Cytotoxic drug-induced lung disease.

Cytotoxic drugs, principally bleomycin, methotrexate and busulfan, have been associated with pulmonary toxicity. Cytotoxic drug-induced lung disease may be difficult to establish with certainty because other causes of pulmonary disease are frequently present. We discuss the clinical, roentgenographic and histologic effects of the administration of bleomycin, methotrexate, busulfan and other cytotoxic agents on the lungs and suggest that these agents may also cause pulmonary malignancies. We note the importance of careful patient monitoring and withdrawal of a demonstrated offending agent.

The clinical assessment of roentgenographically atypical pulmonary sarcoidosis.

We studied 89 patients in whom the clinical diagnosis of sarcoidosis was supported by the findings on tissue biopsy. A chest roentgenogram in 14 of the patients showed one of the following atypical features: large pulmonary nodules, an alveolar parenchymal pattern or a pleural effusion. Diagnoses of infection, malignancy or vasculitis were suggested by interpretations of atypical chest roentgenograms in eight of these 14 patients. Nonspecific and misleading clinical information contributed. The diagnosis of sarcoidosis was corroborated by extrathoracic tissue biopsies in 11 of the 14 patients. Over an average observation period of 38 months, the 14 patients remained classified as having sarcoidosis. This suggests that an extrathoracic tissue biopsy, whose findings are consistent with sarcoidosis, is often sufficient to support a clinical diagnosis of some forms of roentgenographically atypical pulmonary sarcoidosis.

Acute and chronic effects of fire fighting on pulmonary function.

The acute and chronic effects of fire fighting on pulmonary function were studied in 54 fire fighters from Connecticut, 32 smokers and 22 nonsmokers. Baseline studies of maximum expiratory flow-volume curves while breathing air and a mixture of 80 percent helium and 20 percent oxygen revealed obstruction of the small airways in 35 percent (nine) of 26 smokers and 13 percent (two) of 15 nonsmokers. Cigarette smoking appears to be a major contributor to obstruction of the airways in fire fighters. In the nonsmoking group, disease of the small airways was present only in fire fighters with at least 25 years of fire fighting, and none of them had respiratory complaints. In seven fire fighters retested immediately following mild exposure to a fire in a building, no significant changes in pulmonary function were noted. One fire fighter trapped in a fire in a basement had a high level of carboxyhemoglobin (42 percent) and developed a severe obstructive ventilatory defect which persists 2 1/2 years after the fire. The significance of disease of the small airways in fire fighters with chronic exposure remains to be elucidated with long-term studies; however, acute significant exposure may be associated with irreversible pulmonary injury in fire fighters.

Activities of the Conjoint Committee. Enhancement of diagnostic radiologic research and education.

Even though we have made much progress over the last decade, much still needs to be done. I am personally very pleased with the excellent management and authority of my coauthor, Joe Frank, in assuming the Acting Directorship of our DRRP. You will be hearing more from him in the immediate future about this research program, and he will be accessible to all of you, both individually and at our national meetings. We must continue to recruit representatives to fill responsible positions at the NIH, including Director for the DRRP at the National Cancer Institute. Further funding for equipment and personnel within the Diagnostic Radiology Research Laboratory also will be necessary. We are anticipating that the annual laboratory budget will increase further, but to provide additional resources, the Conjoint Committee plans to take an active role in encouraging foundations, corporations, and member societies to assist further with this effort. Most of the other disciplines within medicine--in fact, many individuals in your own medical school within other departments--have spent time at the NIH. It is this high-quality experience, in an environment that can provide both the research background and the cultivated personal relationships and interactions, that will foster a long-term research career. Clearly, the complementary role of both the intramural and extramural programs will allow diagnostic radiology to achieve excellence and true respect in the total research community of the Academy. Many people have been responsible for our success, and I have already mentioned a few.(ABSTRACT TRUNCATED AT 250 WORDS)

Chest radiographic-pathologic correlation in adult leukemia patients.

A radiographic-pathologic correlation study of adult leukemia patients was conducted to determine the frequency and radiographic appearance of leukemic involvement and related complications within the chest. One hundred thirteen autopsy protocols were examined. Radiographic correlation was obtained in 60 of these cases. Autopsy pulmonary findings included hemorrhage in 74% of the cases, infectious infiltrates in 67%, edema or congestion in 57%, and leukemic infiltration in 26%. Only 5% of the chest radiographs were normal. Alveolar or interstitial abnormalities were identified in 90%, pleural effusion in 40%, and lymphadenopathy in 17%. Correlation demonstrated pulmonary infection to be by far the most common cause of radiographic opacity. Because of its frequent occurrence, high associated mortality, and potential reversibility, pneumonia must always be considered first in the differential diagnosis of radiographic opacity in these patients.

