Lung adenocarcinoma invasion in TGFbetaRII-deficient cells is mediated by CCL5/RANTES.

Recently, we identified a lung adenocarcinoma signature that segregated tumors into three clades distinguished by histological invasiveness. Among the genes differentially expressed was the type II transforming growth factor-beta receptor (TGFbetaRII), which was lower in adenocarcinoma mixed subtype and solid invasive subtype tumors compared with bronchioloalveolar carcinoma. We used a tumor cell invasion system to identify the chemokine CCL5 (RANTES, regulated on activation, normal T-cell expressed and presumably secreted) as a potential downstream mediator of TGF-beta signaling important for lung adenocarcinoma invasion. We specifically hypothesized that RANTES is required for lung cancer invasion and progression in TGFbetaRII-repressed cells. We examined invasion in TGFbetaRII-deficient cells treated with two inhibitors of RANTES activity, Met-RANTES and a CCR5 receptor-blocking antibody. Both treatments blocked invasion induced by TGFbetaRII knockdown. In addition, we examined the clinical relevance of the RANTES-CCR5 pathway by establishing an association of RANTES and CCR5 immunostaining with invasion and outcome in human lung adenocarcinoma specimens. Moderate or high expression of both RANTES and CCR5 was associated with an increased risk for death, P=0.014 and 0.002, respectively. In conclusion, our studies indicate RANTES signaling is required for invasion in TGFbetaRII-deficient cells and suggest a role for CCR5 inhibition in lung adenocarcinoma prevention and treatment.

Lung reduction operation and resection of pulmonary nodules in patients with severe emphysema.

BACKGROUND: Severe pulmonary dysfunction has been considered a relative contraindication to surgical resection in patients with solitary pulmonary nodules. We report our initial experience with the combined use of lung volume reduction operation and tumor resection in this patient population. METHODS AND PATIENTS: Between January 1995 and July 1996, 14 patients underwent combined lung volume reduction operation and pulmonary nodule resection. Ten (71%) patients were oxygen dependent, 5 (36%) had a room air partial pressure of carbon dioxide > or = 45, and 5 (36%) were steroid dependent preoperatively. Mean preoperative pulmonary function tests included a forced expiratory volume in 1 second of 680 +/- 98 mL (24% +/- 5% predicted), forced vital capacity of 54% +/- 5% predicted, and a forced expiratory volume in 1 second to vital capacity ratio of 37% +/- 2% predicted. RESULTS: Sixteen lesions were resected in the 14 patients and included 9 non-small cell carcinomas. There was one postoperative death. All other patients are alive and well through a mean follow-up of 22.6 +/- 2.3 months (12 to 35 months). At 6-month follow-up improvements were noted in dyspnea index, forced expiratory volume in 1 second forced vital capacity, and 6-minute walk distance. Mediastinal recurrence at 12-month follow-up developed in 1 patient with two separate bronchioalveolar carcinomas. CONCLUSIONS: Simultaneous lung volume reduction operation and tumor resection should be considered in patients with emphysema with marginal reserve in the hope of maximizing postoperative lung function.

Functional comparison of unilateral versus bilateral lung volume reduction surgery.

BACKGROUND: Lung volume reduction surgery (LVRS) has shown early promise as a palliative therapy in severe emphysema. A number of patients, however, are not candidates for a bilateral operation, or exhibit a predominantly unilateral disease distribution. METHODS: Over 20 months, we performed LVRS in 92 patients selected on the basis of severe hyperinflation with air trapping, diaphragmatic dysfunction, and disease heterogeneity. Twenty-eight patients underwent unilateral LVRS on the basis of asymmetric disease distribution, prior thoracic operation, or concomitant tumor resection. RESULTS: Unilateral LVRS resulted in comparable improvements in exercise capacity and dyspnea as the bilateral procedure, with a similar perioperative mortality and actuarial survival to 24 months. Improvements in spirometric indices of pulmonary function, however, were less in patients undergoing unilateral than bilateral LVRS. CONCLUSIONS: In properly selected patients, unilateral LVRS provides functional and subjective benefits of comparable magnitude to those associated with a bilateral operation. Unilateral LVRS is therefore an option in the therapy of end-stage emphysema in patients with asymmetric disease distribution, a prior thoracic operation, or contraindications to sternotomy, and may have a role as a bridge to transplantation in selected cases.

Extended indications for lung volume reduction surgery in advanced emphysema.

