Progress in the application of molecular testing in the diagnosis and treatment of thyroid cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Yajing ¹ , DENG Juan ² , LUO Si ² ,  TANG Yuan ¹

1. Department of Pathology, West China Hospital, Sichuan university, Chengdu 610041, P. R. China;
2. Shanghai RIGEN Biotechnology Co., Ltd., Shanghai 200237, P. R. China;

Corresponding author：

TANG Yuan, Email: 1202ty@163.com

Keywords：

thyroid cancer; molecular testing; molecular risk stratification; targeted therapy; precision medicine

DOI：

10.7507/1007-9424.202509089

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the recent advances and clinical applications of molecular testing in thyroid cancer, discussing its significance in the era of precision medicine and future perspectives. Methods A systematic review of relevant domestic and international literature was conducted to identify key molecular events closely associated with the development, progression, and prognosis of thyroid cancer, and to evaluate their clinical utility. Results Molecular testing provides critical auxiliary diagnostic information for thyroid nodules with indeterminate fine-needle aspiration results. Furthermore, for diagnosed differentiated thyroid cancer, molecular markers serve as important tools for precise risk stratification, guiding surgical extent, radioactive iodine therapy decisions, and targeted drug applications. Conclusion Molecular testing has become a cornerstone tool in advancing thyroid cancer management toward precision medicine, future efforts should focus on exploring novel molecular markers and optimizing clinical practice guidelines.

