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The influence of light dose-rate delivery was studied in human lung adenocarcinoma A549 cells treated with hematoporphyrin derivative (Photofrin II)-based photodynamic therapy. Clonogenic cell survival curves were generated for cells treated for 2 h with 25 µg/ml of Photofrin II followed by exposure to light delivered at 0.3, 0.15, 0.075, or 0.0375 milliwatts/cm 2 . Cellular sensitizer levels, as determined by fluorescence measurements, remained constant over the entire time course of all light exposures. As the dose rate of light delivery was decreased, a significant increase in cell survival was observed at equal light energies (225 mJ/cm 2 ). The enhancement in survival from the highest to the lowest dose rate used was 1.6-fold (at the 50% survival level). These findings may have important clinical implications relating to photodynamic therapy of tumors and may provide a partial explanation for treatment failure.

A pure "pattern-recognition" approach to lung diseases in immune compromised patients as seen on the chest film is of limited value since any infection can present with several different patterns, and processes such as embolism, aspiration, edema, and hemorrhage may give appearances similar to infection. However certain pulmonary infections do occur commonly in association with one type of immunosuppression but rarely with others. Knowledge of these associations assists in narrowing down the differential diagnosis and in deciding upon the most appropriate next confirmatory diagnostic step.

The effect of electrically maintained ventricular fibrillation on the nonhypertrophied canine heart during normothermic cardiopulmonary bypass was studied. Twenty dogs underwent ventricular fibrillation (7 volt, AC) for 60 minutes, at which time they were either killed immediately (Groups I and III) or taken off bypass for 1 hour (Groups II and IV). No differences occurred in the measured parameters of ischemic injury between those animals subjected to a hemodilution priming agent (Groups I and II) and those having fresh, autologous blood as the priming agent (Group III and IV). Subendocardial blood flow was equal to or greater than subepicardial blood flow in all groups in the control state, in the beating, nonworking heart, after 5 and 60 minutes of ventricular fibrillation, and 60 minutes after cessation of cardiopulmonary bypass (Groups II and IV). Transmural left ventricular bipolar action potential amplitude and local myocardial activation times were unchanged following 60 minutes of ventricular fibrillation. No difference occurred in the level of subendocardial ATP (4.67 ± 0.25 μmoles per gram) and subepicardial ATP (4.74 ± 0.17 μmoles per gram). Subendocardial creatine phosphate levels (10.92 ± 0.34 μmoles per gram) were unchanged from control levels (11.08 ± 0.76 μmoles per gram). However, subepicardial creatine phosphate increased to 13.11 ± 0.56 μmoles per gram. The serum CPK-MB isoenzyme level was zero in all control samples and every 15 minutes thereafter in all experiments. The left ventricular free wall, papillary muscles, and ventricular septum showed no histologic evidence of ischemic injury on hematoxylin and eosin, phosphotungstic acid, hematoxylin, or succinic dehydrogenase enzyme stains. Although the deleterious effects of ventricular fibrillation on the hypertrophied left ventricle are well documented, this study demonstrates that induced ventricular fibrillation is a safe modality to employ during cardiopulmonary bypass of the nonhypertrophied heart.

The use of monochlorobimane (MCIB) as a fluorescence label for glutathione (GSH) quantitatinn was investigated in human tumor cell lines. When MCIB was used with a hamster fibroblast cell line under conditions where GSH was either depleted or elevated, an excellent correlation between bimane-GSH fluorescence and the standard cyclic GSH reductase assay (Tietze's) was accomplished. When the MCIB technique was applied to a human lung adenocarcinoma cell line, little or no GSH labeling was noted even at MCIB levels 1OX higher than that used for the hamster line. HPLC analysis suggested that the source of the problem may be the affinity for MCIB to glutathione S-transferase. By using higher dye concentrations and longer staining times, adequate staining was possible. While the MCIB technique may have problems quantitating GSH levels between cell types, the possibility of examining GSH heterogeneity in solid tumor biopsies remains feasible.

Cunninghamella bertholletiae, an uncommon cause of human infection, has been reported with increasing frequency in recent years. C. bertholletiae belongs to the order Mucorales and produces infections similar to those produced by the other agents of mucormycosis. Infections with this group of organisms have typically been seen either in patients with diabetes mellitus or in those receiving chemotherapy. Recent reports of mucormycosis in dialysis patients receiving deferoxamine for iron or aluminum overload have raised the possibility that deferoxamine therapy is a risk factor for mucormycosis. A case of C. bertholletiae infection in a patient receiving deferoxamine for iron overload unrelated to hemodialysis was investigated in detail, and possible explanations for this patient's infection were assessed.

We have used the St. Jude Medical cardiac valve prosthesis without postoperative anticoagulation in 34 children undergoing valve replacement since March, 1979. The 19 boys and 15 girls ranged in age from 9 months to 21 years. The valve replaced was mitral in 12 patients, aortic in 14, pulmonary in three, and both mitral and aortic in two. One patient had implantation of a St. Jude Medical valve in a pulmonary conduit, and a left-sided tricuspid valve was replaced in two children. There were three operative deaths, all in infants with complex disease. One patient died suddenly at home 5 weeks after valve replacement, probably of ventricular arrhythmia. During follow-up of 1 to 50 months, comprising 646 patient months, no thromboembolic complications have been observed. Although use of the St. Jude Medical prosthesis without anticoagulation is still investigational, our preliminary data suggest that the risk of thromboembolism in unanticoagulated children with this valve is not greater than that in anticoagulated adults. The results justify continuing investigation of the St. Jude Medical prosthesis in children without postoperative anticoagulation.

