Prediction of survival in patients with esophageal carcinoma using artificial neural networks

BACKGROUND: Accurate estimation of outcome in patients with malignant disease is an important component of the clinical decision-making process. To create a comprehensive prognostic model for esophageal carcinoma, artificial neural networks (ANNs) were applied to the analysis of a range of patient-related and tumor-related variables. METHODS: Clinical and pathologic data were collected from 418 patients with esophageal carcinoma who underwent resection with curative intent. A data base that included 199 variables was constructed. Using ANN-based sensitivity analysis, the optimal combination of variables was determined to allow creation of a survival prediction model. The accuracy (area under the receiver operator characteristic curve [AUR]) of this ANN model subsequently was compared with the accuracy of the conventional statistical technique: linear discriminant analysis (LDA). RESULTS: The optimal ANN models for predicting outcomes at 1 year and 5 years consisted of 65 variables (AUR = 0.883) and 60 variables (AUR = 0.884), respectively. These filtered, optimal data sets were significantly more accurate (P < 0.0001) than the original data set of 199 variables. The majority of ANN models demonstrated improved accuracy compared with corresponding LDA models for 1-year and 5-year survival predictions. Furthermore, ANN models based on the optimal data set were superior predictors of survival compared with a model based solely on TNM staging criteria (P < 0.0001). CONCLUSIONS: ANNs can be used to construct a highly accurate prognostic model for patients with esophageal carcinoma. Sensitivity analysis based on ANNs is a powerful tool for seeking optimal data sets.     

Positive correlation between P27Kip1 expression and progression of human esophageal squamous cell carcinoma

p27^Kip1, one of the cyclin-dependent kinase (CDK) inhibitors (CDKIs), blocks progression from G₁ to S phase by binding cyclin D1-CDK4 and/or cyclin E-CDK2 and inhibiting their activities. Reflecting the function of p27 as a CDKIin vitro, a reduced expression of protein p27 has recently been reported to be associated with tumor aggressiveness in some types of human cancers. In the present study, we examined the relationships between immunohistochemically detected expression of p27, cyclin D1, cyclin E proteins and clinico-pathological findings in 77 patients with esophageal squamous cell carcinoma (SCC). Using specific monoclonal antibodies to p27, cyclin D1 and cyclin E proteins, positive immunostaining in the nuclei was observed in 32.5% (25/77), 27.3% (21/77) and 29.6% (21/71) of patients, respectively. There were no statistically significant relationships among the expressions of these 3 proteins. Using the Kaplan-Meier's method, p27 and cyclin D1 expressions were found to be independently associated with poor prognosis. When all parameters were combined into a multivariate regression analysis using the Cox model, the expressions of p27 and cyclin D1 retained a predictive value for survival. In contrast to former reports supporting a tumor-suppressive function of p27, our results suggest that altered expression of p27 and cyclin D1 may be associated with the progression of human esophageal SCC, in which cyclin E may well not play any central role. Int. J. Cancer (Pred. Oncol.) 79:439–443, 1998. © 1998 Wiley-Liss, Inc.     

Artificial neural network for prediction of distant metastasis in colorectal cancer

Background and Objectives: Artificial neural networks (ANNs) are flexible and nonlinear models which can be used by clinical oncologists in medical research as decision making tools. This study aimed to predict distant metastasis (DM) of colorectal cancer (CRC) patients using an ANN model. Methods: The data of this study were gathered from 1219 registered CRC patients at the Research Center for Gastroenterology and Liver Disease of Shahid Beheshti University of Medical Sciences, Tehran, Iran (January 2002 and October 2007). For prediction of DM in CRC patients, neural network (NN) and logistic regression (LR) models were used. Then, the concordance index (C index) and the area under receiver operating characteristic curve (AUROC) were used for comparison of neural network and logistic regression models. Data analysis was performed with R 2.14.1 software. Results: The C indices of ANN and LR models for colon cancer data were calculated to be 0.812 and 0.779, respectively. Based on testing dataset, the AUROC for ANN and LR models were 0.82 and 0.77, respectively. This means that the accuracy of ANN prediction was better than for LR prediction. Conclusion: The ANN model is a suitable method for predicting DM and in that case is suggested as a good classifier that usefulness to treatment goals.     

