Prognostic significance of p21WAF1/CIP1, p27Kip1, p53 and E-cadherin expression in gastric cancer

BACKGROUND: Gastric carcinoma is characterised by numerous genetic and epigenetic alterations that influence cell cycle progression, apoptosis and DNA repair. These alterations include down-regulation of the cyclin-dependent kinase (CDK) inhibitors p21(WAF1/CIP1) and p27(Kip1), and mutations of the tumour suppressor protein p53 and the cell adhesion molecule E-cadherin. Combined evaluation of the prognostic significance of these alterations has not been reported in Mexican Mestizo patients. AIMS: To evaluate p21(WAF1/CIP1), p27(Kip1), p53 and E-cadherin protein expression, including mutant E-cadherin variants with deletion of exon 8 (del 8) or 9 (del 9), in gastric cancer from Mexican patients. METHODS: Immunohistochemistry for the above-mentioned markers, including mutation-specific E-cadherin antibodies, was carried out in 69 gastric carcinomas; expression levels were correlated with histotype, tumour stage and prognosis. RESULTS: Expression of p21(WAF1/CIP1) alone or in combination with p27(Kip1) or in the absence of p53 was associated with favourable prognosis. Staining of del 8 and del 9 E-cadherin was found exclusively in patients negative for p53 and positive for p21(WAF1/CIP1), suggesting that the p21(WAF1/CIP1) regulatory function of p53 was intact. CONCLUSION: Combined evaluation of the prognostic significance of cell cycle regulators and E-cadherin should be performed. Even though patients negative for p53 and positive for p21(WAF1/CIP1) have a favourable prognosis, it may have a negative influence on prognosis if they acquire in addition E-cadherin mutations which have been shown previously to be associated with poor survival.     

Expression profiling of colorectal carcinomas using tissue microarrays: cell cycle regulatory proteins p21, p27, and p53 as immunohistochemical prognostic markers in univariate and multivariate analysis.

With the rapidly growing understanding of tumor biology, molecular staging of cancer is expected to improve prognostication. This would be particularly important for cancers amenable to adjuvant treatment, such as colorectal carcinomas. To generate data for this, the tissue microarray technique may prove useful. Tissue microarrays were constructed with triplicate cores (0.6 mm diameter) from the invasive margins of a consecutive single-institution series of 184 colorectal carcinomas. Immunostaining for p53, p21, p27, Ecadherin, and beta-catenin was scored. Tumor cell proliferation was assessed by mitotic indices and Ki-67 labeling, apoptosis by quantification of apoptotic bodies. Reduced nuclear immunostaining for p21 (<10%) and p27 (< or =50%) and reduced membranous expression of Ecadherin were significantly associated with a poorer clinical course by univariate analysis. beta-catenin immunostaining had no prognostic impact. Mitotic and apoptotic indices as well as Ki-67 labeling below the median were indicators of poor prognosis. Complete absence of p53 nuclear staining was a significant adverse prognostic factor. By Cox regression, p53 = 0%, p53 = 0%, in combination with p27 < or = 50%, the mitotic index and the combined mitotic and apoptotic index added prognostic information to UICC stage. The authors found that growth pattern, lymphohistiocytic response, lymphatic permeation, and venous spread, too, each was a strong prognosticator in addition to UICC stage. The results support that tissue microarrays are a useful tool for screening immunohistochemical markers for prognostic use. An immunopanel of p21, p27, and p53 could be useful for prognostication in colorectal carcinoma in addition to UICC stage.     

Correlation between expression of p53, p21/WAF1, and MDM2 proteins and their prognostic significance in primary hepatocellular carcinoma

Background  

Tumor Protein p53 (p53), cyclin-dependent kinase inhibitor 1A (p21/WAF1), and murine double minute 2 (MDM2) participate in the regulation of cell growth. Altered expression of these gene products has been found in malignant tumors and has been associated with poor prognosis. Our aim was to investigate the expression of the 3 proteins in hepatocellular carcinoma (HCC) and their prognostic significance.     

