Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis.
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PURPOSE: The epidermal growth factor receptor (EGFR) is frequently overexpressed in non-small-cell lung carcinoma (NSCLC), and EGFR inhibitors are promising new therapeutic agents. The molecular mechanisms responsible for EGFR overexpression are poorly understood. MATERIALS AND METHODS: Gene copy number and protein status of EGFR were investigated in microarrayed tumors from 183 NSCLC patients, including squamous cell carcinoma (SCC; 89 patients) and non-SCC (94 patients) histologies. Protein expression was assessed by immunohistochemistry on a scale from 0 to 400 (percentage of positive cells x staining intensity). Gene and chromosome 7 copy numbers were identified by fluorescent in situ hybridization (FISH). RESULTS: EGFR protein overexpression was observed in 62% of the NSCLC (25% scored 201 to 300; 37% scored 301 to 400), more frequently in SCC than non-SCC (82% v 44%; P <.001), and in 80% of the bronchioloalveolar carcinomas. The prevalent FISH patterns were balanced disomy (40%) and trisomy (38%) for EGFR gene and chromosome 7 (40%), whereas balanced polysomy was seen in 13% and gene amplification was seen in 9% of the patients. Gene copy number correlated with protein expression (r = 0.4; P <.001). EGFR overexpression or high gene copy numbers had no significant influence on prognosis. CONCLUSION: EGFR overexpression is frequent in NSCLC, is most prominent in SCC, and correlates with increased gene copy number per cell. High gene copy numbers per cell showed a trend toward poor prognosis. It will be important to evaluate EGFR gene and EGFR protein status and signal protein expression to properly interpret future clinical trials using EGFR inhibitors. (+info)
Expression of epidermal growth factor receptor in plutonium-239-induced lung neoplasms in dogs.
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The expression of epidermal growth factor receptor (EGF-R) was examined in canine lung tumors and in proliferative epithelial foci induced by plutonium-239 to determine if EGF-R was associated with specific neoplastic phenotypes or putative preneoplastic lesions. Seventeen (47%) of 36 canine lung tumors expressed EGF-R. Of these 17 tumors, three tumors hybridized with an erb-B RNA probe, which identified activated cell oncogenes. The expression of EGF-R was not correlated with tumor etiology, e.g., spontaneous versus radiation induced, but did correlate with specific histologic phenotypes. Nineteen (15%) of 127 proliferative epithelial foci in the canine lungs also expressed EGF-R. The phenotypic specificity demonstrated for EGF-R in canine lung tumors parallels that previously shown in human lung tumors. This finding, in addition to the identification of EGF-R in nonneoplastic proliferative lung lesions, indicates that radiation-induced lung tumors in the dog may be a useful animal model to investigate the role of EGF-R in lung carcinogenesis. (+info)
Relation of bronchioloalveolar carcinoma to tobacco.
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OBJECTIVE: To determine whether bronchioalveolar carcinoma is related to tobacco use. DESIGN: Case-control study. SETTING: 11 teaching hospitals of Chicago, Long Island, New York, and Philadelphia, 1977-89. SUBJECTS: 87 patients with histologically diagnosed bronchioloalveolar carcinoma (cases) and 286 non-cancer and 297 cancer patients matched to cases on age, sex, race, hospital, and date of admission. RESULTS: 10% of male cases and 25% of female cases had never smoked. Relative risks of bronchioloalveolar carcinoma (as estimated by the relative odds) were greater for subjects who started smoking at a younger age, smoked for a longer time, or smoked more cigarettes per day. Relative risks decreased proportionally to the duration of smoking cessation. CONCLUSION: Smoking plays an important part in the aetiology of bronchioloalveolar carcinoma but is not the only potential cause because of the large proportion of never smokers among patients with this disease. (+info)
Radiosensitization of human tumor cells with levamisole.
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Levamisole in combination with radiation and chemotherapeutic agents is being studied in clinical trials. The mechanism of interaction of levamisole with these modalities is unknown. In order to determine if there is direct interaction between radiation and levamisole, a series of colony-formation assays was performed with the use of two human tumor cell lines. Cells were exposed to 0-10 Gy of radiation, with or without the addition of 0-1000 microM levamisole. Exposure to levamisole alone had no effect on cell survival; however, the combination of continuous exposure to levamisole at concentrations approaching 1000 microM and radiation revealed a potentiation of radiation-induced cell killing. (+info)
Development of antibodies against p53 in lung cancer patients appears to be dependent on the type of p53 mutation.
