Survivin expression is an independent poor prognostic marker in lung adenocarcinoma but not in squamous cell carcinoma

Survivin is a member of the inhibitors of apoptosis and frequently overexpressed in various cancer cells. Overexpression of survivin in lung cancer cells attenuates antitumor effect of tyrosine kinase inhibitors. However, data from the previous studies on the clinicopathologic implication of survivin in non-small-cell lung carcinoma (NSCLC) are inconsistent. We investigated the expression of survivin in 373 cases of surgically resected NSCLC. Correlations between the expression of survivin and clinicopathologic, molecular features and prognostic significance were analyzed. In adenocarcinoma, the increased expression of survivin was associated with the presence of vascular invasion, lymph node metastasis, and tumor recurrences, but we didn’t find any correlation with survivin expression and clinicopathological parameters in squamous cell carcinoma. Patients with high survivin expression had significantly shorter disease-free survival (DFS; 42.2 vs. 58.8 months; p?=?0.001) and shorter overall survival (OS; 60.8 vs. 71.5 months; p?=?0.009) than those with low survivin expression group in adenocarcinoma. In squamous cell carcinoma, the expression of survivin was not associated with prognosis of the patients (DFS; 48.9 vs. 48.7 months; p?=?0.837, OS; 61.0 vs. 62.4 months; p?=?0.771). Multivariate analysis confirmed that survivin was an independent poor prognostic factor in adenocarcinoma (DFS: hazard ratio (HR), 1.687; 95 % confidence interval (CI), 1.123–2.532; p?=?0.012; OS: HR, 1.965; 95 % CI, 1.108–3.486; p?=?0.021). There was no statistically significant difference in the expression of survivin among different molecular subgroups (p?>?0.05). Our results suggest that survivin is an independent negative prognostic factor in adenocarcinoma, but not in squamous cell carcinoma. The different prognostic roles played by survivin in adenocarcinoma and squamous cell carcinoma highlights the biological differences between these two histologic types.     

Loss of nuclear prothymosin-α expression is associated with disease progression in human superficial bladder cancer

In this paper, we report a study on the clinical relevance of prothymosin-α expression and its correlation with intratumoral Foxp3⁺ and CD8⁺ lymphocytes (Foxp3⁺TIL and CD8⁺TIL) in bladder cancer patients. We used immunohistochemical staining for prothymosin-α, Foxp3, and CD8 on 101 tumor specimens harvested by endoscopic resection. The results were correlated with clinicopathological variables and clinical outcome in bladder cancer patients, particularly in 73 patients with superficial disease, using the log-rank test and Cox proportional hazard model. Overall, of the tumors, 30 % were negative, 34 % showed nuclear, and 37 % showed cytoplasmic prothymosin-α expression. Foxp3⁺TILs were detected in 11 % of patients (nonnuclear vs. nuclear, p?=?0.096). Patients with a history of urothelial carcinoma have a higher frequency of nonnuclear prothymosin-α expression than those without (p?=?0.016, chi-square test). By univariate and multivariate analyses of cases with superficial disease, grade and stage were identified as independent predictors for recurrence-free survival (p?=?0.016 and 0.016, respectively). Higher stage and nonnuclear prothymosin-α expression independently predict shorter progression-free survival (p?=?0.006 and 0.043, respectively). The presence of Foxp3⁺TILs was significantly associated with disease progression by univariate analysis (p?=?0.022), but not by multivariate analysis (p?=?0.147). In vitro assays showed that J82 cells which express ectopically nuclear prothymosin-α exhibit higher growth rate and secrete less TGF-β1 than those with cytoplasmic expression or control cells. Altogether, prothymosin-α expression is a determinant of disease progression in superficial bladder cancer. Foxp3⁺TILs tend to be found more often in bladder cancer with nonnuclear prothymosin-α expression. Future study is required to unravel their interaction.     

