Comparison of HIF-1α and survivin levels in patients with diabetes and retinopathy of varying severity.

PURPOSE: This study measured serum hypoxia--inducible factor-1 (HIF-1α) and survivin levels in patients with diabetes and investigated their association with the severity of retinopathy. METHODS: This study included 88 patients with type 2 diabetes mellitus who underwent routine eye examinations. Three groups were created. Group 1 consisted of patients without diabetic retinopathy. Group 2 included patients with non-proliferative diabetic retinopathy. Group 3 included patients with proliferative diabetic retinopathy. To measure serum HIF-1α and survivin levels, venous blood samples were collected from patients. RESULTS: The mean HIF-1α levels in groups 1, 2, and 3 were 17.30 ± 2.19, 17.79 ± 2.34, and 14.19 ± 2.94 pg/ml, respectively. Significant differences were detected between groups 1 and 3 (p=0.01) and between groups 2 and 3 (p=0.01). The mean survivin levels in groups 1, 2, and 3 were 42.65 ± 5.37, 54.92 ± 5.55, and 37.46 ± 8.09 pg/ml, respectively. A significant difference was only detected between groups 2 and 3 (p=0.002). CONCLUSION: The present study revealed that serum HIF-1α and survivin levels are increased in patients with non-proliferative diabetic retinopathy compared to those in patients without diabetic retinopathy.

Dynamic relationship between postoperative infection and CRP, IL-6, and Livin in patients with bone tumors.

BACKGROUND: The objective of the present study was to investigate the dynamic relationship between postoperative infection and levels of CRP, IL-6, and Livin in patients with bone tumors. METHODS: A total of 126 patients with bone tumors admitted to our hospital from November 2013 to October 2015 were randomly selected and retrospectively analyzed. According to whether postoperative infection occurred, patients were divided into the infected group (N.=52) and the non-infected group (N.=74). Before surgery, and on the 1st, 3rd, 5th, 7th, and 10th day after surgery, the levels of serum CRP and IL-6 of patients in both groups were compared; the relative expression levels of Livin protein of patients in both groups were measured by Western blot. RESULTS: After surgery, the levels of CRP and IL-6 of patients in both groups at all time points were significantly higher than those before surgery and the levels of CRP and IL-6 of the infected group were significantly higher than those of the non-infected group (P<0.05). The levels of CRP and IL-6 reached a peak on the 3rd day after surgery, and CRP declined rapidly. The levels of IL-6 declined slowly. On the 10th day after surgery, the levels of IL-6 of patients in both groups were higher than those before surgery and the levels of IL-6 of patients in the infected group were higher than those of the control group (P<0.05). The levels of Livin protein in patients of both groups were not significantly different (P>0.05). CONCLUSIONS: The increase of the levels of CRP and IL-6 are closely related to infection. Livin has no close relationship with the occurrence of infection.

A scavenging system against internal pathogens promoted by the circulating protein apoptosis inhibitor of macrophage (AIM).

An internal system designed to ward off and remove unnecessary or hazardous materials is intrinsic to animals. In addition to exogenous pathogens, a number of self-molecules, such as apoptotic or necrotic dead cells, their debris, and the oxides or peroxides of their cellular components, are recognized as extraneous substances. It is essential to eliminate these internal pathogens as quickly as possible because their accumulation can cause chronic inflammation as well as autoimmune responses, possibly leading to onset or progression of certain diseases. Apoptosis inhibitor of macrophage (AIM, also called CD5L) is a circulating protein that is a member of the scavenger receptor cysteine-rich superfamily, and we recently found that during acute kidney injury, AIM associates with intraluminal dead cell debris accumulated in renal proximal tubules and enhances clearance of luminal obstructions, thereby facilitating repair. Thus, AIM acts as a marker for phagocytes so that they can efficiently recognize and engulf the debris as their targets. In this chapter, we give an overview of the professional and non-professional phagocytes, and how soluble scavenging molecules such as AIM contribute to improvement of diseases by stimulating phagocytic activity.

