Urinary Survivin Research Articles

Diagnostic evaluation of apoptosis inhibitory gene and tissue inhibitor matrix metalloproteinase‐2 in patients with bladder cancer

Bladder carcinoma is an important worldwide health problem. Both cystoscopy and urine cytology used in detecting bladder cancer suffer from drawbacks where cystoscopy is an invasive method and urine cytology shows low sensitivity in low-grade tumors. This study validates easier and less time-consuming techniques for the estimation of survivin and TIMP-2 in urine of bladder cancer patients to evaluate them in comparison with cytology. This study includes malignant (bladder cancer patients, n = 42), benign (patients with bilharzial cystitis, n = 22) and healthy (n = 21) groups. The studied groups were subjected to cystoscopic examination, detection of bilharzial antibodies, urine cytology, and estimation of urinary survivin by qualitative RT-nested PCR and TIMP-2 by ELISA. Significantly higher positivity rates of urinary survivin and TIMP-2 were observed in the malignant group compared with benign and healthy groups. On associating the two urinary markers with different clinicopathological factors, only TIMP-2 exerted significantly higher positivity rate in invasive stage (100%) than superficial stage (82.3%). Survivin showed 78.6% sensitivity, 95.3% specificity, 94.3% PPV, 82% NPV, and 87% accuracy. When combined with urine cytology, the sensitivity increased to 83.3%. While on applying the cutoff value of urinary TIMP-2 (< or =639.5 pg/mg protein), it showed 93% sensitivity, 83.7% specificity, 85% PPV, 92.3% NPV, and 88.2% accuracy. When combined with urine cytology, the TIMP-2 sensitivity remained 93%. On combining cytology with both urinary survivin and TIMP-2, the highest sensitivity was reached (98%). Survivin and TIMP-2 can be considered as potentially useful urine markers in early detection of bladder cancer.

The diagnostic value of urine-based survivin mRNA test using reverse transcription-polymerase chain reaction for bladder cancer: a systematic review

Survivin has gradually become an important target in diagnosis, prognosis prediction and treatment of tumor. There are many studies on urine-based survivin mRNA test using reverse transcription-polymerase chain reaction (RT-PCR) as a noninvasive examination for bladder cancer. However, its clinical value remains controversial. This study was to evaluate the diagnostic value of urine survivin mRNA detection with RT-PCR for bladder cancer by a systematic review of related studies. With the search terms such as bladder neoplasm, survivin, RT-PCR, sensitivity, specificity and diagnosis, we systematically searched through PubMed, EMBASE, SCI, Cochrane Library, Chinese Biomedical Literature Database (CBM), Chinese Scientific Journal Full-text Database (CSJD), China Journal Full-text Database (CJFD), Chinese Medical Association (CMA) digital periodicals and Google Scholar totally from January 1997 to April 2009 for diagnostic trials with RT-PCR detection of urine survivin mRNA for bladder cancer. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) items were used to evaluate the quality of the included studies. Meta-disc software was used to calculate outcome indicators. Twenty-six studies, totally 2 416 patients, were eligible. Meta-analysis showed that compared with pathologic examination, the summary values of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and summary receiver operating characteristic curve (SROC) of urine-based survivin mRNA test using RT-PCR for bladder cancer were 88%, 94%, 14.56, 0.13 and 0.9736, respectively. Nested RT-PCR got the highest sensitivity, specificity and SROC and the values were 91%, 95% and 0.9805, respectively. The sensitivity and specificity of general RT-PCR were the second highest, which were 87% and 94%, respectively. The sensitivity of quantitative RT-PCR was 80% and the specificity was 93%. Comparing with pathologic examination, the sensitivity and specificity of urine-based survivin mRNA test using RT-PCR are relatively high. It can be used as an important adjunct method for cystoscope in early screening and postoperative monitoring of bladder cancer.