非小细胞肺癌组织中PTEN/p27kip1的表达及其意义

目的检测PTEN、p27kip1、cyclin 3种蛋白在非小细胞肺癌组织的表达及与临床病理特征的关系.方法在60例非小细胞肺癌原发灶(包括37例鳞癌和23例腺癌)中应用免疫组织化学S-P法检测3种蛋白的表达.结果 60例肺癌原发灶中PTEN、p27kip1、cyclin 3种蛋白表达阳性率分别为:48.3%;41.7%;73.3%.PTEN与淋巴结转移显著相关(<0.05)p27kip1、cyclin 与淋巴结转移无关(>0.05)这3种蛋白表达均与肿瘤细胞分化程度显著相关(<0.05)与组织学类型无关(>0.05)60例非小细胞肺癌组织中,PTEN的表达与p27kip1呈显著正相关(P<0.01),而与cyclin 无明显相关(>0.05)p27kip1与cyclin 的表达之间呈显著负相关(P<0.01).结论 PTEN明显地抑制了非小细胞肺癌的浸润和转移,p27kip1表达缺失与肺癌细胞的分化有关,PTEN/p27kip1衰老诱导途径在非小细胞肺癌的恶性进展中起着很重要的作用.     

Prognostic implication of cyclin E expression and its relationship with cyclin D1 and p27Kip1 expression on tissue microarrays of node negative breast cancer

BACKGROUND AND OBJECTIVES: Altered expression of cell-cycle regulators is prevalent in clinical breast cancer. This study was performed to analyze the impact of cyclin E expression to the outcome of breast cancer together with cyclin D1 and p27Kip1. METHODS: The correlation between cyclin D1/E and p27Kip1 expression was analyzed in tissue arrays of 175 node-negative breast cancers treated by the same chemotherapy composed of fluorouracil, cyclophosphamide, and methotrexate. Data from the immunohistochemical assays of three molecules were correlated and were analyzed with clinical outcome of the patients. RESULTS: Cyclin E expression was observed in 48 (27.4%) of 175 breast carcinomas. Cyclin E expression was significantly increased in young age patients and poorly differentiate tumors. Expression of cyclin E was significantly increased in cyclin D1 expressing tumors (P = 0.034). p27Kip1 expression was preserved above the 50% level in 87 tumors (49.7%) and was inversely correlated with cyclin E expression (P = 0.042). Ki67 labeling index was significantly increased in cyclin E-expressing tumors (P = 0.033) and was inversely related with p27Kip1 expression. In multivariate survival analysis, cyclin E expression was significant for the prediction of poor survival of the patients. CONCLUSIONS: Cyclin E expression was associated with poor prognosis and intimately correlated with the expression of cyclin D1 and p27Kip1. Integration of TMA technology allowed a high-throughput analysis for correlating molecular in situ findings with clinico-pathologic information.     

Cyclin D1, p16 and retinoblastoma gene product expression as a predictor for prognosis in non-small cell lung cancer at stages I and II.

The association of the immunohistochemical expressions of cyclin D1, p16 and the retinoblastoma gene product (pRB) with the prognoses of 106 patients with non-small cell lung cancer (NSCLC) at stages I and II after a complete resection was investigated. We used antibodies recognizing nuclear and cytoplasmic cyclin D1, p16 and pRB. In 106 tumors, the positive rates of cyclin D1, p16 and pRB were 46, 54 and 48%, respectively. Cyclin D1-positive (cyclin D1(+)) patients had significantly poorer survival prognoses than cyclin D1-negative (cyclin D1(-)) patients (log-rank test, P=0.0002; Wilcoxon test, P=0.0005), whereas p16-positive (p16(+)) patients had significantly better prognoses than p16-negative (p16(-)) patients (log-rank test, P=0.0063; Wilcoxon test, P=0.0044). The survival period was over 65% for patients with cyclin D1(-)/p16(+) (n=34) at 120 months after surgery, whereas patients with cyclin D1(+)/p16(-) patients (n=22) had a 50% survival period at 49 months. The cumulative survival rate of cyclin D1(+)/p16(-) patients was significantly lower than that of cyclin D1(-)/p16(+) patients (log-rank test, P=0.0004; Wilcoxon test, P=0.0002). The pRB did not influence significantly the survival rate. Our results indicate that cyclin D1 and p16, especially a combination of cyclin D1 and p16, are very useful to predict the prognosis of patient with NSCLC after curative resection independent of pathological stages I and II.     