Between 1982 and 1987, 74 patients (46 men and 28 women) had exploration for presumed metastases from high-grade soft tissue sarcoma of the head/neck, extremity, or trunk. Ages ranged from 11 to 75 years (median 38 years). Thirty (41%) had multiple procedures for recurrences (range two to six explorations). Median postthoracotomy time for the group of patients with histologically confirmed sarcoma (n = 63) was 20.3 months. Patients rendered free of disease at initial thoracotomy had significantly longer postthoracotomy survival times (26.8 months median) than those with unresectable metastatic disease (9 months median); p2

Accurate preoperative evaluation of the inferior vena cava and renal vein in patients with renal cell carcinoma is mandatory to plan a successful surgical approach. The presence of venous extension may alter transfusion and anesthetic requirements, as well as require the addition of a vascular surgeon to the operative team. Venacavography traditionally has been considered the most reliable method to identify tumor thrombus, although magnetic resonance imaging has been proposed as a possible noninvasive alternative. We compared prospectively the accuracy of these 2 methods in 44 consecutive patients with renal cell carcinoma who subsequently underwent nephrectomy. Of the 44 patients 11 (25%) had tumor extension into the inferior vena cava and 17 (39%) had involvement of the renal vein at operation. Venacavography and magnetic resonance imaging correctly identified 9 of the 11 patients (82%) with inferior vena caval thrombus. When the results of both tests were combined, all 11 cases of vena caval extension were identified. Venacavography was slightly more sensitive (71%) in identifying the presence of renal vein thrombus than magnetic resonance imaging (65%) but these differences were not statistically significant. Magnetic resonance imaging better localized the thrombus within the renal vein. We conclude that venacavography and magnetic resonance imaging offer equal diagnostic accuracy in the identification of venous extension of renal cell carcinoma. The combination of both tests results in higher diagnostic yield than either test alone. Neither test by itself is reliable in the presence of a large, bulky adenopathic lesion that compresses the inferior vena cava.

Allele loss is a hallmark of chromosome regions harboring recessive oncogenes. Lung cancer frequently demonstrates loss of heterozygosity on 17p. Recent evidence suggests that the p53 gene located on 17p13 has many features of such an antioncogene. The p53 gene was frequently mutated or inactivated in all types of human lung cancer. The genetic abnormalities of p53 include gross changes such as homozygous deletions and abnormally sized messenger RNAs along with a variety of point or small mutations, which map to the p53 open reading frame and change amino acid sequence in a region highly conserved between mouse and man. In addition, very low or absent expression of p53 messenger RNA in lung cancer cell lines compared to normal lung was seen. These findings, coupled with the previous demonstration of 17p allele loss in lung cancer, strongly implicate p53 as an anti-oncogene whose disruption is involved in the pathogenesis of human lung cancer.

Thoracotomy and median sternotomy have both been advocated for resection of pulmonary metastases, and the advantages of each approach remain disputed. Patients with adult soft-tissue sarcomas undergoing resection of pulmonary metastases at the National Cancer Institute were studied retrospectively to assess the results of each surgical approach. Between 1981 and 1984, 65 patients underwent 78 sternotomies (7 lobectomies, 71 wedge resections); a mean of 9.5 nodules were resected per patient (range, 1 to 61). Resection of all nodules was accomplished in 60 of 71 explorations (84%) in patients with documented metastases. Benign lesions were found during 7 explorations (9%). Thirteen of 30 patients (43%) with unilateral metastases on linear tomography (LT), 45% (9 of 20) of patients with unilateral metastases on computed tomography (CT), and 38% (5 of 13) of patients with unilateral metastases on both CT and LT had bilateral metastases at sternotomy. Survival by type of incision was compared for 84 patients who underwent complete resection of their metastases (42 by sternotomy and 42 by thoracotomy); the minimum follow-up was two years. The groups did not differ significantly with respect to prognostic variables (tumor doubling time, disease-free interval, or number of nodules resected). There was no significant difference in actuarial survival between the two groups. The complication rate was 15% for the sternotomy group and 10% for the thoracotomy group (difference not significant). There were no operative deaths. Median sternotomy results in detection of unsuspected bilateral metastases and avoidance of a second operative procedure, but it does not increase operative morbidity or mortality or compromise overall patient survival.

Thirty-nine patients with potentially resectable cancer of the middle or lower esophagus who had not previously been treated were randomly assigned to receive either immediate operation (n = 20) or operation plus preoperative and postoperative therapy with cisplatin, vindesine, and bleomycin (n = 19). Patients were stratified by tumor size and location and by sex, with no significant differences appearing between the two treatment groups. Median follow-up for both groups was 30 months. The preoperative response rate to chemotherapy was 47%. The postoperative complication rate for patients in the operation-only group was 47%; it was 29% for patients receiving chemotherapy. The overall resectability rates were similar for the two groups. Patients responding to chemotherapy preoperatively had significantly prolonged survival (median greater than 20 months) when compared with either nonresponders (median 6.2 months) or patients receiving only operation (median 8.6 months). A highly significant correlation was noted between a weight loss of less than 10% and response to chemotherapy, which suggested that responses occurred in patients with less advanced disease. We conclude that preoperative and postoperative cisplatin, vindesine, and bleomycin chemotherapy has acceptable toxicity and does not increase the incidence of postoperative complications. The natural history of epidermoid carcinoma of the esophagus is altered and overall survival is prolonged for patients responding to preoperative chemotherapy. Potential responding patients can be identified by the degree of preoperative weight loss.

The acquired immune deficiency syndrome is characterized by the development of multiple recurrent opportunistic infections or unusual neoplasms in individuals with no prior history of immune suppression. This report summarizes the thoracic diseases encountered in such patients before after death and the role of diagnostic techniques currently used in the evaluation of thoracic disease in 15 patients with this syndrome. Efficacy of treatment was determined by correlation with postmortem findings in all patients. Pulmonary disease was present in all 15 patients and necessitated 23 transbronchial biopsies in 11 patients. Pneumocystis carinii pneumonia and cytomegalovirus pneumonia were the most common findings. Nine open lung biopsies in eight patients disclosed either Pneumocystis carinii pneumonia or Kaposi's sarcoma. Esophageal disease was present in four patients, and endoscopic evaluation demonstrated Candida esophagitis (two), esophageal Kaposi's sarcoma (one), and cytomegalovirus esophagitis and Kaposi's sarcoma (one). Mean time to death from diagnosis of acquired immune deficiency syndrome was 7.7 months, with respiratory insufficiency being the most common cause of death (9/15,60 %). Pneumocystis carinii pneumonia was successfully eradicated in 70 % of the patients. Candida esophagitis was ameliorated in both patients with the disease. Unsuspected pulmonary Kaposi's sarcoma, cytomegalovirus pneumonitis, and other infectious pathogens were documented at autopsy. These data reveal that Pneumocystis carinii pneumonia and Candida esophagitis can be managed successfully in patients with acquired immune deficiency syndrome if appropriately diagnosed. The major cause of death in this series was pulmonary insufficiency, often the result of severe cytomegalovirus infection. Thoracic surgeons must continue to play an aggressive and important role in the early diagnosis and management of potentially treatable pulmonary and esophageal disease in these patients.

