thoracotomy and resection of her first rib revealed fibrous dysplasia. Thoracotomy should be considered in these cases for optimal vascular control and identification of thoracic outlet anatomy.

Mediastinal fibrosis is an uncommon disease involving the esophagus, respiratory tract, and great vessels. We report a man who presented with dyspnea on exertion. Computed tomography of the chest demonstrated granulomatous disease with dense calcifications leading to severe stenosis of the main pulmonary artery (PA) and narrowing of the superior vena cava. The results of tuberculosis (TB) interferon-γ release assay and TB-polymerase chain reaction were positive for Mycobacterium tuberculosis. The patient received 2 weeks of treatment for latent TB before undergoing resection of fibrotic tissue and replacement of the main and branch PAs using a homograft.

Half of all patients with infective endocarditis (IE) will require early surgical intervention, and another 40% will eventually undergo surgical treatment for their disease. Although the surgical management of IE is effective, the financial impact of the disease has never been assessed.All patients who underwent valve surgery for native valve IE at the present authors' institution over a 10-year period (1996-2006) were reviewed retrospectively. Hospital charges were identified and adjusted to reflect US$ in 2006. A logistic regression analysis was performed to identify factors affecting charges and the patients' length of stay (LOS).A total of 369 patients (252 males, 117 females; mean age 53 +/- 15 years) underwent surgery for IE. Of these patients, 121 (33%) had preoperative renal failure and 70 (20%) were intravenous drug users. In addition, 159 patients (43%) had aortic IE, 112 (30%) had mitral IE, and 45 (12%) had both aortic and mitral valve IE. Right- and left-sided IE was identified in 42 patients (11%), and 11 (3%) had isolated right-sided IE. The median hospital charges were US$ 60,072 (interquartile range (IQR) US$ 39,386-103,960), with a median LOS of 15 days (IQR 9-29 days). Both, hospital charges and LOS were higher for patients undergoing emergent operations, or those with active IE (p0.001). The 30-day mortality was 2.7%. Regression analyses showed preoperative renal failure (p = 0.007), intraoperative transfusion (p = 0.028) and postoperative gastrointestinal complications (p0.001), renal failure (p = 0.012), heart block (p0.001), in-hospital mortality (p0.001), and patients undergoing emergent procedures (p0.001), or with active infection (p0.001) to be associated with significantly increased hospital charges. Factors that significantly affected LOS were other non-white race (p = 0.039), postoperative gastrointestinal complications (p = 0.001), stroke (p = 0.014), heart block (p0.001), and patients undergoing emergent procedures (p0.001) or with active infection (p0.001).The present series was among the largest to include patients with IE, and the first in which risk factors were assessed for increased hospital charges and resource utilization following surgery for endocarditis. Operations for IE are associated with a significant financial burden to the healthcare system, despite a relatively low percentage of complications. Patients with significant preoperative comorbidities, those with postoperative complications, and those who underwent emergent procedures or who had active IE, were associated with a prolonged LOS and increased hospital charges.

Objectives Simulation may reduce the risks associated with the complex operations of cardiothoracic surgery and help create a more efficient, thorough, and uniform curriculum for cardiothoracic surgery fellowship. Here, we review the current status of simulation in cardiothoracic surgical training and provide an overview of all simulation models applicable to cardiothoracic surgery that have been published to date. Methods We completed a comprehensive search of all publications pertaining to simulation of cardiothoracic surgical procedures by using PubMed. Results Numerous cardiothoracic surgical simulators at various stages of development, assessment, and commercial manufacturing have been published to date. There is currently a predominance of models simulating coronary artery bypass grafting and bronchoscopy and a relative paucity of simulators of open pulmonary and esophageal procedures. Despite the wide range of simulators available, few models have been formally assessed for validity and educational value. Conclusions Surgical simulation is becoming an increasingly important educational tool in training cardiothoracic surgeons. Our next steps forward will be to develop an objective, standardized way to assess surgical simulation training compared with the current apprenticeship model.