Morphology of oleic acid-induced lung injury. Observations from computed tomography, specimen radiography, and histology.

Previously, we reported that oleic acid infusion in dogs produced a patchy and predominantly peripheral increase in lung density. The present study examines in more detail the morphology of the early stages of development of the oleic acid lesion using computed tomography (CT), specimen radiography, and conventional histology. Dogs were sacrificed 10, 30, 60, and 240 minutes after infusion of oleic acid (.05 ml/kg). After freezing in dry-ice, the thorax was scanned and cut into 1-cm thick sections. Frozen sections were then contact radiographed and sampled for histology. Within 10 minutes of infusion, subtle increases in peripheral lung density were visible on the contact radiographs. Patchy areas of peripheral density, resembling secondary lobules, were especially prominent 60 and 240 minutes after infusion. These lesions were often clearly associated with the distal bronchovascular structures. Histologic signs of edema were present in all animals sacrificed 30 or more minutes after receiving oleic acid. These correlative studies provide additional insight into the early subgross development of oleic acid-induced injury by showing the relationship between the developing edema and the bronchovascular structure of the lung.

Transcatheter electrocoagulation of the pulmonary artery: an experimental model in dogs for studying pulmonary thrombosis.

Transcatheter electrocoagulation (TCEC) has been shown to produce permanent arterial occlusion. This study was performed to evaluate the potential of using TCEC of the pulmonary artery as an experimental model of pulmonary thromboembolism. Fourteen lobar or first-order pulmonary arteries were occluded in ten dogs in the acute studies. Eight pulmonary arteries were occluded in eight dogs that were sacrificed 25 to 85 days after TCEC. There were permanent occlusions in seven, and all seven evidence of pulmonary infarction. The animals tolerated the procedure well. The technique may have merit as an experimental model for studying pulmonary thrombosis and infarction.

A CT technique to evaluate the development of carcinogen-induced neoplasia in the rat liver.

Hepatocellular neoplasms, including neoplastic nodules (NN), are the most commonly induced tumors resulting from chemical carcinogen evaluation. Our objective was to image neoplastic nodules using computed tomography. In a preliminary study using rats with diethylnitrosamine (DEN) induced tumors, lesions smaller than 1.5 cm were difficult to identify by CT. Since NN do not take up excess iron whereas normal liver does accumulate iron, we studied iron as a CT contrast material. Hemochromatosis was induced in 15 control rats by subcutaneous injections of iron dextran. A linear increase in iron-loading dose produces a linear CT liver enhancement (r = 0.97): 68, 80, 84, 94, and 104 HU at 0, one, two, four, and six weeks, respectively. No loss of enhancement was noted ten weeks later. Rat hepatic tissue was chemically analyzed after a similar iron-loading regimen. The iron concentration (microgram/g hepatic tissue) progressively increased during the first four weeks of loading and remained stable for three weeks following iron-loading. Four animals that had been given DEN and iron were examined by CT scanning to detect small NN. Iron-enhanced CT allowed the visualization of small lesions (less than 5 mm). Histopathologic sections confirmed a homogeneous pattern of iron uptake in normal liver with a deficiency of iron in NN. We conclude that CT scanning following iron-loading is a noninvasive method to detect small nodules and may provide a method to study the progression or regression of small liver nodules in rodents.

Analysis of the density of pleural fluid analogs by computed tomography.

A noninvasive method for differentiating transudative and exudative pleural effusions could make thoracentesis unnecessary in many cases. Since computed tomography (CT) can be used to measure tissue densities, it has a potential use in assessing density of intrathoracic fluid. This study was performed to test this possibility. Plastic syringes containing water, saline, and three saline-albumin solutions with densities up to 1.021 g/cc were scanned individually in air, in a chest phantom, and in a dog thorax during apnea. We found significant positive correlations between specific gravity and CT density; coefficients ranged from 0.85 to 0.99. Regression lines for the different test conditions were not statistically different. However, CT number variability, as indicated by the average standard deviation (SD), did differ for the test conditions: 1) Syringes alone, average SD was 3.8 HU; 2) chest phantom, average SD was 5.5 HU adjacent to rib and 5.8 HU anterior to vertebral column; 3) dog chest average SD was 19.2 HU with heart motion and 9.4 HU without heart motion. These results suggest that heart motion is a major factor in CT number variability in vivo, and that differentiation of transudates from exudates is not possible with current CT methods.

CT of obstructive lobar collapse.

The varied computed tomographic (CT) appearance of obstructive lobar collapse is described in 25 cases. CT is helpful in understanding the morphology and mechanisms of lobar collapse and in diagnosing atypical cases. The final shape of the collapsed lobe is dependent on the size and location of the obstructing tumor and on the amount of retained lung fluid. Focal bulging of the fissure (S-sign) is the most helpful sign in identifying the obstructing tumor. Differential enhancement could not separate the tumor from collapsed lung in six of eight (75%) of the cases studied with intravenous contrast, a finding at variance with previous reports. The limitations of CT in evaluating mediastinal or pleural invasion in the presence of lobar collapse are discussed.