We have investigated the role of resection in the treatment of patients with isolated pulmonary metastases from Ewing's sarcoma. In a retrospective review, 19 patients with the diagnosis of Ewing's sarcoma treated at the National Cancer Institute from 1965 to 1985 who underwent chest exploration for resection of pulmonary nodules were evaluated. Ten patients (53%) were made disease free by resection of pulmonary metastases, six patients (32%) were found to have unresectable disease, and three patients (16%) were found to have benign pulmonary disease. The actuarial 5 year survival rate of the 10 patients successfully made disease free by resection was 15%, and the median survival of this group was 28 months. In contrast, the median survival of the six patients not made disease free was 12 months, and no patient with residual disease was alive 22 months after thoracotomy (p2 = 0.0047). There were no postoperative deaths and only three minor postoperative complications for 25 operative procedures. Various prognostic variables were analyzed to determine their influence on postmetastasectomy survival. There was no difference in postmetastasectomy survival between patients who underwent resection of synchronous versus metachronous pulmonary metastases (p2 = 0.90). Patients who underwent resection of fewer than four malignant nodules had a significantly longer postmetastasectomy disease-free survival (p2 = 0.0019) and overall survival (p2 = 0.06) than those undergoing resection of four or more nodules. Patients who underwent resection of metastases that developed during chemotherapy had a significantly shorter postmetastasectomy survival that those who underwent resection of metastases that developed after chemotherapy (p2 = 0.0295). Our data show that selected patients with Ewing's sarcoma metastatic to the lungs may benefit from an aggressive surgical approach. Also, a significant proportion of these patients will have benign pulmonary disease and can thus avoid additional intensive systemic therapy.

Les auteurs continuent de suivre les patients afin de voir l'efficacite a long terme de ce medicament

Between 1970 and 1986, 49 patients had resection of presumed pulmonary metastases from malignant melanoma. Sixteen patients were found to have benign disease only despite the appearance of a new nodule in 13. Patients with benign disease had a significantly longer mean survival (169 months) compared with the group with malignant disease (22 months). Median survival for all patients with malignant disease was 13 months. Survival after resection did not correlate with the Clark level of the original lesion, lymph node status, disease-free interval, or number of nodules on preoperative tomograms. Two of 10 patients with 1 nodule resected are long-term survivors (88 and 120 months). Exploration in patients with presumed pulmonary metastases from melanoma is justified to rule out benign disease even if a new solitary nodule is detected. There are no prognostic indicators predicting survival after resection of melanoma metastases, and a significant number of patients will have benign disease.

The ability of coronary collateral vessels to supply an adequate volume of blood to the subendocardium during the resting state and during periods of stress was studied. Regional myocardial blood flow was determined by the radioactive microsphere technique. Ameroid constricting devices were placed around the left circumflex coronary artery in 22 adult mongrel dogs. Three months later, regional myocardial blood flow was measured in a normal area of the left ventricle as well as in the area supplied entirely by coronary collateral vessels. Collateral blood flow was sufficient in the resting state to prevent myocardial ischemia distal to a gradually occluded coronary artery. However, in 10 animals (Group I) without aorta-coronary bypass grafts (ACBG), a selective underperfusion of the collateralized subendocardium occurred during periods of stress. In 12 animals (Group II), this selective underperfusion of the collateralized subendocardium with stress was abolished by placing ACBG's distal to the site of coronary artery occlusion.

Tolerance of esophagus to intraoperative radiotherapy (IORT) was investigated in dogs. Thirteen adult foxhounds were subjected to right thoractomy, mobilization of the intrathoracic esophagus, and IORT to a 6 cm full-thickness esophageal segment using 9 MeV electrons at doses of 0, 2,000, or 3,000 cGy. Dogs were followed clinically and were evaluated at regular intervals after treatment with fiberoptic esophagoscopy, barium swallows, and postmortem histologic evaluations. One sham-irradiated control dog showed no abnormalities during follow-up of 24 months. Seven dogs receiving 2,000 cGy IORT showed transient mild dysphagia and mild esophagitis, but no clinically or pathologically significant complications. Five dogs receiving 3,000 cGy demonstrated severe ulcerative esophagitis within 6 weeks of treatment which progressed to chronic ulcerative esophagitis with stricture formation by 9 months following IORT. One 3,000 cGy dog died at 13 months from an esophageal perforation. On the basis of a pilot experience using 13 experimental animals, it was concluded that intact canine esophagus tolerates IORT well to doses of 2,000 cGy, but doses of 3,000 cGy pose serious and potentially lethal risks. The clinical application of IORT to the treatment of human intrathoracic neoplasms requiring esophageal irradiation should be approached with caution, particularly at doses exceeding 2,000 cGy.

The evolution and transmural distribution of coronary collateral blood flow in acute myocardial infarction was determined in 24 trained, unanesthetized dogs by injection of radioactive microspheres into the coronary circulation. Acute coronary artery occlusion resulted in a greater decrease in subendocardial flow than subepicardial flow in both the central and marginal zones of the infarct. Coronary collateral blood flow was distributed primarily to the marginal zone and to the subepicardium of the central zone of the infarct. The greatest increase in collateral flow occurred between 12 and 18 hours after coronary artery occlusion. By 24 hours after coronary occlusion, blood flow to all areas of the infarct except the subendocardium of the central zone had returned to near control levels. This disproportionate distribution of coronary collateral blood flow during the early stages of myocardial ischemic injury helps to explain the apparent lack of protection of the subendocardium by collateral flow.

