Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia.

PURPOSE: Retinoids have proven chemopreventive efficacy in both preclinical and clinical studies. This trial was designed to confirm the finding of an earlier uncontrolled trial that the synthetic retinoid etretinate had major activity in reversing squamous metaplasia found in the bronchial epithelium of chronic smokers. PATIENTS AND METHODS: We prospectively evaluated 152 smokers with bronchoscopy and obtained biopsies from six sites. Subjects with dysplasia and/or a metaplasia index of greater than 15% were randomly assigned to receive either 1 mg/kg isotretinoin or placebo daily for 6 months. Of 86 subjects randomized (41 isotretinoin, 45 placebo), 69 were reevaluated at the completion of treatment. RESULTS: In the group as a whole, the metaplasia index decreased over time from a mean +/- SE of 35.8% +/- 2.7% at baseline to 28.1% +/- 3.3% at the completion of treatment (P = .01) by repeated measures analysis of variance [ANOVA]); a reduction in the metaplasia index (> 8%) was noted in both isotretinoin and placebo groups (19 of 35 [54.3%] and 20 of 34 [58.8%], respectively). Complete reversal of squamous metaplasia was noted in nine subjects from each group. However, the magnitudes of the mean metaplasia index changes did not differ significantly in the two treatment groups. In both groups, smoking cessation resulted in significant declines in the extent of squamous metaplasia, whereas no significant change in metaplasia index was found among those who continued to smoke. CONCLUSION: Squamous metaplasia was frequently observed in bronchial biopsy samples from chronic smokers. From this study, we conclude that isotretinoin has no effect on squamous metaplasia, a potential intermediate end point of bronchial carcinogenesis. Although determining the exact role of isotretinoin in lung cancer prevention requires further study, the finding that there was a significant decrease in squamous metaplasia in the placebo group emphasizes the critical importance of a placebo-controlled study design in chemoprevention trials using intermediate end points.

Squamous metaplasia of the bronchial mucosa and its relationship to smoking.

We performed flexible fiberoptic bronchoscopy (FFB) on 106 heavy cigarette smokers. Six bronchial biopsy specimens, obtained from the carina and five major bronchi, were screened for squamous metaplasia. Individual biopsy specimens were sectioned into 4-microns sections, and a metaplasia index (MI), or percentage of sections containing squamous metaplasia, was determined. Metaplasia was noted at one or more biopsy sites in 66 of 99 subjects (seven were excluded from the analysis). Twenty-five percent of the subjects showed metaplasia at three or more biopsy sites, and one subject had metaplasia on all six biopsy specimens. The presence of squamous metaplasia varied from 40.4 percent in the right lower lobe to 15.3 percent in the left upper lobe. The subjects were grouped into simple categories based on the number of packs smoked per day and the pack-year history of smoking. Subjects who smoked more than two packs per day (n = 11) had the highest MI (37.4 +/- 4.9 percent, mean +/- SEM). Fifty-seven subjects smoked more than one pack per day but fewer than or equal to two packs per day, and they had a mean MI of 22.3 +/- 2.9 percent. Subjects who smoked one pack per day or less (n = 31) had a mean MI of only 12.9 +/- 2.8 percent. The MI of those who smoked more than two packs per day was significantly greater than the MI of those who smoked one pack per day or less (p < or = 0.003). While the MI varied from 12.9 +/- 3.5 percent in subjects who had smoked less than 20 pack-years to a maximum of 29.1 +/- 4.5 percent in those who had smoked greater than 60 pack-years, no statistically significant difference was detected between these two groups. Thus, we conclude that heavy tobacco use is associated with important alterations of bronchial mucosa. Furthermore, the intensity of tobacco use (packs per day) rather than the number of pack-years appears to be the more important factor in promoting squamous metaplasia of the bronchial mucosa.

Radiation-induced malignant pleural mesothelioma.

