Wnt pathway activation predicts increased risk of tumor recurrence in patients with stage I nonsmall cell lung cancer.

OBJECTIVE: To determine the incidence of Wnt pathway activation in patients with stage I NSCLC and its influence on lung cancer recurrence. BACKGROUND: Despite resection, the 5-year recurrence with localized stage I nonsmall cell lung cancer (NSCLC) is 18.4%-24%. Aberrant Wnt signaling activation plays an important role in a wide variety of tumor types. However, there is not much known about the role the Wnt pathway plays in patients with stage I lung cancer. METHODS: Tumor and normal lung tissues from 55 patients following resection for stage I NSCLC were subjected to glutathione S-transferase (GST) E-cadherin pulldown and immunoblot analysis to assess levels of uncomplexed ß-catenin, a reliable measure of Wnt signaling activation. The ß-catenin gene was also screened for oncogenic mutations in tumors with activated Wnt signaling. Cancer recurrence rates were correlated in a blinded manner in patients with Wnt pathway-positive and -negative tumors. RESULTS: Tumors in 20 patients (36.4%) scored as Wnt positive, with only 1 exhibiting a ß-catenin oncogenic mutation. Patients with Wnt-positive tumors experienced a significantly higher rate of overall cancer recurrence than those with Wnt-negative tumors (30.0% vs. 5.7%, P = 0.02), with 25.0% exhibiting distal tumor recurrence compared with 2.9% in the Wnt-negative group (P = 0.02). CONCLUSIONS: Wnt pathway activation occurred in a substantial fraction of Stage I NSCLCs, which was rarely due to mutations. Moreover, Wnt pathway activation was associated with a significantly higher rate of tumor recurrence. These findings suggest that Wnt pathway activation reflects a more aggressive tumor phenotype and identifies patients who may benefit from more aggressive therapy in addition to resection.

Multicenter analysis of diaphragm pacing in tetraplegics with cardiac pacemakers: positive implications for ventilator weaning in intensive care units.

BACKGROUND: Diaphragm pacing (DP) can replace mechanical ventilation in tetraplegics and in trials has assisted respiration in amyotrophic lateral sclerosis patients. This report describes results of DP in patients with cardiac pacemakers. METHODS: Prospective, single-center and multicenter, nonrandomized, controlled, interventional protocols under U.S. Food and Drug Administration and/or institutional review board approval were evaluated. Patients underwent laparoscopic diaphragm motor point mapping to identify optimal electrode site for implantation. With diaphragm conditioning, patients were weaned from their ventilator. Perioperative and long-term assessments between the cardiac pacemakers and DP were analyzed for any device-to-device interactions. RESULTS: Over 300 subjects were implanted from 2000 to 2010. Twenty tetraplegics with cardiac pacemakers and DP were analyzed from 6 sites. Subjects ranged from 19 to 61 years old with DP implantation 6 months to 24 years postinjury. There were no immediate or long-term device to device interactions. All patients achieved diaphragm-paced tidal volumes exceeding their basal requirements and, after conditioning, all patients could go >4 hours without mechanical ventilators; 71% could go 24 hours continuously. CONCLUSION: DP can be safely implanted in tetraplegics having cardiac pacemakers. Applications for temporary use of DP to maintain diaphragm type 1 muscle fiber and improve posterior lobe ventilation may benefit complex critical care patients.

Predictors of major morbidity and mortality after pneumonectomy utilizing the Society for Thoracic Surgeons General Thoracic Surgery Database.

BACKGROUND: Pneumonectomy is associated with a significant incidence of perioperative morbidity and mortality. The purpose of this study is to identify the risk factors responsible for adverse outcomes in patients after pneumonectomy utilizing The Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTDB). METHODS: All patients who had undergone pneumonectomy between January 2002 and December 2007 were identified in the STS GTDB. Among 80 participating centers, 1,267 patients were selected. Logistic regression analysis was performed on preoperative variables for major adverse outcomes. RESULTS: The rate of major adverse perioperative events was 30.4%, including 71 patients who died (5.6%). Major morbidity was defined as pneumonia, adult respiratory distress syndrome, empyema, sepsis, bronchopleural fistula, pulmonary embolism, ventilatory support beyond 48 hours, reintubation, tracheostomy, atrial or ventricular arrhythmias requiring treatment, myocardial infarct, reoperation for bleeding, and central neurologic event. Patients with major morbidity had a longer mean length of stay compared with patients without major morbidity (13.3 versus 6.1 days, p < 0.001). Independent predictors of major adverse outcomes were age 65 years or older (p < 0.001), male sex (p = 0.026), congestive heart failure (p = 0.04), forced expiratory volume in 1 second less than 60% of predicted (p = 0.01), benign lung disease (p = 0.006), and requiring extrapleural pneumonectomy (p = 0.018). Among patients with lung carcinoma, those receiving neoadjuvant chemoradiotherapy were more at risk for major morbidity than patients without induction therapy (p = 0.049). CONCLUSIONS: The mortality rate after pneumonectomy by thoracic surgeons participating in the STS database compares favorably to that in previously published studies. We identified risk factors for major adverse outcomes in patients undergoing pneumonectomy.