Tumour cell survival mechanisms in lethal metastatic prostate cancer differ between bone and soft tissue metastases

The complexity of survival mechanisms in cancer cells from patients remains poorly understood. To obtain a comprehensive picture of tumour cell survival in lethal prostate cancer metastases, we examined five survival proteins that operate within three survival pathways in a cohort of 185 lethal metastatic prostate metastases obtained from 44 patients. The expression levels of BCL‐2, BCL‐XL, MCL‐1, cytoplasmic survivin, nuclear survivin, and stathmin were measured by immunohistochemistry in a tissue microarray. Simultaneous expression of three or more proteins occurred in 81% of lethal prostate cancer metastases and BCL‐2, cytoplasmic survivin and MCL‐1 were co‐expressed in 71% of metastatic sites. An unsupervised cluster analysis separated bone and soft tissue metastases according to patterns of survival protein expression. BCL‐2, cytoplasmic survivin and MCL‐1 had significantly higher expression in bone metastases (p < 10^?5), while nuclear survivin was significantly higher in soft tissue metastases (p = 3 × 10^?14). BCL‐XL overexpression in soft tissue metastases almost reached significance (p = 0.09), while stathmin expression did not (p = 0.28). In addition, the expression of MCL‐1 was significantly higher in AR‐positive tumours. Neuroendocrine differentiation was not associated with specific survival pathways. These studies show that bone and soft tissue metastases from the same patient differ significantly in expression of a panel of survival proteins and that with regard to survival protein expression, expression is associated with the metastatic site and not the patient. Altogether, this suggests that optimal therapeutic inhibition may require combinations of drugs that target both bone and soft tissue‐specific survival pathways. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Clinical behavior of chromophobe renal cell carcinoma is less aggressive than that of clear cell renal cell carcinoma,independent of Fuhrman grade or tumor size

Chromophobe renal cell carcinoma (chRCC) is the third most common subtype of RCC, after clear cell (ccRCC) and papillary RCC. Its lower incidence and frequent exclusion from clinical trials might be why chRCC characteristics have not been extensively studied. The aim of our study was to examine tumor characteristics and long-term prognosis of chRCC compared to ccRCC. We collected 4,210 evaluable patients subjected to surgery for chRCC (n?=?176) or ccRCC (n?=?4,034) at five centers in Germany (University Hospitals of Hannover, Homburg/Saar, Mainz, Ulm, and Marburg) between 1990 and 2010. Patients with chRCC were significantly younger (mean, 60.1 vs. 62.1 years) and tended to be more frequently female (43.8 vs. 36.5 %). Although Fuhrman grade and median tumor diameter were not significantly different, significantly fewer patients with chRCC than with ccRCC presented with high tumor stage or metastasis at diagnosis (18.5 vs. 43.8 %). Moreover, significantly more chRCC patients were treated with partial nephrectomy (41.5 vs. 26.2 %). Accordingly, 5-year cancer-specific survival (CSS) rates were 83.2 % for chRCC against 75.8 % for ccRCC patients (p?=?0.014, log rank). However, in multivariate analysis, chromophobe subtype was not confirmed as a significant positive prognostic factor for RCC (HR 0.88, 95 % CI 0.63–1.24; p?=?0.48 Cox regression). This is one of the largest studies to date showing that chRCC is associated with a significantly lower risk of locally invasive tumor growth and metastatic disease than ccRCC. We conclude that the clinical behavior of chRCC is less aggressive than that of ccRCC, independent of Fuhrman grade or tumor size.     

Overexpression of matriptase correlates with poor prognosis in esophageal squamous cell carcinoma

Matriptase is one of the type II transmembrane serine proteases and is known to be involved in cancer progression. Increased matriptase expression has been reported in a variety of human cancers, and its association with poor prognosis has been highlighted in some cancer types. However, its exact role in cancer progression and its effect on patient survival in esophageal squamous cell carcinoma (ESCC) are still unclear. We performed immunohistochemical staining of matriptase in 171 ESCC samples after antibody validation and evaluated the association of its expression with clinicopathological parameters and prognosis. High matriptase expression was observed in 38.6 % (66/171) of ESCC samples and more frequently in N3 stage and in poorly differentiated tumors. Both overall survival (OS) and disease-free survival (DFS) were significantly lower for patients with high expression of matriptase than for patients with low expression (5-year OS rate, 38.6 vs 55.3 %; p?=?0.034 and 5-year DFS rate, 30.5 vs 49.4 %; p?=?0.007). High matriptase expression was an independent prognostic factor for OS [hazard ratio (HR), 1.65 (95 % confidence interval (CI), 1.01–2.68); p?=?0.045] and for DFS [HR, 1.79 (95 % CI, 1.14–2.81); p?=?0.012]. In conclusion, higher expression of matriptase is an independent prognostic factor involved in the progression of ESCC, which suggests that matriptase is a factor in ESCC tumor progression and also a potential molecular therapeutic target.     

