Survivin In Patients Research Articles

Survivin as a Novel Biomarker in the Pathogenesis of Acne Vulgaris and Its Correlation to Insulin-Like Growth Factor-I.

Survivin, a member of the inhibitor of apoptosis protein family, has an important role in cell cycle regulation. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone with wide range of biologic effects including stimulation of lipogenesis in sebaceous glands. Their overexpression in some fibrotic disorders suggests a possible implication of both IGF-I and survivin in the pathogenesis of acne and/or acne scars. The current study aimed to assess and correlate serum levels of IGF-I and survivin in patients with active acne vulgaris and postinflammatory acne scars and to evaluate their lesional expressions in comparison to healthy controls. Serum IGF-I and survivin were estimated using commercially available ELISA kits and their tissues expressions were investigated using Western blotting. Our findings suggest that IGF-I and survivin could play potential roles in the pathogenesis of active acne vulgaris and more importantly in postinflammatory acne scars with significant positive correlation coefficient between serum levels of IGF-I and survivin which support IGF-I-/PI3K-/AKT-mediated downregulation of nuclear expression of FoxO transcription factors resulting in enhanced survivin expression.

CD1a+ survivin+ dendritic cell infiltration in dermal lesions of systemic sclerosis.

IntroductionProto-oncogene survivin is a member of the inhibitor of apoptosis (IAP) family of proteins. The presence of serous antibodies against survivin in patients with systemic sclerosis has been previously reported; however, there are few reports regarding the pathophysiological relationship between survivin and systemic sclerosis. We herein investigated the expression and function of survivin in SSc patients.MethodsWe performed immunohistochemistry analyses to determine the expression of XIAP, cIAP and survivin in skin lesions from patients with SSc and non-SSc. The expression levels of survivin in peripheral blood mononuclear cells (PBMCs) obtained from SSc patients and healthy controls were evaluated using RT-PCR and flow cytometry. Additionally, the function of survivin was verified with overexpression experiments using monocyte-derived dendritic cells (Mo-DCs).ResultsThe expression patterns of both XIAP and cIAP were similar, while only the survivin expression differed between the SSc and non-SSc skin lesions. Survivin-overexpressing cells were detected in the SSc dermis frequently. The positive rate of survivin in SSc dermis (64.3 %, 9/14) was higher than that in non-SSc dermis (11.2 %, 1/9). Furthermore, survivin+ cells expressed CD1a, one of the DC markers. Real-time PCR and FACS analyses revealed that the survivin-WT (wild type) expression levels in PBMCs, in particular CD14+ monocytes, from SSc patients were higher than that from healthy controls. Additionally, the overexpression experiments showed that survivin-WT-overexpressing CD1a+ Mo-DCs have the characteristics of promoting cell cycle progression and decreasing apoptotic cells.ConclusionsThese findings suggest that dermal survivin+ CD1a+ cell infiltration may be a potential biomarker of SSc skin lesions. PBMCs and monocytes from SSc patients also overexpressed survivin; therefore, dermal survivin+ DC may be derived from peripheral blood monocytes. Additionally, survivin may be involved in dermal CD1a+ DC proliferation through cell cycle activation and resistance to apoptosis. Survivin may be an important molecule for the pathogenesis of SSc.

Clinical Utility of Altered Expressions of P53,Vascular Endothelial Growth Factor and Survivin in Patients with Bladder Cancer

