• Volume 27,Issue 5,2018 Table of Contents
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    • >述评
    • Application options of endoscopic techniques in thyroid surgery

      2018, 27(5):531-534. DOI: 10.3978/j.issn.1005-6947.2018.05.001

      Abstract (177) HTML (712) PDF 1.22 M (589) Comment (0) Favorites

      Abstract:With the development of endoscopic techniques and perfection of surgical skills in thyroid surgery, endoscopic approaches have been increasingly used in thyroid surgery. However, the indications and appropriate selection of the endoscopic procedures for endoscopic thyroid surgery are still controversial in practical application. There is no doubt that endoscopic techniques offer benefits for the thyroid patients, but the strict adherence to indications, standardized treatment strategies, strong surgical skills and individualized treatment to a specific patient are still of great importance.

    • >专题研究
    • Efficacy comparison of endoscopic thyroidectomy via bilateral areolar approach and conventional open thyroidectomy in treatment of T1 papillary thyroid cancer

      2018, 27(5):535-540. DOI: 10.3978/j.issn.1005-6947.2018.05.002

      Abstract (247) HTML (716) PDF 1.57 M (645) Comment (0) Favorites

      Abstract:Objective: To compare the clinical effects between endoscopic thyroidectomy via bilateral areolar approach and conventional open thyroidectomy in treatment of T1 papillary thyroid cancer (PTC). Methods: The clinical data of 56 patients with T1 PTC undergoing endoscopic thyroidectomy via bilateral areolar approach (endoscopic group) and 56 patients with T1 PTC undergoing conventional open surgery (open surgery group) from January 2016 to December 2017 were retrospectively analyzed. Results: There were no significant differences in preoperative data and surgical procedures between the two groups (all P>0.05). The average operative time in endoscopic group was significantly longer than that in open surgery group (132.1 min vs. 96.7 min, P<0.05), but no significant differences were noted in intraoperative blood loss, the number of dissected lymph nodes, rate of positive lymph nodes and incidence of postoperative complications between the two groups (all P>0.05). In endoscopic group, the operative time and incidence of postoperative temporary hypocalcemia were increased in patients with the diameter of lesion less than 1 cm compared with those with the diameter of lesion from 1 to 2 cm (both P<0.05), but no significant differences were seen in intraoperative blood loss, number of dissected lymph nodes and rate of positive lymph nodes and incidence of postoperative complications between them (all P>0.05). No signs of recurrence or metastasis were noted in both groups during follow-up. Conclusion: Endoscopic thyroidectomy via bilateral areolar approach is safe and feasible for T1 PTC, and it also has similar clinical efficacy to that of open thyroidectomy.

    • Clinical value of routine serum calcitonin measurement for early detection of medullary thyroid carcinoma in patients with thyroid nodules

      2018, 27(5):541-546. DOI: 10.3978/j.issn.1005-6947.2018.05.003

      Abstract (225) HTML (900) PDF 1.07 M (710) Comment (0) Favorites

      Abstract:Objective: To investigate the value of serum calcitonin (Ct) detection for diagnosis of medullary thyroid carcinoma (MTC) in patients with thyroid nodules. Methods: The clinical data of 1 922 patients admitted to the Department of Thyroid Surgery, the First Affiliated Hospital of Zhengzhou University due to thyroid nodules and undergoing surgical treatment from October 2016 to August 2017 were retrospectively analyzed. All patients underwent routine serum Ct detection before operation, and had definite postoperative pathological diagnosis. The relationship between Ct level and MTC was analyzed, and the diagnostic efficiency of Ct for MTC was evaluated by receiver operating characteristic curve analysis. Results: In the 1 922 patients with thyroid nodules, 12 cases (0.62%) were newly diagnosed as MTC. In 155 patients with preoperative Ct value ranging from 10 to 100 pg/mL, 12 patients with preoperative Ct value ranging from more than 100 to 500 pg/mL and 10 patients with preoperative Ct value more than 500 pg/mL, MTC was diagnosed in one case (0.65%), one case (8.33%) and 9 cases (90.00%), respectively. In the 9 MTC patients with preoperative Ct value more than 500 pg/mL, 8 cases (88.89%) had different levels of cervical lymph node metastasis. The cut-off value of serum Ct for diagnosis of MTC was 258.5 pg/mL, with a sensitivity of 90.91% and a specificity of 96.99%. Conclusion: Routine preoperative serum Ct detection is helpful for the early diagnosis of MTC, and it has great importance in patients for receiving thorough surgical resection and avoiding repeated operation.