Prognostic relevance of altered pRb and p53 protein expression in surgically treated non-small cell lung cancer patients

OBJECTIVE: The prognostic value of pRb and p53 altered expression in non-small cell lung cancer (NSCLC) remains debatable. We assessed the occurrence of altered pRb and p53 protein expression, and the prognostic value of these assays considered as separate and combined variables in operable NSCLC. The study group included 195 NSCLC consecutive patients from one institution who underwent curative pulmonary resection between 1994 and 1999. METHODS: Expression of pRb and p53 was assessed immunohistochemically with the use of monoclonal antibodies (LM95.1 and Pab 1801, Oncogene Science, respectively). RESULTS: A lack of pRb and abnormal p53 protein expression were found in 57 (29%) and 92 samples (47%), respectively, whereas both abnormalities (pRb-/p53+) occurred in 24 samples (12%). There was no relationship between altered pRb/p53 expression and major clinico-pathological characteristics, neither was there a significant difference in disease-free and overall survival between particular groups of patients with tumors carrying four possible pRb/p53 phenotypes. In uni- and multivariate analysis, the only variable associated with shortened disease-free and overall survival was stage of disease (p < 0.001) and degree of tumor differentiation (p = 0.005). CONCLUSION: These results suggest that altered pRb and p53 expression does not provide prognostic information in operable NSCLC patients.     

Effect of Radiation Doses to the Heart on Survival for Stereotactic Ablative Radiotherapy for Early-stage Non–Small-cell Lung Cancer: An Artificial Neural Network Approach

IntroductionThe cardiac radiation dose is an important predictor of cardiac toxicity and overall survival (OS) for patients with locally advanced non–small-cell lung cancer (NSCLC). However, radiation-induced cardiac toxicity among patients with early-stage NSCLC who have undergone stereotactic ablative radiotherapy (SABR) has been less well-characterized. Our objective was to assess the associations between cardiac radiation dosimetry and OS in patients with early-stage NSCLC undergoing SABR.Materials and MethodsFrom 2009 to 2014, 153 patients with early-stage NSCLC had undergone SABR at a single institution. The maximum dose, mean dose, V_10Gy, V_25Gy, and V_50Gy to 15 cardiac substructures and the whole heart were analyzed for their association with OS using the Kaplan-Meier method. An artificial neural network (ANN) analysis was performed to modulate confounding behaviors of dosimetric variables to predict for OS.ResultsA total of 112 patients were included in the present analysis. The right ventricle (RV) V_10Gy most negatively predicted for OS, such that patients who had received a RV V_10Gy dose < 4% had significantly longer OS than patients who had received a RV V_10Gy does > 4% (5.3 years vs. 2.4 years). On ANN analysis, 74 input features, including cardiac dosimetry parameters, predicted for survival with a test accuracy of 64.7%. A repeat ANN analysis using dosimetry to dose neutral structure confirmed the predictive power of cardiac dosimetry.ConclusionCardiac dosimetry to subvolumes of the heart was associated with decreased OS in patients with early-stage NSCLC undergoing SABR. These data support the importance of minimizing the radiation dose to cardiac substructures. Further prioritizing the heart as an organ at risk might be warranted. Additionally, cardiac follow-up should be considered.     

p27和cyclin E蛋白表达与膀胱移行细胞癌生物学行为的关系

目的　探讨细胞周期蛋白p2 7和cyclinE表达与膀胱移行细胞癌生物学行为的关系。 方法　对 12 1例膀胱移行细胞癌进行组织病理学分级及分期 ,另取 10例正常膀胱组织作对照 ,采用免疫组织化学SABC法检测各例组织中 p2 7和cyclinE蛋白表达水平 ,并分析其表达与临床病理特征的关系。结果　p2 7和cyclinE蛋白阳性表达率分别为 42 .1% ( 5 1/12 1)和 3 4.7% ( 4 2 /12 1)。p2 7和cyclinE蛋白表达均与肿瘤的组织学分级显著相关 ,但与病理分期无关。p2 7蛋白与cyclinE蛋白表达呈负相关 (P<0 .0 5 )。p2 7阴性组中 ,cyclinE阳性患者 5年生存率低于cyclinE阴性者 (P <0 .0 5 ) ;p2 7阳性组中 ,cyclinE表达状况与患者 5年生存率无显著相关。结论　p2 7和cyclinE是评估膀胱移行细胞癌预后的有价值的指标     