Heart failure is a clinical syndrome that results when the heart is unable to provide sufficient blood flow to meet metabolic requirements or accommodate systemic venous return. This common condition affects over 5 million people in the United States at a cost of $10-38 billion per year. Heart failure results from injury to the myocardium from a variety of causes including ischemic heart disease, hypertension, and diabetes. Less common etiologies include cardiomyopathies, valvular disease, myocarditis, infections, systemic toxins, and cardiotoxic drugs. As the heart fails, patients develop symptoms which include dyspnea from pulmonary congestion, and peripheral edema and ascites from impaired venous return. Constitutional symptoms such as nausea, lack of appetite, and fatigue are also common. There are several compensatory mechanisms that occur as the failing heart attempts to maintain adequate function. These include increasing cardiac output via the Frank-Starling mechanism, increasing ventricular volume and wall thickness through ventricular remodeling, and maintaining tissue perfusion with augmented mean arterial pressure through activation of neurohormonal systems. Although initially beneficial in the early stages of heart failure, all of these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. Treatment strategies have been developed based upon the understanding of these compensatory mechanisms. Medical therapy includes diuresis, suppression of the overactive neurohormonal systems, and augmentation of contractility. Surgical options include ventricular resynchronization therapy, surgical ventricular remodeling, ventricular assist device implantation, and heart transplantation. Despite significant understanding of the underlying pathophysiological mechanisms in heart failure, this disease causes significant morbidity and carries a 50% 5-year mortality.

Context Recent emphasis on systems-based approaches to patient safety has led to several studies demonstrating worse outcomes associated with surgery at night. Objective To evaluate whether operative time of day was associated with thoracic organ transplant outcomes, hypothesizing that it would not be associated with increased morbidity or mortality. Design, Setting, and Participants We conducted a retrospective cohort study of adult heart and lung transplant recipients in the United Network for Organ Sharing database from January 2000 through June 2010. Primary stratification was by operative time of day (night, 7 PM-7 AM; day, 7 AM-7 PM). Main Outcome Measures Primary end points were short-term survival, assessed by the Kaplan-Meier method at 30, 90, and 365 days. Secondary end points encompassed common postoperative complications. Risk-adjusted multivariable Cox proportional hazards regression examined mortality. Results A total of 27 118 patients were included in the study population. Of the 16 573 who underwent a heart transplant, 8346 (50.36%) did so during the day and 8227 (49.64%) during the night. Of the 10 545 who underwent a lung transplant, 5179 (49.11%) did so during the day and 5366 (50.89%) during the night. During a median follow-up of 32.2 months (interquartile range, 11.2-61.1 months), 8061 patients (28.99%) died. Survival was similar for organ transplants performed during the day and night. Survival rates at 30 days for heart transplants during the day were 95.0% vs 95.2% during the night (hazard ratio [HR], 1.05; 95% confidence interval, 0.83-1.32; P = .67) and for lung transplants during the day were 96.0% vs 95.5% during the night (HR, 1.22; 95% CI, 0.97-1.55; P = .09). At 90 days, survival rates for heart transplants were 92.6% during the day vs 92.7% during the night (HR, 1.05; 95% CI, 0.88-1.26; P = .59) and for lung transplants during the day were 92.7% vs 91.7% during the night (HR, 1.23; 95% CI, 1.04-1.47; P = .02). At 1 year, survival rates for heart transplants during the day were 88.0% vs 87.7% during the night (HR, 1.05; 95% CI, 0.91-1.21; P = .47) and for lung transplants during the day were 83.8% vs 82.6% during the night (HR, 1.08; 95% CI, 0.96-1.22; P = .19). Among lung transplant recipients, there was a slightly higher rate of airway dehiscence associated with nighttime transplants (57 of 5022 [1.1%] vs 87 of 5224 [1.7%], P = .02). Conclusion Among patients who underwent thoracic organ transplants, there was no significant association between operative time of day and survival up to 1 year after organ transplant.

