Diversity of gene expression in adenocarcinoma of the lung.

The global gene expression profiles for 67 human lung tumors representing 56 patients were examined by using 24,000-element cDNA microarrays. Subdivision of the tumors based on gene expression patterns faithfully recapitulated morphological classification of the tumors into squamous, large cell, small cell, and adenocarcinoma. The gene expression patterns made possible the subclassification of adenocarcinoma into subgroups that correlated with the degree of tumor differentiation as well as patient survival. Gene expression analysis thus promises to extend and refine standard pathologic analysis.

Advances in the staging of intrathoracic malignancies.

Conventional staging of lung and esophageal tumors has consisted of a thorough history and physical examination, screening laboratory studies, computed tomography, and radionuclide imaging. Newer modalities including positron emission scanning, endoscopic ultrasonography, minimally invasive surgery (laparoscopy and thoracoscopy), and immunohistochemical staining of lymph node tissue. The role of these techniques are subject to much current debate, and they may ultimately add information that is valuable for staging and optimally treating patients with intrathoracic malignancies.

The current role of transhiatal esophagectomy.

Transhiatal esophagectomy is gaining increasing use as the preferred technique for esophagectomy. In this article, the indications, diagnostic evaluation, and technical details of the operative procedure for transhiatal esophagectomy are reviewed. Results of large clinical series are discussed and the potential pitfalls and risks of the procedure are reviewed. Current controversies and future trends are also discussed.

Primary non-small-cell lung cancer: determining the suitability of the patient and tumor for resection.

Choosing resective surgery for patients with bronchogenic carcinoma requires assessments of tumor suitability and patient suitability. Tumor suitability is largely dependent on the assessed stage of the tumor complex, based on characteristics of the primary tumor, detection of lymph node metastases, and detection of distant metastases. Imaging tests that assist in the determination of tumor stage include computed tomographic scans and positron emission tomographic (PET) scans. PET scans are more sensitive and specific than computed tomography. PET is also helpful in screening for distant metastases. Mediastinoscopy is required in most cases of mediastinal adenopathy. Patient suitability is assessed by predicting short-term surgical mortality, and the likelihood of crippling long-term respiratory failure. There is no single test that provides such information. Pulmonary function tests can be used to calculate the "predicted postoperative" function, and several algorithmic approaches have been devised to predict surgical risk. Assessments of regional pulmonary function are obtained with quantitative perfusion scintiscans. Cardiac function is also an important factor.

Dobutamine stress echocardiography for the preoperative evaluation of patients undergoing lung volume reduction surgery.

BACKGROUND: Lung volume reduction surgery has been proposed as a bridge to lung transplantation and as definitive therapy for advanced chronic obstructive lung disease. However, patient selection criteria and optimal preoperative assessment have not been clearly defined. OBJECTIVE: We investigated the feasibility, safety, and value of dobutamine stress echocardiography as a predictor of major early cardiac events in patients who underwent lung volume reduction surgery. METHODS: The study population consisted of 46 patients (21 men and 25 women, mean age 59 +/- 9 years) who underwent dobutamine stress echocardiography (maximum dose 40 microg. kg(-1). min(-1) plus atropine if needed) 180 days or less before lung volume reduction surgery. Adverse cardiac events were prospectively defined and tabulated during hospitalization after the operation and at subsequent outpatient visits. RESULTS: Dobutamine stress echocardiography was interpretable in 45 of 46 (98%) patients. There were no adverse events during testing. The studies revealed normal left ventricular systolic function at rest in all patients and normal right ventricular function in all patients but one. Thirteen patients had right ventricular enlargement. Estimated right ventricular systolic pressure was mildly elevated (>40 mm Hg) in 5 patients. Four patients (9%) had stress tests positive for ischemia. There were no perioperative deaths. Follow-up was available for 44 of 45 patients at a duration of 20.0 +/- 7.0 months. Two major adverse cardiac events occurred in the same patient in whom the results of dobutamine stress echocardiography were positive for ischemia (positive predictive value 25%, 95% confidence interval 0% to 83%; negative predictive value 100%, 95% confidence interval 90 to 100%). CONCLUSION: Despite end-stage chronic obstructive lung disease and poor ultrasound windows, dobutamine stress echocardiography is feasible and safe in patients undergoing evaluation for lung volume reduction surgery. It yields important information on right and left ventricular function and has an excellent negative predictive value for early and late adverse cardiac events.

Heart-lung transplantation for primary pulmonary hypertension.