Investigation of Survivin Gene Polymorphism and Serum Survivin Levels in Patients with Brain Tumors.

BACKGROUND/AIM: The single nucleotide polymorphism -31C/G identified in the survivin gene promoter seems to be associated with over-expression of survivin, an anti-apoptotic protein. In gliomas, increased survivin expression correlated with decreased survival. The aim of the study was to investigate whether survivin gene polymorphism associates with benign and malignant brain tumors and whether it affects survivin serum levels. PATIENTS AND METHODS: Survivin polymorphism -31C>G was genotyped in 82 patients with brain tumors and 65 healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and survivin levels were evaluated by enzyme-linked immuno sorbent assay (ELISA) in patients and controls. RESULTS: Serum survivin levels in patients with malignant tumors were higher than patients with benign tumors (p<0.001). Survivin levels in patients with malignant glial tumors and the frequency of the GG genotype were higher than in patients with benign tumors (p=0.04) and controls (p=0.05). The prevelance of the survivin gene promoter polymorphism -31C>G did not differ between patients and controls. CONCLUSION: Survivin promoter -31C>G gene polymorphism seems to be associated with serum survivin levels in brain tumors of different grades and histologies.

The value of serum survivin level in early diagnosis of cancer.

OBJECTIVE: Survivin is one of the apoptosis inhibitor proteins, and it plays a key role in tumor angiogenesis and cancer progression. This study was conducted to investigate the serum level of survivin to determine its diagnostic value in cancer patients. MATERIALS AND METHODS: Blood samples were taken from cancer patients (n = 67) prior to surgery or chemo/radiotherapy and age-matched healthy volunteers (n = 23). The serum levels of survivin were analyzed by enzyme-linked immunosorbent assays. The difference in serum levels between patients and control was evaluated by using statistical methods. Correlation between the serum levels of survivin and clinicopathological features of cancer patients were also evaluated. RESULTS: The diagnoses of patients were breast cancer (49.3%), colon cancer (25.4%), ovarian cancer (14.9%), and other cancers (10.4%). Serum survivin levels were significantly higher in cancer patients than healthy subjects (196.23 pg/ml vs. 117.73 pg/ml, respectively, P = 0.019). No significant relations were found between serum survivin level and demographic characteristics of cancer. The optimal cut-off value of serum survivin was determined at >120.8 pg/ml, and its serum levels above this cut-off value were associated with 4.198 times increased risk of cancer. CONCLUSION: Our study results may suggest that high serum survivin levels can show 4 times increased risk of cancer in a subject with a high suspicion of cancer. Furthermore, survivin level was not influenced with demographic characteristics of breast, gastric, colorectal, prostate, ovarian cancer, and glioblastome multiforme.

Detection of survivin expression in bladder cancer and renal cell carcinoma using specific monoclonal antibodies.

Survivin, which is highly expressed in the majority of tumors, but not in most normal adult tissues, has been identified to have significant clinical applications. In the present study, using survivin­specific monoclonal antibodies (mAbs), we aimed to establish methods for detecting the expression of survivin in cancer cell lines, serum samples, urine samples and cancer tissues from patients with bladder cancer (BCa) and renal cell carcinoma (RCC), and to evaluate the efficacy of survivin as a tumor marker in the surveillance of BCa and RCC. First, mAbs were labeled with horseradish peroxidase (HRP), and a sandwich enzyme­linked immunosorbent assay (ELISA) with mAbs and HRP­conjugated mAbs was developed to detect survivin expression in serum and urine samples from BCa and RCC patients, with samples from healthy controls (HCs) used for comparison. The HRP­conjugated mAbs were also used to detect survivin expression in cancer cell lines by western blotting. Survivin expression in cancer tissues from BCa patients was also evaluated by immunohistochemistry. The results showed that the sandwich ELISA was successfully established, and significantly higher expression of survivin was subsequently detected in BCa and RCC patients as compared with HCs in both urinary and serum samples (P<0.05), and was more pronounced in urine. The HRP­mAbs could recognize survivin in cancer cell lines. Western blotting and immunohistochemistry results confirmed survivin expression in the 5637 BCa cell line, as well as BCa tissues. In addition, the expressions of survivin in BCa tissues, urine and serum were consistent in our study. In conclusion, the sandwich ELISA successfully established in the present study was of high sensitivity and specificity in the detection of survivin expression. The results also indicated that survivin is a potential tumor marker for the surveillance of BCa and RCC.