Detection of Newly Diagnosed Bladder Cancer, Bladder Cancer Recurrence and Bladder Cancer in Patients with Hematuria Using Quantitative RT-PCR of Urinary Survivin

Background/Aims: Survivin mRNA in urine was measured to detect newly diagnosed bladder cancer, bladder cancer recurrence and bladder cancer in patients with hematuria. Methods: We have investigated urinary survivin mRNA of 118 voided urine specimens, including 24 patients with bladder cancer, 50 with bladder cancer history, 68 not known to harbor bladder cancer, and 55 with hematuria using quantitative reverse transcriptase polymerase chain reaction. β-Actin mRNA expression was also examined and used as an endogenous control to ensure validity of the assay for each sample. Results: The survivin expression in urological patient urine had sensitivities and specificities for all patients of 79 and 93%, for detection of newly diagnosed bladder cancer 83 and 95%, for bladder cancer recurrence 82 and 90%, and for bladder cancer in patients with hematuria 80 and 90%. Conclusion: Our results indicate that quantitative reverse transcriptase polymerase chain reaction of urinary survivin is a sensitive, noninvasive and highly specific assay to detect both newly diagnosed bladder cancer and bladder cancer recurrence. Furthermore, this assay may be useful in stratifying the hematuria population in urological practice.

Evaluation of Survivin Reverse Transcriptase-Polymerase Chain Reaction for Noninvasive Detection of Bladder Cancer

Survivin, a member of the inhibitor of apoptosis gene family, is expressed in most common cancers. We investigated the expression pattern of survivin in the tumors of patients with bladder cancer and assessed the diagnostic potential of RT-PCR detection of survivin mRNA in urine. RT-PCR was used to analyze mRNA expression of survivin in 161 cases of bladder cancer, including TCC in 97, SCC in 53 and adenocarcinoma in 11, and their matched nontumor tissues. Urine specimens (50 ml) were collected from 84 patients in whom bladder cancer was documented by transurethral resection or biopsy, 41 with nonbladder cancer urological diseases and 42 healthy volunteers. Total RNA was extracted from urine sediments and RT-PCR was performed for survivin. Survivin expression was detected in all bladder cancer tissues. In contrast, survivin was not detectable in normal urothelium specimens. Urinary survivin was detected in urine samples from 51 of 53 patients with TCC, 22 of 25 with SCC and 6 of 6 with adenocarcinoma. Overall sensitivity was 94%. Survivin mRNA was not detected in any healthy volunteers. Positive results were obtained in 2 patients with renal cell carcinoma, 1 with hematuria and 1 with a contracted bladder but in none with other urological diseases. Overall specificity was 95%. Survivin mRNA detection in urine sediment using RT-PCR shows high sensitivity and specificity for bladder cancer. It may prove useful for the routine screening and monitoring of patients.

Urinary Survivin Test Compared to the Nuclear Matrix Protein (NMP)-22 Test and Urine Cytology for the Diagnosis of Bladder Cancer

Purpose: The aim of this study was to compare the sensitivity and specificity of the urinary survivin test for the diagnosis of bladder cancer with the nuclear matrix protein (NMP)-22 test and the urine cytology, and we wanted to correlate survivin with the tumor stage and grade. Materials and Methods: Between October 2002 and March 2004, voided urine samples were obtained from 41 patients with bladder cancer and also from 36 controls who had no evidence of bladder cancer. The urinary survivin and NMP-22 levels were measured using a DuoSet IC ELISA kit and an automated chemiluminescent assay system. The results were compared with the cytologic results and the pathologic findings. Results: The comparative results showed the higher sensitivity for the urinary survivin test (78.0%) and the NMP-22 test (75.6%) than for the urine cytology (65.8%) for the detection of bladder cancer. The specificity of urinary survivin (86.1%) and urine cytology (97.2%) were higher than that for the NMP-22 test (66.6%). Measuring the urinary survivin level was a more accurate test than the urinary NMP-22 test and the urine cytology for the detection of lower grade and superficial bladder cancer. Conclusions: The urinary survivin test was superior to urine cytology for sensitivity and specificity, and these two parameters of the urinary survivin test were higher than those of the NMP-22 test. Especially, the urinary survivin test is an accurate diagnostic test for superficial and lower grade bladder tumor. Our results suggested that the urinary survivin test appears to be a reliable diagnostic test to identify patients with bladder cancer. (Korean J Urol 2006;47:1041-1045) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Diagnosis of bladder cancer by urine survivin, an inhibitor of apoptosis: a preliminary report.

