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      Plasma proGRP Concentration is Sensitive and Specific for Discriminating Small Cell Lung Cancer from Nonmalignant Conditions or Non-small Cell Lung Cancer

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          Abstract

          To date, most clinical data on pro-gastrin-releasing peptide (proGRP) have been based on serum concentrations. This study evaluated the agreement between proGRP levels in fresh serum and plasma in patients with various lung diseases. Pairs of serum and EDTA plasma were collected from 49 healthy individuals. At the same time, EDTA plasma of 118 lung cancer patients and 23 patients with benign pulmonary diseases were prospectively collected. Compared to serum, plasma proGRP concentrations were higher by an average of 103.3%. Plasma proGRP was higher in malignancy (336.4 ± 925.4 pg/mL) than in benign conditions (40.1 ± 11.5 pg/mL). Small cell lung cancer (SCLC) patients showed higher levels of proGRP (1,256.3 ± 1,605.6 pg/mL) compared to other types of lung cancer. Based on the ROC curve analyses at a specificity of 95%, the diagnostic sensitivity of plasma proGRP was estimated to be 83.8% in distinguishing SCLC from all the other conditions, and 86.5% for discriminating SCLC from the nonmalignant cases. Among the SCLC cases, limited stage disease had lower levels of plasma proGRP than extensive disease. When measuring circulating levels of proGRP, the use of plasma is preferred over serum. Plasma proGRP has a potential marker for discriminating SCLC from nonmalignant conditions or non-small cell lung cancer.

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          Pro-gastrin-releasing peptide(31-98) is a specific tumor marker in patients with small cell lung carcinoma.

          Gastrin-releasing peptide (GRP) is a specific and an actively secreted product of small cell lung carcinoma (SCLC) cells. Based on this observation, we attempted to develop a new approach for early detection of SCLC and for monitoring therapeutic response in SCLC patients. Recombinant human ProGRP(31-98), a region common to three types of human ProGRP molecules, was synthesized, and a convenient radioimmunoassay system was developed; in this assay, the minimum detectable amount in serum was 10 pM when 0.1 ml of unextracted serum was used. Serum levels of immunoreactive ProGRP(31-98) were measured in 247 normal subjects, 180 patients with nonmalignant pulmonary diseases, 231 patients with non-SCLC, and 140 patients with SCLC. The percentages of subjects with the level greater than 10 pM in normal subjects and patients with nonmalignant pulmonary diseases and with non-SCLC were 1.2, 2.2, and 3.0%, respectively. In contrast, 76% of patients with SCLC had elevated levels; the positive rates in SCLC patients with limited and extensive diseases were 73 and 79%, respectively, indicating that the serum Pro-GRP(31-98) level could serve as a reliable tumor marker in SCLC patients, even at a relatively early stage of this disease. Moreover, changes in the serum ProGRP(31-98) showed excellent correlation with the therapeutic responses in SCLC patients. These results indicate that the determination of serum ProGRP(31-98) levels plays an important role in the diagnosis and treatment of SCLC patients.
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            The diagnostic and prognostic value of ProGRP in lung cancer.

            To investigate the diagnostic and prognostic significance of pro-gastrin-releasing peptide (ProGRP) in non-small cell (NSCLC) and small cell lung cancer (SCLC) and compare this marker with other known serum markers in lung cancer. Serum levels of ProGRP, neuron-specific enolase (NSE), CYFRA 21-1 and carcinoembryonic antigen (CEA) were measured in 37 patients with benign pulmonary disease (BPD), 88 with advanced NSCLC and 37 with SCLC. The ProGRP assay showed a better clinical performance than that of NSE in discriminating between SCLC and BPD or NSCLC, especially at specificity higher than 90%. ProGRP and NSE sensitivity in SCLC at 95% specificity versus the BPD group was 78.4% and 48.6%, (p=0.001) and at 97.7% specificity versus NSCLC, 75.7% and 37.8%, respectively (p=0.001). A significant association of low ProGRP levels with high-grade NSCLC tumors was found (p=0.002). A univariate analysis showed a significant association of ProGRP with survival both in NSCLC and SCLC (p=0.03 and p=0.04, respectively). In multivariate analysis, performance status (PS) and CYFRA 21-1 in NSCLC, and PS, CYFRA 21-1 and serum lactic dehydrogenase in SCLC were found as significant variables with an independent impact on survival. ProGRP is a useful marker in SCLC, with diagnostic performance better than that of NSE and demonstrating association with survival in NSCLC and SCLC limited to univariate analysis.
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              ProGRP: a new biomarker for small cell lung cancer.

              Progastrin-releasing peptide (ProGRP) is a recently identified biomarker of small cell lung cancer (SCLC), a disorder of neuroendocrine tissue differentiation. The upper normal limit of ProGRP in the circulation is 50 pg/ml. Impaired glomerular filtration tends to increase circulating levels and confound the tumor marker significance of modestly elevated values. Excluding patients with renal failure, circulating levels did not exceed 80 pg/ml in benign disease (3% of cases in excess of the upper normal limit) or 120 pg/ml in malignancy other than lung cancer and neuroendocrine tumors (5% of cases in excess of the upper limit). ProGRP serum levels are clearly related to the lung cancer histological type with significantly higher levels observed in SCLC than in nonsmall cell lung cancer (NSCLC). Circulating ProGRP in excess of 120 mg/ml was found in only 4% of cases of NSCLC with another 22% presenting with modestly elevated levels in excess of the upper normal limit. By contrast, abnormal ProGRP results are found in 60-70% and in 75-90% of SCLC patients with local and extensive disease, respectively. ProGRP is a more sensitive biomarker than is neuron-specific enolase (NSE) for SCLC, but thus far has not been found in multivariate analysis to have independent prognostic significance. Preliminary studies suggest ProGRP will have utility in conjunction with NSE in monitoring the therapy of established SCLC.
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                Author and article information

                Journal
                J Korean Med Sci
                JKMS
                Journal of Korean Medical Science
                The Korean Academy of Medical Sciences
                1011-8934
                1598-6357
                May 2011
                21 April 2011
                : 26
                : 5
                : 625-630
                Affiliations
                [1 ]Brain Korea 21 Project, Center for Biomedical Human Resources, Chonnam National University, Gwangju, Korea.
                [2 ]Department of Internal Medicine, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Korea.
                [3 ]Department of Laboratory Medicine, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Korea.
                [4 ]Abbott Diagnostics, Seoul, Korea.
                Author notes
                Address for Correspondence: Myung-Geun Shin, MD. Department of Laboratory Medicine, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, 160 Ilsim-ri, Hwasun-eup, Hwasun 519-890, Korea. Tel: +82.61-379-7950, Fax: +82.61-379-7984, mgshin@ 123456chonnam.ac.kr

                *Hye-Ran Kim and In-Jae Oh contributed equally to this work.

                Article
                10.3346/jkms.2011.26.5.625
                3082113
                21532852
                c55c934b-7b05-4ff5-bb18-2ae0503532f6
                © 2011 The Korean Academy of Medical Sciences.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 December 2010
                : 07 March 2011
                Categories
                Original Article
                Oncology & Hematology

                Medicine
                small cell lung carcinoma,serum,pro-gastrin-releasing peptide (31-98),plasma
                Medicine
                small cell lung carcinoma, serum, pro-gastrin-releasing peptide (31-98), plasma

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