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TM refers to a substance that is synthesized or secreted by gene expression of tumor cells during the occurrence and proliferation of malignant tumors, or abnormally produced or elevated by the body's response to tumors, reflecting the presence and growth of tumors. TM includes proteins, hormones, enzymes (isozymes), polyamines, and oncogene products, which are present in the blood, body fluids, cells, or tissues of patients, and can be measured by methods such as biochemistry, immunology, and molecular biology. Tumor auxiliary diagnosis, differential diagnosis, efficacy observation, monitoring recurrence and prognosis evaluation have certain value.
First, the ideal tumor markers from the clinical diagnosis of tumor needs, the ideal TM should be envisaged to have the following characteristics: 1 high sensitivity, early detection and early diagnosis of tumor; 2 specificity, only tumor patients are positive, can be Differential diagnosis of benign and malignant tumors; 3 can locate the tumor, with organ specificity; 4 related to the severity of the disease, tumor size or stage; 5 can monitor the tumor treatment effect and tumor recurrence; 6 can predict the prognosis of the tumor.
Second, the clinical application of tumor markers With the development of molecular biology and molecular genetics, people gradually realize that cancer is a genetic disease, each cancer has its own molecular biological characteristics, these molecular markers can be used in clinical , detecting cancer cells. High-sensitivity methods such as fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA) can detect small numbers of cancer cells from chromosome, DNA, mRNA, or protein levels. Combined with magnetic beads/flow sorting (MACs/FACs), it can improve the micrometastatic lesions in the test samples, make early diagnosis of recurrence of asymptomatic patients, provide molecular staging and judge prognosis.
(1) Application of tumor screening and screening programs Because most of TMs have neither organ specificity nor good tumor specificity, they may exist in normal people, especially benign lesions, and cross the malignant tumors at the concentration level. At the same time, generally TM is very sensitive at the early stage of canceration (about 15% to 20%). Therefore, TM is usually not suitable for the screening of a wide range of asymptomatic people, only individual indicators (such as alpha-fetoprotein (APF) and prostate specific Sexual antigen (PSA) can be used to screen high-risk populations.
(II) Determination of biological characteristics and disease stage In most cases, there is a certain correlation between TM concentration and tumor size and clinical stage: the larger the tumor, the more the number of cells, the more the tumor cells synthesize and secrete TM. Fast, the higher the concentration of TM in the blood circulation. However, due to the wide range of TM concentrations in various stages of tumors, there will be overlapping phenomena. Therefore, it is not possible to judge the size of the tumor and the clinical stage according to the concentration of TM.
(C) determining the clinical efficacy and prognosis by the TM prior to treatment, follow-up and monitoring the change in concentration effective to know whether the cancer therapy, and prognosis. After cancer treatment, and the effect of concentration between certain correlation TM: â‘ After Treatment TM concentration falls below the level of normal reference suggests effective treatment, the prognosis is good; â‘¡ concentration decreased but not yet reached the normal reference levels, suggesting residual tumor or tumor metastasis; â‘¢ the reference concentration decreased to normal levels, but increased again after a period of time, suggesting that the tumor recurrence or metastasis, and poor prognosis. Usually in the course of monitoring, increasing or decreasing the concentration of TM is closely related to the prognosis of the disease: the higher the TM basal level, the more likely to be in advanced cancer, the prognosis is poor; TM basal level of normal or only slightly elevated, indicating a very no longer possible tumor recurrence or prolonged survival time is long.
(Iv) (TM) number combination, improve the detection efficiency is improved auxiliary therapeutic value (TM), joint detection may be performed a number of (TM), selecting several sensitivity, specificity, complementary TM can make the best combination of joint detection, Improve the positive detection rate of tumors, make up for the lack of sensitivity and specificity. It is best to track and observe each TM test regularly, which can remove the existence of false positives and false negatives, and is the best way to solve the lack of specificity. .
(5) Immunolocalization diagnosis can be performed by radionuclide-labeled anti-tumor monoclonal antibody, injected into the patient, and imaged, ie, radioimmunoimaging (RII), or injected into the patient during surgery to guide the operation. The site of resection, ie radioimmunoguided surgery (RIGS). If the RII test result is positive, the diagnosis may be confirmed after the possibility of eliminating the false positive; however, if the result is negative, the presence of the tumor cannot be excluded because the tumor to be tested may not express the antigenic determinant to which the radionuclide-labeled antibody is directed.
(6) Immunotargeting therapy The radionuclide, toxin or chemotherapeutic drug is combined with an anti-tumor antibody, and the tumor cell membrane-associated antigen against which the antibody is directed, that is, TM is targeted, and guided therapy is performed. The biggest advantage is that the therapeutic substance is close to the tumor cells, has strong killing effect on tumors, and has less influence on normal cells.
Third, the clinical application principles of tumor marker detection
The application value of TM depends on its sensitivity and specificity. However, most of the TMs commonly used in clinical laboratories are not sensitive or specific. In TM detection and clinical application, they should have a comprehensive understanding and a full understanding of the advantages and limitations.