Thoracoscopic segmentectomy compares favorably with thoracoscopic lobectomy for patients with small stage I lung cancer.

OBJECTIVE: As thoracoscopic lobectomy becomes widely applied for treatment of non-small cell lung cancer, thoracoscopic segmentectomy remains controversial for patients with small stage I lung cancers. Questions remain regarding safety, morbidity, mortality, and recurrence rate. This study compared outcomes between thoracoscopic segmentectomy and lobectomy. METHODS: Retrospective review was undertaken of patients who underwent thoracoscopic segmentectomy or lobectomy for clinical stage I non-small cell lung cancer between January 2002 and February 2008. Indications for segmentectomy were tumor smaller than 3 cm, limited pulmonary reserve, comorbidities, and peripheral tumor location. RESULTS: Thirty-one patients underwent segmentectomy and 113 underwent lobectomy. Patients after segmentectomy had worse mean forced expiratory volume in 1 second than after lobectomy (83% vs 92%, P = .04). There were no differences in mean number of nodes (10) and nodal stations (5) resected. Segmentectomy and lobectomy groups had similar median chest tube durations (2 vs 3 days, P = .18), stays (both 4 days), total complications, recurrence rates, and survivals at mean follow-ups of 22 and 21 months, respectively. Lobectomy group had 1 30-day death; segmentectomy group had none. There were 5 (17.2%) recurrences after segmentectomy and 23 (20.4%) after lobectomy (P = .71), with locoregional recurrence rates of 3.5% and 3.6%, respectively. CONCLUSION: Thoracoscopic segmentectomy is a safe option for experienced thoracoscopic surgeons treating patients with small stage I lung cancers. No significant difference in oncologic outcome was seen between thoracoscopic segmentectomy and thoracoscopic lobectomy. Lymph node dissection could be performed as effectively during segmentectomy as lobectomy.

Video-assisted thoracoscopic lobectomy: state of the art and future directions.

BACKGROUND: Thoracoscopic lobectomy is performed with increasing frequency for early-stage lung cancer. Several published reports suggest thoracoscopic resection is safe, with the potential advantage of shorter hospital stay, quicker recovery, and comparable oncologic results. METHODS: Data on 180 video-assisted thoracoscopic surgery (VATS) patients who underwent thoracoscopic lobectomy or sublobar anatomic resection at our institution between January 2002 and December 2006 were reviewed. The conversion rate to thoracotomy, complications, length of stay, and duration of chest tube drainage were determined. Similar variables were evaluated for patients aged older than 80 years, those with a forced expiratory volume in 1 second (FEV1) that was less than 50% predicted, those who had undergone preoperative neoadjuvant therapy, and those who had undergone lung-sparing anatomic resections. RESULTS: Thoracoscopic anatomic lung resection was performed successfully in 166 patients. One of 180 patients (0.6%) died, and 14 patients (9.2%) underwent conversions. Overall median length of stay was 4 days (range, 1 to 98; interquartile range [IQR], 3), and median duration of chest tube drainage was 3 days (range, 0 to 35 days; IQR, 2). The median length of hospital stay and median chest tube duration for the group aged 80 years and older was 5 and 3 days; for the segmental resection group, 4 and 3 days; for the chemotherapy or radiotherapy induction group, 3.5 and 3 days; and for the FEV1 less than 50% group, 5.5 and 4 days, respectively. No patients died in any of these groups. CONCLUSIONS: Thoracoscopic lung resection can be performed safely in selected patients aged 80 years and older, in those with marginal pulmonary function, and in those with pathologic response to neoadjuvant therapy.

Airway stents.

Airway stenting has been well used in the treatment and palliation of patients with malignant stenoses and to a lesser extent in those with benign disease causing airway compromise. Stents are either constructed of silicone or metal, usually a nitinol, a nickel and titanium alloy. The different categories of stents have positive and negative attributes that play a role in choosing the proper stent. This article aims to discuss these issues with regards to malignant and benign tracheobronchial disease.

Electromagnetic navigational bronchoscopy: a surgeon's perspective.