1.	Ali SZ, Baloch ZW, Cochand-Priollet B, et al. The 2023 Bethesda system for reporting thyroid cytopathology. Thyroid, 2023, 33(9): 1039-1044.
2.	殷德涛, 赵乾. 全球及中国甲状腺癌的发病特征及趋势. 中国普外基础与临床杂志, 2025, 32(6): 687-693.
3.	何林烨, 王艺超, 李志辉. 2022年中国甲状腺癌流行情况分析: 基于《中国肿瘤登记年报》2005-2018年数据. 中国普外基础与临床杂志, 2024, 31(7): 790-795.
4.	Du L, Li R, Ge M, et al. Incidence and mortality of thyroid cancer in China, 2008-2012. Chin J Cancer Res, 2019, 31(1): 144-151.
5.	Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent, 2024, 4(1): 47-53.
6.	Zeng H, Zheng R, Sun K, et al. Cancer survival statistics in China 2019-2021: a multicenter, population-based study. J Natl Cancer Cent, 2024, 4(3): 203-213.
7.	Valderrabano P, Eszlinger M, Stewardson P, et al. Clinical value of molecular markers as diagnostic and prognostic tools to guide treatment of thyroid cancer. Clin Endocrinol (Oxf), 2023, 98(6): 753-762.
8.	Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell, 2014, 159(3): 676-690.
9.	Ringel MD, Sosa JA, Baloch Z, et al. 2025 American Thyroid Association management guidelines for adult patients with differentiated thyroid cancer. Thyroid, 2025, 35(8): 841-985.
10.	Moulana FI, Priyani AAH, de Silva MVC, et al. BRAF-oncogene-induced senescence and the role of thyroid-stimulating hormone signaling in the progression of papillary thyroid carcinoma. Horm Cancer, 2018, 9(1): 1-11.
11.	Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol, 2011, 7(10): 569-580.
12.	Karimi AH, Zeng PY, Cecchini M, et al. Novel insights in advanced thyroid carcinoma: from mechanisms to treatments: molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma. Eur Thyroid J, 2025, 14(3): e250057. doi: 10.1530/ETJ-25-0057.
13.	Jeong SH, Hong HS, Lee EH, et al. Analysis of RAS mutation in thyroid nodular hyperplasia and follicular neoplasm in a Korean population. Endocrinol Diabetes Metab, 2018, 1(4): e00040. doi: 10.1002/edm2.40.
14.	Howell GM, Hodak SP, Yip L. RAS mutations in thyroid cancer. Oncologist, 2013, 18(8): 926-932.
15.	Zhang Y, Zheng WH, Zhou SH, et al. Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives. Cell Commun Signal, 2024, 22(1): 460. doi: 10.1186/s12964-024-01837-x.
16.	Landa I, Cabanillas ME. Genomic alterations in thyroid cancer: biological and clinical insights. Nat Rev Endocrinol, 2024, 20(2): 93-110.
17.	Yip L, Ferris RL. Clinical application of molecular testing of fine-needle aspiration specimens in thyroid nodules. Otolaryngol Clin North Am, 2014, 47(4): 557-571.
18.	Cha YJ, Koo JS. Next-generation sequencing in thyroid cancer. J Transl Med, 2016, 14(1): 322. doi: 10.1186/s12967-016-1074-7.
19.	Schumm MA, Shu ML, Hughes EG, et al. Prognostic value of preoperative molecular testing and implications for initial surgical management in thyroid nodules harboring suspected (Bethesda Ⅴ) or known (Bethesda Ⅵ) papillary thyroid cancer. JAMA Otolaryngol Head Neck Surg, 2023, 149(8): 735-742.
20.	Livhits MJ, Zhu CY, Kuo EJ, et al. Effectiveness of molecular testing techniques for diagnosis of indeterminate thyroid nodules: a randomized clinical trial. JAMA Oncol, 2021, 7(1): 70-77.
21.	Patel J, Klopper J, Cottrill EE. Molecular diagnostics in the evaluation of thyroid nodules: current use and prospective opportunities. Front Endocrinol (Lausanne), 2023, 14: 1101410. doi: 10.3389/fendo.2023.1101410.
22.	Mete O, Boucher A, Schrader KA, et al. Consensus statement: recommendations on actionable biomarker testing for thyroid cancer management. Endocr Pathol, 2024, 35(4): 293-308.
23.	Najafian A, Noureldine S, Azar F, et al. RAS mutations, and RET/PTC and PAX8/PPAR-gamma chromosomal rearrangements are also prevalent in benign thyroid lesions: implications thereof and a systematic review. Thyroid, 2017, 27(1): 39-48.