(I) Application Principles of Screening for High-risk Populations The following principles should be followed when screening high-risk populations: (1) TM has high sensitivity to early detection; (2) sensitivity, specificity and reproducibility of assay methods Good (such as AFP and PSA); (3) cost and reasonable screening; (4) patients with abnormally elevated TM in the screening, but asymptomatic and physical signs, must be reviewed and followed up.
(B) the application principle of clinical diagnosis and course monitoring of tumors 1. Dynamic monitoring: The clinical value of TM measurement lies in dynamic observation. Each tumor patient has its own basal level for each TM. In most patients, before the onset of cancer, the normal level of the individual markers is unknown, may be very low, or may be close to the upper limit of the reference range, or even higher than the upper limit. Therefore, the upper limit of the healthy adult reference interval does not make much sense. On the contrary, the dynamic change of the TM level in each patient is crucial, and sometimes even the concentration change in the reference interval is valuable.
Some non-malignant diseases can also cause an increase in TM concentration, but most of them are temporary, and the increase in TM concentration caused by malignant tumors is continuous. Therefore, continuous measurement every 2 to 3 weeks can eliminate false positives. In addition, the dynamic direction and magnitude of changes in serum TM levels are important for determining the efficacy and recurrence of malignant tumors. The treatment is effective, the concentration of TM decreases continuously; the concentration of TM decreases slowly or does not decrease, suggesting that the treatment is ineffective or there is residual tumor tissue after surgery; if the concentration is 3 times (two to four weeks apart), the measured values ​​are greatly increased. High, it indicates a tumor recurrence.
2. Regular testing: Different timetables should be established according to different patients and different tumors. In general, TM should be measured for each patient before treatment, and individual baseline values ​​should be determined by one or two tests. The first TM value is tested for efficacy within 2 to 14 days after treatment (the measurement time should be based on the TM half-life). In the first 1-2 years of the beginning, it should be tested regularly every month. After the concentration of TM is significantly reduced, it is measured once every 3 months. In the third to fifth years, it is tested once every six months. 5th to 7th years, once a year. Each time the treatment plan is changed, or the recurrence and metastasis are suspected, the TM concentration should be determined in time. If the increase is found, it should be reviewed 1 time after 1 month, and 2 times in succession, suggesting recurrence or metastasis.
3, joint detection: the same tumor or different types of tumors may have one or several TM abnormalities, the same TM can also appear in different tumors, thus, multiple indicators can be used to find effective diagnosis and monitoring within a certain range TM. In addition, the occurrence and development of tumor tissues and cells is a complex multi-step process. Tumors often have a variety of TM abnormalities, and TM may be different in different stages of development or different tumor cell types. To improve the diagnostic value of TM, determine which TM or TM can be used as a monitoring indicator for treatment and recurrence and prognosis assessment. However, joint testing indicators must be scientifically analyzed and rigorously screened. Under the above premise, a reasonable combination of several TMs with complementary sensitivity and specificity can be selected to conduct joint detection. Through clinical application, the TM combination of joint detection is evaluated and modified by evidence-based medicine.
Fourth, the problems should be paid attention to during the use of tumor markers (A) When determining the normal reference value and judgment results, the "normal reference value" provided by the laboratory is often far from the clinical findings. It is important to compare changes in TM levels at different times during the observation period or before and after clinical treatment.
(2) The test results must be comprehensively analyzed with other clinical examination results. Because the specificity and sensitivity of TM are limited, the test results cannot be used as a basis for diagnosis. It must be comprehensively analyzed with the results of various diagnostic methods such as clinical patient status, physical examination, X-ray, endoscopy, and ultrasound examination. ,judgment.
(3) In the clinical diagnosis and treatment of tumors, except for a small number of TM (AFP, PSA), most of them are not suitable for primary screening of tumors. TM is mainly used for differential diagnosis, disease course analysis, efficacy monitoring, recurrence or metastasis discovery, treatment guidance and prognosis.
(4) Compare the different markers for a tumor, select the best markers, and complement each other to improve the positive rate of diagnosis. While combining multiple TMs to increase sensitivity, attention should also be paid to the decline in specificity. Therefore, the optimal combination, ie high sensitivity, no significant decrease in specificity, and minimal combination of items, can greatly improve the effectiveness of serum TM detection, avoid blindness, and reduce inspection costs.
(5) Pay attention to indoor quality control, inter-room quality assessment and quality assurance, and strengthen management, including instrument maintenance, reagent selection, experimental conditions and process specifications. Manual ELISA should have a positive, negative control and standard curve for each plate. Although the TM known so far does not have any sensitivity or specificity of 100%, it can provide very useful information for the clinic when its application is reasonable. Therefore, many TM assays have become an adjunct to clinical routine diagnosis. The study of the optimal combination of serum TM should also attract attention in tumor testing.