Is serum survivin expression a predictive biomarker in locally advanced gastric cancer patients treated with neoadjuvant chemotherapy?

BACKGROUND: The potential prognostic value of survivin is variably reported depending on the gastric cancer. OBJECTIVE: Evaluation of the prognostic and predictive significance of serum survivin and its relation with survival and treatment response rates in patients with locally advanced gastric cancer (LAGC). METHODS: Serum samples were prospectively collected from 50 patients with newly diagnosed LAGC. Serum samples of 32 healthy subjects were also collected as control groups for survivin levels. Serum survivin levels were evaluated at baseline and after three cycles of neoadjuvant chemotherapy in LAGC patients. RESULTS: Median survivin level was 147 IU/L (range = 4.4-4936) at baseline and was 27 IU/L (range = 4.2-4737) after neoadjuvant chemotherapy. The difference between survivin levels of the control group (26 IU/L, range = 3.8-1430) and pre-treatment patient group was statistically significant (p< 0.001). Clinical response to mDCF regimen was classified as progressive (progressive disease) and non-progressive groups (partial response + stable disease). Baseline survivin levels were similar between patients in progressive and non-progressive groups (p= 0.55). Survivin levels were significantly reduced after chemotherapy in non-progressive group (p< 0.001). In contrast, serum survivin levels increased in a stepwise fashion from baseline to post-chemotherapy in patients with progressive disease (p= 0.06). Patients were divided into low and high survivin groups according to baseline median survivin levels. Median DFS was 12.4 and 14.6 months for low and high groups, respectively (p= 0.18). Moreover, median OS was 14.4 and 24.9 months for low and high group, respectively (p= 0.14). CONCLUSION: It can be suggested that serum survivin can be used as a predictor of response to chemotherapy- but not survival- in LAGC patients receiving neoadjuvant mDCF chemotherapy. However, large multicenter prospective studies are required to confirm these results.

Serum interleukin-6 and survivin levels predict clinical response to etanercept treatment in patients with established rheumatoid arthritis.

OBJECTIVES: To investigate the correlation of nine potential biomarkers with clinical response to etanercept (ETN) therapy in establish rheumatoid arthritis (RA) patients. METHODS: Seventy-three patients with established RA were enrolled in the prospective cohort study. Sixty-nine of 73 cases were included into final analysis for response after 24-week ETN therapy. Serum expression of nine studied proteins was measured by enzyme-linked immunosorbent assay (ELISA). Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-17A, IL-21, IL-34, RANKL, survivin, and COMP were selected as candidate biomarkers. RESULTS: Serum IL-6 level was increased in responders than in nonresponders at baseline, p = .034; to the contrary, serum survivin level was decreased in responders, p = .009. Receiver operating characteristic (ROC) curve illuminated the combination of IL-6 and survivin expressions could predict clinical response with a high AUC 0.875, 95% CI: 0.771-0.976. Furthermore, we found the combination of IL-6 high expression and survivin low expression increased the responding possibility to nearly 20-fold (OR 19.687, 95% CI: 4.087-94.839, p < .001) compared to IL-6 low or survivin high expression by univariate analysis. However, only survivin low expression (p = .002) and CRP (p = .014) high expression were independent predictive factors for achieving clinical response, while IL-6 lack independent predictive value (p = .267). CONCLUSIONS: Comprehensive measurement of IL-6 and survivin in serum could be served as a convincing biomarker for clinical response in ETN-treated patients with established RA.