The use of preoperative computed tomographic (CT) scans of the chest in carcinoma of the esophagus to associate preoperative staging with postoperative survival is controversial. Thirty-two patients who underwent esophagectomy and reconstruction were examined with respect to a variety of variables available on preoperative evaluation, including lesion width on CT scan, lesion length on CT scan, and barium esophagogram. Each variable was evaluated for its ability to predict the presence of extraesophageal spread of tumor, as determined pathologically by logistic regression analysis. Lesions greater than 3.0 cm in width by CT scan were associated with a significantly higher incidence of extraesophageal spread. Tumor location, gender, histologic grade, presence of in situ lesions, vascular invasion, eosinophilia, nodal metastases, and preoperative chemotherapy had no predictive value for survival. Duration of survival was affected by the presence of esophageal spread of disease and lesion width. These results indicate that preoperative CT scanning can predict extraesophageal spread of tumor, and this is associated with overall survival.

Objectives: Our objective was to analyze the impact of preoperative and postresection solid tumor volumes on outcomes in 47 of 48 consecutive patients undergoing resection for malignant pleural mesothelioma who were treated prospectively and randomized to photodynamic therapy or no photodynamic therapy. Methods: From July 1993 to June 1996, 48 patients with malignant pleural mesothelioma had cytoreductive debulking to 5 mm or less residual tumor by extrapleural pneumonectomy ( n = 25) or pleurectomy/decortication ( n = 23). Three-dimensional computed tomographic reconstructions of preresection and postresection solid tumor were prospectively performed and the disease was staged postoperatively according to the new International Mesothelioma Interest Group staging. Results: Median survival for all patients is 14.4 months (extrapleural pneumonectomy, 11 months; pleurectomy/decortication, 22 months; p 2 = 0.07). Median survival for preoperative volume less than 100 was 22 months versus 11 months if more than 100 cc, p 2 = 0.03. Median survival for postoperative volume less than 9 cc was 25 months versus 9 months if more than 9 cc, p 2 = 0.0002. Thirty-two of forty-seven (68%) had positive N1 or N2 nodes. Tumor volumes associated with negative nodes were significantly smaller (median 51 cc) than those with positive nodes (median 166 cc, p 2 = 0.01). Progressively higher stage was associated with higher median preoperative volume: stage I, 4 cc; stage II, 94 cc; stage III, 143 cc; stage IV, 505 cc; p 2 = 0.007 for stage I versus II versus III versus IV. Patients with preoperative tumor volumes greater than 52 cc had shorter progression-free intervals (8 months) than those 51 cc or less (11 months; p 2 = 0.02). Conclusions: Preresection tumor volume is representative of T status in malignant pleural mesothelioma and can predict overall and progression-free survival, as well as postoperative stage. Large volumes are associated with nodal spread, and postresection residual tumor burden may predict outcome. (J Thorac Cardiovasc Sufg 1998;115:310-8)

Introduction: Lung cancer is the highest cause of mortality among tumor pathologies worldwide. There are no validated techniques for an early detection of pulmonary cancer lesions other than low-dose helical computed tomography scan. Unfortunately, this method has some negative effects. Recent studies have laid the basis for development of exosomes-based techniques to screen/diagnose lung cancers. As the isolation of circulating exosomes is a minimally invasive procedure, this technique opens new possibilities for diagnostic applications. Methods: We used a first set of 30 plasma samples from as many patients, including 10 patients affected by lung adenocarcinomas, 10 with lung granulomas, and 10 healthy smokers matched for age and sex as negative controls. Wide-range microRNAs analysis (742 microRNAs) was performed by quantitative real time polymerase chain reaction. Data were compared on the basis of lesion characteristics, using WEKA software for statistics and modeling. Subsequently, selected microRNAs were evaluated on an independent larger group of samples (105 specimens: 50 lung adenocarcinomas, 30 lung granulomas, and 25 healthy smokers). Results: This analysis led to the selection of four microRNAs to perform a screening test (miR-378a, miR-379, miR-139-5p, and miR-200b-5p), useful to divide population into two groups: nodule (lung adenocarcinomas + carcinomas) and non-nodule (healthy former smokers). Six microRNAs (miR-151a-5p, miR-30a-3p, miR-200b-5p, miR-629, miR-100, and miR-154-3p) were selected for a second test on the nodule population to discriminate between lung adenocarcinoma and granuloma. Conclusions: The screening test showed 97.5% sensitivity, 72.0% specificity, and area under the curve receiver operating characteristic of 90.8%. The diagnostic test had 96.0% sensitivity, 60.0% specificity, and area under the curve receiver operating characteristic of 76.0%. Further evaluation is needed to confirm the predictive power of these models on larger cohorts of samples.

Objective Current video-assisted thoracoscopic surgery training models rely on animals or mannequins to teach procedural skills. These approaches lack inherent teaching/testing capability and are limited by cost, anatomic variations, and single use. In response, we hypothesized that video-assisted thoracoscopic surgery right upper lobe resection could be simulated in a virtual reality environment with commercial software. Methods An anatomy explorer (Maya [Autodesk Inc, San Rafael, Calif] models of the chest and hilar structures) and simulation engine were adapted. Design goals included freedom of port placement, incorporation of well-known anatomic variants, teaching and testing modes, haptic feedback for the dissection, ability to perform the anatomic divisions, and a portable platform. Results Preexisting commercial models did not provide sufficient surgical detail, and extensive modeling modifications were required. Video-assisted thoracoscopic surgery right upper lobe resection simulation is initiated with a random vein and artery variation. The trainee proceeds in a teaching or testing mode. A knowledge database currently includes 13 anatomic identifications and 20 high-yield lung cancer learning points. The "patient" is presented in the left lateral decubitus position. After initial camera port placement, the endoscopic view is displayed and the thoracoscope is manipulated via the haptic device. The thoracoscope port can be relocated; additional ports are placed using an external "operating room" view. Unrestricted endoscopic exploration of the thorax is allowed. An endo-dissector tool allows for hilar dissection, and a virtual stapling device divides structures. The trainee's performance is reported. Conclusions A virtual reality cognitive task simulation can overcome the deficiencies of existing training models. Performance scoring is being validated as we assess this simulator for cognitive and technical surgical education.