    • Analysis of prognostic factors for medullary thyroid carcinoma based on SEER database

      2018, 27(5):547-552. DOI: 10.3978/j.issn.1005-6947.2018.05.004

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      Abstract:

      Objective: To investigate the factors affecting the prognosis of patients with medullary thyroid carcinoma (MTC). Methods: The data of 602 patients with definite pathological diagnosis of MTC were collected from SEER database within 2010 to 2014 by using SEER*Stat software. The survival rates of the patients were analyzed by Kaplan-Meier method and Log-rank test, and the risk factors for survival of the patients were determined by univariate analysis and multivariate Cox regression model. Results: Of the 602 patients, the mean survival time was (54.914±1.209) months, and the 1- and 3-year overall survival rate was 96.9% and 90.8%, respectively. The results of univariate analysis showed that age at diagnosis (χ2=33.232, P<0.001), sex (χ2=4.030, P<0.045), size of primary tumor (χ2=37.060, P<0.001), number of lesions (χ2=6.876, P=0.009), clinical stage (χ2=116.467, P<0.001), primary tumor stage (χ2=72.482, P<0.001), regional lymph node involvement (χ2=14.803, P<0.001), distant metastasis (χ2=94.976; P<0.001), surgical procedure (χ2=80.536, P<0.001) and number of positive lymph nodes (χ2=18.700, P<0.001) were significantly related to the survival rate of the patients. The results of multivariate Cox analysis revealed that age at diagnosis (HR=2.777, 95% CI=1.800–4.285, P<0.001), primary tumor stage (HR=1.675, 95% CI=1.289–2.176, P<0.001) and distant metastasis (HR=5.401, 95% CI=2.720–10.725, P<0.001) were independent risk factors for the prognosis of the patients. Conclusion: The clinical variables that include age at diagnosis, primary tumor stage and distant metastasis can be used as the independent predictive indicators for the prognosis of the MTC patients.

    • Identification of parathyroid glands during thyroid cancer surgery by bright-field microscopy without staining

      2018, 27(5):553-559. DOI: 10.3978/j.issn.1005-6947.2018.05.005

      Abstract (103) HTML (566) PDF 1.59 M (651) Comment (0) Favorites

      Abstract:Objective: To investigate the accuracy and clinical application value of using bright-field microscopy without any staining for identification of parathyroid glands during thyroid cancer surgery. Methods: Among a total of 357 patients undergoing surgical treatment for thyroid cancer during January 2016 to June 2017, 196 suspected inferior parathyroid tissues were found in 115 cases. A sample about 2 mm3 in size was taken from each suspected tissue, and then evenly divided into two parts. One part was crushed on a glass slide by compression method for parathyroid gland identification using bright-field microscopy without staining, and the other one was sent for intraoperative frozen pathological examination. The results of the two methods were compared using the results of frozen pathological examination as gold standard. Results: In 196 suspected inferior parathyroid tissues, 142 were identified as parathyroid tissue, 29 as adipose tissue, 17 as lymph node tissue and 8 as thymus tissue by bright-field microscopy without staining; 146 were diagnosed as parathyroid tissue, 27 as adipose tissue, 16 as lymph node tissue and 7 as thymus tissue by intraoperative frozen pathological examination. The sensitivity and specificity of the bright-field microscopy without staining for detecting parathyroid tissue, adipose tissue, lymph node tissue and thymus tissue were 97.26% and 100.00%, 93.00% and 97.63%, 88.00% and 98.33%, and 83.00% and 98.42%, respectively. The results of consistency test showed that there was a high consistency between the two methods, as shown by the κ value for parathyroid tissue of 0.948, adipose tissue of 0.875, lymph node tissue of 0.835 and thymus tissue of 0.835 and 0.704, respectively. Conclusion: The sensitivity and specificity of bright-field microscopy without staining for parathyroid identification during thyroid cancer surgery are high. It can accurately distinguish parathyroid tissue and other tissues, and thereby reduce inadvertent parathyroidectomy and wrong autologous transplantation. Meanwhile, it has the advantages of simple operation, less time-consuming and low cost. So, it is recommended to be used.

