周围T细胞淋巴瘤survivin表达的临床意义

背景与目的：周围T细胞淋巴瘤（peripheral T-cell lymphoma,PTCL）约占NHL的10％-15％,临床表现进展快、预后差。survivin是凋亡蛋白抑制因子之一,在多种恶性肿瘤患者中都有过表达,是一个预后不良指标。本研究通过检测周围T细胞淋巴瘤肿瘤组织survivin表达情况,探讨其表达与临床预后的关系。方法：采用免疫组化SP法检测51例初治周围T细胞淋巴瘤肿瘤组织survivin表达情况。应用SPSS10．0软件行生存分析并对各临床指标与预后的关系进行单因素和多因素分析。结果：51例周围T细胞淋巴瘤肿瘤组织survivin阳性表达为82．3％（42／51）,survivin表达与性别、年龄、分期、结外病灶数目、PS、LDH、B症状、IPI无显著性相关（JD〉0．05）。本组病例总的5年生存率为32．67％,而survivin阳性组和survivin阴性组患者的5年生存率分别为25．0％和75．0％,差异有显著性（P=0．03）。多因素分析显示survivin表达是周围T细胞淋巴瘤的独立预后指标。结论：survivin表达是周围T细胞淋巴瘤的一个有价值的预后指标,与IPI结合可于早期筛选出常规治疗预后不良的病例,有助于指导治疗及改善预后。     

Nuclear localization of survivin is a positive prognostic factor for survival in advanced non-small-cell lung cancer.

BACKGROUND: Expression of survivin, a member of the inhibitor of apoptosis protein family, is commonly detected in cancers but not in normal differentiated tissues. Survivin is usually localized in the cytoplasm of cancer cells, but nuclear localization has also been described, and we recently reported that survivin is a nuclear-cytoplasmic shuttling protein. PATIENTS AND METHODS: Fifty-three tumor specimens from patients with inoperable non-small-cell lung cancer (NSCLC) (55% stage IIIA, 17% stage IIIB and 28% stage IV) who underwent chemotherapy treatment were evaluated with immunohistochemistry for survivin expression and localization. These two sets of data were processed and tested for correlation with major patient characteristics, response to chemotherapy, and overall and relapse-free survival. RESULTS: Survivin was present only in malignant tissues, and 47/53 (89%) of the specimens were positive. The overall median expression of tumor cells was 40%, and this value was used as a cut-off point for statistical analysis. By dichotomizing the specimens as expressing low or high levels of survivin, a significant association was seen between the expression of survivin and the histology of the tumors (P=0.020), squamous cell carcinoma being the histotype with lower levels of survivin expression. Three patterns of localization were observed: 42% of cases (22/53) showed reactivity confined to the nucleus, 17% (nine of 53) only in the cytoplasm and 30% (16/53) in both the nucleus and the cytoplasm. Interestingly, nuclear survivin levels predicted longer overall and relapse-free survival, in univariate and multivariate analyses. Expression and localization of survivin did not correlate with response to chemotherapy. CONCLUSIONS: Our results indicate that differential localization of survivin may be a prognostic factor for NSCLC. Further studies are warranted.     

Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1.

BACKGROUND: Survivin, a novel inhibitor of apoptosis, is one of the most cancer-specific proteins identified to date. In this study we (a) evaluated the association between survivin and HER2, vascular endothelial growth factor (VEGF) and uPA/PAI-1 expression and (b) defined its effect on clinical outcome in a large breast cancer patient cohort. PATIENTS AND METHODS: Survivin expression was measured by ELISA in primary breast cancer tissue extracts from 420 patients with long-term clinical follow-up. RESULTS: Survivin was detected in 378 (90%) of the 420 primary breast cancer cases. Increased survivin levels were significantly associated with high nuclear grade (P < 0.0001), negative hormone receptor status (P = 0.0028), HER2 overexpression (P = 0.0094), VEGF expression (P < 0.0001), high uPA (P = 0.0002) and PAI-1 levels (P = 0.0002). Using the 25th percentile (1.4 ng/mg) as a cut-off point, patients expressing elevated survivin had a significantly worse disease-free survival (DFS: P = 0.0007, RR 1.97) and overall survival (OS: P = 0.0009, RR 2.11) compared with patients expressing lower levels of survivin. In multivariate analysis, this prognostic value of survivin was independent of both traditional and novel clinicopathologic factors for both DFS (P = 0.0076, RR 1.72) and OS (P = 0.0155, RR 1.76). CONCLUSIONS: The independent prognostic relevance of survivin, when combined with previous data from model systems implicating survivin in the inhibition of apoptosis, suggests that survivin may be a suitable target for future therapeutic strategies.     