Survivin improves the early recognition of rheumatoid arthritis among patients with arthralgia: A population-based study within two university cities of Sweden.

OBJECTIVES: The aim of this study was to validate the use of survivin for preclinical recognition of rheumatoid arthritis (RA) among patients with unexplained arthralgia. METHODS: Serum levels of survivin and the arthritis-specific autoantibodies RF and ACPA were measured in total of 5046 patients with musculoskeletal complains during 12 consecutive months in Gothenburg and in Umeå. Among them, 303 arthralgia patients were identified and prospectively followed. RESULTS: After 48 months, 12.2% of the arthralgia patients developed RA. Most of RA cases had high serum survivin, which increased the relative risk for RA (RR = 5.90, p = 3 × 10-7). Combination of survivin with autoantibodies was present in only 4.6% of the arthralgia patients and increased further the risk of RA and shortened time to RA development. Presence of any single autoantibody in the survivin-negative patients was associated with a minor risk for RA and had RA-free survival similar to the reference group. CONCLUSION: This study shows that measurement of survivin in serum improves estimation of RA risk and prospectively predicts RA development in patients with arthralgia. Survivin may indicate a phase preceding autoantibody production.

Evaluation of serum autoantibodies against tumor-associated antigens as biomarkers in lung cancer.

We evaluated autoantibodies against nine tumor-associated antigens, including p62, p16, Koc, p53, Cyclin B1, Cyclin E, Survivin, HCC1, and RalA as serological markers in lung cancer. Enzyme-linked immunosorbent assay (ELISA) was used to detect autoantibodies in sera from 50 lung cancer patients and 42 normal controls. Then, four tumor-associated antigens of higher values were selected and validated in sera from validation group. Western blot and serum absorption test were used to confirm positive findings from ELISA. When cutoff values were set as mean optical density values plus 3 standard deviation of normal controls, the positive rate of autoantibodies against four tumor-associated antigens (Survivin, Cyclin B1, HCC1, and p53) reached 32%, 20%, 22%, and 18%, with area under the curve values of 0.653, 0.767, 0.622, and 0.623 in sera from 50 lung cancer, respectively (all p < 0.05). Results from the validation group confirmed the results. When lung cancer patients were divided by their clinicopathological characteristics into different subgroups, we have found that serum anti-Cyclin B1 and anti-HCC1 autoantibodies increased in stages 1, 2, and 3 lung cancer; anti-Survivin autoantibodies increased in stages 2 and 3 lung cancer; and anti-p53 autoantibody only increased in stage 1 when compared with their corresponding levels in controls (all p < 0.05). Serum anti-Cyclin B1 and anti-Survivin autoantibodies increased with disease histological grade 2 and 3 (both p < 0.05). And higher serum level of anti-p53 autoantibodies is positively associated with tumor size. Parallel utilization of these four anti-tumor-associated antigens (any positive) can increase sensitivity to 65.0% at 100% specificity with area under the curve of 0.908 ( p < 0.001) in lung cancer detection in validation group. Our results suggest that autoantibodies against these four tumor-associated antigens have higher values in lung cancer detection, and serum anti-Cyclin-B1 has the potential to serve as novel non-invasive biomarkers in early-stage lung cancer.

The long-term prognostic value of survivin expressing circulating tumor cells in patients with high-risk non-muscle invasive bladder cancer (NMIBC).