Survivin is an inhibitor of apoptosis that is expressed in undifferentiated tissues like tumors. Detection of survivin in urine has been proposed as a diagnostic marker for bladder cancer. We evaluated the urine samples of patients with bladder cancer for survivin and compared them with healthy controls. The urine specimens of 20 patients with transitional cell carcinoma (TCC) of the bladder (group 1) and 18 controls without cancer (group 2) were collected before cystoscopy and assessed for survivin by reverse transcriptase polymerase chain reaction. All patients except 1 in group 1 were men. Urine specimens were positive for survivin in 18 (90%) and 9 (50%) patients of groups 1 and 2, respectively (P = .007). Sixteen patients with TCC had urine cytology, of which 6 (37.5%) were positive. Urine survivin was positive in all 10 patients with negative cytology. Nine patients in this group had low-grade tumors. Urine survivin seems to have a higher sensitivity than urine cytology, especially in low-grade bladder cancer. The quantitative measurement of survivin in urine by advanced techniques may provide a better diagnostic and prognostic tool. However, the clinical use of survivin and its association with different stages and grades of TCC still requires more studies.

Serum and Urine Survivin Levels in Breast Cancer

This study was conducted to investigate the serum and urine levels of survivin in patients with breast cancer and the relationships with known prognostic parameters and therapy. Forty-three patients with breast cancer and 21 healthy control subjects were investigated. Serum samples were obtained on the first admission before adjuvant and metastatic treatment were given and after two cycles of chemotherapy. Serum and urine survivin levels were determined using enzyme immunometric assay (EIA) and enzyme-linked immunosorbent assay (ELISA), respectively. There was no significant difference in the baseline serum and urine levels between patients with breast carcinoma and healthy controls (p = 0.19 and p = 0.84, respectively). None of the prognostic parameters analyzed were significantly correlated with the urine survivin concentrations. This was also true for serum survivin values, except for nodal involvement. Serum survivin levels were significantly higher in the patients with nodal involvement compared with node negatives (p = 0.043). However, serum survivin levels were not influenced by the number of involved nodes (p = 0.77). No significant correlation was found between the serum and urine levels of survivin (r = 0.15, p = 0.27). Serum and urine levels did not change significantly after chemotherapy (p = 0.59 and p = 0.50, respectively). In conclusion, the result of this study suggested that serum survivin level could be a sensitive marker for detecting metastases in lymph nodes from breast cancer patients. However, much research continues in this field, and exciting new knowledge will ultimately emerge.

CONTRIBUTION OF THE PROSTATE LIMITS THE USEFULNESS OF SURVIVIN FOR THE DETECTION OF BLADDER CANCER

We determined if urinary survivin is influenced by the prostate and analyzed survivin levels in a healthy control population. This was a blinded, retrospective analysis of frozen urine samples. Three groups were designated. Group 1 patients were diagnosed with prostate cancer and samples were collected immediately prior to radical retropubic prostatectomy. Group 2 patients had already undergone radical retropubic prostatectomy at least 3 months prior to providing a urine sample. Group 3 comprised healthy controls. Groups 1 and 2 patients were recruited at an institutional practice. Group 3 patients were recruited from the local community. The frequency of high survivin scores was much lower in patients who did not have a prostate (p < 0.0002). The survivin score was 2 in 35% and 44% of the patients in groups 1 and 3, respectively, while only 9% of those in group 2 had a survivin score of 2 (p < 0.0002). Of healthy controls 50% had a false-positive survivin score. Urinary survivin predicted prostate cancer poorly with 52% sensitivity and 50% specificity, and it did not predict any biological features of prostate cancer. Urinary survivin markedly decreases after prostatectomy. There is a 50% false-positive rate when using urinary survivin in controls. These 2 features make urinary survivin a poor bladder cancer biomarker.