Aberrant TP53 protein accumulation in the neuronal component of ganglioglioma

Gangliogliomas are characterized by their different phenotypic composition of ganglion cells and glial cells. In contrast to the glial cells that are capable of mitotic activity, the ganglion cells are generally considered to lack a neoplastic nature. The authors report here the first unequivocal case of a ganglioglioma harboring aberrant TP53 product that was expressed predominantly in the neuronal component. GeneChip TP53 assay revealed a point mutation resulting in an exchange of amino acid. This case suggests that ganglion cells can participate in the neoplastic process of gangliogliomas.     

Survivin expression predicts poorer prognosis in anaplastic large-cell lymphoma.

PURPOSE: Survivin, a member of the inhibitor of apoptosis (IAP) family, is not detected in normal adult tissues but is overexpressed in various cancers, including some types of lymphoma. The frequency and prognostic significance of survivin expression in anaplastic large-cell lymphoma (ALCL) is unknown. Materials and METHODS: We assessed for survivin expression in 62 ALCL tumors (30 anaplastic lymphoma kinase [ALK]-positive and 32 ALK-negative) obtained before doxorubicin-based chemotherapy. Given that survivin is a target of the STAT3 signaling pathway and STAT3 is activated in ALCL, survivin expression was also correlated with STAT3 activation. RESULTS: Survivin was expressed in 34 tumors (55%) and did not correlate with ALK. A significant association between survivin expression and STAT3 activation was observed (P =.007, Fisher's exact test). For the ALK-positive group, the 5-year failure-free survival (FFS) was 34% for patients with survivin-positive ALCL compared with 100% for patients with survivin-negative ALCL (P =.009, log-rank test). For the ALK-negative group, the 5-year FFS was 46% for patients with survivin-positive tumors compared with 89% for patients with survivin-negative tumors (P =.03, log-rank test). Overall survival was similarly worse for patients with survivin-positive tumors in both the ALK-positive and ALK-negative groups. Furthermore, multivariate analysis confirmed the independent prognostic value of survivin expression, along with age older than 60 years and Ann Arbor stage III or IV. CONCLUSION: Survivin is expressed in approximately half of ALCL tumors and independently predicts unfavorable clinical outcome. Modulation of survivin expression or function may provide a novel target for experimental therapy in patients with ALCL.     

Quantitatively determined survivin expression levels are of prognostic value in human gliomas.

PURPOSE: Survivin is a novel antiapoptotic gene that has been recently cloned and characterized. Its expression has been found to be of prognostic significance in several tumor types. This is the first study on the prognostic significance of survivin expression in human gliomas. MATERIALS AND METHODS: We used quantitative Western blot analysis with densitometry to determine survivin protein expression levels in 92 glioma cases for which frozen tissue was available for analysis. Survivin positivity and expression levels were correlated with histopathologic features of the tumors, apoptosis (as measured by cleaved, or activated, caspase 3 levels), and clinical outcome. RESULTS: Survivin expression has clear prognostic value in human gliomas. Patients with detectable survivin expression had significantly shorter overall survival times (P <.0001) compared with those without detectable expression when all glioma patients were considered. Although glioblastoma multiforme (GBM) patients had significantly higher rates of survivin positivity and higher levels of survivin expression (P <.0001) than their non-GBM counterparts, the prognostic value of survivin expression seemed to be independent of histology alone. Survivin-positive GBM patients had significantly shorter overall survival times compared with survivin-negative GBM patients (P <.0001). Likewise, survivin-positive non-GBM patients had shorter survival times compared with survivin-negative non-GBM patients (P =.029). Furthermore, increasing levels of survivin expression significantly correlated with reduced survival times when all glioma patients were considered, and markedly so for GBM patients (P <.0001). Increasing survivin levels significantly correlated with reduced expression of cleaved caspase 3, indicating its association with antiapoptotic activity. CONCLUSION: Survivin positivity and protein expression levels, as determined quantitatively, are of significant prognostic value in human gliomas and seem to be associated with reduced apoptotic capacity of these tumors.     