OBJECTIVES: Long-term follow-up study to evaluate the impact on disease-free survival and cancer-specific survival of survivin expression in tissue and CTCs from T1G3 bladder cancer patients. PATIENTS AND METHODS: The study was conducted using tumor tissue and blood samples from 54 patients with a primary diagnosis of T1G3 NMIBC. Survivin was evaluated by reverse transcription-polymerase chain reaction in tumor tissues. CTCs were isolated from blood by CELLection™ Dynabeads (Invitrogen, Carlsbad, CA, USA). Cells were lysed and cDNA was synthesized and analysed for the expression of CD45, CK8 and survivin. The endpoints of this long-termanalysis were disease-free survival, DFS and cancer-specific survival, CSS. RESULTS: Here, we report that, at 9 years of median follow-up, disease-free survival and cancer-specific survival are both significantly influenced by the expression of survivin in tumor tissue (p = 0.006), by the presence of CTCs (p < 0.0001) and by the expression of survivin in CTCs (p < 0.0001). CONCLUSION: The statistically significant impact of survivin expressing CTCs on cancer-specific survival that we observed might be interpreted as the result of the persistence of a subpopulation of highlander cells in the blood of T1G3 bladder patients over time.

Survivin, a key player in cancer progression, increases in obesity and protects adipose tissue stem cells from apoptosis.

Adipose tissue (AT) has a central role in obesity-related metabolic imbalance through the dysregulated production of cytokines and adipokines. In addition to its known risk for cardiovascular disease and diabetes, obesity is also a major risk for cancer. We investigated the impact of obesity for the expression of survivin, an antiapoptotic protein upregulated by adipokines and a diagnostic biomarker of tumor onset and recurrence. In a cross-sectional study of 111 subjects classified by body mass index, circulating levels of survivin and gene expression in subcutaneous AT were significantly higher in obese patients and positively correlated with leptin. Within AT, survivin was primarily detected in human adipocyte-derived stem cells (hASCs), the adipocyte precursors that determine AT expansion. Remarkably, survivin expression was significantly higher in hASCs isolated from obese patients that from lean controls and was increased by proinflammatory M1 macrophage soluble factors including IL-1ß. Analysis of survivin expression in hASCs revealed a complex regulation including epigenetic modifications and protein stability. Surprisingly, obese hASCs showed survivin promoter hypermethylation that correlated with a significant decrease in its mRNA levels. Nonetheless, a lower level of mir-203, which inhibits survivin protein translation, and higher protein stability, was found in obese hASCs compared with their lean counterparts. We discovered that survivin levels determine the susceptibility of hASCs to apoptotic stimuli (including leptin and hypoxia). Accordingly, hASCs from an obese setting were protected from apoptosis. Collectively, these data shed new light on the molecular mechanisms governing AT expansion in obesity through promotion of hASCs that are resistant to apoptosis, and point to survivin as a potential new molecular player in the communication between AT and tumor cells. Thus, inhibition of apoptosis targeting survivin might represent an effective strategy for both obesity and cancer therapy.

Evaluation of tissue metalloproteinase inhibitor TIMP-1 and Survivin levels during third trimester pregnancy - a preliminary report.

OBJECTIVES: A proper implantation of trophoblastic cells and an appropriate metalloproteinases activity is required to cause disintegration of basal membranes of cells. The activity of tissue matrix metaloproteinases can be inhibited by their matrix inhibitors - TIMP-s. Survivin is a member of inhibitor of apoptosis proteins family (IAP), that suppresses caspase activation, influences VEGF expression and promotes proliferative action of endothelial cells. MATERIAL AND METHODS: The aim of the study was to assess concentrations of two independent anti-apoptotic factors. TIMP-1 and survivin in serum of women in their third trimester of pregnancy and in umbilical cord blood of neonates - drawn separately from veins and arteries. The study group consisted of 29 pregnant women in physiological pregnancy and with correct fetal development, in gestational age between 37 to 40 weeks of gestation. Blood used in the study was collected from maternal cubital fossa veins and from neonatal umbilical cords (from veins and from arteries separately). The research was conducted using TIMP-1 and Survivin ELISA kits from R & D Systems according to manufacturers' recommendations and protocols. RESULTS: The concentrations of TIMP-1 were similar and independent of the source of blood samples. Arterial values of TIMP-1 in umbilical cord compared to maternal and fetal veins were slightly lower, but no statistical difference was found. The mean concentrations of Survivin were comparable but we found that in some cases the results in cord blood serum in both vessels-vein and arteries were almost negative. Arterial values of Survivin in umbilical cord compared to maternal blood were higher, but no statistical difference was found. CONCLUSIONS: In III-rd trimester of pregnancy parameters of Timp-1 and Survivin - anti-apoptotic substances concentration were similar in maternal and cord blood in both artery and vein. We found no increased activity of selected antiapoptotic factors.