Objective Osteopontin is a multifunctional phosphoprotein with an important but poorly understood role in non–small cell lung cancer pathogenesis. We hypothesize that osteopontin isoforms ( OPNa , OPNb , and OPNc ) have divergent roles in non–small-cell lung cancer angiogenesis and divergent impact on vascular endothelial growth factor secretion. Methods We examined mRNA expression using reverse transcriptase-polymerase chain reaction primers for 3 osteopontin isoforms in non–small-cell lung cancer and immortalized bronchial epithelial cell lines, and correlated expression with osteopontin secretion into media detected by enzyme-linked immunosorbent assay. Angiogenic properties conferred by osteopontin isoforms were evaluated by transfecting cDNA plasmids specific to each isoform and controls into non–small-cell lung cancer cell lines, H153 and H358 (low endogenous osteopontin) and A549 and H460 (high endogenous osteopontin), analyzing conditioned media on a bovine capillary endothelial platform, and measuring vascular endothelial growth factor levels by enzyme-linked immunosorbent assay. Results OPNa mRNA expression correlated with osteopontin secretion in cell lines ( r = 0.912, P = .0006). OPNa overexpression significantly increased tubule length compared with controls, OPNb had a similar, but less pronounced effect, and OPNc significantly decreased tubule length compared with controls in each cell line. OPNa overexpression was associated with significant increases in vascular endothelial growth factor secretion, whereas OPNb had no effect and OPNc overexpression was associated with significant decreases in vascular endothelial growth factor compared with controls in each cell line. Conclusion We demonstrated divergent effects of osteopontin isoforms on non–small-cell lung cancer angiogenesis and vascular endothelial growth factor secretion. OPNa overexpression was associated with increased bovine capillary endothelial tubule length and vascular endothelial growth factor secretion, whereas OPNc was associated with decreases in both. These findings may lead to therapeutic strategies for selective isoform inhibition in non–small cell lung cancer.

ObjectiveThe inflammatory process of aortic stenosis involves the differentiation of aortic valve myofibroblasts into osteoblasts. Osteopontin, a proinflammatory glycoprotein, both stimulates differentiation of myofibroblasts and regulates the deposition of calcium by osteoblasts. Osteopontin levels are increased in patients with such conditions as end-stage renal disease, ectopic calcification, and autoimmune disease. We hypothesized that increased plasma osteopontin levels might be associated with the presence of aortic valve calcification and stenosis.MethodsVenous blood from volunteers older than 65 years undergoing routine echocardiographic analysis or aortic valve surgery for aortic stenosis was collected. Plasma osteopontin levels were measured by means of enzyme-linked immunosorbent assay. The presence of aortic stenosis was defined as an aortic valve area of less than 2.0 cm2. Aortic valve calcification was assessed by using a validated echocardiographic grading system (1, none; 2, mild; 3, moderate; 4, severe). Comparisons were performed with nonpaired t tests.ResultsAortic stenosis was present in 23 patients (mean age, 78 years) and was absent in 7 patients (mean age, 72 years). Aortic valve calcification scores were 3.5 ± 0.6 and 1.3 ± 0.5 in patients with and without aortic stenosis, respectively (P < .001). Patients with no or mild aortic valve calcification had lower osteopontin levels compared with patients with moderate or severe aortic valve calcification (406.1 ± 165.8 vs 629.5 ± 227.5 ng/mL, P = .01). Similarly, patients with aortic stenosis had higher osteopontin levels compared with patients without aortic stenosis (652.2 ± 218.7 vs 379.7 ± 159.9 ng/mL, P < .01).ConclusionIncreased levels of plasma osteopontin are associated with the presence of aortic valve calcification and stenosis. These findings suggest that osteopontin might play a functional role in the pathogenesis of calcific aortic stenosis.

Introduction:Surgical intervention rates for mesothelioma patients treated at specialized tertiary hospitals are well more than 42%. Mesothelioma surgical strategies in the community are less well defined. This study evaluates the frequency of use and predictors of cancer-directed surgical intervention in a nontertiary-based population and the predictors for surgical intervention.Methods:The Surveillance, Epidemiology, and End Results database was searched from 1990 to 2004. Variables analyzed included age, sex, race, year of diagnosis, region, vital status, stage, surgery, and reasons for no surgery. The association of patient variables on receipt of cancer-directed surgery was evaluated using ϰ2 tests and logistic regression. The incidence of mesothelioma was also evaluated over this period of time.Results:Pathologically proven malignant pleural mesothelioma was identified in 1166 women and 4771 men. The rate of cancer-directed surgery was 22% (n = 1317). Significant predictors of receiving cancer-directed surgery included race, age, and stage (all p < 0.0001). A landmark analysis on the effect of cancer-directed surgery on survival after adjusting for patient and disease characteristics demonstrated a hazard ratio of 0.68 (p < 0.0001). The incidence rate of malignant pleural mesothelioma has remained constant.Conclusions:The rate of surgical intervention in the community is lower compared with tertiary referral centers. Age, stage, and race predict the likelihood of receiving cancer-directed surgery. A lower rate of cancer-directed surgery and worse overall outcome were observed in black patients. As part of quality assurance, referral of patients to centers with multidisciplinary programs that include thoracic surgical expertise should be considered.

