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Objectives. To examine the prognostic significance of the protein expression of E-cadherin, α-, β-, and γ-catenin in early squamous cervical carcinoma (SCC).Methods. We studied 219 patients who underwent radical hysterectomy and bilateral lymphadenectomy at our institution for stage IB SCC between 1987 and 1993. Immunohistochemistry using monoclonal antibodies against E-cadherin, α-, β-, and γ-catenin was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolapse served as controls.Results. Membrane expression for E-cadherin, α-, β-, and γ-catenin was decreased and low expression (≤50% positive cells) was found in 198/219 (90%), 154/219 (70%), 157/219 (72%), and 181/219 (83%) tumors, respectively, and high (>50% positive cells) in 21/219 (10%), 65/219 (30%), 62/219 (28%), and 38/219 (17%) tumors, respectively. In univariate analysis, all classical clinicopathological parameters but none of the investigated proteins were associated with prognosis. In multivariate analysis, only deep stromal invasion was independently related to survival.Conclusion. E-cadherin, α-, β-, and γ-catenin were not independently associated with prognosis in stage IB SCC. [Copyright &y& Elsevier]

Objectives. To examine the prognostic significance of the protein expression of cyclin E, cyclin A and cyclin D3, and of the proliferation markers Ki-67 and BM28 in early squamous cervical carcinoma (SCC).Methods. Tissue blocks from 221 patients who underwent radical hysterectomy and bilateral lymphadenectomy at our institution for stage IB SCC between 1987 and 1993 were available for this study. Immunohistochemistry using monoclonal antibodies against cyclin E, cyclin A, cyclin D3, Ki-67 and BM28 was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolapse served as controls.Results. Cyclin E, cyclin A, Ki-67 and BM28 expression was increased in SCC and high expression was observed in 81.5% (180/221), 35% (78/221), 25.5% (56/221) and 92% (204/221) of tumors, respectively. Cyclin D3 was decreased in SCC and low expression was found in 50.5% (111/220) of tumors. In univariate analysis, all classical clinicopathological parameters but none of the investigated proteins were associated with prognosis. In multivariate analysis, only deep stromal invasion was independently related to survival.Conclusion. Cyclin E, cyclin A and cyclin D3 and the proliferation markers Ki-67 and BM28 are not independently associated with prognosis in stage IB SCC. [Copyright &y& Elsevier]

Abstract: Objectives. : To analyze expressions of the EphB2 and EphB4 receptors in ovarian carcinomas and explore their clinicopathological correlations and prognostic value. Methods. : 115 patients with advanced ovarian carcinoma FIGO IIB to IV were involved. RT-PCR and immunohistochemistry were used to examine the expressions of EphB2/B4 receptor mRNA and protein. Correlations between protein expression and clinicopathological factors were also analyzed. Results. : Ovarian carcinoma patients with age elder than 60 years had higher EphB2 expression than younger patients. Expression of EphB2 and EphB4 protein did not significantly correlate with any other clinical variables, including FIGO stage, residual tumor, histological type and differentiation grade. No significant correlation between mRNA and protein expression level for both of these receptors was seen. It was found that patients with strong immunostaining for EphB2 (P = 0.03) or EphB4 (P = 0.003) receptors had poorer survival, and patients with strong immunostaining for EphB4 receptor showed poorer response to chemotherapy (P = 0.036). Conclusions. : These studies suggest that EphB2 and B4 receptors are of prognostic value and EphB4 receptor may be an independent predictor of chemotherapy response in ovarian cancer patients. [Copyright &y& Elsevier]