Smoking activates cytotoxic CD8+ T cells and causes survivin release in rheumatoid arthritis.

CD8+ T cells have an emerging role in RA. Resent research indicates a causal relationship between the non-exhausted state of CD8+ T cells, defined by lost function of PD-1, and development of arthritis. We investigated how smoking contributes to the non-exhausted phenotype of CD8+ T cells and cause survivin release to serum. We compared serum survivin levels between smokers and non-smokers in 252 RA and 168 healthy subjects. Nicotine effects on CD8+ T cells were studied in peripheral blood of smoking women, bone marrow of nicotine treated mice and in sorted CD8 spleen cells in vitro using flow cytometry and quantitative PCR. Smoking increased the frequency of survivin release in serum of healthy women (OR 3.64, p = 0.025) and in RA patients (OR 1.98, p = 0.039). CD8+ T cells of smokers gained a non-exhausted PD-1 deficient phenotype. Expression of the cytotoxic marker CD107 correlated to survivin levels in serum. In the experimental setting, nicotine exposure led to an accumulation of non-exhausted PD-1-IL-7R+ CD8+ T cells in the bone marrow that is abundant with survivin producing cells. The production of the cytolytic protein perforin in bone marrow correlated to serum survivin levels. In vitro stimulation of nicotinic receptors on murine CD8+ T cells induced repressive transcription factors T-bet and Blimp-1 in support of the non-exhausted phenotype. We conclude that nicotine contributes to autoimmunity by supporting the non-exhausted state of CD8+ T cells resulting in the release of survivin. This presents a new mechanism by which smoking may contribute to the pathogenesis of RA.

Clinical impact of serum survivin positivity and tissue expression of EBV-encoded RNA in diffuse large B-cell lymphoma patients treated with rituximab-CHOP.

Survivin is an inhibitor of apoptosis and is upregulated by Epstein-Barr virus (EBV) latent genes. Given the frequent association of EBV with lymphoid malignancies, survivin is expected to have prognostic value in diffuse large B-cell lymphoma (DLBCL). Thus, we measured the pretreatment serum level of survivin in DLBCL patients and analyzed its association with survival outcome and EBV status, as represented by EBV-encoded RNA (EBER) in DLBCL. Pretreatment serum survivin level was measured in patients registered in a prospective cohort study (n = 210), and serum survivin-positivity was defined as any detectable level of survivin. EBV status was determined using EBER in situ hybridization, and EBER-positivity was defined as 20% of examined cells showing nuclear positivity. Mean serum survivin level was higher in patients with relapsed or refractory disease than with responsive disease (59.89 pg/mL versus 17.34 pg/mL, P = 0.041). Serum survivin-positive patients had worse overall and progression-free survival (P = 0.023 and 0.022, respectively). Serum survivin positivity was associated with unfavorable characteristics including stage. In patients with non-germinal center B-cell type DLBCL, serum survivin-positive patients also had significantly worse survival than serum survivin-negative patients (P < 0.001). EBER-positivity was found in 6.7% (14/210) of patients, and EBER-positive patients had worse survival (P < 0.05). Patients having concomitant positivity for serum survivin and EBER expression (2.8%, 6/210) showed extremely poor prognosis. In the present era of rituximab in DLBCL, DLBCL with serum survivin positivity showed adverse clinical features and followed worse clinical course, especially in non-GCB subtype DLBCL. EBER-positivity was still associated with worse outcomes in DLBCL.