Backgroundand Objectives: Bladder cancer is considered a major problem world wide. Aberrant P53, mutant vascular endothelial growth factor and deregulated expression of survivin were used as biochemical markers for investigation, prognosis and follow up. Aims: This study was conducted to assess the prognostic impact of altered expressions of these parameters in Erbil population with bladder cancer and correlated with other confounding factors age, gender and smoking effects, these factors also correlated with histopathologic characteristics such as grade and stage. Patients and Methods: This prospective study enrolled 50 newly diagnosed patients with bladder cancer, in addition 50 apparently healthy adults age – sex matched were also involved in this study. Serum parameters levels were measured using enzyme linked immunosorbent assay. Patients had these general criteria, newly discovered cases, no deep x-ray therapy, no chemotherapy, no hormonal therapy with histologic and cytologic confirmation of bladder cancer. Statistical Study: Data were analyzed using SPSS v. 18. Results: The mean serum P53,vascular endothelial growth factor and survivin levels in patient and control groups were P53= 1.682 ±0.665, 1.192 ± 0.284, vascular endothelial growth factor = 5.296 ±2.8, 2.000 ±0.704 and survivin = 5.468±0.715, 4.240±0.656 respectively. The statistical analysis revealed that, serum parameters levels were significantly increased in patients as compared with control group p< 0.001. Conclusion: Data revealed for the first time the relation between altered expressions of interested parameters in combination pattern with the incidence of bladder cancer in Erbil population, which has not previously reported in this region.This study tested the hypothesis and supported the concept that higher serum levels of these parameters might be a pathogenic and prognostic factors and a markers of tumor aggressiveness in bladder cancer. Early diagnosis is necessary for maximizing the rate of therapy. The gold standard care for the investigating of bladder cancer is cystoscopy which detects tumors accurately but it is invasive, expensive, and represents a high burden to the patients, and also, small papillary and flat-growing cancer may be missed. Regular cystoscopic examinations performed for monitoring the patients, because the recurrent rate is high. Therefore, this study was conducted to investigate the possibilities for replacing cystoscopy with more accurate, safe, no expensive, noninvasive diagnostic test and to recognize a new approach for providing opportunities for early detection which is an important goal to speed up the therapy of patients.

Expression of Survivin in Patients With Refractory Rheumatoid Arthritis in a Chinese Population

Results: The survivin level was significantly higher in the refractory group than healthy controls (270.04±23.03 pg/ml vs. 116.68±19.07 pg/ml, p<0.05) and treatment-responsive group (270.04±23.03 pg/ml vs. 127.37±11.42 pg/ml, p<0.05). The survivin level in refractory RA patients was positively correlated with the Disease Activity Score 28. Immunohistochemical analysis revealed that survivin expression was significantly higher in the synovial tissues of refractory RA patients compared to treatment-responsive patients and healthy controls. Conclusion: The results of this study showed that survivin is overexpressed in refractory RA patients and the serum survivin level is correlated with disease activity.

Expression of survivin in patients with acute myeloid leukemia

Objective of this study was to detect the expression of Survivin in acute myeloid leukemia (AML) and investigate the relationship of its expression levels with clinical variates and its correlations with BCL-2 ,Bcl-xL and MCL-1. The expression of Survivin, BCL-2, Bcl-xL and MCL-1 were measured by immunohistochemistry in bone marrow biopsy of 63 newly diagnosed AML patients, and the relationship between its expression level and clinical parameters (age, sex, WBC count, diagnosis, prognosis), especially fusion protein AML1/ETO was investigated. The results showed that the expression level of Survivin in newly diagnosed AML patients was higher than that of normal controls (P < 0.01), the expression levels of Survivin did not correlate with age, sex, and WBC counts of patients and so on. There was no significant difference of Survivin expression between different NCCN prognosis groups, either between patients with AML1/ETO or FLT3-ITD mutation and the other patients. Survivin positive patients were got to have lower CR rate but higher relapse rate, however that was not significant in statistics. Indeed, the cumulative survivin rate of Survivin positive patients were lower than that of Survivin negative patients (P = 0.04). Finally, positive correlation between Survivin and MCL-1 was also observed (r = 0.639, P = 0.000). It is concluded that overexpression of Survivin are closely related with occurrence and development of acute leukemia, and may be used as an indicator of prognosis evaluation. In addition, Survivin and MCL-1 may have a relationship of cooperation or interaction.

Role of survivin as prognostic and clinicopathological marker in gastric cancer: a meta-analysis

Survivin has been implicated as a potential prognostic marker in a wide range of malignant tumours. However, the prognostic impact of survivin in gastric cancer remains to be controversial and published data are sometimes heterogeneous. Thus, aim of this study was to review the literature by performing an electronical database search via PubMed and EMBASE to identify eligible studies that assessed the impact of survivin as prognostic marker and its association with clinicopathological variables. Database search until November 21st 2012 retrieved 20 studies comprising 2,695 gastric cancer patients that assessed expression of survivin by immunohistochemistry or RT-PCR analyses in gastric cancer specimens. Meta-analyses of clinicopathological variables revealed an association between the expression of survivin and the presence of lymph node metastases (pooled OR: 0.58; 95% CI 0.35-0.96). In addition, a correlation between the expression of survivin and overall survival for patients with gastric cancer (pooled HR 1.93; 95% CI 1.51-2.48) became evident. More importantly, we were able to exclude a severe heterogeneity (I(2)=31%) or publication bias for the survival analyses. Furthermore, one-way sensitivity analysis and subgroup analyses regarding the method used to detect survivin, the type of survival analysis, the study quality and whether information was provided regarding neoadjuvant therapy supported our initial results. In conclusion, this meta-analysis indicates the prognostic significance of survivin in patients with gastric cancer.