Objectives. To analyze the expressions of the protein and mRNA of EphA2 and EphrinA-1 in squamous cell cervical carcinomas and explore their prognostic value in cervical carcinoma.Methods. Immunohistochemistry was used to assess the protein expressions of EphA2 and EphrinA-1 in 206 patients with squamous cervical carcinoma FIGO stage Ia-IVb. Frozen tissues from 20 cases in which the tumors showed variable EphA2 and EphrinA-1protein expressions were used for laser capture microdissection (LCM). About 50 cancer cells in each frozen section were captured with the LCM method and processed for RT-PCR detection of EphA2 and EphrinA-1 mRNA.Results. Among the 206 squamous cervical carcinomas, 23 (11.2%) showed negative, 94(45.6%) weakly positive, 72 (35.0%) moderately positive, and 17 (8.3%) strongly positive for EphA2 immunostaining. For EphrinA-1 protein expression, 17 tumors (8.3%) showed negative, 95 (46.1%) weakly positive, 71(34.5%) moderately positive, and 23 (11.2%) strongly positive. EphA2 and EphrinA-1 often colocalized in the same tumor areas and vascular endothelial cells. Variable amount of mRNA expressions of EphA2 and EphrinA-1 were observed in the 20 tumors analyzed. There was no significant correlation between the overexpressions of EphA2/EphrinA-1 and age and FIGO stage. High level of EphA2 was significantly associated with overall survival in univariate and multivariate analysis. Moderate to high EphrinA-1 protein expression was significantly associated with overall survival in multivariate analysis. The combined high level of expression of EhpA2 and moderate to high level of expression of EphrinA-1 was a strong predictor of overall survival.Conclusions. High levels of EphA2 together with moderate to high level of EphrinA-1 protein expressions in squamous cervical carcinoma were predictive for a shorter overall survival and these proteins may be valuable prognostic markers. [Copyright &y& Elsevier]

Abstract: Purpose: We have applied the sensitive and specific in situ proximity ligation assay (PLA) to characterize Tyr1068 phosphorylation of the epidermal growth factor receptor (EGFR) in cervical cancer in relation to the protein level and gene dosage. Materials and methods: Pretreatment tumor biopsies from 178 patients were analyzed. EGFR protein level was determined by immunohistochemistry, and Tyr1068 phosphorylation was detected with PLA in 97 EGFR positive tumors. EGFR gene dosage was derived from array comparative genomic hybridization of 86 cases. Results: EGFR was expressed in most tumors, whereas phosphorylation was seen in about half of the EGFR positive ones. A correlation was found between the expression of EGFR and phosphorylated EGFR (p =0.016, membrane; p =0.012, cytoplasm). However, tumor regions with high protein level without phosphorylation were occasionally seen and the percentage of EGFR positive cells was higher than the phosphorylated percentage (p <0.001). Moreover, an increase in the phosphorylation in both the membrane (p =0.014) and cytoplasm (p =0.002) was seen in 11 tumors with gain of EGFR. The protein level was not correlated with gene dosage. Conclusion: In contrast to gain of the EGFR chromosomal region, high EGFR protein level may not necessarily indicate Tyr1068 phosphorylation and thereby receptor activation in cervical cancer. [Copyright &y& Elsevier]

Abstract: Objectives.: To examine the expressions of the protein and mRNA of EPHA2 and EphrinA-1 in epithelial ovarian carcinomas/ovarian cancer cell lines and explore their prognostic value. Methods.: To validate the immunohistochemical method, two ovarian cancer cell lines (OVCAR3 and SKOV3) were examined with RT-PCR, Western blot, and immunohistochemistry for EphA2 and EphrinA-1 expressions. Tumors from 118 patients with advanced epithelial ovarian cancer were then evaluated for EPHA2 and Ephrin A-1 protein expression, and frozen tissues from 30 cases were used for laser capture microdissection (LCM) assistant RT-PCR RNA analysis. Results.: 11 (9.3%), 67 (56.8%), 26 (22.0%), and 14 (11.9%) tumors demonstrated negative, weak, moderate, and strong EphA2 protein expressions, respectively, while 3 (2.5%), 67 (56.8%), 32 (27.1%), and 16 (13.8%) tumors were negative, weak, moderate, and strong for Ephrin A-1 protein expression, respectively. Variable amount of mRNA expression was observed in the 30 tumors analyzed by the method of LCM assistant RT-PCR. There was a trend for association between higher levels of either EphA2 or Ephrin A-1 expression and higher histological grade (P = 0.05 for both factors). No significant correlation between the expressions of EphA2 or Ephrin A-1 and age, histological type, and FIGO stage was observed. Patients with higher levels of EphA2 protein expressions had significantly shorter survival. Cox multivariate analyses revealed that residual tumor after surgery, histological type, and EphA2 protein expression were of independent prognostic significance. Conclusions.: High level of EphA2 protein expression is significantly associated with a shorter patient survival and EphA2 receptor is a valuable prognostic marker for ovarian carcinoma. [Copyright &y& Elsevier]