Immunohistochemical study of cell cycle-associated proteins in adenocarcinoma of the uterine cervix treated with radiotherapy alone: P53 status has a strong impact on prognosis

PURPOSE: Because the incidence of adenocarcinoma of the uterine cervix has recently risen, the evaluation of radiotherapy (RT) for this disease has become an increasingly urgent matter. We analyzed the expression of the cell cycle-associated proteins p53, p27, p21/waf1/cip1, and cyclin D1 in cervical adenocarcinomas in correlation with the prognostic significance in tumors treated with RT alone. METHODS AND MATERIALS: The expression of p53, p27, p21/waf1/cip1, and cyclin D1 was studied using an immunohistochemical method in 53 cases of cervical adenocarcinoma treated only with RT. Patients received RT alone between 1965 and 1994. The mean patient age was 61.8 +/- 12.6 years (range, 36-82 years). The number of patients with Stage I, II, III, and IVA disease was 6, 16, 28, and 3, respectively. RESULTS: The number of patients with p53, p27, p21/waf1/cip1, and cyclin D1 positive tumors was 24, 18, 22, and 8, respectively; no statistically significant correlation was noted. The 5-year disease-free survival rate of p53-positive patients was 30%, significantly lower than the 62% for the p53-negative patients (p = 0.02); no statistically significant correlation was noted between disease-free survival and p27, p21/waf1/cip1, and cyclin D1 expression. No statistically significant correlation was observed between local control and expression of any of the proteins. CONCLUSION: Expression of p53 protein has a statistically significant impact on disease-free survival in adenocarcinoma of the uterine cervix treated with RT alone. However, the clinical significance of p27, p21/waf1/cip1, and cyclin D1 protein expression was not obvious.     

Validation of a clinical prognostic model in Chinese patients with metastatic and advanced pretreated non-small cell lung cancer treated with gefitinib

A clinical prognostic model derived from BR.21 trial was established by Florescu et al., which helped to identify a small group of patients with non-small cell lung cancer (NSCLC) who might be less likely to benefit from erlotinib therapy. Whether the prognostic model derived from Caucasian patients treated with erlotinib will be applied to Asian patients treated with gefitinib is still an open question. We reviewed a multi-center clinical trial of Chinese patients with NSCLC treated with gefitinib. The data were collected and analyzed according to the prognostic model reported by Florescu et al. One hundred and nineteen patients were included in the validation study. Twenty-eight patients, 61 patients, 27 patients, and 3 patients were classified into the Low Risk (LR) group, Intermediate Low Risk (ILR) group, Intermediate High Risk/High Risk (IHR/HR) group, respectively. The median overall survival of LR group was not reached, ILR and IHR/HR group was 8.9 months and 4.5 months, respectively. There was a significant difference in overall survival between LR group versus ILR group and IHR/HR group (P = 0.0003 and 0.0001, respectively). While IHR/HR group appeared to have less survival benefit than ILR group, the difference was not statistically significant (P = 0.148). The result has shown a similar effect as that seen by Florescu et al. in differentiating patient risk groups. Our study provides the potential evidence that the prognostic model might be applied to Asian patients with NSCLC treated with gefitinib and helps clinicians to select patients for gefitinib therapy and stratify patients within second-line clinical trials.     

The cooperative role of p27 with cyclin E in the prognosis of advanced gastric carcinoma

BACKGROUND: Cyclin E and p27 play opposing roles in the cell cycle. This study investigated the protein expression of p27 with cyclin E in the progression and prognosis of gastric carcinoma. METHODS: Of 241 patients with advanced gastric carcinoma, 38 had muscular layer invasion, 113 had subserosal layer invasion, and 90 had serosal invasion. Anti-p27 and cyclin E antibodies were used for immunohistochemical staining. RESULTS: Positive expression of p27 and cyclin E was 32.4% and 38.2%, respectively. Both p27 and cyclin E expression were related to histology of tumors but not to depth of invasion, lymph node metastasis, or stage grouping. A positive correlation was observed between p27 and cyclin E expression (P < 0. 05). Tumors were divided into two groups according to the expression of cyclin E. Within the cyclin E positive tumors, the five-year survival rate was higher in patients with a p27 positive tumor than in those with a p27 negative tumor (P < 0.05). Patients with cyclin E positive tumors showing low expression of p27 had a poor prognosis. In cyclin E negative group tumors, no significant differences were observed irrespective of p27 expression. CONCLUSIONS: Reduced p27 expression is a negative prognostic factor for patients with cyclin E positive tumors.     