Survivin expression and its correlation with cell proliferation and prognosis in epithelial ovarian tumors

Survivin is a new member of the inhibitors of apoptosis proteins (IAP) family, selectively overexpressed in common human cancers but not in normal adult tissues, and associated with aggressiveness of the disease and unfavorable outcomes. Recent study also found that survivin expression is associated with cell proliferation. In order to gain insight into the role of survivin in ovarian tumors, we investigated the expression of survivin in a group of epithelial ovarian tumors, and examined the relationship of its expression with cell proliferation and clinical outcome. Immunohistochemical analysis was performed in 103 cases of epithelial ovarian tumors. Twenty-six of the 103 cases were evaluated by Western blot analysis. The results showed that survivin overexpression was detected in 21.2% (7 of 33) of benign tumors, 47.8% (11 of 23) of borderline tumors, and 51.1% (24 of 47) of ovarian carcinomas. The positive ratio was significantly higher in malignant or borderline tumors than in benign tumors, and the overexpression of survivin was significantly correlated with the size of residual disease. A positive correlation between survivin expression and proliferative activity of tumor cell measured by PCNA index was found. Kaplan-Meier analysis demonstrated that the patients with survivin overexpression have a short overall survival. These findings suggest that survivin overexpression may play a pivotal role in the progression of ovarian tumors and may provide an important prognostic implication for epithelial ovarian carcinomas.     

Nuclear survivin expression predicts poorer prognosis in glioblastoma

Survivin is a member of the inhibitor of apoptosis family, and is expressed in various malignant tumors. Survivin overexpression has been reported to be a poorer prognostic factor in various malignancies. However, the prognostic value of survivin expression in patients with glioblastoma is still controversial. Therefore, in this study the role of survivin as a predictor for survival was investigated in patients with glioblastoma. Tissue specimens were obtained from 66 patients with glioblastoma treated with radiotherapy. Survivin expression was detected by an immunohistochemical method. Nuclear and cytoplasm survivin scores were defined by using the cell positivity and staining intensity. The scores were defined as follows, 0 (no staining), 1 (less than 50% of cell positivity and any staining), 2 (more than 50% of cell positivity and weak to moderate intensity) and 3 (more than 50% of cell positivity and strong intensity). The correlation between survivin scores and the overall survival rate was evaluated. Nuclear and cytoplasm survivin staining were noted in 47 and 58 patients, respectively. The number of patients with nuclear survivin score of 0, 1, 2 and 3, were 19 (28.8%), 26 (39.4%), 9 (13.6%) and 12 (18.2%), respectively. The 3-year overall survival rate of the nuclear survivin score 3 was 0%, significantly lower than the 11.6% of the nuclear survivin score ≤2 (P = 0.0003). Cytoplasm survivin score did not correlate with the prognosis. Nuclear survivin expression may be a useful biomarker for predicting prognosis in patients with glioblastoma.     

Survivin expression in human osteosarcoma is a marker for survival.

AIMS: Osteosarcoma is the most frequent malignant bone tumor with a peak incidence in the second and third decade of life. Evaluation of prognosis of patients with osteosarcoma is limited to clinical parameters whereas molecular markers of tumor aggression have not yet been identified. Inhibition of apoptotic cell death could play a role in the development or progression of neoplasia. Survivin is a member of the inhibitor of apoptosis (IAP) protein gene family and is expressed both during normal fetal development and in human cancer. METHODS: The localization and distribution of survivin was investigated immunohistochemically in high-grade osteosarcomas by an indirect immunoperoxidase method. RESULTS: Survivin was detected in the cytoplasm in 23/40 and in the nucleus in 20/40 cases of osteosarcoma. Nuclear localization of survivin expression was significantly correlated with a prolonged survival (P=0.0347) but cytoplasmic staining showed no correlation with patient outcome. CONCLUSIONS: The results of this study indicates that the evaluation of survivin expression might be a useful prognostic marker in osteosarcoma. Patients with osteosarcoma exhibiting nuclear survivin expression could potentially benefit from stratification of neoadjuvant chemotherapy.     