Proliferating cell nuclear antigen labeling index and p53 expression predict outcome for breast cancer patients with four or more lymph node metastases.

In general, extensive lymph node metastasis indicates poor prognosis in breast cancer. Nevertheless, some patients with this condition survive for a long time without recurrent disease. This study involved 112 breast cancer patients with four or more lymph node metastases and without distant metastasis who underwent surgery. p53 expression was associated with shorter overall and disease-free survival. High PCNA labeling index was associated with shorter overall disease-free survival. p53-negative and low-PCNA patients survived much longer than p53-positive and high-PCNA patients. This study showed that p53-negative or low-PCNA index patients have relatively good prognoses despite extensive lymph node metastasis.     

Survivin and caspase-3 expression in breast cancer: correlation with prognostic parameters, proliferation, angiogenesis, and outcome.

BACKGROUND: Survivin is an inhibitor of apoptosis protein that is overexpressed in most human cancers, including breast, but is not expressed in normal tissue. Survivin is associated with more aggressive behavior and decreased survival in a variety of tumor types. It regulates the G2/M phase of the cell cycle by associating with mitotic spindle microtubules, and it directly inhibits caspase-3 and caspase-7 activity. We used a breast cancer tissue microarray to assess survivin and caspase-3 expression in breast cancer and to correlate both markers with proliferation (MIB-1), angiogenesis (CD31), and prognosis. DESIGN: A breast cancer tissue microarray with a total of 190 1-mm tissue samples (2 from each specimen) were immunostained for survivin, caspase-3, MIB-1, and CD31. The microarray contains 91 cases of breast carcinoma diagnosed at Emory University Hospital between 1992 and 2000, and 4 normal breast tissue controls. Follow-up information was obtained from hospital records and the Winship Cancer Center database. RESULTS: Eighty-four percent of breast carcinoma showed nuclear survivin expression. Normal breast tissue was immunonegative. Fifty-seven percent and 43% of breast cancer showed reduced and absent caspase-3 expression, respectively. Survivin (nuclear) and caspase (nuclear/cytoplasmic) expression showed significant correlation with histologic grade (P=0.008 and 0.041) and MIB-1 expression (P=0.033 and 0.012). Survivin nuclear expression also correlated significantly with tumor stage (P=0.012) and tended to correlate with estrogen receptor (P=0.050). There was no significant correlation between survivin and caspase expression. Furthermore, there was no correlation of both markers with other clinicopathologic parameters (age, tumor size, histologic type, progesterone receptor, Her-2 neu status, lymph node status), angiogenesis (CD31), or outcome (overall and disease-free survival). CONCLUSIONS: Survivin and caspase-3 expression correlate with poor prognostic parameters (higher histologic grade and high proliferation), but not with outcome, in breast carcinoma patients.     

Short-term significance of DNA ploidy and cell proliferation in breast carcinoma: a multivariate analysis of prognostic markers in a series of 308 patients

