**6. Comparative analysis of Fb-3 with other biomarkers**

As underlined afore, many surveys focused on researching new MM biomarkers. The reasons of such interest from the scientific community are not purely academic; in fact, even though in several Western countries exposure to asbestos seems to be confined to few professional contexts, in developing countries such as India and China asbestos is still extracted and exploited. For such reason MM continues to be a recurrent disease nowadays, also by reason of a few high-susceptibility population subgroups. About that, it has been demonstrated that hereditary mutations borne by the gene BRCA-associated protein 1 (BAP1) predispose for a higher incidence of some cancers, among which MM.

Several biomarkers have been proposed for diagnosing MM, among them metabolites, proteins and microRNAs (miRNAs). An ideal biomarker ought to spot selectively MM patients from those with other pathologies and/or asbestos-exposed subjects from non-exposed ones. With a view to an early diagnosis and implementation of surveillance programs, the ideal biomarker detection sample would be the blood, for its low invasiveness and better compliance; the pleural liquid would be less ideal, as it requires a more invasive collection technique.

Presently, mesothelin is MM's only and most extensively studied biomarker, recognized by the American Food and Drug Administration (FDA) and by some EU countries. It is a protein precursor with a molecular weight of 71 kDa from whose cleavage, the *megakaryocyte potentiating factor* (MPF), which is then secreted into the blood and the *glycosylated phosphatidylinositol-linked glycoprotein*, a membrane protein, are originated. Physiologically, mesothelin is expressed at a low grade in mesothelial cells and almost in no way in other tissues; its overexpression is instead observed in several forms of cancer, such as MM, ovaric, lung cancer and pancreatic adenomacarcinoma.

Some surveys highlighted the capability to identify MM patients through dosage of SMRPs (*soluble mesothelin-related peptides*) in the serum, getting a 60–90% sensitivity and an 80–85% specificity, as well managing to distinguish between MM subjects, asbestos-exposed ones, nonexposed subjects, and others with benign pleural pathologies. Other experiments showed the possibility to differentiate, through SMRPs serum values, MM patients from those with pleural secondary metastases. Studies on humans assessed SMRPs' dosage in the pleural exudate (PE-SMRPs), reporting higher sensitivity values than those serum-obtained in spotting MM patients.

A metanalysis compared data coming from 12 studies, basing itself on a total of 717 subjects suffering from mesothelioma and 2851 controls, among whom were healthy subjects as well as others with pleural pathologies. The results the authors reached showed an overall sensitivity of 64% and a specificity of 89% for the SMRPs measured in the serum.

It seems clear how mesothelin is the main term of comparison to ascertain Fb-3 effectiveness and its possible introduction in MM clinical routine.

A survey conducted by Creaney et al. [12] compared Fb-3 and mesothelin values in the plasma and pleural liquid of 202 subjects. The population examined included MM patients (n = 82), patients with benign asbestos-related diseases (n = 49), subjects with malignant exudate (n = 36), and others with benign exudate [35]. The authors underlined an enhanced diagnostic accuracy of mesothelin compared to Fb-3, both in plasma (AUC = 0.822 vs*.* 0.671) and in the pleural liquid (AUC = 0.815 vs*.* 0.588). However, the Fb-3 concentration in the pleural liquid turned out to be a predictive factor for the patient's survival. MM subjects with Fb-3 lower levels in the pleural liquid than the average had significantly longer survival times than those with levels above the average (14.1 vs. 7.9 months). Mesothelin values and other parameters like neutrophil/lynphocite ratio did not appear significantly correlated with the patients' prognosis.

In a survey by Battolla et al., Fb-3 and SMRPs' levels were contextually evaluated in pleural exudate of patients suffering from MM (n = 33), benign pleural lesions (n = 64) and secondary pleural metasteses (n = 23). Samples were analyzed by ELISA, and revealed Fb-3 values similar among MM subjects and the rest of the cohort (geometric mean = 68.1 vs*.* 66.2 ng/ml; P = 0.872) and significantly increased values of SMRPs in MM patients compared with the rest of the group (geometric mean = 14.6 vs. 3.2 nM; P < 0.001).

#### *Fibulin-3 as a Biomarker of Pleuric Involvement by Exposure to Fibers DOI: http://dx.doi.org/10.5772/intechopen.104448*

A survey conducted by Napolitano et al. compared HMGB1 values with mesothelin, Fb-3, and osteopontin (OPN) in the blood. The survey population included: a cohort of subjects who had been treated for pleural exudate derived from benign pathologies (n = 13), from MM (n = 22), and other malignant diseases (n = 25); a group of historically asbestos-exposed workers (n = 20); a group of healthy subjects with no documented exposure to asbestos (n = 20). The results of the study revealed that Fb-3 was the molecule with the highest sensitivity in telling MM subjects from those with other pleural pathologies, followed by HMGB1 hyper-acetylated form, by mesothelin and OPN. The authors concluded that the best diagnostic performance could be obtained combining HMGB1 and Fb-3 values.

Generally speaking, most studies in the literature report a better sensitivity of mesothelin compared with Fb-3, both in plasma and pleural liquid. Instead, comparative studies between Fb-3 and other potential MM biomarkers such as OPN and miRNAs are still missing.