Efficacy of BTA stat, cytology, and survivin in bladder cancer surveillance over 5 years in patients with spinal cord injury

Objectives To evaluate three urine markers, BTA stat, cytology, and urinary survivin levels, in the spinal cord injury (SCI) population. The incidence of bladder cancer in patients with SCI is up to 20 times greater than in the general population. However, bladder cancer biomarkers have not been assessed in this population. Methods Between April 1999 and April 2004, 457 patients with SCI enrolled at the HealthSouth Harmarville Rehabilitation Spinal Cord Clinic donated their urine to our SCI urine repository. BTA stat tests and the survivin assay were performed according to published standards. Cytology specimens were sent to our cytopathology laboratory for analysis. Results A total of 1075 urine specimens from 457 patients were analyzed. Of the 1073 BTA stat tests, 119 showed positive reactions and 954 were negative. In the survivin assays, 47 samples had a score of 1, 38 a score of 2, and 9 a score of 3. No cytology specimens were noted to have malignant cells. During the past 5 years, 3 patients were diagnosed with bladder cancer by cystoscopy and treated for superficial disease. For these patients, none of these three tests (BTA stat, survivin assay, and cytology) was positive before the diagnosis of bladder cancer. Conclusions The BTA stat, survivin assay, and urine cytology were unable to predict bladder cancer cases in our cohort of patients with SCI. Cystoscopy, therefore, remains the gold standard for bladder cancer surveillance in patients with SCI.

Quantitative analysis of survivin mRNA expression in urine and tumor tissue of bladder cancer patients and its potential relevance for disease detection and prognosis

Suppression of apoptosis may favor the onset and progression of cancer. Survivin is an inhibitor of apoptosis that has been suggested as a novel diagnostic/prognostic marker of bladder cancer. In this study, survivin mRNA expression was measured by a sensitive real-time PCR assay in tumor tissue and urine from bladder cancer patients and assessed for its potential diagnostic and prognostic relevance. Specimens from 53 patients with bladder transitional cell carcinoma (TCC) were analyzed, the controls being normal urothelial tissues (n = 14) and urine from benign disease patients (n = 22) and healthy individuals (n = 14). Survivin transcripts were commonly detected in tumor tissues, but not in normal urothelium, and increasing mRNA levels correlate with progressing pathologic stage (p = 0.001) and grade categories (p < 0.004). Higher levels of expression were associated with a reduced time to recurrence in noninvasive TCCs (p = 0.027, log-rank test) and a trend toward shorter disease-free survival in muscle-invasive tumors (p = 0.067). Urinary survivin analysis detects TCC with higher sensitivity (68.6%) and equal specificity (100%) when compared with cytology (31.4% and 97.1%). Our results indicate that tissue levels of survivin mRNA predict disease-free survival in noninvasive TCC and may have a role in bladder cancer progression. When analyzed by RT-PCR in urine, survivin is a highly specific biomarker for TCC detection.

The expression and significance of survivin mRNA in urinary bladder carcinomas.

To investigate the practicability of survivin detection in urine as a novel diagnostic method and prognostic molecular marker of bladder cancer. Nested RT-PCR was used to detect survivin mRNA expression in urine specimens from 20 healthy persons and patients with bladder carcinomas (n=30), prostate cancer (n=10), and renal cancer (n=6). The result show that survivin was not detected in the urine samples of six of 30 patients with bladder cancer, whereas all the results were negative the other 36 persons. The positive rates of survivin and their expression levels increased with the tumors' histological grade. Six of 21 new-onset bladder tumors did not present survivin mRNA expression; however, none of the nine recurrent bladder tumors were negative, and patients with new-onset bladder tumors (0.5973+/-0.1968) had significantly lower survivin levels than those with recurrent ones (1.1627+/-0.1341)( P=2.10228E-05). We also found that survivin expression was not correlated with gender, age, and clinical stage. The high sensitivity and specificity of urine survivin can indicate the occurrence of bladder carcinomas, and its expression level might be correlated with the malignancy and prognosis of bladder carcinomas. In addition, the fact that survivin was only detected in urine samples of patients with bladder cancer, rather than in normal adult tissue (except thymus gland), suggests that survivin can be used as an ideal target in bladder carcinoma treatment.

