Clinicopathological Parameters Of Patients Research Articles

Expression of cellular FLICE/caspase-8 inhibitory protein is associated with malignant potential in endometrial carcinoma

This study aimed to investigate the expression of cellular Fas-associated death domain-like interleukin-1beta-converting enzyme (FLICE)/caspase-8 inhibitory protein (c-FLIP) in endometrial carcinoma and its possible implications. c-FLIP protein was detected in 42 endometrial carcinoma tissues and in 22 normal proliferative endometrial tissues by immunohistochemistry. In addition, c-FLIP messenger ribonucleic acid (mRNA) was evaluated in 20 endometrial carcinomas and in 18 normal proliferative endometria by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) using SYBR Green I(TM). The relationship between c-FLIP protein level and tumor cell proliferation and that between c-FLIP protein level and clinicopathologic parameters of patients with endometrial carcinoma was analyzed. c-FLIP protein expression was significantly higher in neoplastic tissues than in normal tissues (P < 0.01), and similar result was obtained from RT-PCR analysis of c-FLIP mRNA (P < 0.01). Furthermore, c-FLIP protein was significantly associated with proliferating cell nuclear antigen-labeling index (P < 0.01), clinical stage (P < 0.05), the presence of invasion to > 1/2 myometrium (P < 0.05), and lymph node metastasis (P < 0.01). Multivariate analysis of variance also confirmed the association of c-FLIP with clinical stage (P < 0.05) and with lymph node metastasis (P < 0.05), while its association with myometrial invasion was marginal (P = 0.059). It is concluded that c-FLIP might contribute to the carcinogenesis and aggressiveness of endometrial carcinoma and might be a useful prognostic factor in the tumor.

The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy ± chemotherapy

BackgroundSeveral parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols.The purpose of this study was to investigate the inter-relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma (HNSCC) treated by radiotherapy ± chemotherapy.MethodsWe used two subgroups of a retrospective series for which CT-determined tumoral perfusion correlated with local control. In the first subgroup (n = 67), immunohistochemistry for carbonic anhydrase IX (CA IX) and glucose transporter-1 (GLUT-1) was performed on the pretreatment tumor biopsy. In the second subgroup (n = 34), enzyme linked immunosorbent assay (ELISA) was used to determine pretreatment levels of the cytokines vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated.ResultsFor CA IX and GLUT-1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control (p = 0.02) and disease-free survival (p = 0.04) with a trend for regional control (p = 0.06).In the second subgroup, IL-6 pretreatment serum level above the median was the only independent predictor of local control (p = 0.009), disease-free survival (p = 0.02) and overall survival (p = 0.005).ConclusionTo our knowledge, we are the first to report a link in HNSCC between IL-6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL-6 with local control, known to be the most important parameter to judge radiotherapy responses.Furthermore, the combined assessment of CA IX and GLUT-1 correlated independently with prognosis. This is a valuable indication that a combined approach is important in the investigation of prognostic markers.

Expression of KAI1 protein in tissue microarray and its biological significances in patients with lung cancer

KAI1 is a new identified metastasis-suppressor gene whose expression in many types of tumors has been reported. The aim of study is to investigate the role of KAI1 protein in development of lung cancer and its values in predicting the prognosis of lung cancer. The expressions of KAI1 protein were detected in benign pulmonary disease tissue, precancerous disease tissue, lung cancer tissue and metastatic lung cancer tissue in local lymph node using tissue microarray and immunohistochemical method. The relationship between expression of KAI1 protein and clinicopathological parameters of patients with lung cancer was analyzed by Chi-Square test and Fisher exact test. The positive rate of KAI1 expression was 100.0% in 10 cases of benign pulmonary diseases, 66.7% in 12 cases of precancerous diseases, 24.7% in 89 cases of primary lung cancer and 0 in metastatic lung cancer tissue in local lymph node respectively. The KAI1 protein expression in primary lung cancer tissues had no remarkable relationship with age and gender of the patients and the location of cancer, but had significant relationship with the histological type and differentiated degree of tumor, P-TNM stages and lymph node metastatic status. The abnormal expression of KAI1 protein may participate in malignant progression of lung cancer. Its downregulation may promote the invasion and metastasis of tumor cell. Detection of the expression of KAI1 protein may be helpful to predict the prognosis of lung cancer.