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Using immunoblotting techniques we studied the sera from small cell lung cancer and non-small cell lung cancer patients for antibodies directed against p53. We have also characterized the majority of these patients' tumors for p53 mutations. In the sera of 13% of the patients (4 of 40 small cell lung cancer and 2 of 6 non-small cell lung cancer) we found antibodies specific for the p53 tumor suppressor gene product. All of the antibody-positive patients tested had p53 missense mutations and expressed detectable p53 antigen in their tumor cell lines. No anti-p53 antibodies were detected in sera from patients whose tumor had p53 stop, splice/stop, splice, or frameshift mutations (n = 10). Thus, while we find that the ability of lung cancer patients to develop anti-p53 antibodies is correlated with the type of p53 mutation, many patients have tumors with missense p53 mutations and did not develop anti-p53 antibodies. The presence of p53 antibodies was not correlated to stage, prior treatment, sex, or survival. None of these lung cancer patient sera had measurable amounts of p53 antigen. By immunoblotting all six anti-p53 antisera we were able to detect a variety of mutant p53 proteins (including those from antibody-negative patients) and detected wild-type p53 protein. The development of anti-p53 antibodies represents an interesting model system for studying immune responses in cancer patients against mutant oncogene products. (+info)
Epidemiology of bronchioloalveolar carcinoma.
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Descriptive features of bronchioloalveolar carcinoma (BAC) are presented using Surveillance, Epidemiology and End Results Program population-based incidence data from 1973 through 1987, along with risk factors from histologically confirmed cases of BAC identified in a hospital-based case-control study conducted in Louisiana between 1979 and 1982. Compared to the rising incidence of lung cancer overall, BAC rates have remained relatively constant, accounting for less than 3% of all lung cancer. BAC incidence rates were higher in males, yet it explained proportionately more of the total lung cancer incidence in females. In the case-control study, 21 of the 33 cases originally ascertained from hospital pathology records were histologically confirmed as BAC. Most cases smoked cigarettes, with a 4-fold risk for ever smoking. Risks tended to increase with smoking intensity (reaching 10-fold for more than 1.5 packs/day) and duration (reaching 5-fold for more than 45 years of smoking). Following 10 or more years of employment, there was a 4-fold risk associated with motor freight occupations, along with nonsignificant excesses among construction workers, petroleum manufacturers, and sugar cane farmers. Cases were more likely than controls to have had emphysema or to have had a close family member with lung cancer. Although based on small numbers, this study suggests that BAC shares many of the epidemiological characteristics of lung adenocarcinoma. (+info)
Development of mammary preneoplasias in vivo from mouse mammary epithelial cell lines in vitro.
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A series of mouse mammary epithelial cell lines has been established by a protocol that gives highly reproducible results. The mammary epithelial cell lines, designated as FSK lines, were judged to be epithelial based on positive immunostaining for keratin-intermediate filaments, negative immunostaining for vimentin-intermediate filaments, hormonal induction of casein, and the ability to exhibit ductal and alveolar mammary morphogenesis in vivo. The FSK cell lines are dependent on epidermal growth factor and insulin in a low serum (1%) medium. Conditioned medium from spindle cell cultures replaced the requirement for serum and increased the growth of FSK3 and FSK4 4-5 times in collagen gels and 12-14 times in monolayer culture, respectively. Following injection into the mammary fat pad at passages 2-11, the FSK cell lines generated stable transplantable hyperplastic alveolar outgrowth lines. The in vivo outgrowth lines were judged as preneoplastic based on their stable alveolar morphology in vivo and an increased susceptibility for tumorigenesis. The FSK cell lines and their derivative in vivo outgrowth lines provide a new and potentially productive system to examine critical molecular alterations involved in the development of mammary preneoplasias. Furthermore, the reproducibility of the in vitro culture system provides the assurance that stable cell lines of mouse mammary epithelial cells can be generated easily and at will. (+info)
A PITFALL IN THE CYTODIAGNOSIS OF SPUTUM OF ASTHMATICS.
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The sputum of an asthmatic often contains large, well-circumscribed clusters of benign columnar epithelial cells which can be misinterpreted as papillary fragments of an adenocarcinoma. Their presence is a manifestation of the excessive shedding of the mucosa of the lower respiratory tract accompanying an attack of bronchial asthma. These clusters are illustrated and compared with clusters of adenocarcinoma cells. To discriminate between the two types of cluster may be difficult and it is therefore important for the cytologist to know when a sputum is from an asthmatic. (+info)