An AUROC closer to 1 indicates greater discriminatory power, whereas an AUROC of 0

An AUROC closer to 1 indicates greater discriminatory power, whereas an AUROC of 0.5 denotes no diagnostic potential. and tumour cells. Positivity for Mcm2 was found in 46% (98/211) of analysable cases. A significant correlation existed between Mcm2 expression and presence of heavy disease (p = 0.003). Poor disease specific survival Rhoa GLYX-13 (Rapastinel) was observed in patients with DLBCL positive for Mcm2 expression in the univariate analysis (p = 0.0424). Conclusion Mcm2 expression can be used to assess tumour proliferation and may be useful as an additional prognostic marker to refine the prediction of end result in DLBCL. Background In Western countries, diffuse large B-cell lymphoma (DLBCL) is the most common type of mature B-cell lymphomas with a frequency of approximately 30 to 40% [1]. DLBCL is an aggressive but potentially curable disease. However, only about 40 to 45% of patients are cured with combination chemotherapy [2]. Currently, the International Prognostic Index (IPI) is the generally accepted predictor of prognosis [3]. In order to avoid over-treatment of some patients and identify patients at high-risk for early relapse or poor response to standard treatment, individualised prediction of prognosis becomes more and more important. A number of biological markers have been analyzed for their predictive potential, but none has become universally accepted [4-7]. Gene expression profiling has helped to identify at least two subgroups of DLBCL, one with a germinal centre signature and the other with an activated B-cell signature, which show unique clinical outcomes [3,8]. The proliferative capacity of neoplastic cells is an important feature of growing tumours. Assessment of cell proliferation may provide both GLYX-13 (Rapastinel) pathologists and clinicians with more objective prognostic information [9,10]. Expression of Ki-67 as assessed by immunohistochemistry has become the standard proliferation marker [11-13]. In lymphoid neoplasms, it is controversial whether Ki-67 is usually a reliable prognostic indication [14-17]. In DLBCL, a high proliferation index has been associated with an unfavourable clinical end result in some studies [18]. Despite the considerable use of Ki-67, its functional significance still remains unclear [19]. It has been suggested, that Ki-67 plays a role in the ribosome biosynthesis rather than being directly responsible for cell proliferation [20,21]. Therefore, detecting markers directly involved in DNA replication might be a more precise method to evaluate the proliferative behaviour of a tumour. The minichromosome maintenance (MCM) protein family consists of six users of DNA-binding proteins [22]. MCM proteins stand at the end of many signalling pathways involved in cell proliferation [23]. They ensure that synthesis of DNA is initiated only once during each cell cycle. All six proteins are abundant throughout the cell cycle and are broken down rapidly on differentiation or more slowly in quiescence [24,25]. Expression is only observed in cycling cells, there is no expression in quiescent and differentiating cells [25-28]. Antibodies for detection of MCM proteins in routinely processed tissue specimen have been found superior to Ki-67 in defining the proliferative compartments in both normal and abnormal human tissues [27,29-32]. Immunohistochemical assessment of all six MCM proteins has been observed to produce comparable results in a range of tissue sections [33]. MCM proteins have been promoted as markers for malignancy screening, surveillance and prognosis [27,29-31,34-36]. We used a specific monoclonal antibody directed against Mcm2 and a previously validated tissue microarray (TMA) with tissue samples of a large number of DLBCL [37]. Tissue microarrays are highly efficient for the investigation of large series of neoplasms including lymphoma [37-39]. The aim of this study was to systematically investigate if the analysis of Mcm2 expression might provide a novel tool to assess the proliferation of DLBCL and predict clinical end result in patients with this disease. Methods Construction of tissue microarrays and acquisition of clinico-pathologic data Tissue microarrays were constructed as explained previously [39,40]. The TMAs contained a total of 302 tissue samples from tumours, which had been classified prior to this study GLYX-13 (Rapastinel) as diffuse large B-cell lymphomas according to the WHO classification [1]. All samples had been obtained at the time of diagnosis, before any treatment had been given. Four different TMAs were constructed, each made up of tumour samples from different histopathologic institutions (Basel, Bologna, Innsbruck, Zurich). Clinical data of patients with DLBCL at time of primary diagnosis and follow-up had been obtained by critiquing the charts..