Prognostic value of c-FLIPL/s,HIF-1α, and NF-κβ in stage II and III rectal cancer

Locally advanced rectal cancer (LARC) is associated with a 25 % rate of metastases. The prognostic and predictive relevances of the expression of five proteins (c-FLIP_L/s, HIF-1α, β-catenin, p65, and p105/p50 NF-κβ) were assessed. This is a retrospective study. From 1998 to 2009, 152 patients with stage II/III rectal cancer were treated with radio-chemotherapy. TMAs constructed with tumor and normal tissue from the diagnostic endoscopic biopsy and the surgical specimen after chemoradiotherapy were subjected to immunohistochemical (IHC) analysis. Results were correlated with clinical and pathological data, including progression-free survival (PFS). Four different IHC conditions were independent prognostic parameters for PFS: (1) cytoplasmic c-FLIP_L/s (p?=?0.007), (2) nuclear HIF-1α (p?=?0.020), (3) a change in the cytoplasmic p65 between the diagnostic biopsy and the post-treatment specimen (p?=?0.004), and (4) a change in the cytoplasmic c-FLIP_L/s between the diagnostic biopsy and the post-treatment specimen (p?=?0.021). Three different protein expression profiles, combining biomarkers, showed prognostic significance. IHC evaluation of these biomarkers in our three protein expression profiles may help to identify patients with worse prognosis and design more effective therapeutic strategies to personalize the treatment of rectal cancer.     

Long-Term Oncologic Outcomes after Radical Cystectomy for Bladder Cancer at a Single Institution

The aim of this study was to evaluate our experience using radical cystectomy to treat patients with bladder cancer and to describe the associations between pathologic features and clinical outcomes. All 701 patients who underwent radical cystectomy for bladder cancer were evaluated. The patient population consisted of 623 men and 78 women. The overall 5 and 10 yr recurrence-free survival (RFS) rates were 61.8% and 57.7%, respectively, and the 5 and 10 yr cancer-specific survival (CSS) rates were 70.8% and 65.1%, respectively. Multivariate analysis showed that factors significantly predictive of RFS and CSS included extravesical extension (P = 0.001), lymph node metastasis (P = 0.001), and lymphovascular invasion (P < 0.001 and P = 0.007). The 5 and 10 yr RFS rates for patients with lymph node metastasis were 25.6% and 20.8%, respectively, and the 5 and 10 yr CSS rates were 38.6% and 30.9%, respectively. Adjuvant chemotherapy significantly improved RFS (P = 0.002) and CSS (P = 0.001) in patients with lymph node metastasis. Radical cystectomy provides good survival results in patients with invasive bladder cancer. Pathologic features significantly associated with prognosis include extravesical extension, node metastasis, and lymphovascular invasion. Adjuvant chemotherapy improves survival in patients with advanced stage disease.

Graphical Abstract

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Expression of inhibitor-of-apoptosis protein family members in malignant mesothelioma

Inhibitor-of-apoptosis proteins (IAPs) mediate cancer cell survival and chemoresistance. We analyzed the expressions of X-linked IAP (XIAP), survivin, and livin in malignant mesothelioma. Ten effusions were analyzed for XIAP, survivin, and livin expression using immunoblotting. Based on the immunoblotting results, 112 mesotheliomas from 94 patients (pleural, n = 77; peritoneal, n = 35; solid, n = 68; effusions, n = 44) were immunostained for XIAP and survivin expression. Results were analyzed for associations with anatomic site (pleura versus peritoneum), specimen type (solid versus effusion), proliferation (Ki-67 score), and survival. Immunoblotting showed expression of XIAP in 9 of 10 effusions and that of survivin in 4 of 10 effusions, but no expression of livin. Immunohistochemistry showed cytoplasmic XIAP expression in 71 of the 112 (63%) tumors. XIAP expression was significantly higher in peritoneal mesotheliomas than in pleural mesotheliomas (P = .001) and in effusions than in solid lesions (P = .017). Cytoplasmic survivin was found in 75 of the 112 (67%) tumors and showed no site-related difference. Nuclear survivin was expressed in 37 of the 112 (33%) tumors, with a trend for positive association with the Ki-67 score (P = .051). Nuclear survivin (P = .003) and Ki-67 (P = .013) were downregulated in effusions as compared with solid tumors. Higher XIAP expression and Ki-67 score were associated with a trend for poor overall survival (P = .064 for both) in the univariate analysis. XIAP and survivin, but not livin, are frequently expressed in malignant mesotheliomas. Nuclear survivin expression is reduced in effusions as compared with solid lesions concomitantly with reduced proliferation. XIAP is upregulated in mesothelioma effusions and peritoneal mesotheliomas, suggesting a prosurvival role in malignant mesothelioma cells, particularly at these anatomic sites.     