Use of an artificial neural network to determine prognostic factors in colorectal cancer patients

Background & Objectives: The aim of this study was to determine the prognostic factors of Iranian colorectal cancer (CRC) patients and their importance using an artificial neural network (ANN) model. Methods: This study was a historical cohort study and the data gathered from 1,219 registered CRC patients between January2002 and October 2007 at the Research Center for Gastroenterology and Liver Disease of Shahid Beheshti University of Medical Sciences, Tehran, Iran. For determining the risk factors and survival prediction of patients, neural network (NN) and Cox regression models were used, utilizing R 2.12.0 software. Results: One, three and five-year estimated survival probability in colon patients were 0.92, 0.71, and 0.48 and for rectum patients were 0.86, 0.71, and 0.42, respectively. By the ANN model, pathologic distant metastasis, pathologic regional lymph nodes, tumor grade, high risk behavior, pathologic primary tumor, familial history and tumor size variables were determined as ordered important factors for colon cancer. Tumor grade, pathologic stage, age at diagnosis, tumor size, high risk behavior, pathologic distant metastasis and first treatment variables were ordered important factors for rectum cancer. The ANN model lead to more accurate predictions compared to the Cox model (true prediction of 89.0% vs. 78.6% for colon and 82.7% vs. 70.7% for rectum cancer patients). Conclusion: This study showed that ANN model is a more powerful tool in survival prediction and influential factors of the CRC patients compared to the Cox regression model. Therefore, this model is recommended for predicting and determining of risk factors of these patients.     

Immunoreactivity for p27(KIP1) and cyclin E is an independent predictor of survival in primary gastric non-Hodgkin's lymphoma.

Our aim was to assess the prognostic implications of the expression of p27(KIP1) and cyclin E in gastric lymphoma. We investigated the prognostic value of the immunoreactivity of these molecules in 92 cases of primary gastric lymphoma: 34 LGMLs, 24 DLCLMLs and 34 DLCLs. p27 was positive in 88% of LGMLs, 71% of DLCLMLs and 32% of DLCLs (p = 0.004); cyclin E was positive in 9%, 33% and 59% of cases, respectively (p < 0.00001). p27/cyclin E immunoreactivity significantly correlated with histologic category, stage and LDH serum level. p27 immunoreactivity was significantly associated with better survival, whereas cyclin E reactivity was significantly related to worse outcome. Five-year CSS was 94% for patients with p27(+)/cyclin E(-) phenotype (n = 42), 79% for p27(+)/cyclin E(+) (n = 14) or p27(-)/cyclin E(-) (n = 16) phenotype and 60% for p27(-)/cyclin E(+) phenotype (n = 16) (p = 0.02). The prognostic role of p27/cyclin E expression was confirmed when analyzed separately within LGMLs and large-cell lymphomas. Immunoreactivity for p27 and cyclin E is an independent predictor of survival in PGLs that may be an adjunctive tool in identifying high-risk patients. It correlates with histologic category, stage and LDH serum level. p27(-)/cyclin E(+) phenotype is associated with worse survival, probably due to a synergistic effect of both cell-cycle defects. The predictive role of these molecules within each histologic group of PGLs deserves to be confirmed in larger series.     

Low expression of p27(Kip1) is associated with tumor size and poor prognosis in patients with renal cell carcinoma