Prognostic value of survivin in patients with gastric cancer: a systematic review with meta-analysis.

ObjectiveThe prognostic significance of survivin for the survival of patients with gastric cancer remains controversial. Thus, the objective of this study was to conduct a systematic review of the literature evaluating survivin expression in gastric cancer as a prognostic indicator.MethodsRelevant literature was searched using PubMed, EMBASE, and Chinese biomedicine databases. A meta-analysis of the association between survivin expression and overall survival in patients with gastric cancer was performed. Studies were pooled and summary hazard ratios (HRs) were calculated. Subgroup analyses were also conducted.ResultsFinal analysis of 1365 patients from 16 eligible studies was performed. Combined HR suggested that survivin expression had an unfavorable impact on survival of gastric cancer patients (HR=1.39, 95% CI: 1.16-1.68). The unfavorable impact also appeared significant when stratified according to the studies categorized by patients’ ethnicity, detection methods, type of sample, and HR estimate. The combined HR in the English literature showed an inverse effect on survival (HR=1.40, 95% CI: 1.13-1.75), while HR in the non-English literature did not (HR=1.38, 95% CI: 0.93-2.05). When stratified according to the location of survivin expression, combined HR showed that expression in cytoplasm was significantly associated with poor prognosis of gastric cancer patients (HR=1.46, 95% CI: 1.12-1.90). While expression in nucleus was not significantly associated with poor prognosis (HR=1.29, 95% CI: 0.72-2.31), the heterogeneity was highly significant (chi-squared=11.5, I2=74%, p=0.009).ConclusionsThis study showed that survivin expression was associated with a poor prognosis in patients with gastric cancer. Cytoplasmic expression of survivin may be regarded as a prognostic factor for gastric cancer patients. In contrast, survivin expression in nucleus did not have a significant impact on patients’ overall survival.

Prognostic and Clinicopathological Significance of Survivin in Colorectal Cancer: A Meta-Analysis

Survivin/BIRC5 is a potentially interesting prognostic marker and therapeutic target in colorectal cancer (CRC). However, the available data on survivin expression in CRC are heterogeneous. Thus, to clarify the prognostic relevance of survivin in patients with CRC and its association with clinicopathological parameters we performed a meta-analysis. We screened PubMed and EMBASE for those studies that investigated the prognostic value of survivin and its association with clinicopathological parameters in CRC. Data from eligible studies were extracted and included into the meta-analyses using a random effects model. Electronical literature search identified 15 studies including 1934 patients with CRC mostly detecting survivin by immunohistochemistry (IHC). Pooled hazard ratios of 11 studies that performed survival analysis revealed a positive correlation between survivin expression and poor prognosis (HR 1.93; 95% CI: 1.55–2.42; P<0.00001; I2 = 23%). Subgroup analyses with respect to the detection method, HR estimation, global quality score and the country of origin in which the study was conducted supported the stability of this observation. In addition, meta-analyses revealed a significant association between expression of survivin and the presence of lymph node metastases (OR: 0.37; 95% CI: 0.19–0.75; I2 = 61%) or blood vessel invasion (OR: 0.50; 95% CI: 0.28–0.90; I2 = 0%). Expression of survivin indicates poor prognosis and a pro-metastatic phenotype and may be useful in identifying a subgroup of patients that could benefit from a targeted therapy against survivin in CRC.

