Growing evidence suggests that survivin expression in cancer cell nuclei may represent an important prognostic marker to predict disease outcome for cancer patients. Current reports in this research area, however, are inconsistent and propose opposing conclusions regarding the significance and prognostic value of survivin nuclear expression. The aim of our study is to review and discuss the data reported in the original publications. We have also provided new experimental data to support our view regarding the possible reasons for the observed inconsistencies in the literature. This would alert researchers to pay attention to potential pitfalls in the determination of nuclear or cytoplasmic expression of survivin for the future. © 2004 Wiley-Liss, Inc. Key words: survivin expression; cancer; cytoplasmic; nuclear; immunohistochemistry; prognostic marker Among the 19 publications relevant to survivin localization in nuclei or cytoplasm in various cancer tissues, 9 showed that the expression of survivin in cancer cell nuclei is an unfavorable prognostic marker, 1-10 whereas studies from 5 of 19 proposed an opposing notion that the nuclear expression of survivin represented a favorable prognostic marker. 10 -14 The remaining 5 publications did not focus on studying the significance of nuclear expression of survivin in disease outcome, although these reports pointed out the fact that survivin could be expressed in either cytoplasm or nuclei. [15][16][17][18][19] Two of these 5 studies reported that overall, survivin expression was an unfavorable prognostic factor. 16,18 The localization of survivin in nuclei or cytoplasm was determined by immunohistochemistry (IHC) in all 19 reports. One of the 19 publications alternatively carried out Western blots using cell lysates from the fractionated cytoplasm and nuclei for the confirmation of survivin localization. 5 In addition, Nakagawa et al. 20 reported recently that nuclear localization of survivin, as well as cytoplasmic in some cases, was essentially found in acute lymphocytic leukemia (ALL) cells whereas cytoplasmic expression of survivin was predominantly showed in chronic lymphocytic leukemia (CLL) cells. The significance, however, was not investigated. Nuclear expression of survivin is an unfavorable prognostic markerIn hepatocellular carcinoma (HCC), studies from Ito et al. 1 indicated that 14 of 20 (70%) HCC tissues showed nuclear staining of survivin, whereas non-tumor tissues showed little survivin staining. Nuclear survivin expression strongly correlated with the proliferation index. 1 Similarly, studies from Moon et al. 4 showed that 22 of 35 (63%) survivin-positive specimens (total ϭ 47) showed punctate nuclear staining in HCC cells. In contrast, nonmalignant hepatocytes showed only cytoplasmic staining. HCC specimens with nuclear survivin expression showed the highest PCNA (proliferating cell nuclear antigen) labeling index and correlated with tumor cell de-differentiation. 4 Recently, Fields et al. 8 reported that immunohistochemical analyses of 72 hep...

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The mammalian Forkhead Box (Fox) transcription factor FoxM1b is implicated in tumorigenesis. However, the presence of expression and role of FoxM1b in gastric cancer remain unknown. Therefore, we investigated FoxM1b expression in 86 cases of primary gastric cancer and 57 normal gastric tissue specimens. We further investigated the underlying mechanisms of altered FoxM1b expression in and the impact of this altered expression on gastric cancer growth and metastasis using in vitro and animal models of gastric cancer. We found weak expression of FoxM1b protein in the mucous neck region of gastric mucosa, whereas we observed strong staining for FoxM1b in tumor-cell nuclei in various gastric tumors and lymph node metastases. A Cox proportional hazards model revealed that FoxM1b expression was an independent prognostic factor in multivariate analysis (P < 0.001). Experimentally, overexpression of FoxM1b by gene transfer significantly promoted the growth and metastasis of gastric cancer cells in orthotopic mouse models, whereas knockdown of FoxM1b expression by small interfering RNA did the opposite. Promotion of gastric tumorigenesis by FoxM1b directly and significantly correlated with transactivation of vascular endothelial growth factor (VEGF) expression and elevation of angiogenesis. Given the importance of FoxM1b to regulation of the expression of genes key to cancer biology overall, dysregulated expression and activation of FoxM1b may play important roles in gastric cancer development and progression.

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Delay to formalin fixation may invalidate hormone receptors and HER2 analyses. Invalid results of tumor markers could significantly alter the type of adjuvant therapy a patient receives and potentially impact outcome. The purpose of this study was to determine the effects of progressive delay to formalin fixation on breast cancer biomarkers. Ten palpable invasive breast cancers were resected and underwent immediate gross evaluation. For each case, the procured tumor was divided into eight parts and consecutively fixed after 0, 10, 30 min, 1, 2, 4, and 8 h; one section was kept in saline and stored overnight at 41C. Two tissue microarray blocks were constructed. Estrogen and progesterone receptors and HER2 immunohistochemistry and fluorescence in situ hybridization were carried out. Statistical analyses including non-parametric sign test, exact McNemar's test and Page's L test were used. All 10 cases were invasive ductal carcinomas. Q score X6 was identified in five cases for estrogen receptor and four for progesterone receptor. Mean Q score started to decline at the 2 h mark for estrogen receptor and 1 h mark for progesterone receptor. Lowest score was at 8 h mark for estrogen receptor and overnight for progesterone receptor. HER2 fluorescence in situ hybridization started to be compromised for interpretation at the 1 h mark and became statistically significant at the 2 h mark (Po0.03). To avoid delay to formalin fixation as a factor negatively affecting on breast biomarkers, we recommend not to delay formalin fixation for more than 1 h and not to store specimens overnight.