Background The standard of care for colorectal peritoneal carcinomatosis is evolving from chemotherapy to cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with disease limited to the peritoneum. Peritoneal carcinomatosis from colorectal cancer treated with chemotherapy alone results in median survival of 5 to 13 months, whereas CRS with HIPEC for early peritoneal carcinomatosis from colorectal cancer resulted in median survival of 48-63 months and 5 year survival of 51%. Completeness of cytoreduction and limited disease are associated with longer survival, yet early peritoneal carcinomatosis is undetectable by conventional imaging. Exploratory laparotomy can successfully identify early disease, but this approach can only be justified in patients with high risk of peritoneal carcinomatosis. Historical data indicates that patients presenting with synchronous peritoneal carcinomatosis, ovarian metastases, perforated primary tumor, and emergency presentation with bleeding or obstructing lesions are at high risk of peritoneal carcinomatosis. Approximately 55% of these patient populations will develop peritoneal carcinomatosis. We hypothesize that performing a mandatory second look laparotomy with CRS and HIPEC for patients who are at high risk for developing peritoneal carcinomatosis from colorectal cancer will lead to improved survival as compared to patients who receive standard of care with routine surveillance. Methods/Design This study is a prospective randomized trial designed to answer the question whether mandatory second look surgery with CRS and HIPEC will prolong overall survival compared to the standard of care in patients who are at high risk for developing peritoneal carcinomatosis from colorectal cancer (CRC). Patients with CRC at high risk for developing peritoneal carcinomatosis who underwent curative surgery and subsequently received standard of care adjuvant chemotherapy will be evaluated. The patients who remain without evidence of disease by imaging, physical examination, and tumor markers for 12 months after the primary operation will be randomized to mandatory second look surgery or standard-of-care surveillance. At laparotomy, CRS and HIPEC will be performed with intraperitoneal oxaliplatin with concurrent systemic 5-fluorouracil and leucovorin. Up to 100 patients will be enrolled to allow for 35 evaluable patients in each arm; accrual is expected to last 5 years. Trial Registration ClinicalTrials.gov ID: NCT01095523

Background In patients with primary hyperaldosteronism, distinguishing between unilateral and bilateral adrenal hypersecretion is critical in assessing treatment options. Adrenal venous sampling (AVS) has been advocated by some to be the gold standard for localization of the responsible lesion, but there remains a lack of consensus for the criteria and the standardization of technique. Study Design We performed a retrospective study of 114 patients with a biochemical diagnosis of primary hyperaldosteronism who all underwent CT scan and AVS before and after corticotropin (ACTH) stimulation. Univariate and multivariate analyses were performed to determine what factors were associated with AVS lateralization, and which AVS values were the most accurate criteria for lateralization. Results Eighty-five patients underwent surgery at our institution for unilateral hyperaldosteronism. Of the 57 patients who demonstrated unilateral abnormalities on CT, AVS localized to the contralateral side in 5 patients and revealed bilateral hyperplasia in 6 patients. Of the 52 patients who showed bilateral disease on CT scan, 43 lateralized with AVS. The most accurate criterion on AVS for lateralization was the post-ACTH stimulation value. Factors associated with AVS lateralization included a low renin value, high plasma aldosterone-to plasma-renin ratio, and adrenal mass ≥ 3 cm on CT scan. Conclusions Because 50% of patients would have been inappropriately managed based on CT scan findings, patients with biochemical evidence of primary hyperaldosteronism and considering adrenalectomy should have AVS. The most accurate measurement for AVS lateralization was the post-ACTH stimulation value. Although several factors predict successful AVS lateralization, none are accurate enough to perform AVS selectively.