Hydrostatic pulmonary edema. An analysis of lung density changes by computed tomography.

The computed tomographic (CT) appearance of pulmonary edema induced by elevated left atrial (LA) pressure was examined. Dogs, in the prone position, were scanned during suspended ventilation at functional residual capacity. A surgically implanted LA balloon was inflated to elevate LA pressure for 30 to 140 minutes to a mean pressure of 29.8 mm Hg. Lung water, measured gravimetrically, averaged 14.7 ml/kg body weight compared with 5.7 ml/kg in nonedema control dogs. Lung density in dogs with edema was 69.5% higher than base-line density, while in the control group final lung density was only 4% higher than base line. Analysis of regional density indicated that there were greater increases in density in more central and dependent (ventral) zones of the lung and relatively smaller increases in nondependent (dorsal) peripheral zones. These results are in contrast to the previously reported pattern of density change seen with oleic acid injury in which density increases were primarily in peripheral zones of the lung.

A computed tomographic study of the dog lung during hemorrhagic shock and after resuscitation.

A shock model was used to explore the capability of computed tomography (CT) to detect changes in lung density during hypovolemia and after resuscitation. The same level of the lower thorax was scanned repeatedly during base-line, shock (aortic pressure 60 mmHg), and after resuscitation with shed blood. The average baseline CT number (+/- SEM) for 5 areas of interest for four prone dogs was -754 +/- 16 (air = -1000, water = 0). This decreased 7.4% to -810 +/- 15 (P less than .05) during shock. After resuscitation CT density was -773 +/- 17 or 2.5% less than baseline (P greater than .1). A dorsal to ventral gradient of increasing CT density during baseline was maintained in all five areas during shock and post-resuscitation. From baseline to shock there were also significant changes in heart rate, mean aortic pressure, cardiac output, and vascular volume. Extravascular lung volume after resuscitation was equal to baseline volume. We conclude that CT is sufficiently sensitive to detect rapid physiological changes leading to increased or decreased lung density.

Distribution of 15- and 137-mu diameter microspheres in the dog lung in the axial plane.

Oleic acid infusion, as a model of fat embolism, produces a predominantly peripheral lesion in the dog lung. The lung injury corresponds to the peripheral distribution of labeled oleic acid. The basis for this distribution of oleic acid is not known. Our hypothesis for this nonuniform distribution is that particle diameter plays a role in the subsequent distribution of infused oleic acid and the resulting lung injury. We injected 15-mu microspheres 85Sr and then 137-mu microspheres (141Ce) into the right atria of seven dogs, which were killed and the lungs removed. Analysis of the distribution of the two different diameter microspheres within axial slices from the left caudal lobe of each dog revealed a peripheral distribution of the larger diameter microspheres not seen with the smaller microspheres.

A ventilator for magnetic resonance imaging.

Breathing motion severely degrades the quality of magnetic resonance images (MRI) of the thorax and upper abdomen and interferes with the acquisition of quantitative data. To minimize these motion effects, we built an MRI compatible ventilator for use in animal studies. Solid state circuitry is used for controlling ventilation parameters. The ventilator can be triggered internally at frequencies of 0.1 to 30 Hz or it can be triggered externally such as by the MRI pulse sequence. When triggered by the scanner, ventilation is synchronized to occur between image data acquisitions. Thus, image data are obtained when there is no breathing motion and at a minimum lung volume when hydrogen density is maximum. Since the ventilator can be adjusted to operate at virtually any frequency from conventional to high frequency, ventilation can be synchronized to all commonly used repetition times (100 ms to 2000 ms or more; 600 to 30 breaths/min). Scan synchronous ventilation eliminates breathing motion artifacts from most imaging sequences (single and multiple spin echo and inversion recovery). Best image quality is obtained when scan synchronous ventilation is combined with cardiac gating. These methods are also useful for quantitative research studies of thoracic and abdominal organs.

Computed tomographic evaluation of lesions in the thoracic apex.

Fifty patients with clinically suspected lesions of the chest apex underwent computed tomography (CT) and plain film (PF) examinations in an attempt to define the underlying etiology as benign or malignant. CT was slightly more sensitive in diagnosing malignancy (90%) compared with PF (77%), with a higher predictive value of a negative test (85% vs. 70%), although the differences were not statistically significant. The specificity and predictive value of a positive test were similar for CT and PF. CT's advantage was better elucidation of the soft tissues of the chest apex. CT provided additional information beyond PF in 17/20 patients with benign conditions and in 29/30 patients with cancer. In 21 of these 29 cancer patients, CT findings significantly altered subsequent management.