Malignant pleural mesothelioma is a rare and usually fatal disease. Its association with asbestosis is well recognized. The authors report a case of malignant pleural mesothelioma that developed 30 years after the patient underwent radiotherapy for breast cancer. This appears to be the first such case reported in the radiology literature.

Morphologic and immunocytochemical evaluation of 220 fine needle aspirates of malignant lymphoma and lymphoid hyperplasia.

A total of 220 fine needle aspiration (FNA) specimens from 212 patients with clinically suspected or previously histologically confirmed lymphoma were evaluated by cytology in conjunction with immunophenotyping analysis of the aspirate; the results were compared with the histologic diagnosis made on previous or current accessions of lymph node or extranodal tissue. Smears of the aspirates were stained with the Diff-Quik and Papanicolaou stains while immunoperoxidase staining using antibodies against kappa and lambda immunoglobulin light chains and Leu-4 was routinely performed on Cytospin preparations. Where indicated, additional marker studies (including T-200, Leu-1, Leu-2a, Leu-3a + 3b, Leu-M1, B1, Leu-12, IgM, CALLA and TdT) were performed. For the non-Hodgkin's lymphomas, specimens were classified by the cytologic characteristics of the neoplastic cells according to the International Working Formulation scheme. The combination of cytologic smears and immunoperoxidase studies resulted in a diagnosis of lymphoma in 173 cases (79%). The remaining aspirates were interpreted as suspicious for lymphoma (7%), benign (10%) or inadequate for diagnosis (4%). Of the 15 suspicious aspirates, 5 proved to be Hodgkin's disease and 2 to be T-cell lymphoma by subsequent biopsy. The cause of failure in the nine inadequate aspirates were necrosis (3 cases), sclerosis (2 cases) and faulty technique (4 cases). In the cases that had concurrent tissue biopsies, no false-positive diagnoses were rendered. These results indicate that FNA used in association with immunocytochemistry is a reliable tool for establishing the diagnosis and classification of the majority of cases of lymphoma. Optimal immunoglobulin light-chain ratios for defining monoclonality in FNA specimens of B-cell lymphomas are proposed.

Lung cancer classification: the relationship of disease extent and cell type to survival in a clinical trials population.

The staging and histologic cell type of patients in the Lung Cancer Study Group (LCSG) clinical trials program are reviewed and confirmed or resolved at the reference center for anatomic and pathologic classification of lung cancer. A high level of consistency in classification has been achieved through the use of criteria that minimize intraobserver variability. The data obtained from the review project have been used to characterize the relationship of disease extent and cell type to survival in the clinical trials population. Survival characteristics were generated for 1,121 patients who underwent apparent complete resection of nonsmall cell lung cancer and were subsequently entered into various protocols to receive either adjuvant treatment or no further therapy. The end results study provides some insight regarding the biological behavior of squamous cell carcinoma and adenocarcinoma of the lung in terms of the anatomic extent of disease at the time of apparent complete resection. Patients with squamous cell carcinoma had an outcome superior to that of patients with adenocarcinoma in every TNM subset. The differences in survival according to these major cell types were significant overall and in the T1 N0, T1 N1, and T2 N1 subsets but not in the TNM subsets in stage III disease. Histologic cell type and extent of disease are important factors in survival expectations; thus the accuracy and reproducibility of these classifications plays a significant role in the evaluation of differing modalities of treatment.

Drug and radiation sensitivity measurements of successful primary monolayer culturing of human tumor cells using cell-adhesive matrix and supplemented medium.