BACKGROUND: The operation of choice for primary pulmonary hypertension remains controversial, as heart-lung transplantation, single-lung transplantation, and double-lung transplantation have all been advocated. METHODS: We reviewed our institution's experience with heart-lung transplantation for primary pulmonary hypertension. RESULTS: Thirty-nine patients had heart-lung transplantation for primary pulmonary hypertension. Operative mortality rate was 18%, and actuarial survival was 72% at 1 year, 67% at 2 years, and 42% at 5 years. Freedom from obliterative bronchiolitis was 91% at 1 year, 83% at 2 years, and 70% at 5 years. Freedom from obliterative bronchiolitis-related death was 100% at 1 year, 90% at 2 years, and 87% at 5 years. Freedom from accelerated graft coronary disease was 92% at 5 years. The most frequent causes of death were infection, obliterative bronchiolitis, and accelerated graft coronary disease. CONCLUSIONS: Heart-lung transplantation results in survival comparable to that reported for single or double lung transplantation. Obliterative bronchiolitis is a significant cause of late death but seems to occur less frequently with heart-lung transplantation than with lung transplantation alone. Accelerated coronary graft disease is rare in the first 5 years after transplantation.

Combined lung volume reduction and mitral valve reconstruction.

Combined lung volume reduction and mitral valve reconstruction was performed in a 66-year-old man with end-stage emphysema and severe mitral regurgitation. Quality of life, pulmonary function, 6-minute walk, echocardiographic degree of mitral regurgitation, and New York Heart Association heart failure classification all improved substantially. A lung volume reduction operation can safely be combined with complex cardiac operations for patients with disabling dyspnea of a multifactorial nature.

Preoperative echocardiographic evaluation of patients referred for lung volume reduction surgery.

BACKGROUND: The most efficient preoperative assessment for lung volume reduction surgery (LVRS) in patients with advanced emphysema is undefined. This study analyzed the preoperative assessment of patients by surface echocardiography (without and with dobutamine infusion), the results of which were used to exclude patients with significant pre-existing cardiac disease, a contraindication to LVRS, from the surgery. SETTING: A university-based, tertiary care referral center. METHODS: Patients with emphysema who met initial LVRS screening criteria underwent resting and stress surface echocardiography with Doppler imaging. Patients were evaluated prospectively for perioperative cardiac complications. RESULTS: Between July 1994 and December 1996, 503 candidates for LVRS were evaluated. Of these, 207 patients (81.8%) who had echocardiography performed at our institution formed the primary study group. Images were adequate for the analysis of chamber sizes and function in 206 patients (99.5%) undergoing resting echocardiography, and the images were adequate for wall motion analysis in 172 of 174 patients (98.9%) undergoing functional testing. Right heart abnormalities were common (40.1%). Significant pulmonary hypertension (> 35 mm Hg) was uncommon (5 patients, 5.4%) among the 92 patients who subsequently underwent right heart catheterization. Occult ischemia, left ventricular dysfunction, and valvular abnormalities also were uncommon. Thus, although Doppler imaging estimates of right ventricular systolic pressure were imperfect, echocardiographic findings of normal right heart anatomy and function excluded significant pulmonary hypertension. Ninety patients (43%) eventually underwent LVRS (70 bilateral and 20 unilateral). A total of 13 perioperative cardiac events occurred in 10 patients, 6 of whom had undergone preoperative echocardiography. No patient suffered acute myocardial infarction or cardiac death. CONCLUSIONS: Despite potential limitations due to severe obstructive lung disease, surface echocardiographic imaging is a feasible, noninvasive tool in this patient population to identify patients with evidence of cor pulmonale that suggests pulmonary hypertension. The routine use of surface resting and stress echocardiography for preoperative screening obviates the need for invasive right heart catheterization in many patients and results in a low incidence of significant perioperative cardiac complications.

Idiopathic pulmonary fibrosis: predicting response to therapy and survival.

