Kupert et al. BMC Cancer 2011, 11:513 http://www.biomedcentral.com/1471-2407/11/513 Page 7 of 10 Figure 2 Determination of plasma sPLA2-IIa to predict lung cancer by ROC analysis. 96 Lung cancer specimens from the BNLCC relative to 20 healthy donors (a), 96 Lung cancer specimens relative to 29 benign SPN specimens from the BNLCC (b), and 18 T2 stage lung cancer specimens relative to 29 benign SPN specimens from the BNLCC were subjected to ROC analysis. Area under the ROC curve (AUC) and 95% confidence interval (95% CI) were determined. such as diabetes, obesity, and inflammation. In addition, the sensitivity of these plasma biomarkers is usually not very high, especially for early stages of cancer, which is partially due to the heterogeneous nature of cancer. Only a few plasma biomarkers are currently used to screen and diagnose cancers in clinical practice, includ- ing PSA, a-fetoprotein, CA19-9, CA125, and CEA [9-11]. None of these plasma biomarkers are cancer-spe- cific [11]. For example, PSA is tissue-specific but not cancer-specific and has only 21% sensitivity with 4 ng/ ml as the cutoff value [36]. Plasma PSA are elevated in benign diseases, such as in 30 ~ 50% BPH patients, which leads to low specificity [37]. On the other hand, many prostate cancers do not lead to a high PSA and fail to be detected in PSA screening, which also contri- butes to low sensitivity [37-41]. a-fetoprotein (AFP) for hepatocellular carcinoma has 65% sensitivity and 89% specificity, while the addition of VEGF and fucosidase (AFU) tests can increase the sensitivity up to 100% [42,43]. Furthermore, it is also noted that sensitivity of plasma biomarkers, such as CA125, is increased with advanced cancer stages, which is also consistent with our observation of plasma sPLA2-IIa for lung cancer [44]. A few serum biomarkers for lung cancer are cur- rently under investigation, including Cyfra 21.1 and CEA for NSCLC and neuron-specific enolase (NSE) for SCLC [12,26,27]. Our data showed that none of these lung cancer biomarkers, based on the cutoff value reported, has high sensitivity to predict an early stage lung cancer [45]. However, the combined test of sPLA2-IIa, Cyfra 21.1 and CEA increases the power for lung cancer prediction relative to sPLA2-IIa test alone. We did not examine NSE, since there are only three SCLC specimens in the BNLCC cohort. Although Cyfra 21.1 is preferentially for squamous cell carci- noma, we did not find that Cyfra 21.1 shows a high sensitivity for squamous cell carcinoma. Given the het- erogeneous nature of cancer and heterogeneous gene overexpression from one cancer to another, a com- bined blood test including a few plasma biomarkers is essential to increase the sensitivity to predict an early stage lung cancer. In summary, we demonstrated that lung cancer tissues overexpress sPLA2-IIa and there is an elevated level of plasma sPLA2-IIa in lung cancer patients. Multiple lines of evidence support the notion that plasma sPLA2-IIa may represent a novel biomarker for lung cancer: 1) sPLA2-IIa is overexpressed in all squamous cell carci- noma, adenocarcinoma, and bronchioalveolar carcinoma examined and in majority of small cell carcinoma; 2) High levels of plasma sPLA2-IIa predict approximately 48% of early stage lung cancers and up to 67% of T2 stage lung cancers relative to patients with benign SPN; 3) High levels of plasma sPLA2-IIa are associated with advanced lung cancer stages and a decreased overall cancer survival; 4) the combined sPLA2-IIa, Cyfra 21.1 and CEA tests increase the power for lung cancer pre- diction relative to sPLA2-IIa test alone; 5) The com- bined lung cancer blood tests have potential to help with the decision algorithm of lung cancer diagnosis