Detection Level of Salivary Survivin in Patients with OSCC

Abstract Introduction: Survivin is a member of the Inhibitor of Apoptosis (IAP) proteins family, broadly expressed in most solid and haematological malignancies, but almost undetectable in normal adult tissues. Regarding Oral Squamous Cell Carcinoma (OSCC), Survivin expression seems to be correlated with aggressive phenotype and unfavorable outcome. In this work, the effectiveness of Survivin detection in saliva samples as diagnostic tool was investigated. Methods: 55 saliva samples from patients with histological diagnosis of OSCC and 30 samples from healthy controls matched for age and gender were collected. All samples from OSCC were collected before therapy. Saliva was analyzed using Assay Designs human Total Survivin TiterZyme® Enzyme Immunometric Assay (EIA) kit for Survivin detection and quantification. Survivin concentration (pg/ml) was studied in relationship to clinical data. Univariate statistical analysis was performed. Results: 35/55 (63.6%) among OSCC patients were found to be positive for surviving expression in saliva vs 12/30 (40%) among health controls; but the mean value was found to be higher in OSCC group (8,69 pg/ml ± 10,15 vs 2.44 pg/ml ± 4.22) reaching statistical significance (p<0.05). Moreover, samples from patients at an early stage (I+II) displayed a lower content of salivary Survivin than those at advanced stage (III+IV) (7.09 pg/ml ± 8.59 vs 8.13 pg/ml ± 10.94). In addition, cases characterized by lymph node metastasis showed a higher surviving concentration (9.38 pg/ml ± 11.26) than cases without metastasis (5.77 pg/ml ± 8.21). Discussion: Salivary Survivin seems to be an interesting biomarker for OSCC, but its use as a single marker may be not sufficient for the early diagnosis of OSCC

Lower Levels of Survivin in Patients with Leukemic Low Grade B-Cell Lymphomas Expressing LMP1 Oncoprotein of Epstein-Barr Virus

AbstractAbstract 1560 BackgroundEpstein-Barr virus (EBV) is a ubiquitous pathogen that chronically infects B lymphocytes and is implicated in the pathogenesis of lymphoproliferative diseases. Latent membrane protein 1 (LMP1), the major oncoprotein of the virus, has been shown to inhibit apoptosis and trigger survivin expression in malignant cell lines. Although EBV has not been implicated in the pathogenesis of low grade B-cell lymphomas, LMP1-mRNA has been detected in a significant proportion of patients with chronic lymphocytic leukemia (CLL). LMP1 is known for its antiapoptotic properties, but recent data show that LMP1 can simultaneously induce and inhibit apoptosis in B-cells. These opposite functions of LMP1 have not been studied in patients with low grade B-cell lymphomas. ObjectivesOur objectives were to detect LMP1-mRNA in patients with leukemic low grade B-cell lymphomas ant to investigate the postulated apoptotic properties of the protein, by correlating its expression to survivin levels. Patients and MethodsPeripheral whole blood from 64 patients with leukemic low grade B-cell lymphomas was tested by qRT-PCR for the presence of BXLF-1 gene of EBV. The patients' characteristics are shown in table 1. All positive samples were tested by conventional PCR for LMP1-mRNA. Subsequently, survivin m-RNA levels were measured by qRT-PCR in all samples and compared between LMP1 positive and negative patients (Mann-Whitney U Test). ResultsThe BXLF-1 gene was detected in 27/64 (42.1%) patients. LMP1-mRNA was detected in 23/64 (35.9%) patients and in 23/27 (85.2%) EBV-positive patients. Among CLL patients, LMP1-mRNA was detected in 19/44 (43.2%). Finally, surviving-mRNA levels were found to be 8.37 times higher in EBV-negative vs EBV-positive patients, (p=0.002) and 7.19 times higher in LMP1-negative vs LMP1-positive patients (p=0.009). The results are reported in detail in Table 1. DiscussionData from this year's studies suggest that LMP1 may exert both antiapoptotic and apoptotic functions. While the carboxy-terminal domain of LMP1 drives the proliferation and survival of EBV-infected B cells in vitro and in vivo, LMP1 may activate, through its amino-terminal six-transmembrane domains (6TM), the transmembrane receptor proteins PERK, ATF6 and IRE-1, leading to unfolded protein response (UPR) induction. UPR is a cellular stress response that promotes apoptosis. In different environments, LMP1 signaling may show differences regarding its apoptotic effects on B lymphocytes.In our study, we detected LMP1-mRNA in 43.2% of CLL patients, a proportion significantly higher than previously reported (14%). Moreover, for the first time, LMP1-mRNA was detected in patients with other than CLL low grade B-cell lymphomas (Table 1).In patients with leukemic low grade B-cell lymphomas, in the pathogenesis of which EBV is not causally implicated, LMP1 may have apoptotic instead of anti-apoptotic properties, as evidenced by the lower survivin m-RNA levels in LMP1-positive patients. This finding deserves further investigation, in order to reveal the clinical significance of the different functions of LMP1 in non-EBV related lymphomas.Table 1Patients' characteristics and resultsCharacteristicAll patientsEBV(+)1EBV(−)1P*No of Subjects, N (%)64 (100%)27 (42.2)37 (57.8)Age, Mean (range)68.2 (44–82)67.9 (44–82)69.2 (56–79)0.701Male to female ratio1.131.440.950.442Lymphoproliferative disease0.164Chronic lymphocytic leukemia, N (%)44 (68.8)20 (74.1)24 (64.9)Splenic marginal zone lymphoma, N (%)11 (17,2)2 (7.4)9 (24.3)Mantle cell lymphoma, N (%)5 (7,8)3 (11.1)2 (5.4)Hairy cell leukemia, N (%)2 (3.1)1 (3.7)1 (2.7)Follicular lymphoma, N (%)2 (3,1)1 (3.7)1 (2.7)Previous treatment, N (%)15 (23.4)6 (22.2)9 (24.3)0.847Viral load, copies/ml (range)NA2164.2 (79–15600)NANAMeasurable LMP1-mRNA, N (%)23 (35.9)23 (85.2)0 (0)NASurvivin levels211.171.330.001*p for group differences.1EBV(+), EBV(−) are used to indicate positivity for the BXLF-1 gene of EBV by PCR.2Relative gene expression between positive and negative blood samples was calculated by using the 2-delta-CT method. Disclosures:No relevant conflicts of interest to declare.

