Neoadjuvant therapy with anlotinib in a locally advanced and pulmonary metastasis PTC patient harboring TERT promoter and BRAFV600E mutations: a case report.

A 71-year-old woman with recurrent papillary thyroid carcinoma (PTC) was referred to our hospital. A computed tomography scan revealed extensive recurrence in the neck, invading sternocleidomastoid muscle, internal jugular vein, sternal end of the clavicle, strap muscle and skin; and lateral compartment and subclavian lymph nodes were also involved. Multiple pulmonary micrometastases also noticed. The tumor was considered unresectable; however, the patient was unwilling to accept highly invasive surgery. Therefore, we initiated neoadjuvant therapy with anlotinib, 12mg p.o. daily with a 2-week on/1-week off regimen. The tumor shrunk to resectable state after 4 cycles of treatment, and after 3 weeks of withdrawal, successful surgical resection without gross tumor residual was performed. Pathology confirmed as classic PTC harboring coexistent TERT promoter and BRAFV600E mutations by NGS. After anlotinib therapy, apoptosis induction was observed, and proliferation increased, which was due to three weeks of anlotinib withdraw. Structual recurrence was recorded at 6 months after operation due to no further treatment was taken. Our finding suggests that anlotinib could represent as a good treatment option for patients with locally advanced (with or without distant metastasis) PTC; Anlotinib treatment resulted in sufficient reduction of the tumor mass to enable total thyroidectomy and radioactive iodine treatment, providing long-term control of the disease.

Neoadjuvant therapy with anlotinib in a locally advanced and pulmonary metastasis PTC patient harboring TERT promoter and BRAFV600E mutations: a case report

SUMMARY A 71-year-old woman with recurrent papillary thyroid carcinoma (PTC) was referred to our hospital. A computed tomography scan revealed extensive recurrence in the neck, invading sternocleidomastoid muscle, internal jugular vein, sternal end of the clavicle, strap muscle and skin; and lateral compartment and subclavian lymph nodes were also involved. Multiple pulmonary micrometastases also noticed. The tumor was considered unresectable; however, the patient was unwilling to accept highly invasive surgery. Therefore, we initiated neoadjuvant therapy with anlotinib, 12mg p.o. daily with a 2-week on/1-week off regimen. The tumor shrunk to resectable state after 4 cycles of treatment, and after 3 weeks of withdrawal, successful surgical resection without gross tumor residual was performed. Pathology confirmed as classic PTC harboring coexistent TERT promoter and BRAFV600E mutations by NGS. After anlotinib therapy, apoptosis induction was observed, and proliferation increased, which was due to three weeks of anlotinib withdraw. Structual recurrence was recorded at 6 months after operation due to no further treatment was taken. Our finding suggests that anlotinib could represent as a good treatment option for patients with locally advanced (with or without distant metastasis) PTC; Anlotinib treatment resulted in sufficient reduction of the tumor mass to enable total thyroidectomy and radioactive iodine treatment, providing long-term control of the disease.

Errate: Role of Ca²âº in Inhibiting Ischemia-Induced Apoptosis of Parathyroid Gland Cells in New Zealand White Rabbits.

In Figure 1A, the images of CG 24h group and Sham 72h group are duplicated, where the picture of Sham 72h group is correct, now the authors have corrected the picture of CG 24h group. In Figure 2A, the images of CG 72h and CSG 72h groups are duplicated, the images of CG 168h and CSG 168h groups are duplicated，where the pictures of CG 168h and CSG 72h groups are correct, now the authors have corrected the pictures of CG 72h and CSG 168h groups. In Figure 3B, the images of CG 24h group and CSG 72h group are duplicated, where the picture of CSG 72h group is correct, now the authors have corrected the picture of CG 24h group. Reference: Wei-han Cao, Yan-jun Su, Nian-qiu Liu, Ying Peng, Chang Diao, Ruo-chuan Cheng: Role of Ca²âº in Inhibiting Ischemia-Induced Apoptosis of Parathyroid Gland Cells in New Zealand White Rabbits. Med Sci Monit, 2020; 26: e920546. DOI: 10.12659/MSM.920546.

A multicenter, prospective study to observe the initial management of patients with differentiated thyroid cancer in China (DTCC study).