    • Analysis of BRAFT1799A gene mutation and its relations with clinicopathologic features in papillary thyroid cancer

      2018, 27(5):560-566. DOI: 10.3978/j.issn.1005-6947.2018.05.006

      Abstract (340) HTML (647) PDF 1.33 M (658) Comment (0) Favorites

      Abstract:Objective: To investigate the BRAFT1799A gene mutation in papillary thyroid cancer (PTC) tissues and its relations with clinicopathologic features of PTC. Methods: Ninety-seven samples of PTC tissue along with 52 samples of normal thyroid tissue adjacent to PTC and 49 samples of nodular goiter tissue were collected. The BRAFT1799A gene mutations in these tissues were determined by nested PCR. The relations of BRAFT1799A gene mutation with clinicopathologic factors of PTC were analyzed. Results: In the 97 samples of PTC tissue, BRAFT1799A gene mutation was found in 49 samples (60.82%), while no BRAFT1799A gene mutation was found in samples of normal thyroid tissue adjacent to PTC and nodular goiter tissue, and the difference had statistical significance (P<0.05). In PTC patients, the BRAFT1799A gene mutation showed no significant relation with the gender, age and tumor size (all P>0.05), but was significantly related to the clinical stage, multiple foci, extra-capsular invasion, lymph node metastasis, thyroglobulin value after six months of standardized treatment and distant metastases (all P<0.05). Subtype classification of PTC showed that one case was eosinophilic cytoplasm variant PTC, one case was tall cell variant PTC, 46 cases were conventional PTC, and 49 cases were follicular variant PTC; there was no significant difference in mutation rates of the BRAFT1799A gene between conventional PTC and follicular variant PTC (63.04% vs. 61.22%, P>0.05). Conclusion: There is a high mutation rate of BRAFT1799A gene in PTC, and the BRAFT1799A gene mutation may probably have a close relation with the postoperative recurrence and metastasis of PTC.

    • >基础研究
    • Changes in expressions of different molecular markers and their diagnostic values in thyroid papillary carcinoma

      2018, 27(5):567-574. DOI: 10.3978/j.issn.1005-6947.2018.05.007

      Abstract (139) HTML (651) PDF 2.02 M (581) Comment (0) Favorites

      Abstract:Objective: To investigate the changes in expressions of a variety of molecular markers in thyroid papillary carcinoma (PTC) and their diagnostic values for PTC. Methods: The expressions of TPO, CK19, Galectin-3, HBME-1 and Ki-67 in the postoperative pathological specimens from 85 PTC patients and 115 patients with benign thyroid nodules (BTN) were determined by immunohistochemical staining. The diagnostic values of each molecular marker and their combination for PTC were evaluated by using receiver operating characteristic curve (ROC) and binary Logistic regression equation. Results: In PTC tissue compared with BTN tissue, the expression levels of CK19, Galectin-3, HBME-1, and Ki-67 were significantly increased, while the expression level of TPO was significantly decreased (all P<0.05). In single detection of each molecular marker, TPO showed the biggest value of the area under the ROC curve (AUC), which was 0.943; in combined detection, the combination detection of all the 5 molecular markers possessed the biggest AUC value of 0.996, but it showed no significant differences compared with any combinations that included both Galectin-3 and TPO (all P>0.05). Conclusion: The expressions of multiple molecular markers are changed in PTC, and among them, the combination detection of Galectin-3 and TPO may have a relatively high diagnostic value for PTC.

    • Effect of down-regulating the expression of astrocyte elevated gene 1 on apoptosis of breast carcinoma cells

      2018, 27(5):575-580. DOI: 10.3978/j.issn.1005-6947.2018.05.008

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      Abstract:Objective: To investigate effect of down-regulating the expression of astrocyte elevated gene 1 (AEG-1) on cell apoptosis in breast cancer cells. Methods: Through liposome-mediated method, the breast cancer MCF-7 cells were transfected with AEG-1 siRNA (AEG-1 siRNA group) or negative control siRNA (negative control group), and the untreated MCF-7 cells served as blank control group. The transfection effects were observed, and then the apoptosis and the expressions of the apoptosis-associated protein caspase-3 and caspase-9 in each group of cells were determined by flow cytometry and Western blot analysis, respectively. Results: In AEG-1 siRNA group compared with blank control group, the expression of AEG-1 protein was significantly decreased, apoptosis rate was significantly increased, and the expressions of caspase-3 and caspase-9 were significantly up-regulated (all P<0.05). No significant differences were noted in above indexes between negative control group and blank control group (all P>0.05). Conclusion: Down-regulating AEG-1 expression can promote the expressions of caspase-3 and caspase-9, and thereby induce the apoptosis of the breast cancer cells. Thus, AEG-1 may play a role in apoptosis inhibition in breast cancer cells, and the mechanism is probably related to its regulating the expressions of apoptosis-associated proteins.