Urine Detection of Survivin is a Sensitive Marker for the Noninvasive Diagnosis of Bladder Cancer

In a preliminary study urine detection of survivin, an integrator of cell death and mitosis, accurately detected bladder cancer. The objectives of this study were to confirm these findings in a large cohort of subjects undergoing cystoscopy, to assess the diagnostic performance of urine survivin and to test whether evaluation of urine survivin adds independent value to urine NMP22 (Matritech, Cambridge, Massachusetts) and cytology for the detection of bladder cancer. Urine survivin was measured using a Bio-Dot microfiltration detection system (Bio-Rad, Hercules, California) in voided urine specimens collected before cystoscopy in 117 cases and 92 controls. Bladder washout samples for cytology were collected in 174 subjects. Urine levels of NMP22 were measured using a commercially available enzyme-linked immunosorbent assay. Higher levels of urine survivin were associated with an increased risk of bladder cancer (p <0.001) and tumors of higher grade (p = 0.037), but not with invasive stage, after adjustment for the effects of urine cytology, NMP22 and age. The sensitivity, specificity, and positive and negative predictive values of survivin for the diagnosis of bladder cancer (64%, 93%, 92% and 67%, respectively), are superior to those of NMP22 and cytology. Survivin had the highest specificity and positive predictive value for the detection of bladder cancer across each tumor stage and grade. Urine survivin was a strong, independent predictor of the presence of bladder cancer and higher tumor grade. Urine detection of survivin is an accurate diagnostic test for bladder cancer that retains its efficiency regardless of cancer stage and grade.

381 RT-PCR of urine survivin and MN/CA9 for non-invasive diagnosis of transitional cell carcinoma (TCC) of urinary bladder

381 RT-PCR of urine survivin and MN/CA9 for non-invasive diagnosis of transitional cell carcinoma (TCC) of urinary bladder

Detection of Urine Survivin in 40 Patients with Bladder Cancer

We investigated whether urine survivin, an inhibitor of the apoptosis protein, is useful for diagnosing bladder tumor. We measured urine survivin levels in 40 patients with bladder tumors and 9 healthy volunteers. The average urine survivin levels in the 40 patients and 9 healthy controls were not significantly different (3.802+/-8.669 and 1.127+/-1.529, respectively (p=0.3646) ). However, significantly high urine survivin levels were observed in 3 of the 40 patients, but not in healthy volunteers. Urine Cyfra 21-1 was not elevated (1.3 ng/ml) in one patient with a significantly elevated urine survivin level (33.54 ng/ml), while in two patients with elevated Cyfra (320 ng/ml and 240 ng/ml), the urine survivin level was not detectable. With improvements in the sensitivity of our Elisa system for urine survivin and combined use of urine Cyfra 21-1, it is possible that urine survivin will be a useful tumor marker in detecting both new-onset and recurrent bladder tumors.

Effect of Intravesical Treatment of Transitional Cell Carcinoma With Bacillus Calmette-Guerin and Mitomycin C on Urinary Survivin Levels and Outcome

Urine survivin is a predictive/prognostic molecular marker that detects transitional cell carcinoma (TCC) with high specificity and sensitivity. The presence of urine survivin in patients with TCC who receive intravesical instillation of bacillus Calmette-Guerin or mitomycin C may predict recurrence. Urine from 25 subjects receiving 27 intravesical treatments of bacillus Calmette-Guerin or mitomycin C for TCC were collected prior to, during and after treatment. Urinary survivin levels were compared with outcome, as assessed by cytology and cystoscopy with or without biopsy 1 month and up to 12 months after the completion of treatment. Pretreatment survivin levels were higher in subjects in whom TCC recurred following treatment compared with those who achieved remission. Survivin levels increased several-fold during treatment with the highest survivin levels measured in subjects with recurrence. Median posttreatment values of survivin were zero in those who achieved remission and 1.0 ng/ml urine in subjects in whom TCC recurred. The presence of urinary survivin 1 month after the completion of treatment predicts TCC recurrence with 100% sensitivity and 78% specificity. Specificity to predict TCC recurrence increases to 92% after 1 year. No TCC recurred for 1 year in 12 of the 14 subjects with a posttreatment survivin level of 0.1 ng or less per ml urine. Three of the 4 subjects who were survivin positive but in remission 1 month after the completion of treatment had recurrent TCC within 1 year. Subjects who have urinary survivin after the completion of intravesical instillation have a high likelihood of TCC recurrence.