TFF3 and survivin expressions associate with a lower survival rate in gastric cancer

Trefoil factor 3 (TFF3) and survivin with functions of inhibiting apoptosis are involved in the gastric cancer by overexpression. The purpose of this study is to examine the expression of TFF3 and survivin in patients' tissue samples with gastric cancer and analyze the relationship between the protein expression and the different clinical records. By studying the expressions of TFF3 and survivin in gastric cancer through immunohistochemical staining and examining the survival rate via Kaplan-Meier analysis for gastric cancer patients, we found that the TFF3 and survivin positive expressions have a significant relationship with the lower survival rate comparing to that of negative expressions in the analyzed patients (P<0.05). And moreover, patients with double positive TFF3 and survivin expressions have the lowest survival rate. TFF3 or survivin positive expression correlates with the lymph node metastasis, metastasis, and TNM stages of gastric cancer. Survival analysis indicates that survival rate has a close relationship with the age, tumor histology, tumor differentiation, degree of infiltration, lymph node metastasis, distant metastasis, and TNM stages (P<0.01). Our data suggest that TFF3 and survivin expressions play a vital role in gastric cancer development, and these two proteins are important markers for prognosis in gastric cancer. Patients with gastric cancer can increase the survival rate through an earlier diagnosis and appropriate treatment.

979P - Predictive and Prognostic Role of Survivin and P53 Expression in Patients with Advanced Ovarian Cancer Treated with Neoadjuvant Chemotherapy

ABSTRACT Background Qualification of patients with advanced ovarian cancer (AOC) to treatment with primary or interval debulking surgery (IDS) is the subject of controversy. The aim of this study was to assess the expressions of selected proteins of apoptosis to the effects of neoadjuvant chemotherapy (NAC) in patients with AOC. Material and methods We evaluated 60 consecutive patients with AOS (FIGO stage IIIC-IV) treated with NAC, retrospectively. Formalin-fixed, paraffin-embedded tissue specimens were immunohistochemically stained for expression of p53 and survivin in patients given platinum-based NAC undergoing IDS. The expression of survivin was adopted dichotomization by the median expression of the protein found total score (TS) equals 2. For low expression of survivin was TS ≤ 2, while high total score TS> 2 The positive and negative expression of p53 were used to dichotomization study group. Results Median age of 60 patients was 60 years. The optimal IDS was achieved in 69.1% (38/55). We observed significant difference in the percentage of stained nuclei (PS, p = 0.0002), the intensity of staining (IS, p = 0.0003) and TS (p = 0.0001) by comparing the expression of survivin in tumor tissue taken before and after NAC. The expression of p53 in tumor tissue before and after NAC was observed and significant difference was in PS, (p = 0.0424). There were no statistically significant difference in IS and the TS. Expression of survivin and p53 was not related to the results of IDS. Survivin expression was a prognostic factor in AOC patients treated with NAC (p = 0.0484). Expression of survivin and p53 proteins was not a predictor factor in AOC patients. Adverse factors affecting the PFS for AOC patients treated with NAC were: lack of optimal IDS and the lack of an objective response by RECIST criteria (respectively HR was 3.93 (95% CI, 2.07-7.46, p Conclusions High expression of survivin is a useful prognostic factor in patients treated with neoadjuvant chemotherapy for advanced ovarian cancer. This effect is more significant in patients with positive expression of p53. Disclosure All authors have declared no conflicts of interest.