The limitations of the agar suspension culture method for primary culturing of human tumor cells prompted development of a monolayer system optimized for cell adhesion and growth. This method grew 83% of fresh human tumor cell biopsy specimens, cultured and not contaminated, from a heterogeneous group of 396 tumors including lung cancer (93 of 114, 82%); melanoma (54 of 72, 75%); sarcoma (46 of 59, 78%); breast cancer (35 of 39, 90%); ovarian cancer (16 of 21, 76%); and a miscellaneous group consisting of gastrointestinal, genitourinary, mesothelioma, and unknown primaries (78 of 91, 86%). Cell growth was characterized morphologically with Papanicolaoustained coverslip cultures and cytogenetically with Giemsastained metaphase spreads. Morphological features such as nuclear pleomorphism, chromatin condensation, basophilic cytoplasm, and melanin pigmentation were routinely seen. Aneuploid metaphases were seen in 90% of evaluable cultures, with 15 of 28 showing 70% or more aneuploid metaphases. Colony-forming efficiency ranged between 0.01 and 1% of viable tumor cells, with a median efficiency of 0.2%. This culture system uses a low inoculum of 25,000 viable cells per well which permitted chemosensitivity testing of nine drugs at four doses in duplicate from 2.2 X 10(6) viable tumor cells and radiation sensitivity testing at five doses in quadruplicate from 0.6 X 10(6) cells. Cultures were analyzed for survival by computerized image analysis of crystal violet-stained cells. Drug sensitivity studies showed variability in sensitivity and in survival curve shape with exponential cell killing for cisplatin, Adriamycin, and etoposide, and shouldered survival curves for 5-fluorouracil frequently seen. Radiation sensitivity studies also showed variability in both sensitivity and survival curve shape. Many cultures showed exponential cell killing, although others had shouldered survival curves. This method for growing cells from primary human biopsy specimens is more efficient than the agar culture method, enables easier and better biological analysis of the actual cells grown, and permits improved characterization of drug and radiation survival curves.

Prognostic factors in patients with resected stage I non-small cell lung cancer. A report from the Lung Cancer Study Group.

The authors present prognostic information on recurrence and survival for resected Stage I lung cancer patients with squamous cell carcinoma, adenocarcinoma or large cell carcinoma. The data derive from 392 carefully staged patients and include results from the history and physical examination, preoperative laboratory tests, nature of the surgery, complications, initial pathologic findings following surgical resection, and final pathologic review. A simple multivariate model of recurrence, which is used to classify patients into low, intermediate, and high-risk groups, is based on tumor size and location (T1, T2), histologic type (squamous, nonsquamous/mixed) and nodal status (N0, N1). To model survival, the performance status and the presence of empyema, pneumonia, or wound infection were added to the previous factors. Not all factors associated with increased mortality are associated with increased risk of recurrence, and, in particular, postoperative empyema, pneumonia or wound infections carry an increased risk of death only. Serial measurements of performance status and leukocyte count have the potential for monitoring for increased risk of recurrence and death.

Superior vena cava obstruction in small cell bronchogenic carcinoma. Clinical parameters and survival.

A clinical pathologic review with analysis of prognostic factors was conducted in 56 patients who were seen at the University of Texas M. D. Anderson Hospital and Tumor Institute between 1969 and 1980 with the syndrome of superior vena cava (SVC) obstruction secondary to small cell bronchogenic carcinoma. Most patients were men (60%), nonambulatory (61%), and had demonstrable extrathoracic disease (70%). The most common symptoms and signs of SVC obstruction were jugular venous distention (100%), swollen face (88%), and dyspnea (50%). Swollen arms (34%) and engorgement of thoracic veins (32%) were also common. Initial treatment consisted of irradiation alone, 17 patients (30%); chemotherapy alone, 32 patients (57%); or both, 7 patients (13%). Patients receiving chemotherapy initially had poor prognoses, as evidenced by the greater proportion of nonambulatory patients (72%) in this group. All but two patients received chemotherapy at some point during their clinical courses. There were 12 (21%) early deaths; 2 (12%) in the radiation arm; 9 (28%) in the chemotherapy arm; and 1 (14%) in the combined modality group. All treatment modalities were rapidly effective in controlling the symptoms associated with SVC obstruction. Within 1 week from onset of treatment, 9 of 14 (64%) evaluable patients responded to irradiation, 23 of 23 (100%) to chemotherapy, and 5 of 6 (83%) to combined modality treatment. The type of initial treatment did not influence survival significantly, although patients who achieved complete clinical remissions survived longer (median, 62 weeks). Death was usually due to disease progression in distant sites. Multivariate analysis indicated that the most important prognosticators of patients' survival were pretreatment performance status, disease-extent score, and age.