Idiopathic pulmonary fibrosis (IPF) is associated with significant morbidity and mortality despite aggressive therapy. Thirty-eight patients with biopsy-proven IPF were studied to identify pretreatment features that could be used to predict short-term improvement in pulmonary function and improved longer term survival. In all patients, a pretreatment clinical (dyspnea), radiographic (chest radiograph), and physiologic (pulmonary function including exercise saturation) score was generated (CRP). A high-resolution CT scan (HRCT) was independently scored by four radiologists for ground glass (CT-alv) and linear opacity (CT-fib) on a scale of 0-4. Open lung biopsy samples were scored for cellular infiltration, interstitial fibrosis, desquamation, and granulation by an experienced pulmonary pathologist. All patients were treated with 3 mo of high-dose steroids and the CRP scoring repeated. Patients were divided into three groups: responders with a greater than 10-point drop in CRP (n = 10); stable with +/- 10 point change in CRP (n = 14); and nonresponders with > 10 point rise in CRP or death (n = 14). Those responding to steroids were treated for 18 mo in a tapering fashion. In all others, steroids were tapered quickly and oral cyclophosphamide prescribed. Responders (10 of 38) had a lower age (45.1+/-4.3 yr) than nonresponders (61.4+/-3.5 yr) or those remaining stable (53.1+/-3.3 yr) (p = 0.01). Pretreatment CRP was higher in responders (58.8+/-5.6) than nonresponders (40.5+/-4.7) or stable individuals (37.6+/-4.7) (p = 0.01). Cellular infiltration score of the open lung biopsies was higher in responders (7.6+/-0.6) than stable individuals (5.7+/-0.5) (p = 0.04). The CT-alv scores were higher and CT-fib scores were lower in responders than nonresponders. Receiver operating curve (ROC) analysis was employed to identify pretreatment features of longer term survival (follow-up of 29.1+/-2.3 mo). Only CT-fib (p = 0.009) and pathology fibrosis score (p = 0.03) were able to predict mortality. A pretreatment CT-fib score > or = 2.0 demonstrated 80% sensitivity and 85% specificity in predicting survival. Those patients who did not respond to initial steroid therapy demonstrated a worse long-term survival and greater likelihood of decreased pulmonary function. We demonstrate that pretherapy pulmonary function, pathologic and radiographic parameters are different in individuals who respond to initial prednisone therapy. Only HRCT imaging and pathologic fibrosis were able to reliably predict long-term survival in patients with biopsy-proven IPF.

Mycophenolate mofetil for obliterative bronchiolitis syndrome after lung transplantation.

BACKGROUND: The development of obliterative bronchiolitis after lung transplantation portends a poor long-term outcome because of progressive decline in allograft function. There are currently no effective means of treating this condition. METHODS: Thirteen patients in whom obliterative bronchiolitis syndrome developed after lung transplantation were treated with mycophenolate mofetil, an antimetabolite immunosuppressant, at a dose of 1.5 g orally twice daily. Patients were followed up clinically and with pulmonary function testing. RESULTS: Duration of mycophenolate mofetil therapy ranged from 1 week to 24 months (mean duration, 11.4 months). Pulmonary function test results stabilized in the majority of patients with no significant further decline in forced expiratory volume in 1 second. Two patients died of progressive obliterative bronchiolitis, 1 patient is alive with progressive disease, and 1 patient died of an acute infection. The drug was discontinued in 2 additional patients. In no patient did severe leukopenia or cytomegalovirus infection develop; 1 patient had a fungal infection, and 7 patients experienced gastrointestinal side effects. CONCLUSIONS: In the setting of obliterative bronchiolitis syndrome, mycophenolate mofetil is generally well tolerated and is associated with stabilization of pulmonary function test results. These findings suggest that the otherwise progressive process of obliterative bronchiolitis can be slowed.

Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring.

OBJECTIVE: The purpose of our study was to determine if three-level thin-section CT depicts idiopathic pulmonary fibrosis (IPF) pathology as accurately as CT obtained at 10-mm increments throughout the entire lungs. SUBJECTS AND METHODS: Thin-section (1.0- to 1.5-mm) images at 10-mm increments were obtained and scored prospectively in 25 consecutive patients with newly diagnosed IPF who were participating in a Special Center of Research grant for interstitial lung disease. Each patient's lobe was scored by four thoracic radiologists on a scale of 0-5 for both ground-glass attenuation and fibrosis. The radiologists used three images (limited CT) and also used the entire data set (complete CT). CT scores were compared with pathology scores from 67 open and thoracoscopic biopsies. Limited and complete scores were compared with each other (Pearson correlation coefficient). Interobserver variation in the CT scoring system was assessed using kappa values. RESULTS: CT fibrosis scores strongly correlated with pathology fibrosis scores for complete (r = .53, p = .0001) and limited (r = .50, p = .0001) CT. CT ground-glass scores correlated with the histologic inflammatory scores for each lobe on complete (r = .27, p = .03) and limited (r = .26, p = .03) CT. The desquamative subcomponent of the pathology inflammatory score had the highest correlation with the CT ground-glass scores (complete: r = .29, p = .01; limited: r = .33, p = .007). Good interobserver agreement existed for both the alveolar and fibrosis components of the CT scoring system (kappa values ranging from .51 to .83) for each lobe of the lung on limited and complete CT. CONCLUSION: Limited thin-section CT reveals the pathologic changes associated with IPF as well as CT obtained at 10-mm increments. An added advantage of limited thin-section CT is that it exposes patients to less radiation.