Tantalum oxide, silica and latex: effects on alveolar macrophage viability and lysozyme release.

Tantalum an experimental bronchographic material, may be retained in the lungs for a prolonged period following bronchography. The alveolar macrophage (AM) is a cell with potential for clearing tantalum particles from the airways. We studied the in vitro effects of tantalum oxide and two other particles, silca and latex, on rabbit AM viability and lysozyme release over 30 hours. Results indicate: 1) tantalum oxide, silica, and latex particles are ingested by rabbit AM in culture; 2) tantalum oxide and silica are both toxic to AM in vitro; and 3) tantalum oxide exerts its toxic effects less rapidly on AM than does silica. On the basis of these in vitro culture results we conclude that tantalum oxide may be toxic to alveolar macrophages in vivo. Delayed lung clearance of tantalum oxide particles may be due in part to their toxic effects on alveolar macrophages.

Tantalum oxide and alveolar macrophage function.

The alveolar macrophage (AM) has been cited as a potential source for clearing tantalum from the lungs following bronchography. We studied the short term effects of tantalum oxide on rabbit AM viability and metabolism in vitro. AM phagocytosed tantalum oxide particles without cytotoxicity and with a significant rise in glucoxe oxidation. These results suggest that the AM represents an important vehicle for clearance of tantalum particles from airways in vivo.

Regional pulmonary distribution of iodine-125-labeled oleic acid. Its relationship to the pattern of oleic acid edema and pulmonary blood flow.

Oleic acid infusion in dogs produces a patchy, predominantly peripheral lesion on CT scans. This study correlates the pattern of oleic acid injury with the distribution of infused oleic acid and pulmonary blood flow. Radiolabeled oleic acid (I-125, 0.05 ml/kg) and radiolabeled 15-micron microspheres (Co-57) were infused into the right atria of 11 dogs. Oleic acid was given after the microspheres in six dogs and before microspheres in five dogs. Ten minutes after infusion, the lungs were removed. Four transverse slices (0.5 cm thick) of the lower lobes were taken from each dog and cubed. Samples were grouped into three regions of the transverse slice: outer, middle, and inner concentric rings. In both groups, I-125 (oleic acid) activity was greater in the outer than the middle and inner concentric layers (P less than 0.001). When Cobalt-57 microspheres were given before oleic acid, Cobalt-57 activity was marginally lower in the outer layer compared with the middle and inner layers. However, when oleic acid was given first, microsphere activity in the outer layer was significantly lower (P less than 0.001) than the middle layer. Thus, oleic acid was preferentially distributed to the peripheral regions of the lung, similar to the regions of injury on CT. This distribution did not correspond to the pattern of pulmonary blood flow as indicated by the microspheres. Immediately after oleic acid infusion, pulmonary blood flow to the periphery was reduced, reflecting a response to the predominantly peripheral injury by oleic acid.

Work in progress: in vitro analysis of pleural fluid analogs by proton magnetic resonance. Preliminary studies at 1.5T.

To test the potential of 1.5 Tesla magnetic resonance imaging (MRI) for assessing the protein concentration of pleural effusions, five pleural fluid analogs (saline + 0, 2, 4, 6, 8 g albumin/100 mL) and, for comparison, four saline dilutions of whole blood were evaluated in vitro. The relaxation rates (1/T1, 1/T2) of albumin solutions were determined by 1.5 T spectroscopy (MRS) and correlated with albumin concentration (1/T1:slope 0.02, r + 0.89, P less than .05; 1/T2: slope 0.16, r = 0.997, P less than .001). MRI studies of these solutions showed no significant correlation with 1/T1, but 1/T2 showed a positive correlation with albumin concentration (r = 0.98, P less than .01). Both MRI relaxation rates were significantly correlated with blood concentration, and slopes were greater than for albumin solutions. These preliminary studies, demonstrating differences in correlation between relaxation rates and the concentration of albumin and blood, suggest that MRI has the potential for differentiating pleural effusions of different chemical composition.

The General Electric-Association of University Radiologists Radiology Research Academic Fellowship (GERRAF). An industry-academic collaboration to improve clinical research in radiology.

The association of GE Medical Systems and the AUR represents a unique collaboration between academic radiology and industry that bears important potential for elevating the quality of clinical research in radiology and developing a cadre of high-quality radiologist researchers for the future. The establishment of the GERRAF is especially timely given the new imperatives of the rapidly changing health care environment, with its emphasis on expenditure reduction. The ultimate goals of GERRAF are to develop research leaders for radiology that will provide guidance for appropriate clinical practice, better train future researchers, and secure the role of radiologists in caring for patients.