HRCT Scans of Peripheral Non-Small Cell Lung Cancers and their Relationship with Cyclin D1 Expression： a Longitudinal Study

OBJECTIVE To investigate cyclin D1 expression in peripheral lung cancers and its relationship with CT signs and prognosis. METHODS Cyclin D1 expression in peripheral lung cancers and its relationship with the CT imaging and prognosis were analyzed retrospectively by means of SP immunohistochemistry and spiral CT scanning in 92 patients with peripheral lung cancer verified by pathology. RESULTS Cyclin D1 expression was related to deep lobulation,spiculate protuberance,short thin spinules sign and mediastina lymph node metastasis.Cyclin D1 expression was not related to tumor size,cavity,pleural indentation,histological type,differentiation,tumor TNM stage,age or sex.Cyclin D1 was a negative prognostic factor whose over-expression indicated a poor prognosis. CONCLUSION Cyclin D1 expression may play an important role in the occurrence,progress and CT scan results of lung cancers.Cyclin D1 was a negative factor whose over-expression implied a poor prognosis.Detection of the cyclin D1 and observation of the CT scan can be considered as indexes of clinical diagnosis and prognostic evaluation.     

Prognostic Significance of Cyclin D1 and E-cadherin Expression in Laryngeal Squamous Cell Carcinoma

Cyclin D1 and E-cadherin are important factors in the progression and metastasis of cancers. Their role in laryngeal carcinoma has been studied with conflicting results. To define the frequency of cyclin D1 and E-cadherin expression and its correlation with both the clinicopathological characteristics and prognosis of patients with laryngeal squamous cell carcinoma (LSCC). Tumor tissue samples from 75 patients with laryngeal squamous cell carcinoma were examined for cyclin D1 and E-cadherin expression by immunohistochemistry. The relationship between the expression of both molecules and the age and sex of the patient, tumor site, tumor differentiation, lymph node metastasis, tumor invasiveness, TNM stages, tumor recurrence and overall survival was analyzed. Cyclin D1 was found to be a significant independent prognostic factor of lymph node metastasis (p?=?0.000). The multivariate analysis revealed that cyclin D1 and E-cadherin expression wasn’t an independent prognostic factor of local recurrence free survival (LRFS) in patients with LSCC (P?=?0.56 and 0.28) respectively. However, the univariate analysis revealed a significant association between them and LRFS (p?=?0.003 and 0.000) respectively. Also, the group of high cyclin D1 /low E-cadherin expression had the poorest prognosis, so they might serve as potential predictors of the prognosis of the patients with LSCC. E-cadherin was found to affect the overall survival (OAS) significantly by the univariate analysis (p?=?0.01). However, by the multivariate analysis the TNM stage was the only independent prognostic factor of OAS (p?<?0.05). Cyclin D1 can be used as an independent prognostic marker of lymph node metastasis in patients with LSCC and can help to identify those patients with clinically negative lymph nodes but with considerable risk for occult metastasis. Detection of cyclin D1 and E-cadherin status in LSCC may contribute to the identification of patients with high risk factors of local recurrence. However, they don’t appear to be better prognostic predictors than other established markers in LSCC.     

CyclinD1和VEGF在非小细胞肺癌组织中的表达及其与预后的关系

背景与目的:肿瘤的发生与发展由癌基因、抑癌基因及转移相关基因的特性所决定。细胞周期蛋白D1(CyclinD1)为癌基因CCND1的表达产物,血管内皮生长因子(vascularendothelialgrowthfactor,VEGF)可调节肿瘤新生血管的形成,有助于肿瘤侵袭转移。本研究探讨非小细胞肺癌(non-smallcelllungcancer,NSCLC)病理组织中CyclinD1、VEGF的表达及与患者预后的关系。方法:采用免疫组织化学方法测定55例NSCLC和10例肺部非恶性病变病理切片中CyclinD1和VEGF的表达,并对55例NSCLC组织中CyclinD1和VEGF的表达与患者的年龄、性别、吸烟情况、瘤体大小、病理类型、组织分化程度、临床分期、淋巴结转移情况及生存时间进行统计分析。结果:55例肺癌病理组织中,CyclinD1和VEGF表达的阳性率分别是61.82%和74.55%;10例肺部非恶性病变标本中CyclinD1表达均为“-”,VEGF表达均为“-”。CyclinD1和VEGF表达:在不同年龄、性别,吸烟情况,瘤体大小,腺癌和鳞癌,不同组织分化程度,不同临床分期差异均无统计学意义;在有无淋巴结转移分组比较中差异均有统计学意义;表达阳性与阴性组生存分析差异均有统计学意义,提示CyclinD1与VEGF均有负性预后意义。结论:CyclinD1和VEGF在60%以上NSCLC中有表达,两者均可能影响NSCLC的生物学行为和预后。     

