Rac proteins of the Rho-like GTPase family, including the ubiquitous Rac1, the hematopoiesisspecific Rac2, and the least-characterized Rac3 play a major role in oncogenic transformation, tumor invasion and metastasis. However, the prognostic relevance of Rac expression in human tumors has not been investigated yet. In the present study, Rac protein expression was analyzed in benign secretory epithelium, high-grade prostatic intraepithelium neoplasia (HG-PIN), and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Thus, Rac proteins were significantly strongly expressed in HG-PIN (P!0.001) and prostate carcinomas (P!0.001) when compared with benign secretory epithelium. Accordingly, all tumor tissues analyzed by isoform-specific real-time PCR (nZ7) exhibited significantly higher RNA expression levels of Rac (i.e. sum of Rac1 and Rac3 expression levels) than the respective benign counterparts (PZ0.018) and this appeared to result mainly from increased expression of the Rac3 isoform as verified by immunoblotting. Univariate analyses showed statistically significant associations of increased Rac protein expression in prostate cancer (PZ0.045), preoperative prostate-specific antigen levels (PZ0.044), pT stage (PZ0.002), and Gleason score (PZ0.001) with decreased disease-free survival (DFS). This prognostic effect of increased protein expression of Rac remained significant even in a multivariate analysis including all these four factors (relative riskZ3.22, 95% confidence intervalZ1.04-10.00; PZ0.043). In conclusion, our data suggest that increased Rac protein expression in prostate cancer relative to the corresponding benign secretory epithelium is an independent predictor of decreased DFS and appears to result mainly from increased expression of the Rac3 isoform.

The Rac-specific guanine nucleotide exchange factor, Tiam1, plays a major role in oncogenicity, tumour invasion and metastasis but its usefulness as a prognostic marker in human cancer has not been tested yet. In the present study, Tiam1 expression was analysed in benign secretory epithelium, pre-neoplastic high-grade prostatic intraepithelium neoplasia (HG-PIN) and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Tiam1 proved significantly overexpressed in both HG-PIN (Po0.001) and prostate carcinomas (Po0.001) when compared to benign secretory epithelium. Strong Tiam1 overexpression (i.e. X3.5-fold) in prostate carcinomas relative to the respective benign prostatic epithelium was statistically significantly associated with disease recurrence (P ¼ 0.016), the presence of lymph vessel invasion (P ¼ 0.031) and high Gleason scores (GS) (i.e. X7) (P ¼ 0.044). Univariate analysis showed a statistically significant association of strong Tiam1 overexpression with decreased disease-free survival (DFS) (P ¼ 0.03). This prognostic effect of strong Tiam1 overexpression remained significant in multivariate analysis including preoperative prostate-specific antigen levels, pT stage, and GS (relative risk ¼ 3.75, 95% confidence interval ¼ 1.06 -13.16; P ¼ 0.04). Together, our data suggest that strong Tiam1 overexpression relative to the corresponding benign epithelial cells is a new and independent predictor of decreased DFS for patients with prostate cancer.

Gastric adenocarcinomas are associated with a poor prognosis due to the fact that the tumor has often metastasized by the time of diagnosis and prognostic markers are urgently needed to tailor treatment.We examined the expression of the mitotic spindle checkpoint protein BUB1 (budding uninhibited by benzimidazoles 1) and Ki-67 protein expression by immunohistochemistry in 218 patients with primary gastric adenocarcinomas.Tumors with low frequency of BUB1 expression were associated with larger tumor size (pT) (p < 0.001), higher incidence of lymph node metastases (pN) (p = 0.027), distant metastases (pM) (p = 0.006) and higher UICC stage (p < 0.001). Furthermore, BUB1 expression was inversely correlated with residual tumor stage (p = 0.038). Abundant BUB1 protein expression correlated with frequent Ki-67 protein expression (p < 0.001) and low BUB1 expression was associated with shorter survival (p < 0.001). Univariate and multivariate analyses confirmed BUB1 to be an independent prognostic marker in gastric cancer (p = 0.021).

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Objective: To compare the detection rate for trisomy 21 of universal cell free DNA (cfDNA) screening with contingent screening. Methods: Retrospective study at 3 German centers. The study included euploid and trisomy 21 pregnancies where cfDNA and first trimester (FT) screening assessment was carried out. The FT risk for trisomy 21 was computed based on combined screening and stratified into the following classes: high risk >1:10, intermediate risk 1:11 – 2,500, low risk <1:2,500. For universal cfDNA screening, the cfDNA test results were examined. For the contingent screening model, the result of the cfDNA test was taken into account in case of an intermediate FT risk. Different strategies combining maternal age, nuchal translucency, nasal bone, beta-hCG and PAPP-A were evaluated. Screen-positivity was defined as either a high risk after first trimester screening or a cfDNA test indicating a high risk result. An inconclusive cfDNA test was also considered as screen positive. Results: The search of the database identified 2,255 euploid and 163 affected pregnancies. All affected fetuses were identified by universal cfDNA screening. 1.3% of the euploid fetuses were classified as screen positive due to final inconclusive cfDNA test result. The detection and false positive rate of a contingent approach that is based on combined screening and cfDNA screening in the intermediate group would be 98.4% and 0.7%, respectively. With this approach, cfDNA screening would be necessary in only about 27% of all pregnancies. Conclusion: This study demonstrates that a contingent approach provides similar detection rates for trisomy 21 as universal cfDNA screening, by reducing in 73% the number of cfDNA tests.