Although nonneurologic organ dysfunction (NNOD) has been shown to significantly affect mortality in subarachnoid hemorrhage, the contribution of NNOD to mortality after severe traumatic brain injury (TBI) has yet to be defined. We hypothesized that NNOD has a significant impact on mortality after severe TBI. The trauma registry was queried for all patients admitted between January 2004 and December 2004 who died during their initial hospitalization after severe TBI (head Abbreviated Injury Score 3 or greater). Cause of death and contributing factors to mortality were determined by an attending trauma surgeon from the medical record. The data were analyzed using both Fisher's exact and Wilcoxon rank sum. One hundred thirty-five patients met inclusion criteria. Sixty-seven per cent were males, 83 per cent were white, and the mean age was 38.5 years. Mean length of stay was 2.9 days. Fifty-four patients (40%) had isolated TBI (chest Abbreviated Injury Score = 0, abdominal Abbreviated Injury Score = 0). Of the 81 deaths attributed to a single cause, 48 (60%) patients died from nonsurvivable TBI or brain death, whereas 33 (40%) died of a nonneurologic cause. Cardiovascular and respiratory dysfunction (excluding pneumonia) contributed to mortality in 51.1 per cent and 34.1 per cent of patients, respectively. NNOD contributes to approximately two-thirds of all deaths after severe TBI. These complications occur early and are seen even among those with isolated head injuries. These findings demonstrate the impact of the extracranial manifestations of severe TBI on overall mortality and highlight potential areas for future intervention and research.

Background: The purpose of this study was to define donation patterns and lost donor opportunities in severe traumatic brain injury (TBI) patients. Methods: The trauma registry was queried for all deaths after severe TBI in 2004; this was cross matched with the regional organ procurement organization database and subjected to post hoc statistical analysis. Results: One hundred thirty-five patients met criteria for inclusion. Forty percent had isolated TBI. Forty-two patients (31%) were eligible for deceased donation. Seventeen eligible patients (40%) did not convert to donation, 15 from family declining. Twenty-five eligible patients (60%) donated 85 organs (yield 3.4 organs/donor). Yield was similar in both isolated TBI (3.2) and patients with head injuries (3.5). Ineligible patients had higher admission Glasgow Coma Scale scores, lower head Abbreviated Injury Scale scores, and were more likely to develop cardiovascular or pulmonary dysfunction (p < 0.05). Of the 25 donors, 48% did not donate hearts and 84% did not donate lungs, despite the absence of chest trauma in the majority of patients. Conclusion: Less than one-third of severe TBI patients were identified as eligible organ donors and only 40% actually donated. Half of all donors fail to donate hearts and over 80% fail to donate lungs. Within this population, opportunities may exist to improve both donor conversion and organ yield.

Primary small bowel neoplasms (PSBN) are uncommon, accounting for less than 15 per cent of all gastrointestinal tumors. Benign duodenal neoplasms (BDN) are rare, comprising only 10 to 20 per cent of all PSBN. The treatment is generally surgical resection ranging from local excision to pancreaticoduodenectomy depending on size, location, and number of lesions. Patients undergoing surgical treatment for BDN at Vanderbilt University Medical Center from July 1984 to April 2006, were identified and reviewed retrospectively. Medical records were examined for demographics, operative details, results, and complications. Twenty-six patients were identified of which 56 per cent were male and the mean age was 56 +/- 14 years. Lesions were found throughout the duodenum, but the majority (62%) were ampullary. Nearly 75 per cent were adenomas, including over half with dysplasia. Operative interventions and complication rates were: duodenal resection with primary anastomosis (n=3, 0%), local excision (n=6, 50%), ampullary resection (n=10, 30%), and pancreaticoduodenectomy (n=7, 86%). There were no reoperations or mortalities. Mean followup was 14 months. BDN are an increasingly common problem in an era of frequent use of upper endoscopy. The surgical management of these lesions must be tailored to their size, number, location, and malignant potential. A wide variety of surgical procedures can be performed with acceptable morbidity.