Functional T Cells Targeting NY-ESO-1 or Melan-A Are Predictive for Survival of Patients With Distant Melanoma Metastasis

To analyze the prognostic relevance of circulating T cells responding to NY-ESO-1, Melan-A, MAGE-3, and survivin in patients with melanoma with distant metastasis. We examined 84 patients with follow-up after analysis (cohort A), 18 long-term survivors with an extraordinarily favorable course of disease before analysis (> 24 months survival after first occurrence of distant metastases; cohort B), and 14 healthy controls. Circulating antigen-reactive T cells were characterized by intracellular cytokine staining after in vitro stimulation. In cohort A patients, the presence of T cells responding to peptides from NY-ESO-1, Melan-A, or MAGE-3 and the M category according to the American Joint Committee on Cancer classification were significantly associated with survival. T cells responding to NY-ESO-1 and Melan-A (hazard ratios, 0.29 and 0.18, respectively) remained independent prognostic factors in Cox regression analysis and were superior to the M category in predicting outcome. Median survival of patients possessing T cells responding to NY-ESO-1, Melan-A, or both was 21 months, compared with 6 months for all others. NY-ESO-1-responsive T cells were detected in 70% of cohort A patients surviving > 18 months and in 50% of cohort B patients. Melan-A responses were found in 42% and 47% of patients in cohorts A and B, respectively. In contrast, the proportion was only 22% for NY-ESO-1 and 23% for Melan-A in those who died within 6 months. The presence of circulating T cells responding to Melan-A or NY-ESO-1 had strong independent prognostic impact on survival in advanced melanoma. Our findings support the therapeutic relevance of Melan-A and NY-ESO-1 as targets for immunotherapy.

Prognostic Value of Survivin in Patients with Non-Small Cell Lung Carcinoma: A Systematic Review with Meta-Analysis

PurposeThe potential prognostic value of survivin in resected non-small cell lung carcinoma (NSCLC) is variably reported. The objective of this study was to conduct a systematic review of literatures evaluating survivin expression in resected NSCLC as a prognostic indicator.MethodsRelevant literatures were identified using PubMed, EMBASE and Chinese Biomedicine Databases. We present the results of a meta-analysis of the association between survivin expression and overall survival (OS) in NSCLC patients. Studies were pooled and summary hazard ratios (HR) were calculated. Subgroup analyses and publication bias were also conducted.ResultsWe performed a final analysis of 2703 patients from 28 evaluable studies. Combined HRs suggested that survivin overexpression had an unfavorable impact on NSCLC patients' survival with no evidence of any significant publication bias (HR = 2.03, 95%CI: 1.78–2.33, Egger's test, P = 0.24) and no severe heterogeneity between studies (I2 = 26.9%). Its effect also appeared significant when stratified according to the studies categorized by histological type, HR estimate, patient race, cutoff point (5%, 10%), detection methods and literature written language except for disease stage. Survivin was identified as a prognostic marker of advanced-stage NSCLC (HR = 1.93, 95%CI: 1.49-2.51), but not early-stage NSCLC (HR = 1.97, 95%CI: 0.76-5.14), in spite of the combined data being relatively small.ConclusionThis study shows that survivin expression appears to be a pejorative prognostic factor in terms of overall survival in surgically treated NSCLC. Large prospective studies are now needed to confirm the clinical utility of survivin as an independent prognostic marker.

Cathepsin E, Maspin, Plk1, and Survivin Are Promising Prognostic Protein Markers for Progression in Non-Muscle Invasive Bladder Cancer

Bladder cancer is a common cancer with particularly high recurrence after transurethral resection. In this study, we investigated the prognostic value of the protein expression of cathepsin E, maspin, polo-like kinase 1 (Plk1), and survivin in patients with stage Ta and T1 urothelial carcinomas. Transcripts from the four genes encoding these proteins were previously included in gene expression signatures for outcome prediction for Ta/T1 bladder cancer. We used three different tissue microarrays with 693 non-muscle invasive urothelial carcinomas from Danish, Swedish, and Spanish patient cohorts with long-term follow-up. Protein expression was measured by immunohistochemistry, and antibody specificity was validated by Western blotting. In the Danish patient cohort, we found the expression of cathepsin E, maspin, Plk1, and survivin to be significantly associated with progression to stage T2 to T4 bladder cancer (for each marker: log-rank test; P < 0.001). Multivariate Cox regression analysis identified cathepsin E (P < 0.001), Plk1 (P = 0.021), maspin (P = 0.001), and survivin (P = 0.001) as independent prognostic markers. Furthermore, maspin, survivin, and cathepsin E expression significantly subgrouped patients already stratified by European Organization for Research and Treatment of Cancer risk scores. Finally, we successfully validated the results in tumors from 410 patients from both Sweden and Spain. We conclude that all four protein markers may have prognostic value in non-muscle invasive bladder cancer for guiding optimal treatment of patients. Additional prospective studies are needed for further validation of the clinical relevance of this marker panel.