The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal disorder. Fibroplasia and deposition of extracellular matrix are dependent, in part, on angiogenesis. We postulated that an imbalance exists in the expression of angiogenic (IL-8) vs angiostatic (IFN-gamma-inducible protein (IP-10)) CXC chemokines, which favors net angiogenesis in IPF. To test this hypothesis, we obtained open lung biopsies either from normal patients undergoing thoracic surgery for reasons other than interstitial lung disease (control) or from patients with IPF. We found that levels of IL-8 were greater from tissue specimens of IPF patients then from those of controls. In contrast, IP-10 levels were higher from tissue specimens obtained from control subjects than from those from IPF patients. When IL-8 or IP-10 was depleted from IPF tissue specimens, tissue-derived angiogenic activity was markedly reduced or enhanced, respectively. Immunolocalization of IL-8 demonstrated that the pulmonary fibroblast (PF) of IPF lung was the predominant cellular source of IL-8. Isolated PF from IPF patients constitutively produced more IL-8 and less IP-10 than control PF. Conditioned media from IPF-PFs demonstrated constitutive angiogenic activity that was attributable, in part, to IL-8. Depletion of IP-10 from IPF-PF CM resulted in an increase in corneal neovascularization. These findings support the notion that IL-8 and IP-10 are important factors that regulate angiogenic activity in IPF.

Pulmonary smooth muscle proliferation occurring after lung transplantation.

We report the first example of smooth-muscle proliferations occurring in an allograft lung implanted in a recipient who had end-stage emphysema. Smooth-muscle proliferations were detected 46 months following transplantation in a 53-year-old woman. The lesions involved the airways and were bronchoscopically undetectable. Posttransplant smooth-muscle tumors have been described in liver transplant patients and are thought to be due to Epstein-Barr virus. Evidence of virus infection was not found in the current case.

Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function.

Lung-volume reduction surgery (LVRS) improves static lung elastic recoil in selected patients with severe chronic obstructive pulmonary disease (COPD). This explains the increase in FEV1 in many COPD patients who undergo LVRS, but fails to explain clinical improvement in those without changes in FEV1. We prospectively evaluated 17 patients after pulmonary rehabilitation but prior to and again at least 3 mo after bilateral LVRS done via median sternotomy. In addition to pulmonary function, lung elastic recoil, walking distance, and exercise capacity, we evaluated static and dynamic respiratory muscle (RM) function, and dyspnea. In 12 patients we also quantified dynamic hyperinflation (end-expiratory and end-inspiratory lung volume [EELV and EILV, respectively]). After LVRS, FEV1 rose from 26.7 +/- 1.8 to 39.0 +/- 3.7% predicted (p < 0.004), whereas TLC dropped from 134.7 +/- 4.8 to 118.3 +/- 4.4% predicted (p < 0.0002), and RV from 239.6 +/- 14.8 to 180.3 +/- 8.7% predicted (p < 0.0002). Isowork dyspnea decreased as assessed with a visual analogue scale (VAS) (79.6 +/- 5.2 versus 49.3 +/- 7.5 mm, p < 0.005) and the Borg scale (7.1 +/- 0.6 versus 3.5 +/- 0.6, p = 0.002). Walking distance improved significantly and, in the 12 patients in whom they were measured, EELV and EILV decreased at rest and at isowork. Maximal transdiaphragmatic pressure rose from 67.1 +/- 8.3 to 92.0 +/- 7.5 cm H2O (p < 0.03). Resting RM function changed little, but at isowork improved significantly after LVRS. Excluding one outlier, there was a strong linear correlation between the change in Borg-scale score at equivalent work loads before and after LVRS and the change in EELV (% predicted TLC, r = 0.75, p < 0.001), as well as between the change in Borg-scale score and the absolute decrease in end-expiratory pleural pressure (Ppl(e)) (r = 0.78, p = 0.004). Successful LVRS improves not only lung recoil, but also respiratory muscle function, and reduces dynamic hyperinflation. These changes help explain the decreased dyspnea and improved exercise capacity seen after LVRS, and add to current understanding of the mechanisms by which this procedure may help selected patients with severe emphysema.