Objectives: The primary objective of this study was to evaluate the benefit of using a new fluorescence-reflectance imaging system, Onco-LIFE, for the detection and localization of intraepitheal neoplasia and early invasive squamous cell carcinoma. A secondary objective was to evaluate the potential use of quantitative image analysis with this device for objective classification of abnormal sites. Design: This study was a prospective, multicenter, comparative, single arm trial. Subjects for this study were aged 45 to 75 years and either current or past smokers of more than 20 pack-years with airflow obstruction, forced expiratory volume in 1 second/forced vital capacity less than 75%, suspected to have lung cancer based on either sputum atypia, abnormal chest roentgenogram/chest computed tomography, or patients with previous curatively treated lung or head and neck cancer within 2 years. Materials and Methods: The primary endpoint of the study was to determine the relative sensitivity of white light bronchoscopy (WLB) plus autofluorescence-reflectance bronchoscopy compared with WLB alone. Bronchoscopy with Onco-LIFE was carried out in two stages. The first stage was performed under white light and mucosal lesions were visually classified. Mucosal lesions were classified using the same scheme in the second stage when viewed with Onco-LIFE in the fluorescence-reflectance mode. All regions classified as suspicious for moderate dysplasia or worse were biopsied, plus at least one nonsuspicious region for control. Specimens were evaluated by the site pathologist and then sent to a reference pathologist, each blinded to the endoscopic findings. Positive lesions were defined as those with moderate/severe dysplasia, carcinoma in situ (CIS), or invasive carcinoma. A positive patient was defined as having at least one lesion of moderate/severe dysplasia, CIS, or invasive carcinoma. Onco-LIFE was also used to quantify the fluorescence-reflectance response (based on the proportion of reflected red light to green fluorescence) for each suspected lesion before biopsy. Results: There were 115 men and 55 women with median age of 62 years. Seven hundred seventy-six biopsy specimens were included. Seventy-six were classified as positive (moderate dysplasia or worse) by pathology. The relative sensitivity on a per-lesion basis of WLB + FLB versus WLB was 1.50 (95% confidence interval [CI], 1.26–1.89). The relative sensitivity on a per-patient basis was 1.33 (95% CI, 1.13–1.70). The relative sensitivity to detect intraepithelial neoplasia (moderate/severe dysplasia or CIS) was 4.29 (95% CI, 2.00–16.00) and 3.50 (95% CI, 1.63–12.00) on a per-lesion and per-patient basis, respectively. For a quantified fluorescence reflectance response value of more than or equal to 0.40, a sensitivity and specificity of 51% and 80%, respectively, could be achieved for detection of moderate/severe dsyplasia, CIS, and microinvasive cancer. Conclusions: Using autofluorescence-reflectance bronchoscopy as an adjunct to WLB with the Onco-LIFE system improves the detection and localization of intraepitheal neoplasia and invasive carcinoma compared with WLB alone. The use of quantitative image analysis to minimize interobserver variation in grading of abnormal sites should be explored further in future prospective clinical trial.

Three patients with Cushing syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) production underwent direct 22-gauge needle aspiration of bronchial (two cases) and mediastinal (one case) carcinoid tumors. High levels of ACTH were measured in all three tumors. This technique permits absolute identification of an ectopic source of ACTH before surgery.

A patient with a chest wall sarcoma whose original prosthetic reconstruction became infected after a course of radiation therapy is described. After removal of the prosthesis, salvage reconstruction was performed using a transverse rectus abdominis musculocutaneous flap. Management of the infected chest wall prosthesis, with emphasis on the indications for use of the transverse rectus abdominis musculocutaneous flap, is discussed.

The authors describe CT-guided percutaneous aspiration of 13 apparent mediastinal abscesses in 12 extremely ill patients, excluding the diagnosis in 3 and establishing it in 9. Six patients subsequently underwent percutaneous catheter drainage, facilitating elective surgery in 1 and proving curative in 5.

A prospective serial evaluation in 19 patients with soft-tissue and osteogenic sarcomas was performed to determine whether computerized tomography (CT) or conventional linear tomography (LT) detected pulmonary metastases earlier. Analysis of the metastatic nodules was performed radiographically with histologic confirmation by obtaining serial CTs and LTs followed by metastasectomy. Nodules were classified as stable, growing, or developing and by detection on CT and/or LT. CT was the first positive study in a significantly greater number of patients (13 CT, 1 LT; P less than .005), and CT detected the nodules earlier than LT (56 CT first v 7 LT first; P less than .0001). Ninety of 166 nodules resected were detected by CT, LT, or both (54%). The median size of metastatic nodules documented at surgical exploration and first detected by CT was significantly smaller than that first detected by LT (7.6 mm for CT v 13.2 mm for LT; P less than .05). Of 55 histologically documented metastases detected initially either by CT or LT, CT was markedly superior to LT with 50 (91%) first detected only by CT (P less than .001). These data reveal that CT detects more pulmonary metastases earlier than LT and that developing or growing nodules in patients with sarcomas are usually metastases. Decisions regarding metastasis resection in sarcoma patients, therefore, should be based primarily on CT findings.

Photodynamic therapy is a recently introduced treatment for surface malignancies. Since January 1987, 10 patients with endobronchial neoplasms have had bronchoscopic photodynamic therapy at similar dose rates (400 mW/cm) for total atelectasis (2), carinal narrowing with respiratory insufficiency (2), or partial obstruction without collapse (4). Two patients underwent photodynamic therapy as a preliminary to immunotherapy. Histologies included endobronchial metastases (colon, ovary, melanoma, and sarcoma, 1 each; and renal cell, 3) and primary lung cancer (3). The 2 patients with total atelectasis had complete reexpansion after photodynamic therapy, which permitted eventual sleeve lobectomy in 1. Carinal narrowing was ameliorated in the 2 patients seen with inspiratory stridor, thereby permitting hospital discharge. Endoscopically resected fragments after photodynamic therapy exhibited avascular necrosis. These data support further controlled studies of photodynamic therapy by thoracic surgical oncologists to define its limitations as well as to improve and expand its efficacy as a palliative or surgical adjuvant.

A variety of imaging procedures were performed in 28 patients with ectopic adrenocorticotropic hormone (ACTH) syndrome in an attempt to localize the ACTH-producing tumor. Diagnosis was made on the basis of removal of an ACTH-producing tumor or biopsy of metastases in the 19 patients with a proved source and the absence of ACTH gradients in bilateral samples of the inferior petrosal sinuses in the nine patients in whom an ACTH-secreting tumor had not been localized. Eleven bronchial carcinoids, two thymic carcinoids, three pheochromocytomas, and three islet-cell tumors constituted the proved sources. The condition has been cured in eight patients, six are alive with residual tumor, and five have died. Of the nine patients with undetected sites of ACTH production, one has died of pneumocystis pneumonia and eight are being treated medically or with bilateral adrenalectomy. Computed tomography (CT) of the chest and abdomen was the most helpful study in the detection of these tumors. Selective arteriography (bronchial and visceral), systemic and portal venous sampling, and iodine-131 meta-iodobenzylguanidine scintigraphy failed to demonstrate tumors when findings at CT were negative. Bronchial carcinoids constituted most of the ACTH-secreting tumors in this study (58%) and in a review of four large series (47%). To assure early detection of these potentially malignant tumors, pulmonary CT should be performed every 6 months, even after hypercortisolism has been medically or surgically controlled.