24.	Ding M, Wu G, Zhang S, et al. Clinical implications and application of molecular testing in the diagnosis and management of thyroid nodules in the Chinese population. Clin Cancer Res, 2025. doi: 10.1158/1078-0432.CCR-25-0270.
25.	WHO Classification of Tumours Online. https://tumourclassification.iarc.who.int/welcome/.
26.	Zhao H, Zhang ZH, Zhou B, et al. Detection of BRAF c. 1799T>A (p. V600E) mutation using residual routine fine-needle aspiration specimens of papillary thyroid carcinoma. Diagn Cytopathol, 2015, 43(10): 786-790.
27.	Chen H, Song A, Wang Y, et al. BRAFV600E mutation test on fine-needle aspiration specimens of thyroid nodules: clinical correlations for 4600 patients. Cancer Med, 2022, 11(1): 40-49.
28.	Zhang YZ, Xu T, Cui D, et al. Value of TIRADS, BSRTC and FNA-BRAF V600E mutation analysis in differentiating high-risk thyroid nodules. Sci Rep, 2015, 5: 16927. doi: 10.1038/srep16927.
29.	张亚丽, 王冬青, 张贺, 等. 大样本评价BRAF V600E基因检测在甲状腺细胞学诊断中的价值. 中华病理学杂志, 2020, 49(2): 186-188.
30.	管文燕, 郑金榆, 聂岭, 等. 基因检测在甲状腺结节诊断中分层应用模式的研究. 中华病理学杂志, 2024, 53(3): 264-268.
31.	甲状腺细针穿刺细胞病理学诊断专家共识编写组, 中华医学会病理学分会细胞病理学组. 甲状腺细针穿刺细胞病理学诊断专家共识 (2023版). 中华病理学杂志, 2023, 52(5): 441-446.
32.	Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol, 2016, 2(8): 1023-1029.
33.	Nikiforov YE, Baloch ZW, Hodak SP, et al. Change in diagnostic criteria for noninvasive follicular thyroid neoplasm with papillarylike nuclear features. JAMA Oncol, 2018, 4(8): 1125-1126.
34.	广东省医学教育协会甲状腺专业委员会, 广东省基层医药学会细胞病理与分子诊断专业委员会. 甲状腺癌基因检测与临床应用广东专家共识 (2020版). 中华普通外科学文献 (电子版), 2020, 14(3): 161-168.
35.	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会 (CSCO) 分化型甲状腺癌诊疗指南2021. 肿瘤预防与治疗, 2021, 34(12): 1164-1200.
36.	中华医学会内分泌学分会, 中华医学会外科学分会甲状腺及代谢外科学组, 中国抗癌协会头颈肿瘤专业委员会, 等. 甲状腺结节和分化型甲状腺癌诊治指南 (第二版). 中华内分泌代谢杂志, 2023, 39(3): 181-226.
37.	Mauri G, Hegedüs L, Bandula S, et al. European Thyroid Association and Cardiovascular and Interventional Radiological Society of Europe 2021 clinical practice guideline for the use of minimally invasive treatments in malignant thyroid lesions. Eur Thyroid J, 2021, 10(3): 185-197.
38.	Liu J, Liu R, Shen X, et al. The genetic duet of BRAF V600E and TERT promoter mutations robustly predicts loss of radioiodine avidity in recurrent papillary thyroid cancer. J Nucl Med, 2020, 61(2): 177-182.
39.	Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med, 2013, 368(7): 623-632.
40.	中国临床肿瘤学会核医学专家委员会, 中国临床肿瘤学会甲状腺癌专家委员会, 中华医学会核医学分会, 等. 放射性碘难治性分化型甲状腺癌诊治管理指南 (2024版). 中华核医学与分子影像杂志, 2024, 44(6): 359-372.
41.	Rothenberg SM, McFadden DG, Palmer EL, et al. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res, 2015, 21(5): 1028-1035.
42.	Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase Ⅱ ROAR basket study. Ann Oncol, 2022, 33(4): 406-415.
43.	Paspala A, Bompetsi G, Paschou SA, et al. The value of preoperative molecular testing in the management of Bethesda Ⅴ and Bethesda Ⅵ thyroid tumors. Hormones (Athens), 2025, 24(1): 217-229.
44.	Xing M, Liu R, Liu X, et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol, 2014, 32(25): 2718-2726.
45.	Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines task force on thyroid nodules and differentiated thyroid Cancer. Thyroid, 2016, 26(1): 1-133.
46.	Liu J, Gao W, Zheng X, et al. Molecular testing stratifies the risk of structural recurrence in high risk differentiated thyroid cancer: a retrospective cohort study. Front Endocrinol (Lausanne), 2025 Jan 24: 16: 1508404. doi: 10.3389/fendo.2025.1508404.
47.	广东省医学教育协会甲状腺专业委员会, 广东省基层医药学会细胞病理与分子诊断专业委员会. 甲状腺癌RET基因检测与临床应用专家共识 (2021版). 中华普通外科学文献 (电子版), 2022, 16(1): 1-8.
48.	中国医师协会外科医师分会甲状腺外科医师委员会, 中国抗癌协会甲状腺癌专业委员会, 中国研究型医院学会甲状腺疾病专业委员会. 甲状腺髓样癌诊断与治疗中国专家共识 (2020版). 中国实用外科杂志, 2020, 40(9): 1012-1020.
49.	Wells SA, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 2015, 25(6): 567-610.
50.	Castinetti F, Waguespack SG, Machens A, et al. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. Lancet Diabetes Endocrinol, 2019, 7(3): 213-220.