AIM: To determine the importance of tumour DNA ploidy and cell proliferation, as measured by the S phase fraction (SPF), in relation to other established clinicopathological indicators of prognosis in breast cancer. METHODS: A prospective study of 308 patients. Tumours were staged following the TNM system criteria and were classified according to the histological type and grade. DNA flow cytometry was performed on fresh/frozen samples stained with propidium iodide. Hormone receptors were analyzed by immunocytochemistry. A Cox proportional hazards regression model was used for statistical evaluation of the prognostic factors. RESULTS: Median follow up time was 39.6 months (range 3 to 84). A DNA diploid pattern was found in 134 tumours (43.5%) and aneuploid in 174 (56.5%). Median SPF value was 6.1% (range 1% to 27.8%). DNA ploidy and SPF were strongly correlated (p < 0.001), and both were related to histological type (p < 0.001), grade of differentiation (p < 0.001), tumour size (p = 0.006 and p = 0.002), and hormone receptor activity (p < 0.001). DNA ploidy was also related to node status (p = 0.022), but SPF was not. In univariate analysis, there were significant correlations between disease-free survival and age, histological grade, tumour size, node status, DNA ploidy, SPF, and hormone receptor activity; age, tumour size, node status, DNA ploidy, and hormone receptors were predictors of overall survival. In multivariate analysis, only node status (p = 0.001) and DNA ploidy (p = 0.006) retained independent prognostic significance in relation with overall survival, while node status (p < 0.001) and SPF (p < 0.001) were predictors of disease-free survival. DNA ploidy and SPF continued to predict disease-free and overall survival in lymph node positive (pN1) patients but not in the lymph node negative (pN0) group. CONCLUSIONS: DNA ploidy and SPF are strongly intercorrelated and have independent prognostic value for predicting the short term clinical outcome of breast carcinoma patients.     

Tandem high-dose chemotherapy in high-risk primary breast cancer: a multivariate analysis and a matched-pair comparison with standard-dose chemotherapy.

Stem cell-supported high-dose chemotherapy (HDCT) is currently being evaluated in patients with high-risk primary breast cancer (HRPBC), as defined by extensive axillary lymph node involvement. Conclusive results from randomized studies with sufficient patient numbers and follow-up are pending. We retrospectively analyzed 144 HRPBC patients enrolled in a single-arm trial of tandem HDCT at the University of Heidelberg to evaluate the prognostic value of nodal ratio, HER2/neu status, and cytokeratin-positive bone marrow cells and to compare the outcomes of these patients with those of a conventionally treated control group of 91 patients matched by nodal ratio, tumor size, combined hormone-receptor status, and HER2/neu status. The tandem HDCT regimen consisted of 2 cycles of induction chemotherapy followed by 2 cycles of blood stem cell-supported high-dose ifosfamide, 12 g/m2; carboplatin, 900 mg/M2; and epirubicin, 180 mg/m2. Conventionally treated patients received a regimen containing anthracycline without taxanes (52 patients) or CMF (cyclophosphamide, methotrexate, and 5-flurouracil; 39 patients). With a median follow-up of 3.8 years, disease-free, distant disease-free, and overall survival rates were 62%, 65%, and 84%, respectively. In univariate analysis, besides the hormone receptor status (P = .007), HER2/neu overexpression was the strongest predictor of earlier death (P = .017). In multivariate analysis, a nodal ratio of > or =0.8 was found to be the only independent predictor of relapse (relative risk [RR] = 2.09; 95% confidence interval [CI], 1.21-3.60; P = .008) and only the absence of hormone receptors was associated with earlier death (RR = 3.59; 95% CI, 1.45-8.86; P = .006). Despite a trend toward later distant relapse after HDCT compared with standard-dose chemotherapy with a median follow-up of 3 years (P = .059), thus far, matched-pair analysis has not demonstrated significantly better survival rates after HDCT in all matched patients (P = .786) or in the subgroups of anthracycline-treated patients and patients with and without overexpression of HER2/neu. So far, the follow-up time has been too short to draw definite conclusions; however, patients with a nodal ratio of > or =0.8, receptor-negative tumors, or HER2/neu overexpression are at high risk for relapse and death, irrespective of the kind of adjuvant chemotherapy.     

The prognostic significance of DNA topoisomerase II-alpha (Ki-S1), p21/Cip-1, and p27/Kip-1 protein immunoexpression in oligodendrogliomas.