Intraoperative radiation therapy (IORT) is capable of delivering high doses of radiation to mediastinal structures while sparing lung parenchyma, heart, and other locoregional tissues. A canine model of pulmonary resection and IORT was investigated by performing a pneumonectomy in 15 adult foxhounds followed by 0 cGy, 2,000 cGy, 3,000 cGy, or 4,000 cGy. No clinical complications developed in 4 animals in the 2,000-cGy group. However, 2 of the 8 animals given a high dose died of esophageal hemorrhage or carinal necrosis. Esophagitis occurred in 10 of 12 animals, and none of the animals experienced bronchial stump dehiscence. In a limited Phase I protocol, 4 patients with non-small cell lung cancer were treated with resection and 2,500 cGy of IORT to two separate ports encompassing the superior and inferior mediastinum. Two patients experienced life-threatening bronchopleural fistulas, and 2 patients died as a consequence of esophageal problems. One patient had recurrence with brain metastases, and the 1 long-term survivor is free from disease. As opposed to the animal model of thoracic IORT, the clinical study demonstrated major toxicity with respiratory and esophageal morbidity. The therapeutic usefulness of thoracic IORT in the management of lung cancer must be questioned in view of this small but consistent series of patients. Further carefully designed clinical studies using lower doses of IORT are needed.

Pulmonary infiltrates in the patient with acquired immunodeficiency syndrome (AIDS) may be associated with a spectrum of unusual neoplastic and infectious process. Transbronchial biopsy frequently reveals the cause of these infiltrates; however, when transbronchial biopsy is nondiagnostic or contraindicated, or if the patient fails to improve after a diagnostic transbronchial biopsy, further investigation is warranted to direct appropriate therapy. Efficacy of 23 open-lung biopsies in 19 AIDS patients with pulmonary infiltrates was evaluated to define the indications for and the diagnostic yield of open-lung biopsy. Pulmonary infiltrates were recognized for a mean duration (+/- standard error) of 16 +/- 2 days before open-lung biopsy and were associated with fever and cough. These patients did not have prior transbronchial biopsy, and open-lung biopsy was diagnostic in all of these. Prior transbronchial biopsy performed in the remaining 16 patients was nondiagnostic in 10. Open-lung biopsy was diagnostic in 70% of these patients (Pneumocystis carinii pneumonia, 2 patients; Kaposi's sarcoma, 3 patients; Kaposi's sarcoma and Legionella pneumophila, 1 patient; cytomegalovirus, 1 patient). The other 6 patients having a previous diagnostic transbronchial biopsy failed to improve with therapy, and open-lung biopsy resulted in a therapeutic change in 67% of these patients. Two deaths were attributable to open-lung biopsy in patients with postoperative thrombocytopenic hemorrhage. Open-lung biopsy should be performed in AIDS patients when transbronchial biopsy is nondiagnostic or contraindicated, or in patients who fail to improve with appropriate therapy after diagnostic transbronchial biopsy, especially in patients with Kaposi's sarcoma.(ABSTRACT TRUNCATED AT 250 WORDS)

While the appearance of a mediastinal mass in a patient in remission from Hodgkin's disease frequently indicates recurrence, a number of benign processes may present in a similar manner. Tissue confirmation of relapse should be obtained prior to initiating further chemotherapy to avoid the morbidity of unnecessary treatment. We present a case of thymic hyperplasia that developed in a patient previously treated for Hodgkin's disease. Thymic hyperplasia is a poorly understood, apparently benign process that may be confused with recurrent lymphoma. Total excision of such a mass is recommended to rule out coexistent malignancy.

The majority of patients with pulmonary metastases from primary soft tissue sarcomas have peripheral lesions that can be removed by wedge excision. A subset of these patients, however, present with, or develop, clinically significant endobronchial metastases. These patients require a preoperative evaluation that includes pulmonary function testing and a detailed endoscopic evaluation of the bronchial tree. We described three of these patients from the National Cancer Institute and review the clinical histories of eight additional previously reported cases.

IORT may be a potentially useful adjunctive treatment combined with surgery and/or external beam irradiation in treating locally advanced lung and esophageal tumors. To begin investigation of this modality, the tolerance of intact mediastinal structures to IORT was studied using adult American Foxhounds (wt. 25–30 kg). Groups of six animals received IORT to doses of 20, 30, or 40 Gy to two separate intrathoracic ports, using 9 MeV electrons to treat a portion of the collapsed right upper lobe, and 12 MeV electrons to treat the mediastinal structures. A group of three dogs received thoracotomy with sham irradiation. Two dogs from each treatment dose group, as well as one sham-irradiated control, were sacrificed electively at 1, 3, and 12 months following IORT. There were no acute nor late IORT related mortalities. Post-operative weight loss was minimal (average 4.5% of pre-operative weight) for all dogs. Serial esophograms showed no inflammation or ulceration. No cardiac nor pulmonary changes were noted clinically. At autopsy, the irradiated lung showed evidence of acute pneumonitis at 1 month with progressive fibrosis at 3 months and 1 year. Esophageal reactions were minimal, with only two dogs (one 30 Gy and one 40 Gy) demonstrating histologically confirmed esophagitis at 1 month. Tracheal changes were minimal. Cardiac damage was evident in the right atrial tissues. In several dogs, this cardiac damage ranged from myocardial vascular changes to frank ischemic necrosis noted at 1 and 3 months, and dense fibrosis at 1 year. The phrenic nerves showed normal function, but had evidence of perineural fibrosis. The large vessels demonstrated only mild histologic evidence of irradiation. The results of this large animal study suggest that intact mediastinal structures will tolerate small volume IORT to doses of 20 Gy without significant clinical sequellae. Although the histologic changes in the right atrium and contralateral lung are worrisome, no cardiac nor pulmonary problems arose over the 1 year follow-up. Irradiation of the contralateral lung and other sensitive structures can be reduced by careful selection of electron beam energy and use of custom lead shielding.