Expression of podocalyxin-like protein is an independent prognostic biomarker in resected esophageal and gastric adenocarcinoma

Background

Podocalyxin-like protein (PODXL) is a cell surface transmembrane glycoprotein, the expression of which has been associated with poor prognosis in a range of malignancies. The aim of this study was to investigate the impact of PODXL expression on survival in esophageal and gastric adenocarcinoma.

Methods

The study cohort consists of a consecutive series of 174 patients with esophageal (including the gastroesophageal junction) or gastric adenocarcinoma, surgically treated between 2006 and 2010 and not subjected to neoadjuvant treatment. Immunohistochemical expression of PODXL was assessed in tissue microarrays with cores from primary tumors, lymph node metastases, intestinal metaplasia and adjacent normal epithelium. Survival analyses were performed on patients with no distant metastases and no macroscopic residual tumor.

Results

In the majority of cases, expression of PODXL was significantly higher in cancer cells compared to normal epithelial cells and was significantly associated with lymph node metastases and high grade tumors. In esophageal adenocarcinoma, Kaplan-Meier analyses revealed that patients with PODXL negative tumors had a superior time to recurrence (TTR) and overall survival (OS) compared to patients with PODXL positive tumors. In gastric adenocarcinoma, patients with PODXL negative tumors had a superior TTR and a trend towards an improved OS. In esophageal and gastric adenocarcinoma combined, the prognostic significance of PODXL expression on TTR was confirmed in unadjusted Cox regression analysis (HR?=?5.36, 95 % CI 1.68-17.06, p?=?0.005) and remained significant in the adjusted model (HR?=?3.39, 95 % CI 1.01-11.35, p?=?0.048). Moreover, the impact of PODXL expression on OS was also confirmed in unadjusted analysis (HR?=?2.52, 95 % CI 1.31-4.85, p?=?0.006) and remained significant in the adjusted model (HR?=?2.03, 95 % CI 1.04-3.98, p?=?0.039).

Conclusions

In esophageal and gastric adenocarcinoma, PODXL expression is an independent prognostic biomarker for reduced time to recurrence and poor overall survival. This is the first report on the prognostic role of PODXL in esophageal adenocarcinoma and validates recent findings in gastric cancer.

     

High GOLPH3 expression is associated with a more aggressive behavior of epithelial ovarian carcinoma

Overexpression of GOLPH3 (Golgi phosphoprotein 3, 34 kDa) is associated with the progression of many solid tumor types leading to an unfavorable clinical outcome. The present study examined the association between GOLPH3 expression and tumor development, clinicopathological factors, and prognosis of epithelial ovarian carcinoma. GOLPH3 expression was examined by immunohistochemistry in 18 normal ovarian samples, 28 benign tumors, 55 serous borderline ovarian tumors, and 135 epithelial ovarian carcinomas. The association of GOLPH3 expression with clinical characteristics, response to chemotherapy, and overall survival of epithelial ovarian carcinoma patients was analyzed on fresh tissue samples. GOLPH3 mRNA and protein expression in ovarian cancer and normal ovarian tissues were detected by real-time quantitative RT-PCR and Western blotting, respectively. The results are the following: (1) GOLPH3 immunostaining localized to the cytoplasm in two patterns, condensed into large granules with perinuclear distribution, and dispersed in the cytoplasm as fine granules. (2) GOLPH3 expression was higher in epithelial ovarian carcinoma than in normal ovarian tissues at the mRNA and protein level. The frequency of high-level expression of GOLPH3 increased progressively from benign (cystadenoma) to borderline neoplasms to malignant lesions. (3) Dispersed cytoplasmic GOLPH3 expression in epithelial ovarian carcinoma patients was highly correlated with FIGO stage (p?<?0.001), tumor histological grade (p?=?0.003), lymph node involvement (p?=?0.001), and chemotherapy response (p?=?0.034). (4) A dispersed pattern of GOLPH3 expression was an independent prognostic factor for poor overall survival. Patients with low dispersed cytoplasmic GOLPH3 expression had significantly longer overall survival than patients with high dispersed cytoplasmic expression. In contrast, GOLPH3 condensed expression was not correlated with clinicopathological features, chemotherapy response, or prognosis. GOLPH3 gene expression might play a role in tumorigenesis in epithelial ovarian carcinoma as upregulation of GOLPH3 expression is associated with a more aggressive tumor phenotype. GOLPH3 immunohistochemistry may be of value to predict the outcome of ovarian carcinoma patients.     