Survivin p53蛋白在鼻NK/T淋巴瘤中的表达及其与细胞凋亡和预后的关系

目的:探讨Survivin、p53蛋白在鼻NK/T淋巴瘤中的表达及其与细胞凋亡和预后的关系。方法:应用TdT介导的dUTP缺口末端标记(TUNEL)技术和免疫组织化学链霉菌抗生物素蛋白-过氧化酶连接法(SP法),检测24例鼻NK/T淋巴瘤和17例良性淋巴结病变中细胞凋亡和Survivin、p53蛋白的表达水平。结果:Survivin、p53蛋白在鼻NK/T淋巴瘤表达的阳性率分别为45.8%(11/24)和62.5%(15/24);Survivin表达上调与p53高表达密切相关(P<0.05);凋亡指数与Survivin、p53蛋白明显呈负相关(P<0.005)。Survivin过表达者的平均生存时间明显短于阴性者(P=0.03),但p53表达和细胞凋亡指数与患者的预后无相关性(P>0.05)。结论:Survivin基因异常表达引起的凋亡抑制可能在鼻NK/T淋巴瘤的发生进展中有一定的作用,且与p53异常表达显著相关。Survivin表达可能是鼻NK/T淋巴瘤的一个新的预后不良因子。     

Benign tumors from the human nervous system express high levels of survivin and are resistant to spontaneous and radiation-induced apoptosis

Survivin, an inhibitor of apoptosis, is over-expressed in foetal tissues and human cancers, but it is almost undetectable in normal tissues. Here we have assessed the level of the survivin protein in some benign tumors of the nervous system: meningioma, schwannoma, low-grade ependymoma, pilocytic astrocytoma and pituitary adenoma. Using immuno-blot analysis we present evidence that these low-grade tumors are positive for survivin expression. In agreement, flow cytometrical analysis showed that both spontaneous and radiation-induced apoptosis levels are very low in these neoplasms. Using host cell reactivation assay we have also shown that these tumor cells are proficient in the repair of -ray-induced DNA damage. However, they are deficient in the removal of ultraviolet (UV) light-induced DNA photolesions, especially the shwannoma- and the pituitary adenoma-derived cells. These results suggest that survivin overexpression may be an early event in the stepwise tumoregenesis and hence could be responsible for the onset as well as the growth advantage during tumoregenic progression of malignant as well as benign neoplasms.     

Autoantibodies to the inhibitor of apoptosis protein survivin in patients with brain tumors

Survivin is a member of the inhibitor of apoptosis protein (IAP) family and is frequently expressed in cancers, including meningiomas and gliomas. Survivin may be associated with tumor progression and poor prognosis of patients with brain tumors. Using ELISA and immunoblot analysis we asked whether survivin is capable of eliciting a humoral immune response in patients with meningiomas and gliomas. Survivin-specific antibodies were detected in 5 of 42 (11.9%) patients with meningiomas and 3 of 35 (8.6%) patients with malignant gliomas of the WHO grades 3 and 4, but not in healthy controls. Tumors of patients with detectable anti-survivin antibodies demonstrated survivin expression in at least 20% of the tumor cells as assessed by immunohistochemistry. We conclude that patients with meningiomas and malignant gliomas can mount a high-titer IgG immune response against the 'universal' tumor-associated antigen survivin. Anti-survivin antibodies may represent attractive tools for diagnosis and follow-up of brain tumors.     

Mutations of the p53 Gene and Loss of Heterozygosity at Chromosome 17p13.1 are Associated with Increased Survivin Expression in Breast Cancer

Expression of survivin, a member of the inhibitor-of-apoptosis (IAP) family, is elevated in fetal tissues and in various human cancers originating in the breast, lung, prostate, colon, pancreas, and stomach. Since overexpression of the survivin gene has been linked to poor patient survival in several cancers, survivin may be an important prognostic marker. Mechanisms up-regulating survivin gene expression in cancer are poorly understood. Recently, wild-type p53 was found to repress expression of the survivin gene by binding to the survivin promoter, thereby inhibiting promoter activity. Further, loss of heterozygosity (LOH) at 17p13 distal to the p53 gene is associated with more aggressive behavior of breast cancers. We therefore tested the hypothesis that not only p53 gene mutation but also LOH at 17p13 can up-regulate survivin expression in breast cancer. Survivin mRNA expression was greater in cancers than in uninvolved tissues (p < 0.0001). Mutations of the p53 gene were detected in 5 of 25 tumors; higher survivin gene expression was evident in these. LOH at the D17S938 locus (17p13.1) was found in 10 of 25 tumors, and most of these also showed increased survivin gene expression. Thus expression of survivin may be regulated not only by p53 but additionally by a putative tumor suppressor gene located at 17p13 distal to the p53 gene.     