Survivin isoform expression in arsenic trioxide-treated acute promyelocytic leukemia cell line and patients: The odd expression pattern of survivin-2α.

AIM: Survivin, an inhibitor of apoptosis protein, is overexpressed in most cancers and is associated with chemotherapy resistance, increased tumor recurrence and shorter patient survival. Several survivin splice variants have been described, and none of their expressions have been defined in acute promyelocytic leukemia (APL). METHODS: Expression of the survivin gene isoforms (survivin, -2α, -2B, -ΔΕx3 and -3B) were analyzed in 50 peripheral blood and 19 bone marrow samples that were collected at different phases of the disease (diagnostic, remission and relapse) in APL patients treated with arsenic trioxide (ATO) as a front-line therapy. In addition, the human APL-derived cell line (NB4) was analyzed for the expression of survivin isoforms and capsase-3 in response to the ATO. RESULTS: Survivin and its variants were overexpressed significantly in patient's bone marrow samples compared to peripheral blood or normal samples. Their expression was decreased after ATO treatment in both NB4 cells (except survivin-2α) and APL patients along with PML-RARα copy number reduction. Downregulation of survivin isoforms was associated with an increase in both caspase-3 gene expression and its enzymatic activity levels. In a patient who did not respond to ATO treatment, expression of survivin isoforms (except survivin-2α) were highly increased during the induction therapy. CONCLUSION: Survivin isoforms are upregulated in APL patients, and their expression is diminished during the ATO treatment. In addition, overexpression of survivin and its variants (except survivin-2α) are associated with unfavorable results, suggesting that they may play an important role in mechanisms underlying the resistance of APL cells to ATO.

Identification of bile survivin and carbohydrate antigen 199 in distinguishing cholangiocarcinoma from benign obstructive jaundice.

AIM: To investigate whether bile survivin and carbohydrate antigen 199 (CA199) can be helpful in distinguishing cholangiocarcinoma (malignant obstructive jaundice) from benign obstructive jaundice. METHODS: Receiver operating characteristic curve was used to evaluate the feasibility of bile survivin and CA199 in differentiating cholangiocarcinoma from benign obstructive jaundice. RESULTS: The area under the curve for survivin and CA199 in bile and serum were 0.780 (p < 0.001), 0.6 (p = 0.084), 0.746 (p < 0.001) and 0.542 (p = 0.464), respectively. Combination of bile survivin and CA199 could improve the diagnostic capability. CONCLUSION: Bile survivin and CA199 are significantly increased in patients with cholangiocarcinoma and may be useful biomarkers in differentiating distinguishing cholangiocarcinoma from benign obstructive jaundice.

Detection of survivin, carcinoembryonic antigen and ErbB2 level in oral squamous cell carcinoma patients.

INTRODUCTION: The aim of this study was to detect the survivin, carcinoembryonic antigen (CEA) and ErbB2 in the saliva, serum and local tumor-exfoliated cells of oral squamous cell carcinoma (OSCC) patients, for providing reliable tumor markers for the early detection of oral malignant cancer. MATERIALS AND METHODS: The saliva, serum, and local tumor-exfoliated cell samples of 26 OSCC patients without chemotherapy and 10 non-cancer patients were collected in Department of Oral and Maxillofacial Surgery, School of Stomatology, Peking University. The contents of survivin, CEA and ErbB2 using were detected usingenzyme-linked immunosorbent assay. RESULTS: The survivin and CEA levels in saliva and local tumor-exfoliated cells of OSCC patients were significantly higher than those in the non-cancer patients (P < 0.05), but there was no significant difference in the content of the above factors in the serum sample between two groups. There was no significant difference in the ErbB2 content in the saliva, serum or local tumor-exfoliated cells between two groups. CONCLUSION: Survivin and CEA levels are significantly increased in the saliva and local tumor-exfoliated cells in OSCC patients, and they can be used as reliable markers for the early detection of oral malignant cancer.