The Flip Side of NIFTP: an Increase in Rates of Unfavorable Histologic Parameters in the Remainder of Papillary Thyroid Carcinomas

The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed to replace noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) both to promote more conservative management of these tumors and spare patients the psychological burden of a cancer diagnosis. This reclassification will lower the incidence of papillary thyroid carcinoma (PTC). In addition, it could result in an increase in the rates of unfavorable histologic prognosticators for PTC overall because NIFTPs had previously accounted for many of the PTCs without these features. Our aim was to evaluate the potential impact of the reclassification of NIFTP on the rates of extrathyroidal extension, lymphovascular invasion, and lymph node metastases in PTC. We identified all PTCs clinically over 1 cm diagnosed on surgical resection between August 2010 and August 2012. The histopathologic characteristics, including PTC subtype, tumor size, presence of extrathyroidal extension and lymphovascular invasion, and surgical margin and lymph node status were all recorded. Based on these parameters, cases were classified according to the American Thyroid Association (ATA) risk stratification system for structural disease recurrence. Tumor slides for cases initially diagnosed as FVPTC were reviewed to identify tumors that would now be classified as NIFTPs. Our cohort included 348 cases of PTC, of which 94 (27%) would now be classified as NIFTPs. After excluding NIFTPs from the PTC category, there were increased rates of extrathyroidal extension (26% up from 19%, p = 0.046), lymphovascular invasion (37% up from 27%, p = 0.0099), and lymph node metastases (26% up from 19%, p = 0.045) among the remaining PTCs. Based on these changes in histologic features, 10% fewer cases were defined as ATA low risk (62% down from 72%, p = 0.0081). Our results indicate that the downgrading of some carcinomas to NIFTP will increase the rates of higher risk histologic parameters in the remaining PTCs by statistically significant margins. Although the overall survival for PTC is very high and would likely not be changed significantly by the introduction of NIFTP, additional studies evaluating the impact of the NIFTP shift are warranted.     

Immunohistochemical expression of nuclear and cytoplasmic survivin in gastrointestinal carcinoma

Survivin is a protein that is highly expressed in many embryonic tissues, as well as most human tumors. Prior studies have reported both positive and negative correlations between survivin expression and cancer prognosis, but these associations remain controversial. In the present study, we assessed the expression of nuclear and cytoplasmic survivin in gastrointestinal carcinomas. Using these data, we determined the correlation between nuclear and cytoplasmic survivin and, further, investigated correlations between survivin expression and clinicopathological parameters. Seventy-two advanced gastric adenocarcinomas and 78 colorectal adenocarcinomas were analyzed for survivin expression by immunohistochemistry. Expression of both nuclear and cytoplasmic survivin was significantly higher in colorectal carcinomas than in gastric carcinomas (P < 0.01). There was a positive correlation between nuclear and cytoplasmic expression of survivin (r = 0.42, P < 0.001). In gastric carcinomas, the level of survivin protein expression was associated with tumor differentiation, patient age, and lymphatic invasion (P < 0.05, 0.01, and 0.01, respectively). In colorectal carcinomas, the level of nuclear survivin expression was significantly higher in females than in males (P < 0.05). There were no significant associations between survivin expression and most of the clinicopathological parameters. Nevertheless, there was a trend towards an inverse correlation between nuclear survivin expression and tumor aggressiveness in gastric carcinoma; there was a similar trend for cytoplasmic survivin expression. In summary, our results suggest that levels of nuclear and cytoplasmic survivin expression differ between gastric carcinoma and colorectal carcinoma.     