Survivin expression correlates with clinical stage,histological grade,invasive behavior and survival rate in endometrial carcinoma

Survivin is a new member of the inhibitor of apoptosis family of anti-apoptotic proteins. It has been reported that survivin is expressed during fetal development and in cancer tissues. Because suppression of apoptosis is important for carcinogenesis and tumor growth, we investigated the expression of survivin in human endometrial carcinomas. We analyzed serial frozen sections for survivin protein expression in 31 cases of endometrial carcinoma and 20 cases of normal endometria by fluorescent immunohistochemistry. We analyzed the relationship between the percentages of survivin-stained cells and the patient's characteristics, including clinical stage, histological grade, presence of invasion to >1/2 myometrium, clinical outcome, and survival rate. Survivin was weakly detected in some normal endometria in the proliferative phase (0-5.1%) and in the secretory phase (0-15.8%). There was, however, abundant survivin immunoreactivity in the nucleus and/or cytoplasm of the endometrial carcinoma cells. Scoring on the basis of the percentage of positive cells indicated that survivin expression was significantly associated with proliferating cell nuclear antigen-labeling index, clinical stage, histological grade, the presence of invasion to >1/2 myometrium, clinical outcome, and survival rate (P<0.01, respectively). We conclude that the survivin protein is a defining diagnostic marker for endometrial carcinomas that may also yield prognostic information.     

弥漫大B细胞淋巴瘤survivin和caspase-3表达的临床意义

目的探讨弥漫大B细胞淋巴瘤survivin、caspase-3表达与临床预后的关系。方法收集1997年至2000年间初治弥漫大B细胞淋巴瘤94例,用免疫组化SP法检测其survivin、caspase-3表达情况。应用SPSS10．0软件进行生存分析,并对各临床指标与预后的关系进行单因素和多因素分析。结果94例弥漫大B细胞淋巴瘤的survivin和caspase-3阳性表达率分别为68．1％和76．6％,其表达与国际预后指数（IPI）显著相关（P〈0．05）。survivin和caspase-3表达阳性患者的复发率高,survivin阳性患者的5年生存率（31．3％）明显低于survivin表达阴性患者（64．0％,P〈0．05）。多因素分析显示,survivin表达是弥漫大B细胞淋巴瘤的独立预后指标。结论survivin和caspase-3可作为弥漫大B细胞淋巴瘤的疗效和预后指标,与IPI结合可在早期筛选出常规治疗预后不良的病例,有助于指导临床治疗,改善预后。     

弥漫大B细胞淋巴瘤survivin表达与临床预后关系探讨

目的:探讨弥漫大B细胞淋巴瘤survivin表达与临床表现的关系。方法:收集本院自1997年至1999年的初治弥漫大B细胞淋巴瘤共63例,均接受治疗并进行随访。用免疫组化SP法检测其survivin表达情况。应用SPSS10.0软件行生存分析并对各临床指标与预后的关系进行单因素和多因素分析。结果:63例弥漫大B细胞淋巴瘤病例中有43例survivin表达阳性,阳性率为68.3%,其表达与性别、年龄、分期、结外病灶数目无明显相关关系,与PS、LDH、B症状、IPI显著相关(P<0.05)。其5年总生存率为50.04%。survivin表达阳性的弥漫大B淋巴瘤患者的总生存率明显低于survivin表达阴性患者(P=0.0001),二者的5年生存率分别为30.36%和90%。多因素分析显示,survivin表达是弥漫大B细胞淋巴瘤的独立预后指标。结论:survivin是弥漫大B细胞淋巴瘤的一个极有价值的预后指标,与IPI结合可于早期筛选出常规治疗预后不良的病例,有助于指导治疗及改善预后。