Real-time determination of human telomerase reverse transcriptase mRNA in gastric cancer

To set up a real-time fluorescent quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay, to detect human telomerase reverse transcriptase (hTERT) messenger RNA in gastric carcinomas, and to evaluate quantitative determination of hTERT mRNA in the diagnostic value of gastric carcinomas, and to analyze the correlation between the expression level of hTERT mRNA and clinicopathological parameters in patients with gastric cancer. A real-time quantitative RT-PCR (RQ-PCR) based on TaqMan fluorescence methodology and the LightCycler system was used to quantify the full range of hTERT mRNA copy numbers in 35 samples of gastric carcinomas and corresponding adjacent non-cancerous tissues. The normalized hTERT (NhTERT) was standardized by quantifying the number of GAPDH transcripts as internal control and expressed as 100X (hTERT/GAPDH) ratio. Variables were analyzed by the Student's t-test, chi2 test and Fisher's exact test. NhTERT from gastric carcinomas and corresponding adjacent non-cancerous tissues was 6.27+/-0.89 and 0.93+/-0.18, respectively (t = 12.76, P<0.001). There was no significant association between gastric cancer hTERT mRNA expression level and patient's age, gender, tumor size, location and stage (pTNM), but a significant correlation was found between hTERT mRNA expression level in gastric carcinomas and the degree of differentiation. Quantitative determination of hTERT mRNA by RQ-PCR is a rapid and sensitive method. hTERT might be a potential biomarker for the early detection of gastric cancer.

The Role of E-cadherin/β-catenin Complex and Cyclin D1 in Head and Neck Squamous Cell Carcinoma

To determine the relationship between expression pattern of E-cadherin, beta-catenin and cyclin D1, and clinicopathologic parameters in patients with head and neck squamous cell carcinomas (HNSCC). The authors evaluated the immunohistochemical expression pattern of E-cadherin, beta-catenin in relationship with cyclin D1 overexpression, degree of histologic differentiation, clinical stage, and nodal status in 146 head and neck squamous cell carcinomas (HNSCC). The authors also evaluated the expression of E-cadherin/beta-catenin complex, E-cadherin/cyclin D1, and beta-catenin/cyclin D1 double staining with confocal laser scanning microscope. Aberrant expressions in 78% of E-cadherin, 77% of beta-catenin, and 69% of cyclin D1 in the HNSCC were observed. There was correlation of aberrant expression of E-cadherin and nodal status. Cyclin D1 overexpression was also correlated to clinical stage and nodal status. Significant relation was observed between E-cadherin and beta-catenin expression patterns. Co-expression of E-cadherin and beta-catenin was significantly detected. However, there was no correlation of cyclin D1 overexpression with E-cadherin or beta-catenin expression patterns. These results suggest that aberrant expression of E-cadherin, E-cadherin/beta-catenin complex, and cyclin D1 may be involved in clinical stage and/or nodal status, and analysis of the pattern of E-cadherin, cyclin D1, and E-cadherin/beta-catenin complex may be good prognostic marker of HNSCC.

Expression of platelet-derived growth factor-alpha alpha receptor is associated with tumor progression in clear cell renal cell carcinoma.

Platelet-derived growth factors (PDGFs) exert their biologic function by binding to 3 different tyrosine kinase receptor isoforms. Especially the PDGF-alpha alpha receptor binds PDGF proteins with high specificity, which results in growth stimulation. The expression of the receptor and its ligand was studied in human renal cell carcinomas (RCCs) by immunohistochemical analysis, and the expression of PDGF-alpha alpha receptor and PDGF-AA was correlated with clinicopathologic parameters of patients with clear cell RCC (CCRCC). In CCRCC, the mean expression of PDGF-alpha alpha receptor and PDGF-AA was 38.8% (range, 0.0%-96.0%) and 18.4% (range, 0.0%-90.0%), respectively. PDGF-alpha alpha receptor expression was significantly higher in grade 3 and grade 4 tumors compared with grade 1 and grade 2 tumors (P = .027; Mann-Whitney test), and high receptor expression correlated with tumor progression in univariate analysis (P = .0253; log-rank test), while PDGF-AA expression had no prognostic influence on the outcome of patients with CCRCC. Therefore, immunohistochemical detection of high PDGF-alpha alpha receptor expression in CCRCC is associated with adverse outcomes. Furthermore, the PDGF receptor-factor interaction loop may be considered as a possible target for novel therapeutic strategies.

Bfl-1 gene expression in breast cancer: its relationship with other prognostic factors.

The Bfl-1 gene, which was isolated from human fetal liver and only recently described, is a member of the Bcl-2 gene family. Reverse transcriptase-polymerase chain reaction was performed on RNA drawn from 30 breast cancer tissues to compare the expression of the Bfl-1 gene with other prognostic factors. The median relative ratio was 3.0 (range, 0.12-26.83) and the Bfl-1 gene expression rate was 36.7% (11/30). There was no statistically significant relationship between the clinicopathologic parameters of patients and the expression value of Bfl-1 gene. The level of Bfl-1 gene expression was higher in more advanced breast cancers than in early cancers. There was no significant relationship between the expression values and currently acknowledged prognostic factors, but a higher expression pattern was noticed in the groups of positive hormone receptors and negative p53 and negative c-erbB2, albeit statistically not significant. It seems that the increased expression of the Bfl-1 gene serves as a contributory factor in breast cancer, in the same way that another group of genes, the Bcl-2 family, contributes to apoptosis.