Administration of nitroprusside (NP) and epinephrine (EP) was investigated in 2 groups of dogs during periods of acute myocardial ischemia. Blood flow to a normal area, to a marginal area of ischemia, and to an area of maximal ischemia was measured using the radioactive microsphere technique before periarterial balloon occlusion of the left anterior descending coronary artery, during NP infusion alone, and in combination with EP. In 10 awake, unanesthetized animals (group 1), NP infusion alone significantly increased blood flow to the subendocardium of the maximally ischemic zone. NP-EP infusion increased transmural and regional flow significantly to the marginal and normal zones. In a second group of 8 anesthetized animals, NP-EP infusion significantly increased coronary sinus flow without a corresponding increase in myocardial oxygen consumption, cardiac index, or left ventricular stroke work. As in group 1, significant increases in transmural flow were noted to the marginal and normal zones with NP-EP infusion. These findings suggest that the combination of a vasodilating agent and an inotropic agent will improve coronary flow during periods of acute myocardial ischemia, and favorably alter the ratio of oxygen supply to oxygen demand.

Lung cancer cells are susceptible to photodynamic therapy (PDT) using 630 nm light and dihematoporphyrin ether (DHE). A light scattering media, intralipid (IL), was compared to balanced salt solution (PBS) for PDT of A549 human lung cancer cells. Differences in cellular DHE content after IL or PBS exposure were determined. Cells were incubated in 25 micrograms/ml DHE for 2 hr and then incubated in various concentrations of IL or PBS at room temperature for 2.5 to 10.0 min. Significant amounts of DHE were lost from IL-incubated cells compared to cells incubated in PBS. After 5 min in 1% IL, cellular DHE content was 0.32 +/- 0.04 microgram DHE/10(6) cells compared to 0.56 +/- 0.11 microgram DHE/10(6) cells in PBS-incubated cells (P less than 0.05). Despite this, superior PDT cytotoxicity was noted when cells were treated in IL with energy densities greater than or equal to 105 mJ/cm2. At an energy density of 210 mJ/cm2, the survival fraction (SF) of cells treated in 1% IL was 0.004 +/- 0.001 compared to 0.071 +/- 0.022 in PBS-treated cells (P less than 0.05). SF was dependent upon the IL concentration with the greatest cell killing noted with 1% IL. An apparent loss of cellular DHE ("DHE washout") was confirmed by demonstration of a higher SF of cells incubated in IL, rinsed, and subsequently PDT-treated in PBS with 157.5 mJ/cm2 (SF = 0.85 +/- 0.11) compared to cells incubated and treated in PBS (SF = 0.50 +/- 0.03, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Vena caval injuries are relatively rare and are associated with a high mortality before the patient arrives at a medical facility and even after initial resuscitation and operative intervention. Survival is directly related to (1) the location of the injury, (2) the amount of active bleeding, and (3) the type and number of associated injuries. To achieve maximum survival in patients with serve injury, rapid transportation to an emergency room is necessary. Resuscitation must then be aggressive, with rapid transferral to the operating room, and the surgeon must know the various techniques available for repair.

Photodynamic therapy (PDT) using a dihematoporphyrin ether (DHE) sensitizes malignant cells to damage by 630-nm light. This study investigated in vitro PDT sensitivity of human lung cancer cells (A549) and those factors which influence cell survival as determined by the colony formation assay. After incubation for 2, 4, or 6 hr with [DHE] of 2.5, 25, or 50 micrograms/ml, A549 received red light at dose rates of 0.27 or 0.09 mW/cm2 and energies of 0-250 mJ/cm2. Neither 630-nm light alone nor DHE alone affected cell survival. A dose rate of 0.27 mW/cm2 required less energy than 0.09 mW/cm2 for 90% cytotoxicity (180 mJ/cm2 vs 250 mJ/cm2, P less than 0.05). The energy required for 90% cytotoxicity with 25 micrograms/ml [DHE] was dependent on DHE incubation time (2 hr, 90% cytotoxicity not reached; 4 hr, 116 mJ/cm2; 6 hr, 69 mJ/cm2; P less than 0.05). In contrast, cellular [DHE] as measured by fluorescence, plateaued after 2 hr of incubation. Fluorescence microscopy revealed a time-dependent redistribution of fluorescence from the cell membrane to perinuclear and intracytoplasmic organelles. A 99% cytotoxicity required significantly less energy as [DHE] was increased (2.5 micrograms/ml, no cytotoxicity; 25 micrograms/ml, 243 mJ/cm2; 50 micrograms/ml, 111 mJ/cm2; P less than 0.05). Intracellular [DHE] was directly dependent on the incubating media [DHE] (2.5 micrograms/ml, 0.09 +/- 0.01 micrograms/10(6) cells; 25 micrograms/ml, 0.80 +/- 0.07 micrograms/10(6) cells; 50 micrograms/ml, 1.31 +/- 0.11 micrograms/10(6) cells; P less than 0.05). PDT cytotoxicity was inversely proportional to concentration of serum in the DHE media. These data illustrate that lung cancer in vitro is sensitive to PDT and is influenced by dose rate, energy input, and DHE environmental manipulations. These factors may be important in increasing the efficiency of PDT of thoracic malignancies in vivo.

Saline lavage of the major bronchial segments was performed in five patients immediately preceding lobectomy to remove an ACTH-producing bronchial carcinoid. Lavage fluid from each bronchus was concentrated, and ACTH determinations were performed. Elevated concentrations of ACTH were not demonstrated in the aspirate from the bronchus containing the known tumor. Two additional patients with ectopic ACTH syndrome from an unknown primary source also underwent selective segmental bronchial lavage for ACTH determination. Neither patient demonstrated ACTH gradients in the lavage specimens. One was found to have an ACTH-producing bronchial carcinoid 18 months after negative lavage. Selective segmental bronchoscopic lavage with measurement of ACTH levels on the aspirate is not an effective technique for detecting ACTH-producing bronchial carcinoid tumor. (J Clin Endocrinol Metab 69: 1302, 1989)

Virtually all of the chapters in this book to this point have emphasized that every patient with a mechanical valve prosthesis should be on warfarin anticoagulation. We have developed experimental, clinical data over the past five years that supports the proposition that such anticoagulants are not always needed.