Endoscopic cytology and biopsy diagnosis of esophageal carcinoma.

We examined 107 cytology and biopsy specimens taken simultaneously from 103 patients to determine the efficacy of cytologic esophageal brushing in the diagnosis of esophageal carcinoma. After review of all material, cytology was positive in 84% of cases, biopsy in 86%, and combined specimens (cytology and biopsy) in 94%. However, agreement as to histologic type was reached in only 53 of the 63 specimens originally reported as positive by both cytology and biopsy.

Spontaneous regression of breast carcinoma: follow-up report and literature review.

A case of spontaneous complete regression of metastatic breast carcinoma (malignant pleural effusion and bone metastases) with previously reported from M. D. Anderson Hospital and Tumor Institute. The patient did not receive any form of hormonal manipulation or systemic chemotherapy. This patient has now relapsed after 72 months of spontaneous complete remission, and a follow-up of her clinical history is presented. A search of the literature for previously reported instances of spontaneous regression of breast carcinoma indicates that this event is exceedingly rare.

Fibrous histiocytoma of lung--a clinicopathological study of two cases.

Two cases of fibrohistiocytic tumours of the lung are presented and histogenesis of this group of this group of tumours is discussed. An essentially biphasic pattern of histiocytes and fibroblasts, and the presence of myofibroblasts and undifferentiated mesenchymal cells is similar to the fibro histiocytic neoplasms in other locations.

Diagnosis of eosinophilic granuloma of bone by cytology, histology, and electron microscopy of transcutaneous bone-aspiration biopsy.

The cytological, histological, and ultrastructural morphology of transcutaneous bone aspirates from five patients with eosinophilic granuloma of bone were studied. Use of this combined approach enabled us to make a definitive diagnosis of eosinophilic granuloma from a small quantity of tissue without having to resort to open biopsy. By light microscopy, eosinophilic granuloma is composed of a polymorphous infiltrate of characteristic lobulated histiocytes, eosinophils, polymorphonuclear leukocytes, and giant cells. Each specimen examined ultrastructurally demonstrated the characteristic Langerhans granule-containing histiocyte. Eosinophilic granuloma is a benign lesion which is readily diagnosed by this technique, and more aggressive diagnostic procedures usually are not warranted.

The comparative diagnostic accuracy of cancer-cell detection obtained with Ficoll-Hypaque gradient separation and standard centrifugation technics on body-cavity fluids.

Ninety-two consecutive samples of body-cavity fluids from patients with confirmed or suspected cancer were compared for accuracy of diagnosis using a Ficoll gradient test and a standard centrifugation test. The percentage of positive test results was 76% (70/92) with the Ficoll test and 64% (59/92) with the routine test. The Ficoll and routine tests also gave a significant difference in the classification of malignancy, with the latter test giving a significantly higher proportion of negative or inconclusive test results. Besides the improved test results, the Ficoll gradient test has the further advantages of being less expensive and requiring only standard laboratory equipment. Elimination of blood and cellular debris by the procedure results in quick and easy cytologic screening. The Ficoll test is strongly recommended for those clinical fluids suspected to be positive for malignancy, especially where the routine test is negative or inconclusive.

Oncocytic carcinoid tumor of the lung.

A case of bronchial carcinoid tumor is reported in which a marked degree of transformation to mitochondrion-rich cells (oncocytes) was present. Ultrastructural observations demonstrated a transition between the two cell types, and revealed an alteration in mitochondria suggestive of a degenerative change in these organelles.

Fine-needle aspiration biopsy of the liver.

Percutaneous fine-needle aspiration biopsy of focal liver lesions was performed in 36 patients. Of the biopsies, 83% yielded enough cytologic material for a correct diagnosis, without significant complications. The primary indication for the biopsy was to document the presence of malignancy and avoid a diagnostic laparotomy.