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  • 1625 australia We then analyzed Ki proliferation index as a


    We then analyzed Ki-67 proliferation index as a categorical variable by using 15%, essentially the median Ki-67 value in the entire study group (see above), to delineate low and high proliferation subgroups. By Fisher\'s exact test, both the type 1 versus non-type 1 EWS-FLI1 comparison (P = 0.047; Table 2) and the EWS-FLI1 versus EWS-ERG comparison (P = 0.02; Table 3) remained statistically significant. To further dissect the relative contributions of these variables to proliferation index in ES/PNET, we performed a logistic regression analysis of factors determining Ki-67. In an analysis including EWS-FLI1 type 1 versus non-type 1 and IGF-1R, the latter remained significant (P = 0.049), but EWS-FLI1 transcript type was no longer significant (P = 0.3), suggesting that the impact of the latter on Ki-67 values may be due largely to its correlation with IGF-1R expression. No significant correlations were seen between Ki-67 or transcript type and stage at diagnosis or tumor volume. Tumors metastatic at diagnosis were larger than those presenting with localized disease only (1390 ml vs. 242 ml respectively; P = 0.001). No other correlations were identified among the parameters studied. There were no significant differences in the proportion of apoptotic cells, as detected by the TUNEL assay, among the groups.
    Discussion The consistent involvement of transcription factors in the gene fusions observed in many small cell sarcomas suggests a central role for these 1625 australia in the regulation of proliferation and differentiation of mesenchymal cells.EWS-FLI1 is an aberrant transcription factor, and experimental evidence suggests that EWS-FLI1 initiates and maintains tumorigenicity in ES/PNET. Indeed, specific inactivation of EWS-FLI1 in ES/PNET cell lines results in reduced proliferation and loss of tumorigenicity.9, 10, 11 Ki-67 is expressed in late G1, S, G2, and M phases, and hence correlates closely with growth fraction in all tumor types. Although its function is not well known, nuclear overexpression of Ki-67 has been associated with tumor progression and poor prognosis in many different tumors, including sarcomas.21, 22, 23, 24 There have been few systematic studies of proliferation markers in ES/PNET. Our median Ki-67 value with the MIB1 antibody (14%) was slightly higher than the range of proliferative rates previously reported for this tumor (7–10%) using other techniques.25, 26, 27, 28 The significant positive correlation between proliferative rate and IGF-1R expression level (P = 0.04) found in the present study is consistent with the known cellular biology of IGF-1R29, 30 and supports the validity of the immunohistochemical methods used to evaluate these two parameters. Our Ki-67 data, whether analyzed as continuous or categorical variables, suggest that tumors with EWS-FLI1 type 1 have, on average, a lower proliferative rate than ES/PNET with non-type 1 EWS-FLI1. Our logistic regression analysis further suggests that the partial association of type 1 EWS-FLI1 and lower IGF-1R expression may account at least in part for the association of Ki-67 and EWS-FLI1 fusion type. IGF-1R is widely expressed by proliferating cells throughout development.29, 30 IGF-1 and its receptor, IGF-1R, are expressed in many human tumors,29, 30 including various sarcomas. In at least some ES/PNET, they appear to constitute a functional autocrine or paracrine loop.12, 14 Blockade of IGF-1R stops proliferation and induces apoptosis in ES/PNET.12, 13, 14 Consistent with these studies, we found a significant positive correlation in ES/PNET between Ki-67 proliferative index and the proportion of cells expressing IGF-1R. Tumors with EWS-FLI1 Type 1 fusions had significantly fewer cells immunoreactive for IGF-1R. The simplest model accounting for these associations of fusion type, IGF-1R expression, and proliferative rate would suggest that the IGF-1R gene is a direct or indirect target of EWS-FLI1 and therefore subject to differential regulation by alternative forms of this aberrant transcription factor. Few regulatory targets of EWS-FLI1 or native FLI1 have so far been identified.32, 33, 34, 35 There are contradictory data on IGF-1R regulation by EWS-FLI1. In a study recently reported in abstract form, Shum et al found IGF-1R gene expression to be decreased following induction of EWS-FLI1 in a human embryonal kidney cell line (EcR293). On the other hand, Toretsky et al reported no significant difference in endogenous IGF-1R protein levels in mouse fibroblast cell lines with or without stably transfected human EWS-FLI1, leading them to conclude that IGF-1R expression is not regulated by the fusion protein. Whether these experimental models are representative of IGF-1R regulation in ES/PNET is unclear, however. The human and murine IGF-1R promoter regions are not identical, and mouse fibroblasts, human embryonal kidney cells, and human ES/PNET cells may differ in cell type-specific transcriptional cofactors.