Survivin: A Potential Target of Adoptive Immunotherapy for Pediatric Sarcomas (101.19)

Abstract Cell based immunity is driven by CD8+ cytotoxic T cells bearing TCR that recognize specific tumor-associated peptides bound to class I MHC molecules. Survivin, an inhibitor of apoptosis protein (IAP), is a tumor-associated antigen that is widely expressed in nearly all human cancer cells and undetectable in most normal tissues. Although there is evidence for cytotoxic T cell responses against survivin in patients, tolerance to self antigens can be a limiting factor in generating highly avid T cells capable of killing tumor cells. An alternate approach involves peptide immunization of HLA-A2 transgenic mice that express the human class I HLA-A2 molecule, which could in principle generate more highly avid TCRs to human antigens. In this study, we vaccinated A2 transgenic mice with a modified survivin epitope, Surv96M (LMLGEFLKL) and successfully generated CD8+ CTL clones that react against Survivin96-104 and a human pancreatic cancer line. The α- and β- chains for the TCR of reactive CTLs were cloned and inserted into an retrovirus vector incorporating 2A linker peptides between coding sequences of α- and β- chains of TCRs against survivin. Transduction of survivin specific TCR retrovirus constructs into human PBMCs yielded up to 70% TCR redirected lymphocytes and specific effector function as measured by IFNgamma release following co-culture with peptide-pulsed targets and one A2+ pediatric osteosarcoma line. Ongoing work is underway to increase the TCR affinity to potency.

Correlation between anti-survivin antibody and survivin mRNA expression in head and neck cancer patients

Conclusions: Survivin may act as a major cancer antigen in head and neck cancer, and the present study revealed a link between systemic anti-survivin antibody responses and survivin expression in cancer tissues in patients with head and neck cancer. Objectives: Survivin is highly expressed in cancer cells, but is expressed at low levels or not at all in normal tissues. Little is known about the relationship between survivin expression and antibody responses to survivin in patients with head and neck cancer. Methods: Anti-survivin antibody responses in sera of head and neck cancer patients were investigated by enzyme-linked immunosorbent assay. The expression of survivin mRNA in the cancer tissues from larynx and hypopharynx was examined by quantitative RT-PCR. Results: Sera from 42 of 55 patients (76.4%) were positive for anti-survivin. High levels of anti-survivin were detected in patients in the advanced stage of disease. Most cancer tissues, but not normal adjacent tissues, expressed survivin mRNA, and a significant correlation between the levels of anti-survivin antibody in the serum and survivin mRNA in cancer tissues was detected.

Expression of Survivin protein in extrahepatic cholangiocarcinoma and its relationship with the prognosis

To investigate the expression of Survivin in patients with extrahepatic cholangiocarcinoma (EHCC) and its relationship with clinicopathological features of EHCC, and the correlation between the expression of Survivin and lymph node micrometastasis, tumor markers, and the prognosis of EHCC. The expression of Survivin protein in paraffin-embedded specimens of 59 patients with EHCC and their 20 para-carcinoma tissues were evaluated by S-P method of immunohistochemical staining. The correlation between the expression of Survivin and the lymph node micrometastasis, clinicopathological features of EHCC and the prognosis of EHCC were analyzed. The positive expression rate of Survivin protein was 67.8% (40/59) in paraffin-embedded specimens of 59 patients with EHCC and was 20.0% (4/20) in para-carcinoma tissues, and difference between carcinoma tissues and para-carcinoma tissues was significant (P<0.01). Histological differentiation in EHCC had a negative correlation with the expression of Survivin protein, while the expression of Survivin protein in EHCC had a positive correlation with TNM of EHCC, lymphatic vessel infiltration, lymph node metastasis and perineural invasion (P<0.05). The serum CA19-9 levels in the positive group with expression of Survivin protein was (290,300+/-55 500) U/L and was obviously higher than that in the negative group [(113,300+/-31,400) U/L, P<0.05]. The mean survival time of the patients with negative expression of Survivin protein was higher than that of the patients with positive expression (43.5 vs. 21.1 months, P<0.01). Screened to significance univariate, the multivariate analysis through Cox proportional hazard model analysis showed that lymph node metastasis, residual tumor margins, and expression of Survivin protein were independent prognosis factors of the patients with EHCC (P<0.05, P<0.01, P<0.01). The expression of Survivin protein in EHCC has a negative correlation with histological differentiation, while has a positive correlation with lymphatic vessel infiltration and serum CA19-9 concentrations. The expression of Survivin protein maybe an independent prognosis factor of the patients with EHCC.