OBJECTIVE: To evaluate a possible association between clinical outcome of patients with oligodendroglioma and expression of 2 cyclin-dependent kinase inhibitors, p21/Cip-1 (p21) and p27/Kip-1 (p27), and of DNA topoisomerase II-alpha (Ki-S1), which has been recently used as a marker of cellular proliferation. DESIGN: Ninety-one specially selected patients with cerebral oligodendrogliomas treated with surgery and radiotherapy were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to p21, p27, and Ki-S1. A computerized color image analyzer was used to count immunostained nuclei. RESULTS: The mean Ki-S1 labeling index (LI) was found to be significantly prominent for World Health Organization (WHO) high-grade tumors (9.5% vs. 3.2% for WHO low-grade tumors). In contrast, the mean p27 LI was significantly higher for low-grade tumors (43.3% vs 25.7% for high-grade tumors). The number of p21-positive cases and the mean p21 LI were found to be relatively equal for low- and high-grade tumors. For low-grade oligodendrogliomas, the progression-free and overall survival times were found to be significantly shorter for tumors with p27 LIs less than 20%. For high-grade oligodendrogliomas, survival times were significantly reduced for tumors with Ki-S1 LIs greater than 10%. Regression-tree analysis identified 4 groups of oligodendrogliomas with distinctly different outcomes: (1) 32 patients with low-grade tumors and p27 LIs greater than 20%; (2) 14 patients with low-grade tumors and p27 LIs less than 20%; (3) 25 patients with high-grade tumors and Ki-S1 LIs less than 10%; and (4) 20 patients with high-grade tumors and Ki-S1 LIs greater than 10%. CONCLUSIONS: Immunoreactivity for Ki-S1 and p27 was found to be useful for further subdividing oligodendroglioma prognoses among low-grade and high-grade tumors. It seems unlikely that p21 immunohistochemistry will be of value for determining clinical outcomes for patients with oligodendrogliomas.     

p27KIP-1, cyclin A and cyclin D1 protein expression in ductal carcinoma in situ of the breast: p27KIP-1 correlates with hormone receptor status but not with local recurrence

Using whole sections of formalin-fixed paraffin-embedded material the expression of p27(KIP-1), cyclin A and cyclin D1 was examined in 60 cases of ductal carcinoma in situ (DCIS) using routine immunohistochemistry with a median follow up of 95 months (range 10-139 months) to identify any association with disease recurrence. Fifty-six patients were treated by local excision and radiotherapy and four by mastectomy without radiotherapy. There was a highly significant positive association between p27(KIP-1) and estrogen receptor/progesterone receptor (ER/PR) status (P = 0.002, P = 0.02) and with p27(KIP-1) and cyclin D1 expression (P = 0.002). A trend between cyclin A and PR status (P = 0.08) was also identified. These findings mirror those described in invasive ductal carcinoma, but there were no associations of any biomarker with histological parameters such as nuclear grade or with local recurrence on univariate analysis, which was present in four of the 56 locally excised group (7.1%). Further examination of a larger cohort may be worthwhile to explore the possible role as adjunctive predictive markers to aid clinical decision making.     

Immunohistochemical analysis of Ki-67, p53, p21, and p27 in benign and malignant apocrine lesions of the breast: its correlation to histologic findings in 43 cases.

We examined Ki-67, p53, p21, and p27 immunolocalization in 43 cases of apocrine lesions of the breast and correlated these findings with histologic parameters to understand their biologic significance. Twenty cases were benign, 1 case was borderline, and 22 cases were diagnosed as malignant, including 9 intraductal and 13 invasive apocrine carcinomas. Both the ratio of Ki-67-positive cases (17 of 21 [88.9%] versus 1 of 19 [5.3%]; P < .001) and the Ki-67 labeling index of positive cases examined (15.0% versus 2.7%; P < .005) were significantly higher in malignant than in benign apocrine lesions. None of the benign or borderline cases was immunohistochemically positive for p53, but 15 of 22 malignant cases (68.2%) demonstrated p53 (P < .001). In addition, the ratio of p53-positive cases was significantly higher in high nuclear grade cases (11 of 13 [84.6%]) than in intermediate nuclear grade cases (4 of 9 [44.4%]; P < .05). P53 immunoreactivity was also positively correlated with the nuclear grade of carcinoma cases examined in this study. Neither p21 nor p27 demonstrated any correlation with histologic parameters or findings of the apocrine lesions. Results of these studies suggest that Ki-67 and p53 may be good markers for differentiation between benign and malignant breast apocrine lesions.     