The Role of Mediators of Cell Invasiveness, Motility, and Migration in the Pathogenesis of Silent Corticotroph Adenomas

Silent corticotroph adenomas (SCAs) represent a distinct subset of clinically non-functioning pituitary adenomas. There are two variants of SCA; type I are densely granulated basophilic tumors and type II are sparsely granulated and chromophobic tumors. SCAs are known to be aggressive than the more common non-functioning gonadotroph adenomas (NFGAs). Cell–matrix interactions play an important role in the pathogenesis of pituitary adenomas. In this study, we compared 19 SCAs and 50 NFGAs with known fibroblast growth factor receptor-4 (FGFR4) status using semi-quantitative immunohistochemistry to localize β1-integrin, osteopontin, and matrix metalloproteinase-1 (MMP-1) as cytoplasmic, membranous, or mixed cytoplasmic-membranous staining to achieve scores of 1–4. Staining for β1-integrin was significantly higher in SCAs (100 %, score 3.3) than in NFGAs (96 %; score 2.6) (p?=?0.0482); there was no statistical difference within subgroups of SCA (type II score 3.4; type I score 2.8) (p?=?0.2663). Osteopontin immunoreactivity was also higher in SCAs (100 %, score 3.7) than in NFGAs (42 %, score 0.8) (p?=?0.0001); there was no statistical difference within subgroups of SCA (type II score 3.6; type I score 3.9) (p?=?0.2787). In contrast, MMP-1 immunoreactivity was lower in SCAs (89 %; score 2.5) than in NFGAs (98 %; score 3.6) (p?=?0.0005); there was no statistical difference within subgroups of SCA (type II score 2.7; type I score 2.0) (p?=?0.30704). The MMP-1 results correlated with FGFR4 expression (NFGA 96 %, type II SCA 71 %, type I SCA 40 %). Our data indicate that the biological aggressivity of SCAs compared with NFGA may be due to high osteopontin expression; in contrast, high MMP-1 is characteristic of NFGAs that also express more FGFR4. Further investigations are warranted to clarify the underlying regulatory mechanisms of these markers. The high osteopontin or FGFR4/MMP-1 expression levels in SCAs and NFGAs, respectively, indicate the potential for therapeutic strategies targeting osteopontin or FGFR4/MMP-1 for inoperable tumors of these types.     

Low BRAF and NRAS expression levels are associated with clinical benefit from DTIC therapy and prognosis in metastatic melanoma

Metastatic melanoma is characterized by a poor response to chemotherapy. Furthermore, there is a lack of established predictive and prognostic markers. In this single institution study, we correlated mutation status and expression levels of BRAF and NRAS to dacarbazine (DTIC) treatment response as well as progression-free and overall survival in a cohort of 85 patients diagnosed with advanced melanoma. Neither BRAF nor NRAS mutation status correlated to treatment response. However, patients with tumors harboring NRAS mutations had a shorter overall survival (p < 0.001) compared to patients with tumors wild-type for NRAS. Patients having a clinical benefit (objective response or stable disease at 3 months) on DTIC therapy had lower BRAF and NRAS expression levels compared to patients progressing on therapy (p = 0.037 and 0.003, respectively). For BRAF expression, this association was stronger among patients with tumors wild-type for BRAF (p = 0.005). Further, low BRAF as well as NRAS expression levels were associated with a longer progression-free survival in the total population (p = 0.004 and <0.001, respectively). Contrasting low NRAS expression levels, which were associated with improved overall survival in the total population (p = 0.01), low BRAF levels were associated with improved overall survival only among patients with tumors wild-type for BRAF (p = 0.013). These findings indicate that BRAF and NRAS expression levels may influence responses to DTIC as well as prognosis in patients with advanced melanoma.     

High expression of spindle assembly checkpoint proteins CDC20 and MAD2 is associated with poor prognosis in urothelial bladder cancer

Aneuploidy is a result of the abnormal expression of spindle assembly checkpoint (SAC) proteins and resulting abnormal spindle function during mitosis. High expression of cell division cycle 20 homolog (CDC20) and mitotic arrest defective protein 2 (MAD2), key components of the SAC, has been reported in various carcinomas. However, the clinicopathological significance of CDC20 and MAD2 expressions in urothelial carcinoma of the human bladder (UCB) is unknown. We therefore studied the expression of CDC20 and MAD2 in UCB specimens by immunohistochemistry. High expression of CDC20 and MAD2 was observed in 59.0 % (200/339) and 51.0 % (173/339) of UCB cases, respectively. Most high-grade tumor cells exhibited diffuse nuclear and/or cytoplasmic staining for CDC20 and MAD2, whereas most low-grade tumor cells and normal urothelial cells were not stained. CDC20 overexpression was associated with advanced age (p?=?0.010), high grade (p?<?0.001), advanced stage (p?<?0.001), non-papillary growth pattern (p?<?0.001), and distant metastasis (p?=?0.042). Similarly, high MAD2 expression correlated with high grade (p?<?0.001), advanced stage (p?<?0.001), and non-papillary growth pattern (p?<?0.001). In univariate survival analyses, high CDC20 expression correlated with shorter recurrence-free survival (RFS) (p?=?0.032) and poorer overall survival (OS) (p?=?0.007) in patients with UCB, whereas high MAD2 expression was associated with poorer OS (p?=?0.008). In multivariate analyses, high CDC20 expression correlated with shorter RFS of patients with Ta stage UCB (hazard ratio, 1.91; p?=?0.01). In conclusion, increased expression of CDC20 and MAD2 is related to poor prognosis of UCB.     