Diagnostic yield of flexible bronchoscopy is often limited by the size and location of the lesion of interest. Novel technologies have evolved that can improve the accuracy and expand the applicability of flexible bronchoscopy in rendering a tissue diagnosis for pulmonary nodules. One recent technical advance uses electromagnetic guidance to improve the ability of the bronchoscopist to navigate within the lung parenchyma as well as to localize and biopsy mediastinal pathology. We have gained a preliminary experience with navigational bronchoscopy using electromagnetic guidance to successfully biopsy peripheral lung lesions, place fiducial catheters to aid stereotactic radiotherapy, and to biopsy mediastinal lymph nodes in the staging of lung cancer. Not only will navigational bronchoscopy lead to improvements in the diagnostic yield of standard flexible bronchoscopy, but we envision potential therapeutic modalities that can be used this system.

Sequential 5-Aza 2'-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells.

cDNA arrays were used to examine gene induction in CALU-6 and H460 lung cancer cells mediated by sequential 5-aza 2'-deoxycytidine (DAC)/depsipeptide FK228 (DP) exposure in order to identify translational end points for clinical trials evaluating these agents. In both cell lines, sequential DAC/DP treatment induced expression of tissue factor pathway inhibitor-2 (TFPI-2), an inhibitor of Factor VII: tissue factor signal transduction known to diminish the malignant phenotype of cancer cells. TFPI-2 expression was diminished or absent in 16 of 32 cell lines established from thoracic malignancies. Sequential DAC/DP treatment induced TFPI-2 in cancer cells deficient for TFPI-2 expression in the basal state. Promoter methylation coincided with loss of TFPI-2 expression in a number of cancer lines. TFPI-2 promoter methylation was observed in one of five pulmonary adenocarcinomas, and seven of seven esophageal adenocarcinomas, but not corresponding normal tissues. DP enhanced acetylation of TFPI-2-associated histones in CALU-6 cells. DP or PDBU, alone, induced TFPI-2 expression in cancer cells deficient for TFPI-2 expression in the absence of promoter methylation. In these cells, DP-mediated TFPI-2 induction was abrogated by calphostin. Induction of TFPI-2 by distinct, yet cooperative mechanisms involving chromatin remodeling and PKC signaling strengthens the preclinical rationale for sequential administration of DNA demethylating agents and HDAC inhibitors in cancer patients. Furthermore, induction of TFPI-2 may be a useful surrogate marker of treatment response in individuals receiving sequential DAC/DP infusions.

Pharmacokinetics of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques.

OBJECTIVE: Although paclitaxel is widely used as a systemic agent for the treatment of solid tumors, limited information is available concerning administration of this taxane by regional techniques. The present study was undertaken to evaluate the pharmacokinetics and acute toxicity of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques to ascertain its potential for the regional therapy of unresectable pulmonary neoplasms. METHODS: Adult sheep underwent 90 minutes of retrograde isolated lung perfusion with escalating doses of paclitaxel and moderate hyperthermia using a protein-free, oxygenated extracorporeal circuit and a steady perfusion pressure of 14 to 16 mm Hg. An additional animal received paclitaxel by means of 1-hour central venous infusion. Paclitaxel concentrations in lung tissues, perfusates, and systemic circulation were determined by high-performance liquid chromotography techniques. Cytotoxicity of paclitaxel in cancer cells and in normal human bronchial epithelial cells was evaluated in vitro using 4, 5-dimethylthiazo-2-yl-25-dipagnyl tetrazolium bromide assays. Lung tissues were examined by hematoxylin-and-eosin techniques. RESULTS: Paclitaxel concentrations (maximum concentration and area under the plasma concentration time curve) in perfused tissues increased with escalating perfusate doses. Uptake of drug into lung parenchyma appeared saturable at high paclitaxel exposure; a substantial pharmacokinetic advantage was observed. Paclitaxel concentrations in systemic circulation were undetectable or exceedingly low after perfusion. Histopathologic examination of lung tissues harvested 3 hours after completion of isolated lung perfusion revealed no immediate toxicity, even at a paclitaxel exposure 20-fold higher than that achievable after 1 hour of intravenous administration at the maximum tolerable dose in human subjects. Moderate hyperthermia enhanced paclitaxel-mediated cytotoxicity 5- to 100-fold in cultured cancer lines. No paclitaxel toxicity was observed in cultured normal human bronchial epithelial cells after exposure to paclitaxel under normothermic or hyperthermic conditions. CONCLUSIONS: These data support further evaluation of paclitaxel administered by hyperthermic retrograde isolated lung perfusion techniques for the treatment of unresectable malignant pulmonary tumors.