Triple-negative breast cancer: immunohistochemical correlation with basaloid markers and prognostic value of survivin

Among the subgroups of breast cancer, basaloid type has the shortest disease-free survival. Survivin is an apoptosis inhibitor and its prognostic and predictive value in breast cancer is under investigation. In this study, we examined the basaloid markers CK5/6, CK14, CK17, and EGFR in triplet-negative patients and evaluated the impact of survivin on survival. Thirty patients with breast cancer in triplet-negative form admitted to Erciyes University Medical Oncology Department between 2001 and 2005 were included in the study. Median follow up and age were 45 months (range 5-76 months) and 47 years (range 23-76), respectively. Eighteen patients (60%) were premenopausal and 12 (40%) were postmenopausal. In total, 2, 12, and 14 patients had stage I, II, and III disease, respectively. When cytokeratines and survivin were analyzed independently, association between CK5/6 positivity and lymph node involvement was statistically significant (P = 0.014). In 70% of patients, CK5/6 or EGFR was found positive, and positive results were only had statistically significant correlation with age and menopausal status (P = 0.049 and 0.049, respectively). Ten patients (33.3%) totally and nine patients (42.8%) in the basaloid subgroup had positive staining for survivin. Survivin was not correlated with any of the clinical or histopathological features. While correlation between the number of involved lymph nodes, lymphovascular invasion, histopathological grade, and disease-free survival was statistically significant (P = 0.036, 0.002, and 0.035, respectively), this is not valid for CK5/6, EGFR, and survivin. CK5/6 or EGFR was accepted as determinants of basaloid breast cancer. The correlation between basaloid form and other histopathological markers did not reveal any significant difference with respect to prognostic and clinical parameters. We were unable to demonstrate the prognostic impact of survivin in patients with basaloid form or triplet-negative breast cancer.

Changes of activated circulating endothelial cells and survivin in patients with non-small cell lung cancer after antiangiogenesis therapy

Although antiangiogenesis therapy plays an important role in anti-neoplastic treatment with its recognized efficacy and slight adverse effect, there is no prospective clinical trial to define ideal markers for predicting efficacy of antiangiogenic therapy. This study was undertaken to investigate the changes of activated circulating endothelial cells (aCECs) and survivin after anti-angiogenesis therapy and their significance in predicting the efficacy of the therapy. Patients of non-small cell lung cancer (NSCLC) treated with chemotherapy with or without Endostar were observed. The amount of activated CECs was detected by flow cytometry, and the expression of survivin mRNA was determined by real-time polymerase chain reaction (PCR). After treatment, the amount of activated CECs decreased significantly in clinical benefit cases (P = 0.021 in chemotherapy alone, P = 0.001 in chemotherapy plus Endostar), increased in disease progressive cases (P = 0.015 in chemotherapy alone, but P = 0.293 in chemotherapy with Endotatar). After therapy, the expression of survivin mRNA decreased in clinical benefit cases (P = 0.001) and increased in disease progressive cases (P = 0.018). A positive correlation was found between activated CECs and survivin in the chemotherapy group pre- and post-therapy (P = 0.001 and 0.021, respectively), but only in the chemotherapy with Endostar group pre-therapy (P = 0.030) rather than post-therapy. A positive correlation was found between the decreased activated CECs after therapy and time to progression (TTP) (r = 0.322, P = 0.012); a negative correlation was found between the amount of survivin mRNA in serum post-therapy and TTP (r = -0.291, P = 0.048). Activated CECs and survivin may be ideal markers forecasting efficacy and prognosis of NSCLC. The former can reflect more sensitively antiangiogenic efficacy and the latter is more sensitive to shrinkage or swelling of tumors. Their combination can evaluate more accurately the efficacy of antiangiogenic therapy of NSCLC.