Cell proliferation in breast cancer is a major determinant of clinical outcome in node-positive but not in node-negative patients.

The growth rate of a tumor cell population depends on two major factors: the percentage of proliferating cells (cell growth fraction) and the rapidity of their duplication (cell proliferation rate). The authors evaluated the prognostic and predictive value of both kinetics parameters in a large series of breast cancer patients (n=504). The cell growth fraction was determined by MIB-1 immunostaining, the cell proliferation rate by AgNOR analysis. Ki-67 LI (labeling index) and AgNOR area were significantly associated with histotype, histologic grade, tumor size, estrogen/progesterone receptor status, patient age, and lymph node involvement (P<0.005). In the entire series of patients, both kinetics variables were significantly and independently associated with the clinical outcome, but their prognostic relevance was quite different when node-negative and node-positive patients were considered separately. Although in node-positive patients Ki-67 LI and AgNOR area were the unique independent predictors of disease-free and overall survival, they were excluded by the multivariate Cox model in node-negative patients, where only tumor size and estrogen receptor status retained a significant P-value. These results show that in breast carcinoma the cell growth fraction and the cell proliferation rate have a different prognostic impact with respect to the lymph node status and are major determinants of clinical outcome in node-positive patients only. Within this subgroup, the rapidity of cell proliferation as assessed by AgNOR analysis also served as a sensitive predictor of the response to adjuvant treatments.     

Biological significance of p27 and Skp2 expression in renal cell carcinoma. A systematic analysis of primary and metastatic tumour tissues using a tissue microarray technique

p27 (p27/kip1) is involved in cell-cycle control, and loss of p27 expression may result in tumour development and/or progression. Association with Skp2 targets p27 for degradation. Using a tissue microarray technique, 171 primary renal cell carcinomas (RCCs) and 58 RCC metastases were immunostained for p27 and Skp2. p27 Immunoreactivity was noted in 83 of 129 (64%) clear cell, 6 of 22 (27%) chromophobe and 15 of 20 (75%) papillary tumours as well as 44 of 58 (76%) metastases. In clear cell cancers, high p27 expression (50% of tumour cells) decreased with rising tumour stage (50% pT1/pT2 versus 20% pT3; P<0.001) and grade (44% G1/G2 versus 21% G3/G4; P=0.008). None of 22 chromophobe cancers showed high expression in contrast to 46 of 129 (36%) clear cell tumours (P<0.001). Skp2 expression was noted in 8 of 129 (6%) clear cell cancers and 11 of 55 (20%) metastases (P=0.008). Immunoreactivity increased with rising tumour stage (1% pT1/pT2 versus 11% pT3; P=0.03) and grade (1% G1/G2 versus 15% G3/G4; P=0.004) and was associated with sarcomatoid morphology (P<0.001). In multivariate analysis, patients with low p27 expression and Skp2 immunoreactivity in clear cell cancers had a less favourable outcome. In conclusion, p27 and Skp2 proved to be additional biomarkers in renal cancer pathology with both prognostic and diagnostic impact.     

Relationship and prognostic significance of phospho-(serine 166)-murine double minute 2 and Akt activation in node-negative breast cancer with regard to p53 expression

