Valve surgery for infective endocarditis is associated with high hospital charges.

BACKGROUND AND AIM OF THE STUDY: 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. METHODS: 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). RESULTS: 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 (p < 0.001). 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 (p < 0.001), renal failure (p = 0.012), heart block (p < 0.001), in-hospital mortality (p < 0.001), and patients undergoing emergent procedures (p < 0.001), or with active infection (p < 0.001) 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 (p < 0.001), and patients undergoing emergent procedures (p < 0.001) or with active infection (p < 0.001). CONCLUSION: 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.

Operative management for recurrent and metastatic adrenocortical carcinoma.

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 was 1.7 years, compared to 6.6 years for 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.

Liver resection and ablation for metastatic adrenocortical carcinoma.

BACKGROUND: 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. METHODS: This study is a retrospective review of patients who underwent liver resection or radiofrequency ablation (RFA) for ACC from 1979 to 2009. RESULTS: 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). CONCLUSIONS: 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.

Association of operative time of day with outcomes after thoracic organ transplant.

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.

Liver resections in metastatic gastric cancer.

BACKGROUND: The 5-year survival of patients receiving standard-of-care chemotherapy for metastatic gastric cancer (MGC) to the liver is <2%. This review examines the published data on liver resections for MGC and analyses the rationale for potentially aggressive surgical management. METHODS: A search of the PubMed and Scopus databases was used to identify studies published in English from 1990 to 2009 that reported on 10 or more patients who underwent liver resections for MGC. All available clinicopathologic data were analysed. In particular, we examined longterm survival and the characteristics of individuals surviving for >5 years. RESULTS: Nineteen 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. CONCLUSIONS: Despite 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.

Effect of Diabetes Mellitus on Complication Rates of Coronary Artery Bypass Grafting.

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.

How we die: the impact of nonneurologic organ dysfunction after severe traumatic brain injury.

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.

Secondary abdominal compartment syndrome after severe extremity injury: are early, aggressive fluid resuscitation strategies to blame?

INTRODUCTION: Secondary abdominal compartment syndrome (ACS) is the development of ACS in the absence of abdominal injury. The development of secondary ACS has been viewed by some authors as an unavoidable sequela of the aggressive crystalloid resuscitation often employed in the treatment of severe shock. We hypothesized that poor resuscitation techniques, including early and excessive crystalloid administration, places patients with extremity injuries at risk for developing secondary ACS. METHODS: The Trauma Registry of the American College of Surgeons database was queried for all patients with an extremity Abbreviated Injury Scale (AIS) score of 3 or greater and abdominal AIS score of 0 treated at our institution between January 1, 2001 and December 31, 2005. The study group included those patients who developed secondary ACS, whereas the comparison cohort included those who did not develop secondary ACS. RESULTS: Forty-eight patients developed secondary ACS and were compared with 48 randomly selected patients who had an extremity AIS score of 3 or greater and an abdomen AIS score of 0. There were no differences between the groups with respect to age, sex, race, or individual AIS scores. However, the secondary ACS group had a slightly higher Injury Severity Score (25.6 vs. 21.4, p = 0.02), significantly higher operating room crystalloid administration (9.9 L vs. 2.7 L, p < 0.001), and more frequent use of a rapid infuser (12.5% vs. 0.0%, p = 0.01). Multiple logistic regression identified prehospital and emergency department crystalloid as predictors of secondary ACS. CONCLUSIONS: Aggressive resuscitation techniques, often begun in the prehospital setting, appear to increase the likelihood of patients with severe extremity injuries developing secondary ACS. Early, large volume crystalloid administration was the greatest predictor of secondary ACS.

Donor conversion and organ yield in traumatic brain injury patients: missed opportunities and missed organs.

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.

Resection of benign duodenal neoplasms.

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.

The Paradoxical Relationship Between Donor Distance and Survival After Heart Transplantation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, p < 0.01; 30-day HR 0.47, p < 0.01). CONCLUSIONS: 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.

Late Complications Following Continuous-Flow Left Ventricular Assist Device Implantation.

Left ventricular assist devices have become standard therapy for patients with end-stage heart failure. They represent potential long-term solutions for a growing public health problem. However, initial enthusiasm for this technology has been tempered by challenges posed by long-term support. This review examines these challenges and out current understanding of their etiologies.

Mediastinal Fibrosis of the Pulmonary Artery Secondary to Tuberculosis.

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.

Extracorporeal membrane oxygenation for profound cardiogenic shock due to cocaine toxicity.

Cocaine toxicity can result in myocardial infarction from coronary vasospasm. The current treatment algorithm includes intravenous and/or intracoronary vasodilator administration with an expectantly quick resolution of symptoms and signs of ischemia. However, in situations in which myocardial injury persists, the optimal management is uncertain. We present a case in which extracorporeal membrane oxygenation effectively stabilized a patient with ongoing hemodynamic instability who experienced repeated episodes of myocardial injury and ventricular tachyarrhythmias due to cocaine toxicity. .

Palliative iliac vein-to-right atrium bypass in a patient with a prior vena cava ligation for invasive renal cell carcinoma.

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.

Simulation in cardiothoracic surgical training: where do we stand?

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.

The pathophysiology of heart failure.

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.

Thoracic outlet syndrome caused by fibrous dysplasia of the first rib.

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.

Polycomb repressor complex-2 is a novel target for mesothelioma therapy.

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.

Mithramycin represses basal and cigarette smoke-induced expression of ABCG2 and inhibits stem cell signaling in lung and esophageal cancer cells.

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.