Expression of glucose transporter-1 in human gastric carcinoma: association with tumor aggressiveness, metastasis, and patient survival.

Malignant cells show increased glucose uptake in vitro and in vivo, which is believed to be facilitated by glucose transporters (Gluts). Expression of Glut1, one of the Gluts, has been described in malignancies of the esophagus, colon, pancreas, lung, and brain, but to the authors' knowledge the significance of Glut1 expression in human gastric carcinoma has not been elucidated. The objective of the current study was to examine the expression and distribution of Glut1 and its relation to clinicopathologic parameters in patients with gastric carcinoma. Immunohistochemistry with anti-Glut1 antibody was performed on 617 gastric carcinomas and 50 tubular adenomas of the stomach. Glut1-positive and Glut1-negative carcinomas were analyzed for their clinicopathologic characteristics including histologic subtype, depth of invasion, vascular permeation, lymph node and hepatic metastasis, peritoneal dissemination, and prognosis. None of the adenomas expressed Glut1, whereas 182 of 617 carcinomas (29.5%) were positive for the protein. Signet ring cell carcinoma and mucinous adenocarcinoma rarely were positive (2.0% and 6.3%, respectively) and papillary adenocarcinoma (44%) showed slightly higher positivity for Glut1 than tubular (32%) or poorly differentiated adenocarcinoma (28%). Glut1-positive tumor cells were localized mainly in the central part of tumor nests with or without peripheral distribution (92%) but peripheral distribution alone was very limited (8%) (P = 0.0001). Glut1 positivity was associated with depth of invasion (P = 0.0001), lymphatic permeation (P = 0.0001), venous invasion (P = 0.0001), lymph node metastasis (P = 0.0001), hepatic metastasis (P = 0.0001), and carcinoma stage (P = 0.0001). However, peritoneal dissemination was not found to be associated with Glut1 positivity (P = 0.0833). The survival of patients who had tumors that expressed Glut1 was significantly shorter than that of patients with Glut1-negative tumors (P = 0.0001). In human gastric carcinoma, Glut1 is expressed late in carcinogesis and increases with disease progression. Glut1 expression is associated with tumor aggressiveness and patient survival.

Nuclear profiles of cancer cells reveal the metastatic potential of gastric cancer.

Nuclear profiles have been reported as useful prognostic predictors in various cancers. Data from computerized morphometry are objective and can be quickly derived using conventional microscopic analysis, but image analysis of nuclear features has only rarely been applied to investigations of gastric cancer. The aim of this study was to evaluate the correlation between one of these morphological nuclear features and the clinicopathological parameters in patients with gastric cancer. The morphometric nuclear feature (nuclear area) was analysed in 400 patients with gastric cancer. In each case, 300 cancer nuclei on routine haematoxylin and eosin-stained slides were analysed through the use of a computer-assisted image analysis system which traced the nuclear profiles (magnificationx400) on a computer monitor. The morphometric data were compared with the patients' clinicopathological status and survival rate. The mean nuclear area (NA) of cancer cells from 400 cases of gastric cancer was 47.2 microm(2). The NAs of cancer cells from tumours with microvessel invasion (lymphatic or venous invasion), lymph node metastasis or hepatic metastasis at the time of operation were significantly larger than those of cancer cells from tumours without such invasion or metastases. Cytokeratin (CK) immunostaining was performed on 2577 lymph nodes from 91 patients with advanced gastric cancer (pT3, pN0, pM0, stage II) to detect micrometastases. CK-positive lymph nodes were detected in 350 of 2577 lymph nodes (13. 6%) and in 62 of 91 patients (68.1%). The mean NA of cancer cells from 62 tumours with micrometastases (44 microm(2)) was larger than that of cancer cells from 29 tumours without micrometastases (38.8 microm(2), p=0.043), and a significant positive correlation was detected between the NAs of cancer cells from 91 tumours and the number of micrometastatic lymph nodes of 91 patients (rho=0.278, p=0. 008). Cancer cells with large NA correlated strongly with haematogenous and lymph node recurrence or relapse after gastrectomy and the NA of cancer cells was identified as an independent prognostic factor in gastric cancer. Nuclear morphometry is an objective, reproducible, and technically uncomplicated procedure. The NA of cancer cells correlates closely with the metastatic potential of gastric cancer. Nuclear morphometry may therefore be useful for the selection of patients who are at risk of haematogenous or lymph node metastatic recurrence after surgery.

Computerized nuclear morphometry: a new morphologic assessment for advanced gastric adenocarcinoma.