Prognostic significance of p21waf1, cyclin D1 and retinoblastoma expression detected by immunohistochemistry in non-small cell lung cancer.

p21waf1 is a downstream effector of p53, and mediates growth arrest by inhibiting the action of G1 cyclin-dependent kinases. Cyclin D1 is a cell-cycle regulator essential for G1 phases progression and a candidate proto-oncogene implicated in the pathogenesis of several human tumor types. Cyclin D1 overexpression and the absence of retinoblastoma (Rb) protein have been frequently seen in various types of cancer, including lung cancer. The aim of this study was to clarify the relationship between the expressions of p21waf1, cyclin D1, and Rb protein, and to investigate the correlation between these protein expressions and the clinical features of the patients, and their prognoses. We immunohistochemically examined 92 samples of resected non-small cell lung cancer for p21waf1, cyclin D1, and Rb expression. Of the 92 specimens examined, 43 cases (46.7%) showed p21waf1 expression, 23 cases (25.0%) showed cyclin D1 overexpression, and 61 cases (66.3%) showed Rb expression. No correlation was observed between the expressions of p21waf1, cyclin D1, and Rb. There was no association of p21waf1 and cyclin D1 immunoreactivity with gender, disease stage, or histological types of the tumor. Regarding the prognosis in 79 cases with complete resection, no statistical differences were observed according to the degree of expression of these three factors. However, when unfavorable prognostic factors were considered to be the positive expression of p21waf1, positive of cyclin D1, and negative of Rb, the 5-year disease-free survival rate in the group with 2 or 3 unfavorable prognostic factors was 21.1%, which was statistically poorer than the 45.4% in the group with 0 or 1 unfavorable prognostic factor (p=0.0138). We conclude that examination of the expression of cell cycle regulators, such as p21waf1, cyclin D1, and Rb, is useful as a prognostic indicator, when these proteins' expression is analyzed in combination.     

Prognostic Significance of Cyclin D1 Over-expression in Colorectal Cancer: An Experience from Madinah,Saudi Arabia

Background and study aim: Cyclin D1 is a key regulatory protein in the cell cycle and is over-expressed inmany tumors, including endometrial, thyroid, urothelial, breast, brain gliomas, and esophageal cancers. The mainaim of the present study is to examine the expression pattern of cyclin D1 and its correlation with the differentclinicopathological features in patients with colorectal camcer (CRC) from the Madinah region of Saudi Arabia.Patients and methods: The archival tumor blocks were analyzed using immunohistochemistry for Cyclin D1over-expression in 324 CRC patients diagnosed from January 2006 to December 2017, at the Department of Pathology,King Fahad Hospital, Madinah, Saudi Arabia. Results: Cyclin D1 over-expression was absent in normal mucosa, while15% cases of adenoma showed its over-expression. In CRC, Cyclin D1 was expressed at high levels in 24.1% of case.No significant correlation was observed between Cyclin D1 over-expression and age, gender, tumor size, type andlocation. However, Cyclin D1 over-expression exhibited a significant correlation with tumor differentiation (p=0.04),lymph node involvement (p=0.001), lymphovascular invasion (p=0.001), distant metastasis (p=0.006) and AJCC staging(p=0.001). The Kaplan-Meir analysis revealed a shorter period of survival with Cyclin D1 over-expression (p=0.000).The Cox-regression model analysis showed that Cyclin D1 over-expression was an independent prognostic markerin CRC (p=0.000). Conclusion: Cyclin D1 over-expression increases during normal-adenoma-carcinoma sequence.The significant association observed between Cyclin D1 over-expression, advanced tumor stage and short survivalperiod clearly suggest the role of Cyclin D1 in the carcinogenesis and progression of CRC.     

Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma.

PURPOSE: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non-small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival. EXPERIMENTAL DESIGN: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non-small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival. RESULTS: Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21(Waf1) overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively). CONCLUSIONS: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.     