BACKGROUND: Proliferative activity in tumors depends on regulation of the cell cycle. p27(Kip1) (p27) plays a pivotal role as a negative regulator of the cell cycle. A decrease in p27 expression has been reported in many kinds of tumors, but little is known regarding p27 in patients with renal cell carcinoma (RCC). METHODS: Expression of p27 and the related cyclins (cyclin A, cyclin E, and cyclin D1) was examined immunohistochemically in 67 patients with of clear cell RCC. The Ki-67 labeling index (MIB-1 LI) and clinicopathologic parameters related to a poor prognosis also were analyzed. To determine their prognostic significance, univariate and multivariate survival analyses were performed. RESULTS: In tumors, there was considerable immunoreactivity for cyclin A, cyclin D1, and MIB-1, and the mean values for each were 1.08%, 16.1%, and 1.5%, respectively. Cyclin E expression was rare. The expression of p27 was correlated strongly with the expression of cyclin A (correlation coefficient, 0.432; P < 0.0004) and cyclin D1 (correlation coefficient, 0.476; P < 0.0004). Also, an inverse correlation was present between p27 expression and tumor size (P = 0.0377). In univariate analysis, the unfavorable prognostic factors were high TNM stage (P < 0.0001), large tumor size (P = 0.0016), high histologic grade (P = 0.0104), and low p27 expression (P < 0.0001). In multivariate analysis, high TNM stage (P = 0.0035) and low p27 expression (P = 0.0235) were independent prognostic factors for disease specific survival in patients with RCC. CONCLUSIONS: The results of this study suggest that low p27 expression may be a significant and independent, unfavorable prognostic factor in patients with renal cell carcinoma.     

Clinical implication of cyclin B1 in non-small cell lung cancer

Cyclin B1 plays an important role in the mitotic cycle, in which it regulates the G2-M transition, and has been suggested to play a role in development and progression of various cancers. The present study was undertaken in order to clarify the role of the cell cycle regulator cyclin B1 in non-small cell carcinoma (NSCLC). We retrospectively investigated 174 patients with NSCLC who previously underwent complete resection. There were two study groups: the squamous cell carcinoma (SCC) group (n=62); and the non-SCC group (n=112). Expression of cyclin B1 in cancer cells was analyzed immunohistochemically. The rate of cyclin B1 positivity in cancer cells ranged from 0% to 56.5% (average 10.9%). Seventy-four cases (42.5%) were designated as cyclin B1 positive in the present study. Cyclin B1 expression was observed more frequently in SCC cases than in non-SCC cases. In SCC, cyclin B1 expression demonstrated significant correlation with gender (p<0.01) and histological type (p<0.01). In non-SCC, only gender was correlated with cyclin B1 expression. Five-year survival rates for cyclin B1-positive and cyclin B1-negative cases were 45.8 and 57.9%, and 10-year survival rates were 39.3 and 51.4%, respectively. Patients with positive cyclin B1 staining showed a lower survival rate than those with negative staining (p=0.11). The prognostic value in SCC cases was p=0.48. In non-SCC cases, the survival rate of non-SCC patients who were positive for cyclin B1 was significantly lower than that of patients who were negative (p<0.01). Using multivariate analysis, tumor size (p=0.037) and N factor (p=0.026) were found to be independent prognostic parameters. Cyclin B1 expression was not an independent prognostic factor in the present series. These data suggest that elevated levels of cyclin B1 expression may be an indicator of poor prognosis in NSCLC, particularly in non-SCC.     

Cyclin D1 overexpression is a critical event in gallbladder carcinogenesis and independently predicts decreased survival for patients with gallbladder carcinoma.

This study was designed to test the hypothesis that cyclin D1 overexpression is involved in the multistep process of gallbladder carcinogenesis and can be used to predict poor prognosis for patients with gallbladder carcinoma (GBC). Cyclin D1 expression was examined immunohistochemically in a series of specimens, including 8 normal epithelia, 8 benign adenomyoma lesions, 6 precancerous adenomas, and 37 carcinomas of the gallbladder. Four of the 6 (67%) adenomas and 15 of the 37 (41%) adenocarcinomas demonstrated cyclin D1 overexpression (>5% nuclear staining), whereas all normal epithelia and adenomyoma lesions were negative for cyclin D1. Kaplan-Meier curves showed that cyclin D1 overexpression was significantly related to decreased overall survival (P < 0.05) in patients with GBCs. The Cox proportional hazards model identified cyclin D1 overexpression as an independent prognostic marker for death (P = 0.024; risk ratio, 4.2; 95% confidence interval, 1.2-14.7). To test whether cyclin D1 overexpression is a critical event in gallbladder neoplasms, cyclin-dependent kinase inhibitor p27Kip1 was introduced to ascertain how cyclin D1 affects clinical outcomes. Subsequently, neoplasms were divided into three groups on the basis of the combination of cyclin D1 expression and p27Kip1 status, which had been determined previously. Group 1 showed no abnormality in either cyclin D1 or p27Kip1 expression. Group 2 showed aberrant expression of one of the two proteins, whereas group 3 showed concurrent abnormalities in both proteins. Results indicated that overall survival was greatest in group 1, followed by a significant decrease in group 2 and a more precipitous decrease in group 3. In conclusion, cyclin D1 overexpression is an early event in gallbladder carcinogenesis and independently predicts decreased survival for patients with GBC.     

