Asbestos Exposure and Serum Osteopontin
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《新英格兰医药杂志》
To the Editor: Pass et al. (Oct. 13 issue)1 report that elevated osteopontin levels in workers with pleural disease who have been exposed to asbestos support a diagnosis of mesothelioma. The authors acknowledge that other cancers express osteopontin, and they mention the need for further studies. The expression of osteopontin in numerous benign inflammatory and fibrotic lung diseases,2 which considerably limits the potential use of osteopontin as a tumor marker, was not discussed. In addition to the osteopontin levels associated with lung carcinoma, similar levels are seen in tuberculosis, interstitial lung diseases, and cardiac disease.2,3 These clinical entities pose diagnostic difficulties in patients with asbestos-related pleural disease. Therefore, measurement of osteopontin levels is unlikely to help diagnostically in this clinical scenario.
The functional diversity of osteopontin in part reflects allelic variation and extensive post-translational modification.2 Certain isoforms of osteopontin have differing biologic functions.4 Tumor-derived osteopontin functions in a manner distinct from non–tumor-derived osteopontin.5 Much as specific isoforms may account for the role of osteopontin in cancer, future studies may define variants with higher diagnostic potential. Until then, the specificity of osteopontin measurement is too low for it to be used as a screening tool for mesothelioma.
Anthony W. O'Regan, M.D.
National University of Ireland, Galway
Galway, Ireland
anthony.oregan@whb.ie
David Serlin, M.D.
Jeffrey S. Berman, M.D.
Boston University School of Medicine
Boston, MA 02118
References
Pass HI, Lott D, Lonardo F, et al. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 2005;353:1564-1573.
O'Regan A. The role of osteopontin in lung disease. Cytokine Growth Factor Rev 2003;14:479-488.
Suezawa C, Kusachi S, Murakami T, et al Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: correlation with left-ventricular volume and function. J Lab Clin Med 2005;145:33-40.
Ashkar S, Weber GF, Panoutsakopoulou V, et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 2000;287:860-864.
Crawford HC, Matrisian LM, Liaw L. Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. Cancer Res 1998;58:5206-5215.
To the Editor: Pass et al. report that serum osteopontin levels were elevated in patients with pleural mesothelioma, indicating that osteopontin can be a useful biomarker for this disease. We examined osteopontin levels in the pleural fluid of 9 patients with pleural mesothelioma and 27 patients with various nonmalignant diseases. Levels of pleural-fluid osteopontin in patients with pleural mesothelioma were higher than those in patients without this disease (mean ; 22,692± 5014 ng per milliliter vs. 9575±1923 ng per milliliter ; P<0.001). Receiver-operating-characteristic analysis showed an area under the curve of 0.885. At the most accurate cutoff value of 11,436 ng per milliliter (with an accuracy of 0.811), the sensitivity and specificity were 100 percent and 77.8 percent, respectively. Patients with early pleural mesothelioma sometimes have pleural effusion with no other abnormal radiographic findings.1 Cytologic findings are sometimes inconclusive.2 Our findings indicate that levels of osteopontin in pleural fluid are informative for the early detection of pleural mesothelioma.
Akio Hiraki, M.D., Ph.D.
University of Texas Health Science Center at San Antonio
San Antonio, TX 78229
a-hiraki@za2.so-net.ne.jp
Keisuke Aoe, M.D., Ph.D.
Hiroshi Ueoka, M.D., Ph.D.
National Hospital Organization Sanyo National Hospital
Ube 755-0241, Japan
References
Scott B, Mukherjee S, Lake R, Robinson BWS. Malignant mesothelioma. In: Hansen H, ed. Textbook of lung cancer. London: Martin Dunitz, 2000:273-93.
Whitaker D. The cytology of malignant mesothelioma. Cytopathology 2000;11:139-151.
The authors reply: Dr. O'Regan and colleagues have raised important questions regarding the role of osteopontin in both malignant and nonmalignant diseases. The presence of elevated levels of osteopontin in various pulmonary diseases emphasizes two points: the importance of choosing for study the appropriate high-risk cohort of people exposed to asbestos, and the importance of following this cohort prospectively. We show in our report that the degree of elevation of osteopontin levels in asbestos-exposed subjects who were matched both in age and their smoking status (current or former smokers) to the subjects in the mesothelioma cohort depends on the presence of fibrosis and plaque. In the population we studied, lung cancer and mesothelioma are the chief risks.1 For any biomarker to be robust, it must be relevant to the most common cancers in the cohort. A validation study based on our results will be performed by the Early Detection Research Network of the National Cancer Institute, and it will address the issues of specificity raised by Dr. O'Regan et al.
With regard to the data from Hiraki et al.: their area under the curve is very promising and is similar to what we found for serum levels; however, these data must be compared specifically with data on effusions from subjects exposed to asbestos who do not have cancer, as opposed to those with "various nonmalignant diseases." We plan to investigate their findings with our collection of more than 70 samples of pleural effusions from patients with mesothelioma and effusions from control subjects (unpublished data). Future studies should also investigate whether combining measurements of osteopontin with other promising markers, such as soluble mesothelin-related protein, increases their sensitivity and specificity for mesothelioma in both pleural effusions and serum.2
Harvey I. Pass, M.D.
New York University School of Medicine
New York, NY 10016
harvey.pass@med.nyu.edu
Michele Carbone, M.D., Ph.D.
