For malignancies, early detection, early diagnosis and early treatment are important means of prevention and treatment. Physical examination and effective screening methods have been proven to be able to effectively reduce the social burden of malignancies [16, 17]. From 1990 to 2015, the overall cancer mortality rate fell 25% in the United States, which can be attributed to the introduction of high-quality cancer screening and the emergence of new screening methods . TAP, with the classification standard of 121µm2, has been used as detection index of malignancies in clinic. This study evaluated the diagnostic ability of TAP level, analyzed the heterogeneity among different populations, and further investigated its relevance with clinical parameters for exploring more mechanisms. The results will be discussed in detail, respectively.
The accurate standard for malignancies screening is pathological examination, but it has limitation and is not suitable for most people. Therefore, indirect screening is still the most used diagnostic method in clinic . This study showed our TAP level results were statistically consistent with the clinical standards, preliminary indicating that the method was reliable. We found the levels of TAP in malignancies patients were higher than those in precancerous lesion patients, and so on in precancerous lesion and benign patients. As the host cells became cancerous, TAP levels gradually increased, which suggested that TAP level could not only indicate the occurrence of malignancies, but also predict the development of malignancies. Further research showed that TAP level could be used as indicators to separate malignancies from benign diseases. Currently, our hospital recommended the cut off value to be 121µm2 as a parameter to distinguish TAP positive and TAP negative. In this study, the ROC curve analysis showed that the cut-off value could be 124.5, which has the highest sensitivity and specificity. The difference may be due to the different states of tumor patients, the limited sample size, and the population heterogeneity. Following up newly diagnosed patients, we found that the levels of TAP were decreased significantly after surgery of removing the tumors in these patients. This further indicated the TAP index had exceptional sensitivity to monitor malignancies.
Indirect malignancies screenings always accompanied with impaired screening effectiveness due to a decline in the performance characteristics including false positives and false negatives . In this study, we analyzed population heterogeneity in the physical examination subjects. Our result showed that the positive ratio of TAP was 3.7%, including 3.1% male and 4.6% female. According to the American Cancer Society's 2019 report  on the incidence of malignancies from 1975 to 2015, the total incidence of malignancies in the United States in 2015 was about 425/100,000, including about 460/100,000 men and about 410/100,000 women, which was obviously lower than the positive ratio of TAP in our physical examination populations. Although the several precancerous patients whose positive TAP might had increased the overall TAP-positive rate,it still indicated that the sensitivity of TAP detection was high, but the specificity was poor.
Our result showed that the positive rate of TAP test in females was higher than that in males, indicating that TAP levels may be affected by the gender. To this end, this study further compared the TAP levels of different genders of physical examination subjects, and found that the levels of TAP in female were significantly higher than those in males, which further indicates that the TAP levels among different gender population with heterogeneous. Therefore, different distinguished standard should be formulated and based on gender to strengthen accuracy.
Further analysis found that the TAP levels in the subjects over 60 were significantly higher than those in younger subjects. Additionally, the TAP level increased with age. Clinically, age was an independent risk factor for many malignancies, the median age of onset in many malignancies is greater than 60 years old . The incidence of malignancies has correspondingly increased with age [22, 23]. The trend changing with age in TAP detection was consistent with tumors incidence, which further indicated that TAP detection had higher sensitivity, and also reflected the high reliability of the data in this study.
Pulmonary nodules were common abnormal results in chest XCT examinations. A number of circulating biomarkers and tumor markers, such as plasma microRNAs and circulating cytokines, have been suggested as possible candidates to aid malignant risk assessment for pulmonary nodules, but validation studies are currently lacking [24, 25]. Clinically, regular follow-up examination is recommended for people with small pulmonary nodules. Chest XCT scan is usually performed in physical examination. The positive rate of pulmonary nodules showed an upward trend in the TAP-positive population, but there was no statistical significance between TAP-positive with TAP-negative populations, and no statistical difference in the number and the sizes of pulmonary nodules. The cause of pulmonary nodules was diverse. Pulmonary nodules may not lead to obvious clinical symptoms in the early stage, but they may become malignant later . There was no significant statistical correlation between lung nodules and TAP levels in this study, which may be due to small subject numbers. However, the positive rate of pulmonary nodules in TAP-positive patients was on the rise, suggesting that TAP detection may be one of the indicators for regular follow-up of pulmonary nodule-positive patients.
Clinically, tumor biomarkers [27, 28] were commonly used as indicators for detecting malignancies with high sensitivity and specificity. These tumor biomarkers usually tend to be malignancy type specific. Therefore, it is important to find new detection methods that are sensitive to multiple malignancies. Correlation analysis between TAP levels and tumor biomarker levels in this study did not show statistically differences, which indicated that TAP was not a simple extension of the traditional tumor biomarkers, but an independent indicator of tumor screening. TAP detection combined with some variety tumor biomarkers could substantially detect a variety of tumors. TAP detection could screen a variety of malignancies. However, the specificity was poor because TAP level could not reflect one or more malignancies like traditional tumor biomarkers. Thus, it was more suitable for initial screening than for diagnosis.
We had further analyzed the correlation between TAP level and laboratory parameters in physical examination subjects. The study found that there was statistically difference in hemoglobin levels between the TAP positive and the TAP negative subjects. As the diagnostic criteria of hemoglobin were different in gender groups, we also found TAP levels were different between male and female. Further analysis and study on larger samples and mechanisms will be required to determine relationship among gender, hemoglobin and TAP to ascertain the diagnostic criteria.
There were still several limitations in this study. Firstly, different stages of malignant tumor patients might lead to statistical heterogeneous. Secondly, this study showed that there were differences of TAP levels in different gender groups. Due to the large heterogeneity of the patients and the limited of sample size, the accurate of diagnostic criterion in different gender people were insufficient. Thirdly, the number of cases varies greatly among different patients, especially the number of patients with precancerous lesions is small, and the statistical results are less reliable. Finally, this study indicated that there were possible links among TAP, gender and hemoglobin. Therefore, we will perform statistical analysis on larger sample data, complete relevant fundamental experiments, and explore related mechanisms in the future.
In conclusion, TAP level was higher in female and elevated with age. TAP was a potential biomarker for screening and following-up of malignancies, which was sensitive to multiple malignancies. There may be some potential links between TAP and hemoglobin, which deserve further investigation.