Overexpression of cyclin D1 is associated with poor survival in epithelial ovarian cancer

OBJECTIVE: In order to assess the prognostic role of the cell-cycle regulator cyclin D1 in epithelial ovarian cancer, 70 patients have been studied during an observation period of 8 years. METHODS: The cyclin D1 protein content was analyzed by Western blotting, and classed as negative, positive and highly positive by densitometric scanning. The relationship between cyclin D1 expression and clinicopathological variables was determined. Univariate and multivariate survival analyses were also carried out. RESULTS: Patients with highly positive cyclin D1 tumors had shorter overall survival than patients with positive cyclin D1 (median survival 31 vs. 49 months; p = 0.058). Furthermore, in patients with stage III/IV tumors and residual disease greater than 2 cm, cyclin D1 expression significantly influenced clinical outcome (p = 0.047 and 0.040, respectively). In the Cox's regression model, cyclin D1 expression and residual disease were identified as the most important predictors of survival (p = 0.016 and 0.002, respectively). In patients with high cyclin D1 expression and residual disease after debulking surgery greater than 2 cm, the relative risks of death were to 2.48 and 3.7, respectively, compared to their correspondent counterparts. CONCLUSION: The overexpression of cyclin D1 is significantly related to a more aggressive tumor phenotype and poor prognosis in ovarian carcinoma.     

p27(kip1) expression in breast carcinomas: an immunohistochemical study on 512 patients with long-term follow-up

p27(Kip1) (p27), a cyclin-dependent kinase inhibitor, has an important role in the progression of cells from G(1) into S phase of the cell cycle. p27 may act as a tumor suppressor, and several reports suggest that loss of its expression in breast carcinoma is related to tumor progression and poor prognosis. We evaluated p27 immunohistochemical expression in 512 consecutive cases of breast carcinoma with 9 years of median-term follow-up. p27 expression was heterogeneous and frequently less intense than in normal cells. Low p27 expression (<50% of reacting cells) was associated with grade III tumors, N0 status, estrogen receptor-negative status, and low cyclin D1 expression. In the whole series of cases, p27 expression did not predict outcome. In node-negative cases (249 patients), high p27 expression indicated poor prognosis. p27 was not prognostically relevant in the group of 223 patients with pT1 disease or in the group of 154 patients <50 years of age. We also investigated the prognostic value of the combined expression of p27 and cyclin D1, but no differences in survival were seen in this bivariate analysis.     

The prognosis in spindle-cell sarcoma depends on the expression of cyclin-dependent kinase inhibitor p27(Kip1) and cyclin E

The aim of the present study was to examine the prognostic significance of p27^Kip1 and cyclin E expression in patients with spindle-cell soft tissue sarcomas. In 46 cases of spindle-cell sarcoma including 17 pre-operative biopsy materials, the expression of p27^Kip1 and cyclin e was immunohistochemically examined. The expression of p27^Kip1 decreased in the nuclei of metastatic primary tumor cells (stage IV), whereas the expression of cyclin E increased in those lesions. On univariate analysis, when the expression of p27^Kip1 and cyclin E was analyzed together, patients with spindle-cell sarcoma exhibiting low expression of p27^Kip1 and high expression of cyclin E showed lower distant-metastasis-free survival (DMFS) and overall survival (OS) than those with other combinations of the two parameters (both P <0.0001). Multivariate analysis revealed that patients with low p27^Kip1 and high cyclin E expression also showed a decrease in DMFS ( P =0.0007, relative risk=21.3) and OS (P=0.005, relative risk=20.8). These results suggest that the combination analysis of p27^Kip1 and cyclin E expression even in biopsy specimens allows the prediction of the clinical behavior of spindle-cell sarcoma. (Cancer Sci 2003; 94: 412–417)