1. Ali SZ, Baloch ZW, Cochand-Priollet B, et al. The 2023 Bethesda system for reporting thyroid cytopathology. Thyroid, 2023, 33(9): 1039-1044.
2. 殷德涛, 赵乾. 全球及中国甲状腺癌的发病特征及趋势. 中国普外基础与临床杂志, 2025, 32(6): 687-693.
3. 何林烨, 王艺超, 李志辉. 2022年中国甲状腺癌流行情况分析: 基于《中国肿瘤登记年报》2005-2018年数据. 中国普外基础与临床杂志, 2024, 31(7): 790-795.
4. Du L, Li R, Ge M, et al. Incidence and mortality of thyroid cancer in China, 2008-2012. Chin J Cancer Res, 2019, 31(1): 144-151.
5. Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent, 2024, 4(1): 47-53.
6. Zeng H, Zheng R, Sun K, et al. Cancer survival statistics in China 2019-2021: a multicenter, population-based study. J Natl Cancer Cent, 2024, 4(3): 203-213.
7. Valderrabano P, Eszlinger M, Stewardson P, et al. Clinical value of molecular markers as diagnostic and prognostic tools to guide treatment of thyroid cancer. Clin Endocrinol (Oxf), 2023, 98(6): 753-762.
8. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell, 2014, 159(3): 676-690.
9. Ringel MD, Sosa JA, Baloch Z, et al. 2025 American Thyroid Association management guidelines for adult patients with differentiated thyroid cancer. Thyroid, 2025, 35(8): 841-985.
10. Moulana FI, Priyani AAH, de Silva MVC, et al. BRAF-oncogene-induced senescence and the role of thyroid-stimulating hormone signaling in the progression of papillary thyroid carcinoma. Horm Cancer, 2018, 9(1): 1-11.
11. Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol, 2011, 7(10): 569-580.
12. Karimi AH, Zeng PY, Cecchini M, et al. Novel insights in advanced thyroid carcinoma: from mechanisms to treatments: molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma. Eur Thyroid J, 2025, 14(3): e250057. doi: 10.1530/ETJ-25-0057.
13. Jeong SH, Hong HS, Lee EH, et al. Analysis of RAS mutation in thyroid nodular hyperplasia and follicular neoplasm in a Korean population. Endocrinol Diabetes Metab, 2018, 1(4): e00040. doi: 10.1002/edm2.40.
14. Howell GM, Hodak SP, Yip L. RAS mutations in thyroid cancer. Oncologist, 2013, 18(8): 926-932.
15. Zhang Y, Zheng WH, Zhou SH, et al. Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives. Cell Commun Signal, 2024, 22(1): 460. doi: 10.1186/s12964-024-01837-x.
16. Landa I, Cabanillas ME. Genomic alterations in thyroid cancer: biological and clinical insights. Nat Rev Endocrinol, 2024, 20(2): 93-110.
17. Yip L, Ferris RL. Clinical application of molecular testing of fine-needle aspiration specimens in thyroid nodules. Otolaryngol Clin North Am, 2014, 47(4): 557-571.
18. Cha YJ, Koo JS. Next-generation sequencing in thyroid cancer. J Transl Med, 2016, 14(1): 322. doi: 10.1186/s12967-016-1074-7.
19. Schumm MA, Shu ML, Hughes EG, et al. Prognostic value of preoperative molecular testing and implications for initial surgical management in thyroid nodules harboring suspected (Bethesda Ⅴ) or known (Bethesda Ⅵ) papillary thyroid cancer. JAMA Otolaryngol Head Neck Surg, 2023, 149(8): 735-742.
20. Livhits MJ, Zhu CY, Kuo EJ, et al. Effectiveness of molecular testing techniques for diagnosis of indeterminate thyroid nodules: a randomized clinical trial. JAMA Oncol, 2021, 7(1): 70-77.
21. Patel J, Klopper J, Cottrill EE. Molecular diagnostics in the evaluation of thyroid nodules: current use and prospective opportunities. Front Endocrinol (Lausanne), 2023, 14: 1101410. doi: 10.3389/fendo.2023.1101410.
22. Mete O, Boucher A, Schrader KA, et al. Consensus statement: recommendations on actionable biomarker testing for thyroid cancer management. Endocr Pathol, 2024, 35(4): 293-308.
23. Najafian A, Noureldine S, Azar F, et al. RAS mutations, and RET/PTC and PAX8/PPAR-gamma chromosomal rearrangements are also prevalent in benign thyroid lesions: implications thereof and a systematic review. Thyroid, 2017, 27(1): 39-48.
24. Ding M, Wu G, Zhang S, et al. Clinical implications and application of molecular testing in the diagnosis and management of thyroid nodules in the Chinese population. Clin Cancer Res, 2025. doi: 10.1158/1078-0432.CCR-25-0270.