    • Expressions of Oct-4, SOX2 and KPNA2 in triple-negative breast cancer and their clinical significance

      2018, 27(5):581-587. DOI: 10.3978/j.issn.1005-6947.2018.05.009

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      Abstract:

      Objective: To investigate the expressions of Oct-4, SOX2 and KPNA2 in triple-negative breast cancer (TNBC) and their clinical significance. Methods: The expressions of Oct-4, SOX2 and KPNA2 in the cancer tissues from 30 TNBC patients and 30 non-TNBC patients were determined by immunohistochemical staining. The relations of their expressions with clinicopathologic factors and prognosis of the TNBC patients were analyzed. Results: In TNBC tissue compared with non-TNBC tissue, the positive expression rates of Oct-4 protein (86.7% vs. 73.3%, P<0.05) and SOX2 protein (90.0% vs. 70.0%, P<0.05) were significantly increased, while the positive expression rate KPNA2 protein showed no significant difference (P>0.05). The expressions of Oct-4, SOX2 and KPNA2 were positively correlated to each other in TNBC tissue (Oct-4 and SOX2: r=0.680, P<0.0001; Oct-4 and KPNA2: r=0.581, P=0.0008; SOX2 and KPNA2: r=0.770, P<0.0001). In TNBC patients, the Oct-4 expression was significantly related to age, histological grade, lymph node metastasis and TNM stage, the SOX2 expression was significantly related to lymph node metastasis and TNM stage, and the KPNA2 expression was significantly related to lymph node metastasis (all P<0.05); the overall survival rate in cases with positive Oct-4, SOX2 or KPNA2 expression was significantly lower than that in those with corresponding negative expression (all P<0.01). Conclusion: The expressions of Oct-4 and SOX2 are increased in TNBC tissue, and they may jointly participate with KPNA2 in the malignant progression of TNBC.

    • >临床研究
    • Efficacy analysis of Dunhill operation for bilateral multinodular goiter

      2018, 27(5):588-593. DOI: 10.3978/j.issn.1005-6947.2018.05.010

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      Abstract:Objective: To investigate the clinical efficacy of Dunhill operation (hemithyroidectomy plus contralateral subtotal resection) in treatment of bilateral multinodular goiter. Methods: The clinical data of 58 patients undergoing Dunhill operation and 60 patients undergoing bilateral subtotal thyroidectomy from January 2011 to January 2017 in the Fourth Affiliated Hospital of Harbin Medical University were retrospectively analyzed. All patients were confirmed to have bilateral multinodular goiter by intraoperative pathological diagnosis. Results: The preoperative data showed no significant difference between the two groups of patients (all P>0.05). In Dunhill operation group compared with bilateral subtotal thyroidectomy group, the average operative time was significantly prolonged (95.41 min vs. 52.48 min, P=0.000) and the incidence of hypocalcemia on the first postoperative day was significantly increased (12.1% vs. 1.7%, P=0.031), while there were no significant differences in the intraoperative blood loss, number of cases receiving parathyroid autotransplantation, incidence of recurrent laryngeal nerve injury, incidence of hypocalcemia on the third postoperative day and incidence of hypoparathyroidism between the two groups (all P>0.05). The recurrence rate in Dunhill operation group was significantly lower than that in bilateral subtotal thyroidectomy group during follow-up period (P=0.027). Conclusion: Dunhill operation is safe and effective in treatment of multinodular goiter, and also can effectively reduce the postoperative recurrence of the disease. So, it is recommended to be used in clinical practice.