Stage Ta-T1 Bladder Cancer: The Relationship Between Findings At First Followup Cystoscopy And Subsequent Recurrence And Progression

We studied the relationship of first cystoscopy findings with recurrence and progression rates in a large, population based series of patients with bladder cancer. All 463 patients with an initial diagnosis of stage Ta-T1 bladder cancer in western Sweden in 1987 to 1988 were followed at least 5 years. The 355 patients who were treated with transurethral resection only until repeat cystoscopy or longer were selected for this report. Negative first cystoscopy findings were associated with significantly decreased recurrence and progression rates for all grades, and for stage Ta and T1 tumors. However, some patients with initial high grade carcinoma (WHO 2 to 3) had stage progression despite negative first cystoscopy. On multivariate analyses first cystoscopy findings and papillary urothelial neoplasm of low malignant potential versus grades 1 to 3 but not stage and the number of tumors had prognostic significance for time to recurrence. Only first cystoscopy findings and grade had prognostic significance for time to stage progression. Our data support other groups who recommend a less intense cystoscopy followup schedule in patients with negative cystoscopy findings 3 months after initial transurethral bladder resection. We recommend that patients with initial papillary urothelial neoplasm of low malignant potential and low grade carcinoma (WHO 1) with negative first cystoscopy findings undergo repeat cystoscopy at month 12. In our opinion followup should not be less intense in patients with high grade carcinoma (WHO 2-3), even in those with stage pTa disease.

Bladder cancer detection with urinary survivin an inhibitor of apoptosis

Bladder cancer detection with urinary survivin an inhibitor of apoptosis

Urine detection of survivin and diagnosis of bladder cancer.

Dysregulation of apoptosis may favor onset and progression of cancer and influence response to therapy. Survivin is an inhibitor of apoptosis that is selectively overexpressed in common human cancers, but not in normal tissues, and that correlates with aggressive disease and unfavorable outcomes. To investigate the potential suitability of survivin detection in urine as a novel predictive/prognostic molecular marker of bladder cancer. Survey of urine specimens from 5 groups: healthy volunteers (n = 17) and patients with nonneoplastic urinary tract disease (n = 30), genitourinary cancer (n = 30), new-onset or recurrent bladder cancer (n = 46), or treated bladder cancer (n = 35), recruited from 2 New England urology clinics. Detectable survivin levels, analyzed by a novel detection system and confirmed by Western blot and reverse transcriptase polymerase chain reaction (RT-PCR), in urine samples of the 5 participant groups. Survivin was detected in the urine samples of all 46 patients with new or recurrent bladder cancer using a novel detection system (31 of 31) and RT-PCR (15 of 15) methods. Survivin was not detected in the urine samples of 32 of 35 patients treated for bladder cancer and having negative cystoscopy results. None of the healthy volunteers or patients with prostate, kidney, vaginal, or cervical cancer had detectable survivin in urine samples. Of the 30 patients with nonneoplastic urinary tract disease, survivin was detected in 3 patients who had bladder abnormalities noted using cystoscopy and in 1 patient with an increased prostate-specific antigen level. Patients with low-grade bladder cancer had significantly lower urine survivin levels than patients with carcinoma in situ (P =.002). Highly sensitive and specific determination of urine survivin appears to provide a simple, noninvasive diagnostic test to identify patients with new or recurrent bladder cancer.