Background: Beta-blocker use in elective noncardiac surgery has been associated with a reduction in mortality and cardiovascular complications. Traumatic brain injury (TBI) is often associated with a hyperadrenergic state. We hypothesized that adrenergic blockade would confer improved survival among TBI patients. Methods: Retrospective review of the Trauma Registry of the American College of Surgeons database at a Level I trauma center was conducted. All trauma patients admitted from January 2004 to March 2005 with head Abbreviated Injury Scale score of 3 or greater were evaluated. Patients with length of stay 30 days were excluded. Beta-blocker exposure was defined as receiving beta-blockers for 2 or more consecutive days. Results: In all, 420 patients met in. clusion criteria: 174 patients exposed to beta-blockers [BB(+)] and 246 not exposed [BB(-)]. Mean age in BB(+) group was 50 years and 36 years in BB(-) group (p < 0.001). Mean Injury Severity Score was 33.6 for BB(+) group and 30.8 for BB(-) group (p = 0.01). Predicted survival (by Trauma and Injury Severity Score) for BB(+) group was 59.1% compared with 70.3% for BB(-) group (p < 0.001). Observed mortality for BB(+) group was 5.1%, 10.8% for BB(-) group (p = 0.036). Adjusted incidence rate ratio of mortality among those exposed to beta-blockers compared with those not exposed was 0.29 (95% confidence interval). Conclusions: Beta-blocker exposure was associated with a significant reduction in mortality in patients with severe TBI. This reduction in mortality is even more impressive, considering that the BB(+) group was older, more severely injured, and had lower predicted survival.

Limited information is available regarding epigenetic mechanisms by which cigarette smoke mediates initiation and progression of thoracic malignancies. In order to examine this issue, lung and esophageal cancer cells (A549, Calu-6, NCI-SB-ESC1 and NCI-SB-ESC2), were cultured in normal media (NM) with or without cigarette smoke condensate (CSC) under clinically relevant exposure conditions. Microarray analysis revealed that five day CSC exposure significantly up-regulated ABCG2, encoding a xenobiotic pump highly expressed in cancer stem cells. Quantitative reverse transcription-PCR (qRT-PCR), western blot, and immunohistochemistry experiments confirmed up-regulation of ABCG2 in cultured cancer lines, but not normal small airway epithelial cells (SAEC) or immortalized esophageal squamous cells (HET1A) exposed to CSC. Flow cytometry experiments demonstrated that CSC increased the side population (SP) of cultured cancer cells. Transient transfection experiments using ABCG2 promoter reporter constructs revealed that deletion of xenobiotic response elements as well as SP-1 sites markedly attenuated ABCG2 induction by CSC. Chromatin immunoprecipitation (ChIP) experiments revealed that CSC-mediated induction of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor (AHR), SP-1, and Nrf2, as well as increased levels of RNA pol II and H3K9Ac within the ABCG2 promoter. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AHR, SP-1, and Nrf2 levels within the ABCG2 promoter, down-regulated ABCG2 expression, decreased S P, inhibited in-vitro proliferation of lung and esophageal cancer cells, and markedly diminished growth of established tumor xenografts. Microarray analysis revealed significant down-regulation of numerous stem-cell related pathways in lung cancer cells following mithramycin exposure. Collectively, these findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical evaluation of mithramycin for targeting cancer stem cells in thoracic malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A54.

Objective: Previously, we reported that cigarette smoke condensate dramatically increases tumorigenicity of lung cancer cells via epigenetic silencing of Dickkopf-1(Dkk-1), which encodes an inhibitor of Wnt stem cell signaling. Furthermore, we demonstrated that knock-down of Dkk-1 up-regulates Wnt5A in lung cancer cells. Expression of this non-canonical Wnt ligand correlates with adverse outcome in lung cancer patients. The present study was undertaken to ascertain if Wnt5A directly modulates the malignant phenotype of lung cancer cells. Methods: Calu-6, H358, A549, and H841 lung cancer lines were transduced with lentiviral vectors expressing Wnt5A or control sequences. Cell count, scratch, and matrigel assays were used to evaluate in-vitro proliferation, migration, and invasion of transduced cells. Similar experiments were performed with exogenous recombinant Wnt5A (rWnt5A). Nude mouse xenograft experiments were used to assess tumorigenicity of lung cancer cells transduced with Wnt5A or vector controls. Canonical and non-canonical Wnt signal pathways were evaluated using western blot, promoter-reporter, and focused quantitative RT-PCR array techniques. Results: Wnt5A transduced lung cancer cells exhibited significantly increased proliferation, migration, and invasion relative to vector controls (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5156.