High cyclin E and low p27/Kip1 expressions are potentially poor prognostic factors in lung adenocarcinoma patients

Cyclin E is an important regulator of entry into the S phase of the cell cycle. p27/Kip1 (p27) binds to cyclin E/Cdk2 complex and negatively regulates cell proliferation. We immunohistochemically examined the expression of cyclin E and p27 in 98 cases of resected lung adenocarcinoma to evaluate the prognostic significance of cyclin E and p27. Cyclin E was expressed in 16 cases (16%), and p27 was expressed in 41 cases (42%). Using Kaplan-Meier survival analysis, patients with cyclin E positive (P=0.0017) and p27 negative (P=0.011), both individually and in combination (P<0.0001), had a worse prognosis. We also analyzed the relationship of these findings to clinicopathological parameters, which revealed that cyclin E-positive, p27-negative cases had a higher Ki67 expression (P=0.012) and a higher rate of lymph node metastasis (P=0.0078) than other groups. Our results suggested that cyclin E over expression, in association with p27 reduction in particular, may potentially be a poor prognostic factor in lung adenocarcinoma patients. However, to verify the prognostic significance of these factors, a multivariate analysis of a larger number of patients should be undertaken.     

Cyclin A在非小细胞肺癌中的表达及临床意义

目的 :观察细胞周期因子CyclinA在非小细胞肺癌 (NSCLS)中的表达 ,探讨其临床意义。方法 :采用免疫组化SP法 ,观察 66例非小细胞肺癌患者及 12例正常肺组织中细胞周期因子CyclinA的表达 ,并对其与临床预后关系进行了相关分析。结果 :在 66例非小细胞肺癌病例中 ,CyclinA表达阳性率分别为 90 9%。CyclinA与肿块大小、病理分级和TNM分期间显著相关 ,P <0 0 5 ,与年龄、性别、组织学类型及淋巴结转移间无显著相关 ,P >0 0 5。与阴性患者相比 ,CyclinA阳性患者生存时间明显缩短 ,P =0 0 0 6,估计增加相对风险为 3 6;分析显示 ,CyclinA给出最佳预后诊断信息。LN/CyclinA ,P=0 0 0 12 ,两因子协同的预后判断价值优于最佳单个因子。结论 :CyclinA过表达与非小细胞肺癌不良预后有关     

Cyclin D1 in Breast Cancer

Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over- expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c- erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over- expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over- expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.     

A risk-stratification model of non-small cell lung cancers using cyclin E, Ki-67, and ras p21: different roles of G1 cyclins in cell proliferation and prognosis

A large number of biological factors that seem to have important prognostic significance have been identified in non-small cell lung cancers (NSCLCs). In the present study, we have characterized expression of cyclin D1 and cyclin E in a cohort of 217 resected NSCLCs from a single institution by immunohistochemistry to analyze their expression in relation to the growth fraction determined by Ki-67 and to prognosis, and then we have constructed a risk-stratification model of cancer death by multiple biological factors in p-stage I NSCLCs. The cyclin E labeling index (LI) was significantly associated with the Ki-67 LI (r = 0.45; P < 0.001). Tumors having high-level cyclin E expression (cyclin E LI > or =30%) showed a significantly higher Ki-67 LI than tumors having low-level cyclin E expression (cyclin E LI <30%; P < 0.001), whereas positive or negative cyclin D1 expression was not associated with the Ki-67 LI (P = 0.1). Cyclin E expression was a significant and independent unfavorable prognostic factor (hazards ratio = 2.09; P = 0.03), as reported previously (Clin. Cancer Res., 6: 11-16, 2000), whereas cyclin D1 expression was not. These findings indicate different roles of cyclin D1 and cyclin E in cell proliferation and in the prognosis of NSCLCs. Furthermore, we stratified this cohort of p-stage I NSCLCs into different survival groups by using biological factors, including cyclin E, Ki-67, and ras p21, which previously we have found to be independent prognostic factors among 10 factors studied in p-stage I NSCLCs. Four groups of patients with markedly different survivals were identified with 5-year survival rates that ranged from 96% for patients with no factors altered to 41% for patients with all three factors altered (P < 0.001). This combination of biological factors was a significant and independent prognostic factor (hazards ratio = 7.94; P = 0.001).     