BACKGROUND: Lung volume reduction surgery has shown early promise as a palliative therapy in severe emphysema. Selection of potential candidates has been based on certain functional and anatomic criteria, and a variety of operative contraindications have been proposed. METHODS: Over 15 months, we performed lung volume reduction surgery in 85 patients selected on the basis of severe hyperinflation with air trapping, diaphragmatic dysfunction, and disease heterogeneity. Patients were not excluded on the basis of severe hypercapnia, steroid dependence, profound pulmonary dysfunction, or inability to complete preoperative rehabilitation. RESULTS: We observed significant improvements in pulmonary function, exercise capacity, and dyspnea, with an acceptable 30-day perioperative mortality of 7% and actuarial survival of 90% and 83% at 6 and 12 months, respectively. In each "high-risk" group, perioperative mortality, actuarial survival to 1 year, and functional results were equivalent, and in some cases superior, to those in the corresponding "low-risk" patients. CONCLUSIONS: Severe hypercapnia, steroid dependence, profound pulmonary dysfunction, and inability to complete preoperative rehabilitation do not preclude successful lung volume reduction surgery and should not be regarded as absolute exclusionary criteria.

Use of transesophageal echocardiography in the detection and consequences of an intracardiac bullet.

A 17-year-old male sustained a gunshot injury to the chest. Transesophageal echocardiography showed the presence of a retained bullet in the pericardium and the absence of an intracardiac shunt, which provided important information for the treatment of the patient.

Delayed myocardial laceration after intrapericardial pneumonectomy.

Curative resection for large central bronchogenic tumors may require radical or intrapericardial pneumonectomy. Myocardial herniation through the pericardial defect is a rare early postoperative complication. Prevention of cardiac herniation and subsequent hemodynamic compromise is always necessary after intrapericardial pneumonectomy.

Pericardial repair of a tracheal laceration during transhiatal esophagectomy.

Transhiatal esophagectomy has recently been popularized for both benign and malignant esophageal disease. While we were performing a transhiatal esophagectomy for a squamous cell cancer of the upper third of the esophagus, a tear in the membranous trachea near the carina occurred. This was repaired through the cervical incision with a free pericardial patch. This solution to a potentially catastrophic complication of transhiatal esophagectomy gave a satisfactory result without early or late postoperative respiratory complications.

Diverticuloplasty for severe mucosal injury after cricopharyngeal myotomy.

Cricopharyngeal myotomy with either diverticulopexy or diverticulectomy is the recommended therapy for Zenker's diverticulum. Mucosal injury during myotomy is rare and usually can be managed by direct mucosal closure. A technique is described to repair a serious mucosal defect that may occur during cricopharyngeal myotomy.

Resection of pulmonary metastasis to the azygous lobe from a malignant fibrous histiocytoma.

A 55-year-old man developed a pulmonary metastasis to the azygous lobe from a malignant fibrous histiocytoma of the thigh. The azygous lobe was not identified at the initial resection. A simple technique for the identification and mobilization of the azygous lobe is presented. Preoperative identification of this anatomic variant may assist in resection of parenchymal neoplasms.

Staging: the key to rational management of lung cancer.

Staging is the quantitative assessment of malignant disease and allows logical groupings of patients with a similar extent of disease for prognostic, therapeutic, and analytic purposes. In bronchogenic carcinoma a stage is assigned based on size, location, and the extent of invasion of the primary tumor, as well as the presence of any regional or metastatic disease. Selecting the most appropriate treatment for a patient with bronchogenic carcinoma depends on precise staging. The extent of local invasion and presence of metastatic disease will determine the likelihood of complete resection and possible cure. Careful assessment of the history, blood chemistry, radiographic studies, bronchoscopy, mediastinoscopy, and exploration (thoracotomy) are all important staging tools. Routine radionuclide scans have no useful role when there is no clinical or laboratory evidence of metastases. The T status of a tumor is best judged by bronchoscopy and at thoracotomy. Thoracic surgeons must be familiar with the techniques available to determine T status intraoperatively and use this information when planning resection. Computed tomography of the chest has fallen short in predicting direct invasion of the mediastinum and chest wall. Cervical and anterior mediastinoscopy remain important tools in determining operability. Intraoperative assessment of node involvement determines the extent of resection and likelihood of cure.

Improved survival after resection of pulmonary metastases from malignant melanoma.

The value of resecting pulmonary metastases from malignant melanoma was retrospectively examined. Between 1981 and 1989, 56 patients (35 men and 21 women with a mean age of 49 years) had 65 pulmonary resections for histologically proven metastatic melanoma after treatment of the primary tumor. In patients undergoing thoracotomy, 50% (28/56) had pulmonary metastases as the initial site of recurrence. Twenty-eight patients (50%) had local-regional recurrence before the development of lung metastases. Eight lobectomies, two segmentectomies, and 55 wedge excisions were done. Fifty-four patients (54/56, 96%) underwent complete resection, and there were no operative deaths. The postthoracotomy actuarial survival was 25% at 5 years (median interval, 18 months). Location of the primary tumor, histology, thickness, Clark level, local-regional lymph node metastases, or type of resection was not associated with improved survival. Patients without regional nodal metastases before thoracotomy had a median survival of 30 months compared with 16 months for all others (p = 0.04). Patients with lung as the site of first recurrence had a median survival of 30 months compared with 17 months for patients with initial local-regional recurrence (p = 0.038, log-rank test). Despite systemic spread, patients with isolated pulmonary metastases from melanoma may benefit from metastasectomy.