The Akt signalling pathway plays a central role in tumourigenesis. Activation of Akt is related to a more aggressive phenotype in various human cancers, including breast cancer. Its activation contributes to cancer progression via pleiotropic effects, including suppression of apoptosis and modulation of cell cycle regulation. Murine double minute 2 (MDM2) is an oncoprotein that inhibits the function of p53 tumour suppressor protein. Cell culture studies show that Akt-related phosphorylation of MDM2 at serine 166 allows MDM2 to gain nuclear entry and fulfil its p53 regulating function. This study was designed to analyse the relationship of phospho-MDM2 (pMDM2) expression with Akt activation to determine a possible prognostic relevance of pMDM2 in node-negative breast cancer with respect to Akt activation and p53 status. pMDM2, phospho-Akt (pAkt) and p53 protein expression status were analysed immunohistochemically in 121 paraffin-embedded breast cancer cases. Expression of pMDM2 correlated with Akt activation (P<0.001). Univariate analysis identified pMDM2 as a prognostic factor (P=0.0458) in node-negative breast cancers. The unfavourable prognostic significance was even more pronounced in tumours with a pMDM2⁺/pAkt⁺ immunophenotype (P=0.0205). Stratification into a p53-negative subgroup further strengthened the adverse prognostic influence. These data confirm that MDM2 phosphorylation at serine 166 is mediated by Akt kinase. Besides the prognostic impact of pMDM2, our findings suggest that Akt-mediated modulation of the MDM2/p53 complex contributes to increased tumour aggressiveness especially in p53-negative breast cancers. However, due to the relatively small number of patients in this cohort, the results obtained need to be confirmed by larger cohorts.     

Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas

PTEN (MMAC1/TEP1), a tumor suppressor gene on chromosome subband 10q23.3, is variably mutated and/or deleted in a variety of human cancers. Germline mutations in PTEN, which encode a dual-specificity phosphatase, have been implicated in at least two hamartoma tumor syndromes that exhibit some clinical overlap, Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. Among several series of ovarian cancers, the frequency of loss of heterozygosity (LOH) of markers flanking and within PTEN, is approximately 30 to 50%, and the somatic intragenic PTEN mutation frequency is <10%. In this study, we screened primary adenocarcinomas of the ovary for LOH of polymorphic markers within and flanking the PTEN gene and for intragenic mutations of the PTEN gene and compared them to PTEN expression using immunohistochemistry. Furthermore, we sought to detect the expression of the presumed downstream targets of PTEN, such as P-Akt, p27, and cyclin D1 by immunohistochemistry. LOH at 10q23 was observed in 29 of 64 (45%) cases. Of the 117 samples, 6 somatic intragenic PTEN mutations, 1 germline mutation, and 1 novel polymorphism were found in 7 (6%) patients. Immunostaining of 49 ovarian cancer samples revealed that 13 (27%) were PTEN immunostain-negative, 25 (51%) had reduced staining, and the rest (22%) were PTEN expression-positive. Among the 44 informative tumors assessed for 10q23 LOH and PTEN immunostaining, there was an association between 10q23 LOH and decreased or absent staining (P = 0.0317). Of note, there were five (11%) tumors with neither mutation nor deletion that exhibited no PTEN expression and 10 (25%) others without mutation or deletion but had decreased PTEN expression. Among the 49 tumors available for immunohistochemistry, 28 (57%) showed P-Akt-positive staining, 24 (49%) had decreased p27 staining, and cyclin D1 was overexpressed in 35 (79%) cases. In general, P-Akt expression was inversely correlated with PTEN expression (P = 0.0083). These data suggest that disruption of PTEN by several mechanisms, allelic loss, intragenic mutation, or epigenetic silencing, all contribute to epithelial ovarian carcinogenesis, and that epigenetic silencing is a significant mechanism. The Akt pathway is prominently involved, but clearly not in all cases. Surprisingly, despite in vitro demonstration that p27 and cyclin D1 lies downstream of PTEN and Akt, there was no correlation between p27 and cyclin D1 expression and PTEN or P-Akt status. Thus, in vivo, although PTEN and Akt play a prominent role in ovarian carcinogenesis, p27 and cyclin D1 might not be the primary downstream targets. Alternatively, these observations could also suggest that pathways involving other than Akt, p27 and cyclin D1 that lie downstream of PTEN play roles in ovarian carcinogenesis.     