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.     

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.     

Role of COX-2, VEGF and cyclin D1 in mammary infiltrating duct carcinoma

Cyclooxygenase-2 (COX-2) has an important role in the promotion of carcinogenesis, tumor invasion and angiogenesis. Vascular endothelial growth factor (VEGF) is a proangiogenic factor that is up-regulated in various tumors. VEGF has been shown to interact with COX-derived prostaglandins in angiogenesis. Cyclin D1 gene overexpression and amplification have been shown to play a role as prognostic factors in many human cancers. To better understand the roles of these genes in mammary carcinoma, the immunohistochemical expression patterns of COX-2 and VEGF were evaluated in relationship with cyclin D1 overexpression, tumor stage, clinicopathologic parameters and patient survival in 128 mammary infiltrating duct carcinomas. The expressions of COX-2/VEGF, COX-2/cyclin D1, and VEGF/cyclin D1 were evaluated using double immunofluorescein staining with a confocal scanning laser microscope. A positive expression was seen in 41% for COX-2, 47% for VEGF, and 66% for cyclin D1 in the cases with breast cancer. There was correlation in positive expression of COX-2 or VEGF with histologic grade, lymph node metastasis, and tumor size. Conversely, a significant inverse relation was observed between VEGF and patient age. There was a correlation in overexpression of cyclin D1 with lymph node metastasis, survival rate and survival length. Significant correlations were observed between COX-2 and VEGF as well as COX-2 and cyclin D1. Co-expression of only COX-2 and VEGF was detected with significance. These results indicate that elevated COX-2 or VEGF expression or cyclin D1 overexpression is more common in breast cancer patients with poor prognostic characteristics and is partly associated with an unfavorable outcome. The present findings support the efforts to initiate clinical trials on the efficacy of COX-2 inhibitors in adjuvant treatment of breast cancer.     

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.     

Cyclin D1 overexpression is an indicator of poor prognosis in resectable non-small cell lung cancer.

Cyclin D1 is one of the G1 cyclins that control cell cycle progression by allowing G1 to S transition. Overexpression of cyclin D1 has been postulated to play an important role in the development of human cancers. We have investigated the correlation between cyclin D1 overexpression and known clinicopathological factors and also its prognostic implication on resected non-small-cell lung cancer (NSCLC) patients. Formalin-fixed and paraffin-embedded tumour tissues resected from 69 NSCLC patients between stages I and IIIa were immunohistochemically examined to detect altered cyclin D1 expression. Twenty-four cases (34.8%) revealed positive immunoreactivity for cyclin D1. Cyclin D1 overexpression is significantly higher in patients with lymph node metastasis (50.0% vs 14.4%, P = 0.002) and with advanced pathological stages (I, 10%; II, 53.8%; IIIa, 41.7%, P = 0.048; stage I vs II, IIIa, P = 0.006). Twenty-four patients with cyclin D1-positive immunoreactivity revealed a significantly shorter overall survival than the patients with negativity (24.0 +/- 3.9 months vs 50.1 +/- 6.4 months, P = 0.0299). Among 33 patients between stages I and II, nine patients with cyclin D1-positive immunoreactivity had a much shorter overall survival (29.7 +/- 6.1 months vs 74.6 +/- 8.6 months, P = 0.0066). These results suggest that cyclin D1 overexpression is involved in tumorigenesis of NSCLCs from early stage and could be a predictive molecular marker for poor prognosis in resectable NSCLC patients, which may help us to choose proper therapeutic modalities after resection of the tumor.     

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.     