To evaluate the correlation between the morphologic nuclear features and clinicopathologic parameters in patients with advanced gastric cancer. Nuclear profiles have been reported as useful prognostic predictors in various cancers. Data from computerized morphometries are objective and quickly derived using conventional microscopic analysis. However, this image analysis of nuclear features has rarely been applied to investigations of gastric adenocarcinoma. Moreover, it remains to be shown what types of biologic factors influence the nuclear features. Morphometric nuclear features (nuclear area, perimeter, and shape) were analyzed in 202 patients with serosal-invaded gastric cancer (stage II and III) who underwent curative gastrectomy. In each case, 300 cancer nuclei were analyzed on routine hematoxylin and eosin-stained slides through the use of a computer-assisted image analysis system by tracing the nuclear profiles (magnification x400) on a computer monitor. The morphometric data were compared with patient survival, clinicopathologic status, DNA ploidy pattern of tumors, expression of p53 protein, and proliferative activity of cancer cells. Lymph node metastasis, lymphatic invasion, and venous invasion were more frequently detected in patients with large nuclear areas. Significant correlations were detected between the size of the nuclear area of cancer cells and the biologic factors of tumors, such as expression of p53, Ki-67 labeling index, and DNA ploidy pattern. The 5-year survival rate of the 100 patients in the large-nuclear group (nuclear area >45.3 microm2) was 47.6% and was significantly lower than the 74.4% rate of the 98 patients in the small-nuclear group (nuclear area < or =45.3 microm2). Moreover, the nuclear area was found to be an independent prognostic factor in the multivariate analysis. Gastric cancer cells with a large nuclear area express mutated p53 protein and have high proliferative activity. Moreover, such cancer cells have high potential for invasion to the microvessels in the gastric wall. Thus, nuclear morphometry is a new and useful morphologic predictor for metastatic potential in advanced gastric cancer.

Computerized nuclear morphometry of hepatocellular carcinoma and its relation to proliferative activity.

Nuclear profiles have been reported as useful prognostic predictor in various cancers. Data from computerized morphometries are objective and can be quickly derived using conventional microscopic analysis. However, it remains to be shown what types of pathological and biological factors influence the nuclear features. The aim of this study was to evaluate the correlation between the morphological nuclear features and clinicopathological parameters in patients with hepatocellular carcinoma (HCC). Morphometric nuclear features (nuclear area, perimeter, and shape) were analyzed in 76 patients with hepatocellular carcinoma who underwent hepatectomy at our hospital. In each case, 300 cancer nuclei were analyzed randomly on routine hematoxylin&eosin-stained slides through the use of a computer-assisted image analysis system that allowed us to trace the nuclear profiles (magnification x400) on a computer monitor. The morphometric data were compared with patient survival, clinicopathologic status, and the proliferative activity of cancer cells. The mean nuclear area of poorly differentiated carcinoma was significantly larger than that of moderately and well differentiated carcinoma (P = 0.0003). Significant correlation was detected between the nuclear area of cancer cells and proliferative activity associated with proliferating cell nuclear antigen labeling index (PCNA LI) of cancer cells (r = 0.372, P = 0.0008). Moreover, blood vessel invasion of cancer cells or intrahepatic metastasis were more frequently detected in patients with large nuclear areas. Even though the nuclear area was not an independent prognostic factor in the multivariate analysis, the 5-year survival rate of the 35 patients who had tumors with large nuclear areas (>50 microm2, 25.9%) was significantly lower than that of the 36 patients who had tumors with small nuclear areas (< or =50 microm2, 63.3%, P = 0.001). The nuclear area of HCC correlates with cell differentiation and cell proliferative activity. Moreover, HCC with a large nuclear area has high potential for blood vessel invasion and intrahepatic metastasis. Thus, nuclear morphometry can be used as an useful morphological predictor for malignant potential in patients with HCC.

Clinicopathological characteristics of p53 overexpression in endometrial cancers

Using immunohistochemical methods, we analyzed the association between nuclear p53 overexpression and various clinicopathological parameters in patients with endometrial cancers. Formalin-fixed and paraffin-embedded tissue sections from 139 cases of endometrial cancer (endometrioid type, 126; serous papillary type, 12; and clear-cell type, 1) were stained with anti-p53 monoclonal antibody (MAb) DO7. Overexpression of p53 was associated with high malignant potential, including extensive muscular invasion, advanced surgical stage, high histological grade, serous papillary type and a personal history of cancer. Lymph-node metastasis was also related to p53 overexpression with marginal significance. Survival curves determined by the Kaplan-Meier method and univariate analysis showed p53 overexpression to be associated with a poor outcome in endometrial cancer patients. However, multivariate analysis using the stepwise Cox proportional-hazard model showed that whereas lymph-node metastasis, a personal history of cancer and muscular invasion were related to poor survival rates, p53 overexpression was not. Consequently, p53 overexpression itself does not appear to be an independent prognostic factor in endometrial cancer, although a still larger sample of patient material would be required to assess this issue definitively.