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.

Nitric oxide usage after posttraumatic pneumonectomy.

Pneumonectomy is rarely required in the surgical management of thoracic traumatic injuries with high mortality rates. Right heart failure due to elevated pulmonary artery pressure and the adult respiratory distress syndrome have been leading causes of mortality reported after posttraumatic pneumonectomy. The beneficial effect of inhaled nitric oxide has been shown in pulmonary hypertension and in adult respiratory distress syndrome. We report the use of inhaled nitric oxide in the perioperative management of a patient undergoing emergent pneumonectomy.

A survey of physician attitudes and practices concerning cost-effectiveness in patient care.

OBJECTIVE: To identify physicians' views regarding cost-containment and cost-effectiveness and their attitudes and experience using cost-effectiveness in clinical decision making. DESIGN: A close-ended 30-item written survey. SUBJECTS: 1,000 randomly selected physicians whose practices currently encompass direct patient care and who work in the California counties of Sacramento, Yolo, Placer, Nevada, and El Dorado. OUTCOME MEASURES: Physician attitudes about the role of cost and cost-effectiveness in treatment decisions, perceived barriers to cost-effective medical practice, and response of physicians and patients if there are conflicts about treatment that physicians consider either not indicated or not cost-effective. RESULTS: Most physicians regard cost-effectiveness as an appropriate component of clinical decisions and think that only the treating physician and patient should decide what is cost-worthy. However, physicians are divided on whether they have a duty to offer medical interventions with remote chances of benefit regardless of cost, and they vary considerably in their interactions with patients when cost-effectiveness is an issue. CONCLUSION: Although physicians in the Sacramento region accept cost-effectiveness as important and appropriate in clinical practice, there is little uniformity in how cost-effectiveness decisions are implemented.

Expression of Egr-1 in late stage emphysema.

The transcription factor early growth response (Egr)-1 is an immediate-early gene product rapidly and transiently expressed after acute tissue injury. In contrast, in this report we demonstrate that lung tissue from patients undergoing lung reduction surgery for advanced emphysema, without clinical or anatomical evidence of acute infection, displays a selective and apparently sustained increase in Egr-1 transcripts and antigen, compared with a broad survey of other genes, including the transcription factor Sp1, whose levels were not significantly altered. Enhanced Egr-1 expression was especially evident in smooth muscle cells of bronchial and vascular walls, in alveolar macrophages, and some vascular endothelium. Gel shift analysis with (32)P-labeled Egr probe showed a band with nuclear extracts from emphysematous lung which was supershifted with antibody to Egr-1. Egr-1 has the capacity to regulate genes relevant to the pathophysiology of emphysema, namely those related to extracellular matrix formation and remodeling, thrombogenesis, and those encoding cytokines/chemokines and growth factors. Thus, we propose that further analysis of Egr-1, which appears to be up-regulated in a sustained fashion in patients with late stage emphysema, may provide insights into the pathogenesis of this destructive pulmonary disease, as well as a new facet in the biology of Egr-1.

Lung volumes before and after lung volume reduction surgery: quantitative CT analysis.

The volume and severity of pulmonary emphysema in individual lungs were measured by means of quantitative computed tomography (CT) studies in 28 patients (14 women, 14 men, median age 65 yr) who underwent either bilateral (n = 15) or unilateral (n = 13) lung volume reduction surgery (LVRS). Spirometric, total body plethysmographic, and CT data (at TLC and RV) were correlated before and after LVRS. Lung volumes determined by CT correlated well with volumes obtained by total body plethysmography (p < 0.0001). For individual lungs after LVRS, CT-derived mean lung capacity decreased 13% and residual volume 20% (p < 0.00001 for each), while mean total functional lung volume (TFLV, defined as the volume of lung with CT attenuation greater than -910 Hounsfield units) increased 9% (p < 0.01), and the mean ratio of the air space to tissue space volume (V(AS)/V(TS)) decreased more at RV (23%) than at TLC (14%) (p < 0.0005 for each). In contrast, unilateral LVRS did not affect exhalation from the unoperated lung (2% reduction in RV, p = NS). The magnitude of the postoperative response (CT-derived TLC, RV, TFLV, V(AS)/V(TS)) of each operated lung was comparable for unilateral and bilateral LVRS. Thus, a lung's response to LVRS was independent from that of the contralateral lung. Moreover, postoperative alterations in TFLV and FEV1 correlated significantly (r = 0.80, p < 0.0001), which suggests that the expansion of functioning tissue may contribute to the mechanism by which LVRS palliates airway obstruction.

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.

Verapamil crystalloid cardioplegia: an experimental evaluation of dose-response relationships.

Calcium channel blockers have been advocated as agents which enhance myocardial protection during ischemia and reperfusion. Unfortunately, while cellular integrity is preserved, myocardial function is depressed as a result of the negative inotropic effects of these agents. In order to assess the efficacy of verapamil cardioplegia, 25 isolated perfused rabbit hearts were studied. A model of normothermic ischemic arrest was utilized, employing either verapamil-free crystalloid cardioplegia or cardioplegia containing verapamil in concentrations of 0.5, 1.0, or 5.0 mg/liter. All three verapamil-treated groups demonstrated increased postischemic left ventricular developed pressure and improved postischemic compliance when compared with the untreated group (P less than 0.05). However, myocardial function was significantly depressed at 15 min of reperfusion in the 1.0 and 5.0 mg/liter verapamil-treated groups when compared with the 0.5 ml/liter group (P less than 0.05). These data suggest that the addition of verapamil to crystalloid cardioplegia results in enhanced myocardial function while minimizing the early reperfusion depression associated with higher dose therapy.

Preservation of myocardial function with mannitol reperfusate.

Reperfusion of the globally ischemic myocardium with mannitol has been shown to preserve myocardial function. However, it remains unclear whether the mechanism of mannitol protection relates to its hyperosmolar or free radical scavenging properties. Three groups of isolated, perfused rabbit hearts underwent 45 min of normothermic ischemia without cardioplegia in an experimental paradigm analogous to the clinical situation of coronary artery thrombosis with subsequent reperfusion. Six hearts were reperfused with an isosmolar solution, eight hearts were reperfused with a mannitol-containing solution (20 mOsm/liter), and five hearts were reperfused with a solution containing additional sodium chloride (10 meq/liter, 20 mOsm/liter) to control for the hyperosmotic effects of mannitol. Left ventricular developed pressure, its derivative dP/dt, and diastolic compliance were all significantly improved in the mannitol-reperfused hearts when compared with the hypertonic saline and control groups (p less than .05). There were no intergroup differences in myocardial edema formation, oxygen consumption, or lactate production. These data indicate that mannitol reperfusion offers significant myocardial protection independent of hyperosmolar properties. Free radical scavenging activity appears to be the most credible explanation for these observations, although confirmation of this mechanism awaits further biochemical and cellular investigation.

Mediastinal cutaneous fistulae arising as a complication of major cardiac surgery: the value of sinography and injection of methylene blue in their radical excision and immediate repair.

The management of chronic sternal wound infections is a difficult problem. Fistulography can be extremely useful in defining the extent of the infection. Staining the fistula with methylene blue aids the surgeon in the operative dissection and removal of infected material. A technique of reconstruction is described using an omental flap to fill in the retrosternal space and partially de-epithelialised pectoralis major myocutaneous flaps to cover the sternum.