The significance of c-erbB-2 overexpression and p53 expression in patients with axillary lymph node--negative breast cancer: a tissue microarray study

We conducted this study to examine whether the expression of c-erbB-2 and p53 is the prognostic indicator for patients with early-stage breast cancer in which axillary lymph node metastasis is absent. We examined 326 patients with early-stage breast cancer in which axillary lymph node metastasis is absent. Tissue microarrays were constructed. Following this, immunohistochemical staining was done for estrogen receptor (ER), progesterone receptor (PR), c-erbB2, and p53. The results were as follows: (1) expression of c-erbB-2 was correlated with other clinicopathologic factors (eg, patient's age, presence of menopause, tumor size, histologic and nuclear grade, and presence of hormone receptors such as ER and PR); and (2) expression of p53 was correlated with survival rate, patient's age, presence of menopause, and tumor size. However, these results were not statistically significant. In conclusion, our results indicate that expression of c-erbB-2 and p53 did not have any prognostic value in patients with early-stage breast cancer in which axillary lymph node metastasis is absent.     

High expression of CEACAM19, a new member of carcinoembryonic antigen gene family,in patients with breast cancer

Carcinoembryonic antigen (CEA) family members play important roles in malignancies and are introduced as biomarkers in different types of cancers. Among them CEACAM19 (CEAL1) gene, a new member of the CEA family, remains to be fully elucidated. The aim of this study was investigating the mRNA expression level of CEACAM19 in tumor samples of breast cancer patients compared to breast tissue of normal individuals. We evaluated the expression level of this gene in 75 breast tumors by using real-time quantitative PCR. Also, we studied the correlation between CEACAM19 expression and clinicopathological features and hormone receptors status, including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 of patients. Out of the enrolled patients, six of them (7.9%) showed low expression, ten (13.2%) showed normal expression and 59 (77.6%) showed high expression of CEACAM19. There was a significant correlation between high expression of CEACAM19 gene in tumor samples compared to normal tissues (P = 0.039). No significant correlation was seen between clinicopathological factors and disease-free survival with mRNA levels of CEACAM19 in tumor samples, while the difference between the expression of CEACAM19 in ER/PR-positive and ER/PR-negative breast cancer patients was statistically significant (P = 0.046). In conclusion, CEACAM19 showed high expression in tumor samples compared to normal mammary tissue. In addition, CEACAM19 may represent as a novel therapeutic target in certain subgroups of breast cancer patients such as ER/PR-negative. Critical roles of CEA proteins in tumor progression may nominate them as robust potential targets for therapeutic intervention in near future.     

Loss of heterozygosity at 18q21 region in gastric cancer involves a number of cancer-related genes and correlates with stage and histology,but lacks independent prognostic value

Identification of neuroendocrine differentiation in tumours has important implications for prognosis and therapy. The aim of the present study was to evaluate monoclonal antibodies against synaptic vesicle protein 2 (SV2) as histopathological markers for neuroendocrine differentiation in tumours of the gastrointestinal tract and pancreas. Paraffin blocks from 211 gastrointestinal tumours were examined by immunocytochemistry, using a monoclonal antibody against SV2. Virtually all endocrine tumours of the gastrointestinal tract (11/11 gastric, 53/53 ileal, 16/21 appendiceal, and 22/22 rectal) and pancreas (24/24) were positively labelled. SV2 labelling was also demonstrated in gastrointestinal pacemaker cell tumours (8/8), while adenocarcinomas of the gastrointestinal tract and pancreas were negative, with the exception of occasional adenocarcinomas demonstrating weak SV2 labelling (stomach 1/22, rectum 1/29, and pancreas 0/21). Western blotting of tumour biopsies confirmed expression of SV2 in endocrine tumours of the gastrointestinal tract and pancreas. No relationship was observed between SV2 expression in tumours and hormone production or malignant potential. In conclusion, SV2 is expressed in neuroendocrine tumours of the gastrointestinal tract and pancreas, but not in non-endocrine tumours. The SV2 monoclonal antibody can therefore be used as a general marker for neuroendocrine differentiation in gastrointestinal and pancreatic tumours.     