Clinical significance of high levels of survivin and transforming growth factor beta-1 proteins in aqueous humor and serum of retinoblastoma patients.

PURPOSE: To evaluate the diagnostic and prognostic values of survivin and transforming growth factor beta-1 (TGF-B1) expression in aqueous humor and serum of retinoblastoma (RB) in comparison to the conventional RB marker lactate dehydrogenase (LDH) and to elucidate a possible correlation between them and the clinicopathological features of the disease. METHODS: This prospective, comparative study included 88 newly diagnosed children with RB and 80 age-matched controls with ophthalmic conditions other than tumors prepared for intraocular surgeries. Concentrations of survivin, TGF-B1, and LDH were measured in serum and aqueous humor before and 6 months after completion of therapy. RESULTS: High serum and aqueous humor concentrations of the three proteins were detected in RB patients before treatment compared to the control group (P < 0.01), with a significant reduction of serum concentrations after treatment (P < 0.01). For the highest sensitivity and specificity, the optimal cutoff values of serum and aqueous survivin were 12.9 pg/ml and 25.2 pg/mg, with a significant positive correlation between aqueous survivin and RB staging and presence of optic nerve infiltration (r = 0.43, P = 0.04); the best cutoff values of serum and aqueous TGF-B1, 370.7 pg/ml and 39.8 pg/mg, with a significant positive correlation between aqueous TGF-B1 and poor differentiation of the tumor (r = 0.69, P = 0.001). CONCLUSIONS: The high sensitivity, specificity, and accuracy of serum and aqueous humor survivin and TGF-B1 proteins make them promising markers for early detection and follow-up of RB patients.

Correlation of local and systemic expression of survivin with histopathological parameters of cutaneous melanoma.

Background/Aim: Survivin is a multifunctional protein abundantly expressed in tumors of various types, including melanoma. There are still sparse data regarding relationship of melanoma cell survivin expression with accepted histopathological characteristics as well as serum concentration. The aim of this study was to investigate the association of local tumor survivin expression (primary tumor and metastatic lesions) and serum concentration with clinical and histopathological parameters in melanoma patients. Methods: The level of survivin expression was determined immunocytochemically in tumor tissue and with ELISA test in the serum of 84 melanoma patients diagnosed from 2009 to 2013 at the Institute for Pathology and Forensic Medicine and Institute for Medical Research at Military Medical Academy, Belgrade, Serbia. Results: The intensity of survivin expression was significantly higher in the patients whose tumor had ulceration, higher mitotic index, higher Clark and Breslow stage, that made vascular invasion or spread through lymphatic vessels in primary tumor, and was significantly higher in the patients with metastatic disease. Survivin expression and the number of survivin positive cells in metastatic lesions were significantly associated with the duration of disease free interval (DFI). The patients with high expression score had almost double shorter DFI comparing to those with weak local survivin expression and a small number of survivin+cells (9 ± 7 vs 19 ± 13 months, respectively). The degree of tumor infiltrating lymphocytes presence in tumor tissue was significantly associated with serum survivin concentration, with lowest average level detected in samples of patients with the highest degree of infiltration. Serum survivin concentrations were highest in samples of melanoma patients with IA American Joint Commission on Cancer (AJCC) clinical stage, pT1a histological stage, patients whose tumors were still in horizontal growth phase, without signs of lympho-hematological disease spreading, with the highest number of mitoses and the smallest Clark index. Conclusion: Survivin expression in tumor tissue and its serum concetration significantly correlate with clinical and histopathological parameters. Serum levels could be important in initial follow-up as indicators of those patients that would have aggressive local tumor growth and spreading. Survivin determination in tumor tissue is of great significance in estimation of DFI.