To our knowledge, this is the first meta-analysis of the diagnostic efficacy of telomerase activity for bladder cancer. We found that TA is ideal among various indicators and also proves its excellent diagnostic performance.
BC, as a malignant tumor with high morbidity and mortality, has received wide attention from all walks of life, both in its diagnosis and treatment[36]. as we know, cystoscopy has long been the gold standard for the diagnosis of BC. Although it is quite reliable, as an invasive examination, at least it needs to be operated under local anesthesia, inducing strong discomfort to the patient. [7]. People need a diagnosis that is not only simple, but also minimizing the damage caused by the examination. Measures, which also make the continuous detection and development of BC test methods, which also gradually move people's attention from macro to micro, and began to explore the role of some markers in urine in the detection and diagnosis of BC[18, 19]. Telomeres are composed of repeated gene sequences and related proteins. Their main role is to avoid end-to-end fusion and nuclear cleavage during chromosome division[18]. Telomerase can reverse the fact that telomeres become shorter due to division. This is one of the essential conditions for the permanent life of tumor cells[9]. So we suspect that in tumor cells, telomerase activity is higher than in normal cells. Many scholars have studied the relationship between TA and BC, but due to the factors of detection technology and sample size, the conclusions are not only inconsistent, but even some differences in some evaluation indicators. We integrated and analyzed the research done by relevant authors and included enough samples for meta-analysis, aiming at comprehensive evaluation. Diagnostic validity of TA in BC will provides better guidance for clinical practice.
A number of studies have shown that the sensitivity of the telomerase assay for urothelial carcinoma is lower in voided urine specimens than bladder washings[17, 22, 24]. However, the urine is easier to obtain for the bladder washings, which is beneficial to the patient's cooperation. In our meta-analysis, the overall sensitivity is 0.79 (95% CI: 0.72-0.84), the specificity is 0.91 (95% CI: 0.87-0.94), and the Yoden index is 0.7. AUC is 0.92 (95% CI: 0.90-0.94), which is in line with our expectations, and through these composite indicators, it also shows that TA has a good effect in terms of diagnostic accuracy. In general, the diagnostic test can be considered to have a high value when sensitivity and specificity are >0.7. In the study we included, the results of sensitivity in 16 articles reached this value, which also indicates the superiority of TA in the diagnosis of BC and is consistent with our predictions. However, the sensitivity values provided in the other 2 studies were significantly lower [17, 22]. The reason we analyze it may be that the technical level of the test, the sample size, and some bias between the samples lead to different final results. In terms of specificity results, 21 of the studies we have included have reached 0.7 or higher, which shows that the results are not very different between the studies, which also confirms our conjecture and indicates that in the diagnosis of BC, the excellent specificity of TA. The higher the value of DOR, the better diagnostic ability of this diagnostic method. In our study, the DOR value was 37.90 (95% CI: 23.32-61.59),suggesting that the overall accuracy was high. The overall PLR value was 8.91 (95% CI: 5.91-13.43), which means that people with BC have a TA 8.91 times higher than normal, and a total NLR of 0.24 (95% CI: 0.15- 0.37), understood as the normal person suffering from BC is 25%. In the criteria for judging, PLR>10, NLR<0.1, the diagnostic efficiency of this method is higher. From this aspect, it can be concluded that the diagnostic efficiency of TA for BC is suboptimal.
To investigate the TA relationship between different staging and grading, we performed a subgroup analysis. In terms of staging, we drafted Tis, Ta, and T0 as low-stage tumors, while T2-T4 was high. In early grading, grade 1 was a low-grade tumor, and 2 and 3 were high-grade tumors. Thus, through meta-analysis, the association between them was shown. From the results, there was no absolute difference in TA between high-stage and low-stage tumors (P>0.05); and between different grades, meta-analysis. The results showed that the TA of the low-grade tumor was significantly lower than that of the high-grade tumor (P=0.001). We believe that this is because the higher the grade, the lower the degree of differentiation, the stronger the invasive ability, and the higher the TA, which is consistent with the results of Bravaccini[7] et al. Of course, detecting TA is not the only non-invasive method used to aid in the diagnosis of BC, other markers, such as nuclear maxtrix protein (NMP)-22, bladder tumor antigen (BTA), Cytokeratin 20. Studies have reported that BTA and cytokeratin 20 are very insensitive to low-grade tumors. For grade 1 tumors, the sensitivity of BTA and cytokeratin is 13% and 6%, respectively. NMP-22 has a specificity of 70% in the diagnosis of BC. [9, 22, 25]. Therefore, even on some individual indicators, these markers may work better, but the diagnostic performance should pay more attention to the composite indicators. As can be seen from our meta-analysis, the overall diagnostic ability of TA is better.
We follow the PRISM guidelines for meta-analysis[37]. However, at present, our meta-analysis has limitations. First, in the research we have included, most of the research samples are from Europe and the United States, Asia is less, and there is only one in Africa, which may lead to deviations in our research due to differences in races. Third, in each group of controlled studies, the patients studied may have other diseases besides BC. Since the mechanism is not clear, the interaction between the diseases may lead to higher or lower accuracy of the results. Finally,in the subgroup analysis, we combined the different stages and graded tumors into a self-control. Due to the influence of the original data, it was not able to be detailed enough in different stages and grades. Compared with cystoscopy, although not further clinically applied, TA does have a higher advantage in diagnosing BC with its relatively high sensitivity and non-invasive mode of operation. A larger sample size, tighter design, and longer follow-up randomized controlled trials are also needed to validate.