Epidermal growth factor receptor expression correlates with poor survival in gastric adenocarcinoma from Mexican patients: a multivariate analysis using a standardized immunohistochemical detection system.

The aim of the study was to determine epidermal growth factor receptor (EGFR) expression in gastric adenocarcinoma by standardized immunohistochemistry and to correlate EGFR expression with clinical features and patient survival. EGFR expression was investigated in paraffin sections of resection specimens of 89 gastric carcinomas from Mexican Mestizo patients using standardized immunohistochemistry with antigen retrieval (Dako EGFRpharmDx assay detection system). Membrane staining of EGFR was evaluated in the neoplastic cells and graded using a semiquantitative score (0-3+). Of the 89 carcinomas examined, staining of neoplastic cells was weak in 17 (19.1%, score 1+), moderate in 16 (18.0%, score 2+), and strong in nine cases (10.1%, score 3+). EGFR reactivity was heterogeneous, frequently showing completely negative up to 3+ positive areas within an individual tumor. EGFR reactivity score correlated with distant metastases (P=0.002) and clinical stage (P=0.033). EGFR score 0/1+ was significantly associated with an increase in patient survival when compared to score 2+/3+ (P=0.0006). In a multivariate analysis, EGFR positive cells in muscularis or subserosa (P=0.004), distant metastases (P=0.016) and residual disease (P=0.039) were significantly correlated with decreased survival. The prognosis was associated with the EGFR reactivity score (P=0.003), distant metastases (P=0.0001) and residual disease (P=0.012) in a univariate analysis. EGFR reactivity in neoplastic cells is an independent prognostic factor in gastric adenocarcinoma. The relevance of the heterogeneity in EGFR expression with regard to tumor progression, metastasis and anti-EGFR therapy needs to be studied.     

Stromelysin-3 protein expression in invasive breast cancer: relation to proliferation, cell survival and patients' outcome.

Matrix metalloproteinases constitute one of the major extracellular matrix degrading enzymic families implicated in cancer development. Stromelysin-3 in particular, a member of the matrix metalloproteinases belonging to the stromelysins' subgroup, seems to be closely related to invasiveness and tumor progression. In this study, we proceeded to the evaluation of stromelysin-3 protein's expression in paraffin sections of 133 cases of invasive breast carcinomas and statistically estimated its relations with known clinicopathological prognostic parameters and patients' survival, proliferation markers Ki-67 and TopoIIalpha and the antiapoptotic protein bcl-2. Presence of stromelysin-3 was immunodetected, in the 73% of our cases, in stromal cells (65%) and in epithelial tumor cells (26.26%). Stromelysin-3 epithelial positivity presented statistically significant correlations with TopoIIalpha and Ki-67 proliferation indices (P =.042 and P =.031, respectively) and worse disease outcome through multivariate statistics (P =.014). Stromelysin-3 fibroblastic expression was significantly associated with nuclear grade (P =.024), ductal histological type (P =.037), TopoIIalpha (P =.001) and Ki-67 (P =.019), inversely with bcl-2 protein (P =.027) and with adverse overall survival through univariate analysis (P =.017). The subgroup of patients with stromelysin-3 co-expression in stromal and malignant epithelial cells showed statistically significant associations with Ki-67 and TopoIIalpha (P =.019, P <.0001, respectively), an inverse one with bcl-2 protein (P =.027) and furthermore with impaired survival (P =.002) through multivariate analysis. In conclusion, stromelysin-3 protein expression correlated with proliferation indices TopoIIalpha and Ki-67 and the anti-apoptotic protein bcl-2, data confirming stromelysin-3's contribution to breast cancer progression. Moreover its expression was shown to have a direct negative effect on patients' survival, especially in the subgroup of patients with simultaneous epithelial and stromal expression.