    • Application of “the most inferior approach” in dissection of recurrent laryngeal nerve during thyroid surgery

      2018, 27(5):594-600. DOI: 10.3978/j.issn.1005-6947.2018.05.011

      Abstract (133) HTML (751) PDF 1.91 M (639) Comment (0) Favorites

      Abstract:Objective: To investigate the clinical efficacy of using “the most inferior approach” in identification of the recurrent laryngeal nerves (RLNs) during thyroid surgery. Methods: The clinical data of 22 patients undergoing thyroidectomy in Huainan No.1 People’s Hospital from December 2017 to April 2018 were retrospectively analyzed. All patients underwent identification and dissection of the RLNs through “the most inferior approach” to protect and avoid injury of the RLNs during surgical procedure. Results: Thyroid lobectomy was the main surgical procedure for the 22 patients, including unilateral or bilateral thyroid lobectomy in 17 cases for benign thyroid diseases, and radical resection in 7 cases for malignant tumor of the thyroid. All the RLNs of the operative sides (26 RLNs) were found during surgery, and no damage of the RLNs occurred in any of the patients. Thyroid surgery was safely performed in all patients. Conclusion: “The most inferior approach” is the concept of a way and method for exposure of the RLNs besides the conventional “superior, middle and inferior approaches”, and is also standardized and easily reproducible. This method is recommended to be used for its safety, simpleness and high accuracy, especially in patients with anatomical abnormalities caused by thyroid enlargement or severe adhesions, as well as in those with history of thyroid surgery requiring a repeat thyroidectomy.

    • Efficacy and safety of immediate breast reconstruction with extended latissimus dorsi myocutaneous flap after nipple-areolar-sparing mastectomy for breast cancer

      2018, 27(5):601-607. DOI: 10.3978/j.issn.1005-6947.2018.05.012

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      Abstract:Objective: To investigate the efficacy and safety of immediate breast reconstruction with extended latissimus dorsi myocutaneous flap after nipple-areolar-sparing mastectomy for breast cancer. Methods: The clinical data of 32 patients undergoing immediate breast reconstruction with extended latissimus dorsi myocutaneous flap after nipple-areolar-sparing mastectomy (observation group) and 34 patients undergoing conventional modified radical mastectomy (control group) in the Department of Surgical Oncology of the First Affiliated Hospital of Bengbu Medical College were retrospectively analyzed. The complications and outcomes between the two groups were compared and the postoperative breast appearances of the patients in observation group were analyzed. Results: There were no significant differences in age, tumor size and pathological stage between the two groups of patients (all P>0.05). The overall incidence of postoperative complications in observation group and control group showed no significant difference (37.5% vs. 32.4%, P>0.05). All patients were followed-up for 18 to 60 months with a median period of 44 months. Local recurrence occurred in 2 cases in observation group and 3 cases in control group, and distant metastasis occurred in 3 cases each in observation group and control group. The 3-year disease-free survival rate in observation group and control group showed no significant difference (87.5% vs. 91.2%, P>0.05). The excellent and good rate of the postoperative breast appearance was 90.6% in observation group. Conclusion: Immediate breast reconstruction with extended latissimus dorsi myocutaneous flap after nipple-areolar-sparing mastectomy is a safe and effective procedure, and it offers satisfactory postoperative breast appearance with no increase of the risks of complications as well as local recurrence and distant metastasis.

    • Values of Ki-67 expression level in predicting pathological complete response following neoadjuvant chemotherapy in breast cancer patients

      2018, 27(5):608-614. DOI: 10.3978/j.issn.1005-6947.2018.05.013

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      Abstract:Objective: To investigate the impact of Ki-67 expression level on efficacy of neoadjuvant chemotherapy (NAC) in breast cancer patients. Methods: A total of 261 patients with relatively complete clinicopathologic data undergoing NAC were collected. The relations of pathological complete response (pCR) after NAC with Ki-67 expression and other clinicopathologic factors such as molecular subtype and hormone receptor status of the patients were analyzed. Results: The results of univariate analysis showed that pCR after NAC of the patients was significantly related to the status of progestrone receptor (PR) and epidermal growth factor receptor 2 (Her-2) as well as molecular subtype and Ki-67 expression; the results of multivariate analysis revealed that only the Ki-67 expression level was the independent predictive factor for pCR after NAC (OR=5.476, 95% CI=2.637–11.372, P<0.05). In addition, among the patients with positive estrogen receptor (ER) expression, the pCR rate in cases with high Ki-67 expression was 4.282-fold of that in those with low Ki-67 expression (OR=4.282, 95% CI=1.694–10.825, P=0.002), in PR positive cases was 0.303-fold of that in PR negative ones (OR=0.303, 95% CI=0.113–0.810, P=0.017), and in Her-2 positive cases was 2.607-fold of that in their negative counterparts (OR=2.607, 95% CI=1.023–6.642, P=0.045). Conclusion: In breast cancer patients, high Ki-67 expression level is a predictive indicator for high pCR rate after NAC. Meanwhile, it may be helpful for better individualized NAC planning with combined considerations of the status of other hormone receptors.