Immunohistochemical localization of survivin in serous tumors of the ovary.

The aim of this study was to determine the immunohistochemical distribution of survivin in benign, borderline, and malignant serous tumors of the ovary. Survivin was localized by an indirect immunoperoxidase method in 42 cases of serous tumors of the ovary (15 cystadenomas, 15 borderline tumors, and 12 cystadenocarcinomas). Nuclear staining and cytoplasmic staining were separately scored. Cytoplasmic staining was detected in 27% of adenomas/borderline tumors and in 58% of carcinomas. Nuclear staining was detected in 87% of adenomas/borderline tumors but in only 42% of carcinomas. Although the differences in the intensity of cytoplasmic staining between adenomas and borderline tumors versus carcinomas were not significant, the differences in the intensity of nuclear staining between low-grade versus malignant tumors were significant. These findings suggest that survivin is widely expressed in benign, borderline, and malignant serous tumors but that nuclear localization of survivin is more common in benign or borderline tumors than in malignant serous tumors of the ovary. The molecular mechanisms that determine the subcellular distribution of this protein may reflect the role of survivin in the regulation of apoptosis during the processes of malignant transformation.     

Nuclear survivin is associated with disease recurrence and poor survival in patients with cutaneous malignant melanoma

AIMS: Survivin is expressed in neoplastic cells and appears to be associated with resistance to therapy and shorter survival in various types of tumours. The aim of the present study was to determine whether nuclear or cytoplasmic expression of survivin is related to disease recurrence and overall survival of patients with Stage I and II melanoma according to the American Joint Committee on Cancer (AJCC) staging system. METHODS AND RESULTS: Immunohistochemistry was performed on formalin-fixed paraffin-embedded sections of primary cutaneous melanoma from 50 patients. Survival rates were estimated using the Kaplan-Meier method and compared using the log rank test. Association of clinical variables (gender, age, tumour location, thickness, Clark level and AJCC stage) with survivin expression was analysed by Fisher's exact test. Patients with nuclear immunoreactivity for survivin had an increased risk of disease recurrence during the first three postoperative years (P < 0.05) and of death (P < 0.05). Cytoplasmic immunoreactivity was not correlated with either survival or clinical variables. CONCLUSIONS: Nuclear presence of survivin may be an independent biomarker for disease recurrence and overall survival in patients with Stage I and II melanoma.     

Podoplanin expressing cancer associated fibroblasts are associated with unfavourable prognosis in adenocarcinoma of the esophagus

Overexpression of the mucin-type sialoglycoprotein podoplanin in cancer associated fibroblasts (CAFs) was recently shown to be associated with tumor progression, metastasis and poor prognosis in lung and breast cancer. Here we investigate the role of podoplanin expressing CAFs in esophagal adenocarcinoma (AC), its precursor lesions and metastases. Podoplanin expression was investigated immunohistochemically in 200 formalin-fixed, paraffin embedded specimens of invasive esophagal ACs, their corresponding metastases and 35 precursor lesions. Podoplanin expressing CAFs (CAF+) were observed in 22 % of patients with invasive AC, but not in precursor lesions. CAF+ correlated with tumor stage (p = 0.004), lymphovascular tumor invasion (p = 0.018) and lymph node metastasis (p = 0.0016). Patients with CAF+ had a significant shorter disease free and overall survival (p < 0.05, Cox regression). Podoplanin expressing CAFs were only rarely observed in lymph node and distant metastases, as well as in local recurrences of ACs. Podoplanin expression in AC tumor cells was seen in only four cases. In around 20 % of patients with esophagal AC, podoplanin expressing CAFs are evident, defining a high risk subgroup. In these patients, podoplanin expressing CAFs might represent new therapeutical targets.