25. WHO Classification of Tumours Online. https://tumourclassification.iarc.who.int/welcome/.
26. Zhao H, Zhang ZH, Zhou B, et al. Detection of BRAF c. 1799T>A (p. V600E) mutation using residual routine fine-needle aspiration specimens of papillary thyroid carcinoma. Diagn Cytopathol, 2015, 43(10): 786-790.
27. Chen H, Song A, Wang Y, et al. BRAFV600E mutation test on fine-needle aspiration specimens of thyroid nodules: clinical correlations for 4600 patients. Cancer Med, 2022, 11(1): 40-49.
28. Zhang YZ, Xu T, Cui D, et al. Value of TIRADS, BSRTC and FNA-BRAF V600E mutation analysis in differentiating high-risk thyroid nodules. Sci Rep, 2015, 5: 16927. doi: 10.1038/srep16927.
29. 张亚丽, 王冬青, 张贺, 等. 大样本评价BRAF V600E基因检测在甲状腺细胞学诊断中的价值. 中华病理学杂志, 2020, 49(2): 186-188.
30. 管文燕, 郑金榆, 聂岭, 等. 基因检测在甲状腺结节诊断中分层应用模式的研究. 中华病理学杂志, 2024, 53(3): 264-268.
31. 甲状腺细针穿刺细胞病理学诊断专家共识编写组, 中华医学会病理学分会细胞病理学组. 甲状腺细针穿刺细胞病理学诊断专家共识 (2023版). 中华病理学杂志, 2023, 52(5): 441-446.
32. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol, 2016, 2(8): 1023-1029.
33. Nikiforov YE, Baloch ZW, Hodak SP, et al. Change in diagnostic criteria for noninvasive follicular thyroid neoplasm with papillarylike nuclear features. JAMA Oncol, 2018, 4(8): 1125-1126.
34. 广东省医学教育协会甲状腺专业委员会, 广东省基层医药学会细胞病理与分子诊断专业委员会. 甲状腺癌基因检测与临床应用广东专家共识 (2020版). 中华普通外科学文献 (电子版), 2020, 14(3): 161-168.
35. 中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会 (CSCO) 分化型甲状腺癌诊疗指南2021. 肿瘤预防与治疗, 2021, 34(12): 1164-1200.
36. 中华医学会内分泌学分会, 中华医学会外科学分会甲状腺及代谢外科学组, 中国抗癌协会头颈肿瘤专业委员会, 等. 甲状腺结节和分化型甲状腺癌诊治指南 (第二版). 中华内分泌代谢杂志, 2023, 39(3): 181-226.
37. Mauri G, Hegedüs L, Bandula S, et al. European Thyroid Association and Cardiovascular and Interventional Radiological Society of Europe 2021 clinical practice guideline for the use of minimally invasive treatments in malignant thyroid lesions. Eur Thyroid J, 2021, 10(3): 185-197.
38. Liu J, Liu R, Shen X, et al. The genetic duet of BRAF V600E and TERT promoter mutations robustly predicts loss of radioiodine avidity in recurrent papillary thyroid cancer. J Nucl Med, 2020, 61(2): 177-182.
39. Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med, 2013, 368(7): 623-632.
40. 中国临床肿瘤学会核医学专家委员会, 中国临床肿瘤学会甲状腺癌专家委员会, 中华医学会核医学分会, 等. 放射性碘难治性分化型甲状腺癌诊治管理指南 (2024版). 中华核医学与分子影像杂志, 2024, 44(6): 359-372.
41. Rothenberg SM, McFadden DG, Palmer EL, et al. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res, 2015, 21(5): 1028-1035.
42. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase Ⅱ ROAR basket study. Ann Oncol, 2022, 33(4): 406-415.
43. Paspala A, Bompetsi G, Paschou SA, et al. The value of preoperative molecular testing in the management of Bethesda Ⅴ and Bethesda Ⅵ thyroid tumors. Hormones (Athens), 2025, 24(1): 217-229.
44. Xing M, Liu R, Liu X, et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol, 2014, 32(25): 2718-2726.
45. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines task force on thyroid nodules and differentiated thyroid Cancer. Thyroid, 2016, 26(1): 1-133.
46. Liu J, Gao W, Zheng X, et al. Molecular testing stratifies the risk of structural recurrence in high risk differentiated thyroid cancer: a retrospective cohort study. Front Endocrinol (Lausanne), 2025 Jan 24: 16: 1508404. doi: 10.3389/fendo.2025.1508404.
47. 广东省医学教育协会甲状腺专业委员会, 广东省基层医药学会细胞病理与分子诊断专业委员会. 甲状腺癌RET基因检测与临床应用专家共识 (2021版). 中华普通外科学文献 (电子版), 2022, 16(1): 1-8.
48. 中国医师协会外科医师分会甲状腺外科医师委员会, 中国抗癌协会甲状腺癌专业委员会, 中国研究型医院学会甲状腺疾病专业委员会. 甲状腺髓样癌诊断与治疗中国专家共识 (2020版). 中国实用外科杂志, 2020, 40(9): 1012-1020.
49. Wells SA, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 2015, 25(6): 567-610.
50. Castinetti F, Waguespack SG, Machens A, et al. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. Lancet Diabetes Endocrinol, 2019, 7(3): 213-220.

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