    • >文献综述
    • Application progress of intraoperative neuromonitoring of the external branch of the superior laryngeal nerve during endoscopic thyroid surgery

      2018, 27(5):615-621. DOI: 10.3978/j.issn.1005-6947.2018.05.014

      Abstract (149) HTML (506) PDF 1.56 M (542) Comment (0) Favorites

      Abstract:In endoscopic thyroid surgery, the visualization of the external branch of the superior laryngeal nerve (EBSLN) is insufficient and the time to exposure of the EBSLN is variable, due to the space constraints, application of energy-based devices, interference between the working arms and different perspectives resulted from different approaches. So, the protection of the EBSLN is more difficult than that in open surgery, and furthermore, the conventional methods have several limitations for its protection. The application of intraoperative neuromonitoring technique with standardized process can not only allow precise positioning but also provide quantitative indicators to improve the surgical safety. Here, the authors address the application progress of intraoperative neuromonitoring of the EBSLN during endoscopic thyroid surgery based on a review of literature in China and abroad.

    • Preoperative molecular diagnosis of differentiated thyroid cancer: development status and future prospects

      2018, 27(5):622-628. DOI: 10.3978/j.issn.1005-6947.2018.05.015

      Abstract (166) HTML (536) PDF 1.07 M (519) Comment (0) Favorites

      Abstract:Among numerous thyroid nodules, the accurate identification of differentiated thyroid cancer (DTC), which is the main type of thyroid malignancy, is a critical component in preoperative evaluation of thyroid nodules, and is also the first step toward reducing diagnostic surgery and realizing the proper management of DTC. The molecular diagnosis may play an important role in this process. Based on review of the literature of the last 5 years, the authors address the progress in the field of molecular diagnosis, with the emphasis on application population and diagnostic efficiency evaluation, as well as the commercially available molecular diagnostic tools together with their application values, considerations of health economics, and the misconceptions.

    • Progress and discussion of methods for intraoperative identification of parathyroid glands

      2018, 27(5):629-634. DOI: 10.3978/j.issn.1005-6947.2018.05.016

      Abstract (143) HTML (531) PDF 1.08 M (514) Comment (0) Favorites

      Abstract:The incidence of thyroid diseases is increasing year by year. Surgery is one of the most important treatment options for thyroid diseases, in which, the intraoperative protection of the recurrent laryngeal nerve and identification of the parathyroid glands are always the important issues. The promotion of neural monitoring has provided strong support for intraoperative localization and protection of the recurrent laryngeal nerves, but the intraoperative identification of parathyroid glands is still a challenge for thyroid surgeons. Based on literature review, the authors extract the development in methods for intraoperative identification of parathyroid glands, so as to provide support for rapid intraoperative identification of parathyroid glands for surgeons.

    • Research progress of influential factors for thyroid nodules

      2018, 27(5):635-641. DOI: 10.3978/j.issn.1005-6947.2018.05.017

      Abstract (193) HTML (947) PDF 1.14 M (780) Comment (0) Favorites

      Abstract:In recent years, the prevalence rates of thyroid nodules and thyroid carcinoma have been rising gradually. Meanwhile, the young-onset trend is becoming more pronounced. The authors analyze and summarize the influential factors for thyroid nodules, and hope to provide guidance for clinical staff and relevant health care departments, so as to control and reduce the incidence of thyroid nodules, and to improve the people's quality of life.

Governing authority:

Ministry of Education People's Republic of China

Sponsor:

Central South University Xiangya Hospital

Editor in chief:

WANG Zhiming

Inauguration:

1992-03

International standard number:

ISSN 1005-6947(Print) 2096-9252(Online)

Unified domestic issue:

CN 43-1213R

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