V. Common biological significance of tumor markers (1) Alpha-fetoprotein (AFP) is applied to the detection of primary hepatocellular carcinoma, ovarian embryo sinus cancer, and testicular non-spermatogonia. AFP is the best TM in the diagnosis of primary liver cancer. 60%~70% of patients with primary liver cancer in China are AFP positive. Where AFP>500μg/L for 1 month or AFP>200μg/L for 2 months without evidence of hepatitis activity, exclude pregnancy and gonads, both internal and external embryonic tumors, should be highly suspected of liver cancer. The clinical value of AFP in primary liver cancer includes: (1) the specificity is second only to pathological examination in various diagnostic methods, and the false positive rate is 2%; (2) one of the best early diagnosis methods available. Diagnosis is made 6 to 12 months before the onset of symptoms; (3) sensitively reflects changes in the condition and treatment; (4) contributes to the findings of subclinical recurrence and metastasis.
(2) Carcinoembryonic antigen (CEA) is applied to malignant tumors differentiated from endoderm, such as glandular tumors (breast cancer, lung adenocarcinoma, gastric cancer, colon cancer, rectal cancer), and the positive rate is higher. Cancerous pleural effusion, gastric juice can be positive before the serum. Because CEA is also found to be elevated in some benign tumors such as intestinal polyps, the specificity is not strong and cannot be used for tumor screening tests, but it can be used as one of the clinical staging indicators and disease dynamic detection items for colorectal cancer.
(C) carbohydrate antigen (CA19-9), also known as gastrointestinal cancer antigen, for the detection of pancreatic cancer, cholangiocarcinoma, colon cancer, gastric cancer can also have a higher positive detection rate. Among them, serum CA19-9 was significantly elevated in patients with pancreatic cancer and gallbladder cancer, and the patients were more prominent in advanced stage, with sensitivity ranging from 65% to 87% and specificity ranging from 78% to 94%. In addition, CA19-9 can also be used as a joint detection index for AFP in patients with liver cancer, especially for patients with AFP-negative primary liver cancer, CA19-9 has a fairly positive detection rate.
(4) The use of carbohydrate antigen (CA125) in the differential diagnosis of gynecological malignancies, such as ovarian epithelial cell carcinoma, serous cystic carcinoma, endometrial carcinoma, mucinous cystic carcinoma, clear cell carcinoma, malignant fibrous epithelial cancer, Malignant mesothelioma, germ cell carcinoma, etc., CA125 levels can be significantly increased. It also has certain reference value for the diagnosis of liver cancer, lung cancer and colon cancer.
(5) Carbohydrate antigen (CA15-3) is an antigen associated with human breast cancer, and is a specific indicator for breast cancer tracking and surveillance. It is also a good indicator for monitoring recurrence after breast cancer treatment. When breast cancer is associated with liver and bone metastasis, CAl5-3 is elevated. Ovarian cancer, endometrial cancer has a certain positive detection rate.
(VI) Carbohydrate antigen (CA724) isolated a tumor-associated protein from liver metastases of breast cancer, with a sensitivity to gastric cancer of 60%, higher than CA19-9 and CEA, and suitable for postoperative patients with gastric cancer and chemotherapy. As a therapeutic observation and tracking of recurrence indicators. Carbohydrate antigens also have certain sensitivity to biliary system, colon, rectum and pancreatic tumors, and can be used as reference indicators for joint detection.
(7) Serum ferritin is the most abundant protein in iron in addition to hemoglobin in human body. It can be used for the detection of primary liver cancer. Combined with AFP, it can significantly improve the positive rate of detection. In the digestive tract tumor, nasopharyngeal carcinoma, breast cancer, bone metastasis and liver and lymphatic gland metastasis can be significantly increased, can be used as a dynamic observation after treatment, is conducive to metastatic cancer discovery or prognosis.
In addition, there are lung cancer antigens CYFRA21-1, neuron specific enolase, prostatic acid phosphatase, prostate specific antigen, alkaline phosphatase and isoenzyme, creatine kinase and isoenzyme, lactate dehydrogenase and co-workers. Enzymes have a great effect on the diagnosis of tumors, the recovery after observation and treatment, and the judgment of metastasis and prognosis. The English abbreviation of the common TM and the main clinical applications are shown in Table 1 (omitted).
Since the 1980s, TM has begun to emerge in large numbers. There are thousands of monoclonal antibodies available, and new antibodies are being introduced. However, no marker has been found to be unique to cancer cells. The pathological diagnosis is still The most reliable means of judging tumors. Although TM can not be used for clinical diagnosis, it has unique value in the monitoring of curative effect, prognosis, indication of recurrence and high-risk population, and its development space will be more extensive and deep.
Tumors are high-risk and high-mortality diseases that pose a serious threat to human health. Studies have shown that one out of every four deaths is a tumor, so early diagnosis and early treatment are the most effective in preventing and reducing cancer and reducing mortality. Method. Since Herberman proposed the concept of tumor markers (TM) in 1978, many tumor-related biochemical and immunological indicators have been discovered, providing a possible way to achieve early detection of tumors. At present, with the progress of tumor molecular biology and immunology and the human genome project, this field has become a hot spot in tumor basic and clinical research.