Prognostic significance of cyclin A in gastric cancer

High level of cyclin A promotes carcinogenesis, and overexpression of cyclin A has been associated with poor prognosis of cancer patients. We validated the prognostic role of cyclin A in gastric cancer and evaluated its correlation with expression of an mRNA stability factor HuR. From 342 consecutive histologically confirmed gastric cancer patients were obtained 325 representative tissue specimens for cyclin A and 316 for HuR immunohistochemistry. Specimens were stained by cyclin A and HuR specific monoclonal antibodies. Nuclear immunostaining detected in > or =5% of the tumor cells was considered the cut-off for cyclin A positivity. Positive HuR immunoreactivity was scored as nuclear or cytoplasmic. Associations between scores, clinicopathological factors and survival were calculated by the chi2-test, Fisher's exact test, Kaplan-Meier test and Cox model. Cyclin A detected in the nuclei of cancer cells was positive in 55% (179 of 325) of the specimens; 40% (127 of 316) of the specimens had cytoplasmic and 88% (279 of 316) nuclear immunoreactivity of HuR. Cyclin A expression was an independent prognostic factor for poor survival. Cyclin A immunoreactivity was associated with old age, high stage, proximal location of the tumor, intestinal type, noncurative resection, advanced penetration depth and with nodal metastases but not distant metastases. Furthermore, cyclin A expression was associated with cytoplasmic HuR expression, whereas no association with nuclear HuR was evident. Cyclin A is an independent prognostic factor in gastric cancer, and one mechanism for its overexpression may depend on cytoplasmic localization of HuR.     

Prognostic significance of cyclin E overexpression in resected non-small cell lung cancer

Cyclin E plays a pivotal role in the regulation of G1-S transition and relates to malignant transformation of the cells. However, the clinical significance of cyclin E expression in patients with non-small cell lung cancer remains unknown. We examined the expression of cyclin E in 242 resected non-small cell lung cancer in pathological stages I-IIIa and analyzed its relation to clinicopathological factors. Cylin E overexpressions were observed frequently in deeply invasive tumors. Multivariate analysis revealed that complete resection, pathological stage, and cyclin E expression were independent prognostic indicators. When cyclin E and proliferating cell nuclear antigen are combined, the cases negative for both had a significantly better prognosis than the other cases. We concluded that cyclin E overexpression relates to deeply invasive tumors and is correlated with poor prognosis. New therapeutic options may be provided by combination of cyclin E expression and proliferating cell nuclear antigen overexpression.     

Prognostic impact of survivin, cyclin D1, integrin beta1, and VEGF in patients with small adenocarcinoma of stage I lung cancer

The purpose of this study was to investigate the impact of survivin, cyclin D1, integrin beta1, and vascular endothelial growth factor (VEGF) in tumor on survival of patients with small adenocarcinoma of the lung. Seventy-two patients with pathologic stage I resected tumors <2 cm in diameter were entered into the study. Each patient underwent curative surgical resection for lung cancer between July 1992 and November 1999. The resected tumors were subjected to immunostaining for each gene. Thirty-five, 26, 6, and 16 patients had tumors with >10% survivin-, >20% cyclin D1-, >10% integrin beta1-, and >10% VEGF-positive cells, respectively. When the survival of 72 patients was compared according to each gene expression, the overall survival of patients with positive expression of survivin, cyclin D1, and integrin [beta]1 was significantly worse than that of individuals whose tumors had negative expression of each gene. By multivariate analysis controlling for each gene expression, no gene expression was an independent marker of poor prognosis, however, the overall survival of the complex gene expression (2 or more gene-positive) group (n = 35) was significantly worse than that of 0 or 1 gene-positive group (n = 37; log-rank test, P = 0.0011; Wilcoxon test, P = 0.0011). When the association between survival and pathologic factors, including lymphatic invasion, venous invasion, type of bronchioalveolar carcinoma, and complex gene positive expression was analyzed, only complex gene-positive expression was found to be a significant independent factor (hazard ratio = 0.085, P = 0.0299). It can be concluded that multiple increased expression of oncogene is a poor prognostic factor in patients with small adenocarcinoma of the lung.     

细胞周期素A的表达与非小细胞肺癌增殖及预后的关系

目的：探讨非小细胞肺癌中 ｃｙｃｌｉｎ Ａ的表达与细胞增殖活性及预后的关系。方法：采用免疫组化法检测 ｃｙｃｌｉｎ Ａ在６０例非小细胞肺癌中的表达,采用流式细胞术分析ＤＮＡ含量。结果：在非小细胞肺癌中 ｃｙｃｌｉｎ Ａ的阳性率为４８．３％（２９／６０）,ｃｙｃｌｉｎ Ａ阳性者的Ｓ期细胞比例［（１４．４±３．９）％］明显高于阴性者［（９．４±３．５）％］,ｃｙｃｌｉｎ Ａ的表达与患者预后有关。结论： ｃｙｃｌｉｎ Ａ的表达与肿瘤细胞增殖活性增高密切相关,是判断非小细胞肺癌患者预后的一个可参考指标。