Abstract: The CTNNB1 gene and its product β-catenin, a regulator of the Wnt signalling pathway, is often mutated and deregulated in human malignancies. Down stream targets of the Wnt signalling pathway are linked to genomic instability. In this study, the impact of β-catenin expression on genomic instability in ovarian carcinoma, as determined by DNA ploidy, was investigated. Expression of β-catenin was examined by immunohistochemistry in 253 ovarian carcinomas. The results were related to genomic instability and clinicopathological features of the patients. Membrane associated staining of β-catenin was detected in nearly all cases with no correlation to clinical parameters. Most of the samples also had cytoplasmic (84%), while only 13% had nuclear β-catenin localisation. A significant association between β-catenin expression (cytoplasmic and nuclear) and histological subtype and degree of differentiation was observed. Nuclear β-catenin was almost exclusively present in endometroid carcinomas. 53% of all endometroid tumours were positive for nuclear β-catenin expression (P &#60;0.0001). Mucinous carcinomas had the highest degree of cytoplasmic β-catenin expression (92%), followed by endometroid (92%), mixed (90%), serous (82%), unclassified adenocarcinomas (81%), carcinomas clear cell and (70%), (P =0.01). Tumours with differentiation grade 1 (16%) and 2 (24%) had higher nuclear β-catenin expression than grade 3 and clear cell carcinomas (6%) (P =0.012). Better prognostic outcome was found for patients with nuclear β-catenin localisation as compared to the cases without (P =0.027). In conclusion, the study showed no correlation between β-catenin expression in ovarian carcinoma and FIGO stage and genomic instability as determined by DNA ploidy status. However, nuclear β-catenin expression was strongly associated with endometroid histological subtype. Finally, in ovarian cancer, although β-catenin staining seems to be of prognostic importance with respect to nuclear staining in univariate analysis, only DNA ploidy status, histological grade and FIGO staging were of independent prognostic significance in multivariate analysis. [Copyright &y& Elsevier]

: ObjectivesTo examine the prognostic significance of the protein expression of the cyclin-dependent kinase (cdk) inhibitors p27, p21, and p16 in early squamous cervical cancer (SCC).: MethodsFrom 212 patients who underwent radical hysterectomy and bilateral lymphadenectomy at our institution for stage IB SCC between 1987 and 1993, tissue blocks were available for this study. Immunohistochemistry using monoclonal antibodies against p27, p21, and p16 was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolaps served as controls.: Resultsp21 and p16 expression were increased in SCC and high expression was observed in 20% (44/221) and 43% (94/220) of tumors, respectively. p27 was decreased in SCC and low expression was found in 80% (177/221) of tumors. In univariate analysis all classical clinicopathological parameters were associated with prognosis. Low p16 expression was significantly related to decreased overall (P = 0.036) but not disease-free survival (P = 0.103). In multivariate analysis, deep stromal invasion but none of the cdk inhibitors was independently related to survival.: ConclusionThe cdk inhibitors p27, p21, and p16 are not independently associated with prognosis in stage IB SCC. [Copyright &y& Elsevier]