Loyola University Cancer Center
Maywood, IL 60153
Anil Wali, Ph.D.
Karmanos Cancer Institute
Detroit, MI 48201
References
Selikoff IJ, Hammond EC, Seidman H. Latency of asbestos disease among insulation workers in the United States and Canada. Cancer 1980;46:2736-2740.
Robinson BW, Creaney J, Lake R, et al. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 2003;362:1612-1616.
The functional diversity of osteopontin in part reflects allelic variation and extensive post-translational modification.2 Certain isoforms of osteopontin have differing biologic functions.4 Tumor-derived osteopontin functions in a manner distinct from non–tumor-derived osteopontin.5 Much as specific isoforms may account for the role of osteopontin in cancer, future studies may define variants with higher diagnostic potential. Until then, the specificity of osteopontin measurement is too low for it to be used as a screening tool for mesothelioma.
Anthony W. O'Regan, M.D.
National University of Ireland, Galway
Galway, Ireland
anthony.oregan@whb.ie
David Serlin, M.D.
Jeffrey S. Berman, M.D.
Boston University School of Medicine
Boston, MA 02118
References
Pass HI, Lott D, Lonardo F, et al. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 2005;353:1564-1573.
O'Regan A. The role of osteopontin in lung disease. Cytokine Growth Factor Rev 2003;14:479-488.
Suezawa C, Kusachi S, Murakami T, et al Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: correlation with left-ventricular volume and function. J Lab Clin Med 2005;145:33-40.
Ashkar S, Weber GF, Panoutsakopoulou V, et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 2000;287:860-864.
Crawford HC, Matrisian LM, Liaw L. Distinct roles of osteopontin in host defense activity and tumor survival during squamous cell carcinoma progression in vivo. Cancer Res 1998;58:5206-5215.
To the Editor: Pass et al. report that serum osteopontin levels were elevated in patients with pleural mesothelioma, indicating that osteopontin can be a useful biomarker for this disease. We examined osteopontin levels in the pleural fluid of 9 patients with pleural mesothelioma and 27 patients with various nonmalignant diseases. Levels of pleural-fluid osteopontin in patients with pleural mesothelioma were higher than those in patients without this disease (mean ; 22,692± 5014 ng per milliliter vs. 9575±1923 ng per milliliter ; P<0.001). Receiver-operating-characteristic analysis showed an area under the curve of 0.885. At the most accurate cutoff value of 11,436 ng per milliliter (with an accuracy of 0.811), the sensitivity and specificity were 100 percent and 77.8 percent, respectively. Patients with early pleural mesothelioma sometimes have pleural effusion with no other abnormal radiographic findings.1 Cytologic findings are sometimes inconclusive.2 Our findings indicate that levels of osteopontin in pleural fluid are informative for the early detection of pleural mesothelioma.
Akio Hiraki, M.D., Ph.D.
University of Texas Health Science Center at San Antonio
San Antonio, TX 78229
a-hiraki@za2.so-net.ne.jp
Keisuke Aoe, M.D., Ph.D.
Hiroshi Ueoka, M.D., Ph.D.
National Hospital Organization Sanyo National Hospital
Ube 755-0241, Japan
References
Scott B, Mukherjee S, Lake R, Robinson BWS. Malignant mesothelioma. In: Hansen H, ed. Textbook of lung cancer. London: Martin Dunitz, 2000:273-93.
Whitaker D. The cytology of malignant mesothelioma. Cytopathology 2000;11:139-151.
The authors reply: Dr. O'Regan and colleagues have raised important questions regarding the role of osteopontin in both malignant and nonmalignant diseases. The presence of elevated levels of osteopontin in various pulmonary diseases emphasizes two points: the importance of choosing for study the appropriate high-risk cohort of people exposed to asbestos, and the importance of following this cohort prospectively. We show in our report that the degree of elevation of osteopontin levels in asbestos-exposed subjects who were matched both in age and their smoking status (current or former smokers) to the subjects in the mesothelioma cohort depends on the presence of fibrosis and plaque. In the population we studied, lung cancer and mesothelioma are the chief risks.1 For any biomarker to be robust, it must be relevant to the most common cancers in the cohort. A validation study based on our results will be performed by the Early Detection Research Network of the National Cancer Institute, and it will address the issues of specificity raised by Dr. O'Regan et al.
With regard to the data from Hiraki et al.: their area under the curve is very promising and is similar to what we found for serum levels; however, these data must be compared specifically with data on effusions from subjects exposed to asbestos who do not have cancer, as opposed to those with "various nonmalignant diseases." We plan to investigate their findings with our collection of more than 70 samples of pleural effusions from patients with mesothelioma and effusions from control subjects (unpublished data). Future studies should also investigate whether combining measurements of osteopontin with other promising markers, such as soluble mesothelin-related protein, increases their sensitivity and specificity for mesothelioma in both pleural effusions and serum.2
Harvey I. Pass, M.D.
New York University School of Medicine
New York, NY 10016
harvey.pass@med.nyu.edu
Michele Carbone, M.D., Ph.D.
Loyola University Cancer Center
Maywood, IL 60153
Anil Wali, Ph.D.
Karmanos Cancer Institute
Detroit, MI 48201
References
Selikoff IJ, Hammond EC, Seidman H. Latency of asbestos disease among insulation workers in the United States and Canada. Cancer 1980;46:2736-2740.
Robinson BW, Creaney J, Lake R, et al. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 2003;362:1612-1616.