BACKGROUND: To assess the gaps between the initial management of patients with differentiated thyroid cancer (DTC) in real clinical practice and the recommendations of the 2012 Chinese DTC guidelines. METHODS: This multicenter, prospective study was conducted at nine tertiary hospitals across China. Eligible patients were those having intermediate or high-risk DTC after first-time thyroidectomy. During 1 year of follow-up, comprehensive medical records were collected and summarized using descriptive statistics. RESULTS: Of 2013 patients, 1874 (93.1%) underwent standard surgery according to the guidelines (including total lobectomy plus isthmusectomy and total/near total thyroidectomy), and 1993 (99.0%) underwent lymph node dissection; only 56 (2.8%) had postoperative complications. Overall, 982/2013 patients (48.8%) received radioactive iodine (RAI) therapy after thyroidectomy. Of all enrolled patients, 61.4% achieved the target serum thyroid-stimulating hormone level, with a median time to target of 234.0 days (95% CI: 222.0-252.0). At 1 year of follow-up, proportions of patients with excellent response, incomplete structural response, biochemical incomplete response, and indeterminate response were 34.6, 11.2, 6.6, and 47.5%, respectively; recurrence or metastasis occurred in 27 patients (1.3%). During the overall study period, 209 patients (10.4%) had at least one adverse event: 65.1% of cases were mild, 24.9% moderate, and 10.1% severe. CONCLUSIONS: This was the first large-scale prospective study of how patients with DTC in China are treated in actual practice. Initial DTC management is generally safe and adheres to the 2012 Chinese guidelines but could be improved, and the level of guideline adherence did not produce the anticipated treatment response at 1 year of follow-up.

The role of P62 in the development of human thyroid cancer and its possible mechanism.

BACKGROUND: Thyroid cancer is the most common malignancy in human endocrine system. Increasing evidence has indicated that p62 plays a key role in tumorigenesis. The roles and underlying molecular mechanisms of P62 in thyroid cancer, however, remain to be elucidated. METHODS: The expression levels of P62 in thyroid tumor tissues and thyroid cancer cells were detected by western blotting and qRT-PCR. Then, the effects of up-regulation or down-regulation of P62 on thyroid cancer cell proliferation, migration, invasion, cell cycle and apoptosis were measured by CCK-8 assay, transwell assay, flow cytometry and transwell assay, respectively. In terms of the mechanism, P62 could stimulate thyroid cancer progression by the activation of nuclear factor-kappa B (NF-κB) signaling pathway. RESULTS: P62 was highly expressed in thyroid tumor tissues. Furthermore, high expression of p62 was observed in PTC cell lines, and especially in the K1 and TPC-1 cells. In vitro, the up-regulation of p62 promoted cell proliferation, migration, and invasion of thyroid cancer cells, whereas the knockdown of p62 resulted in the opposite effect. Knock-down of P62 increased the number of cells in the G0/G1 phase but reduced it in the S and G2/M phase. Moreover, we confirmed that overexpression of p62 inactivated NF-κB pathway with sequencing analysis and bioinformatics analysis. CONCLUSION: This research work suggested that p62 could promote PTC cell proliferation, migration, and invasion via NF-κB signaling pathway. Furthermore, p62 is a potential biomarker which might be closely related to the tumorigenesis in PTC. Its potential role as a therapeutic target for PTC is worthy of further study.

CASC2 inhibits the growth, migration, and invasion of thyroid cancer cells through sponging miR-18a-5p/FIH1 axis.

Long noncoding RNA (lncRNA) Cancer Susceptibility 2 (CASC2) has been proved to contribute to the development of cancers. However, the mechanism behind the action of CASC2 in thyroid cancer is not quite clear. We demonstrated that CASC2 was downregulated in thyroid cancer. We noted that CASC2 overexpression restrained the growth, migration, and invasion of thyroid cancer cells, whereas CASC2 depletion caused opposite trends. Bioinformatics analysis predicted that hypoxia inducible factor 1 subunit alpha inhibitor (FIH-1) was potentially targeted by miR-18a-5p, which was confirmed by luciferase reporter assay. Upregulation of FIH-1 abrogated the promotive effect of miR-18a-5p on the growth and invasion of thyroid cancer cells. In addition, CASC2 serves as a competing endogenous RNA (ceRNA) and a ''sponge'' for miR-18a-5p, thereby regulating the expression of FIH-1. These data elucidated the CASC2/miR-18a-5p ceRNA network in thyroid cancer pathogenesis.

Exploration of the Potential Biomarkers of Papillary Thyroid Cancer (PTC) Based on RT2 Profiler PCR Arrays and Bioinformatics Analysis.

BACKGROUND: Papillary thyroid carcinoma (PTC) has increased rapidly over recent years, and radiation, hormone effects, gene mutations, and others were viewed as closely related. However, the molecular mechanisms of PTC have not been cleared. Therefore, we intended to screen more accurate key genes and pathways of PTC by combining RT2 profiler PCR arrays and bioinformatics methods in this study. MATERIALS AND METHODS: RT2 profiler PCR arrays were firstly analyzed to identify differential expression genes (DEGs) in PTC. RT-qPCR were performed to verify the most significant differential expression genes. The TCGA database was used to further verify for expanded data. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was analyzed. To construct the protein-protein interaction (PPI) network, we used STRING and Cytoscape to make module analysis of these DEGs. RESULTS: Sixteen differentially expressed genes were presented in RT2 profiler PCR arrays, including 13 down-regulated DEGs (DEGs) and three up-regulated DEGs (DEGs), while 13 stable DEGs were eventually verified. A total of 155 DEGs were presented in the TCGA database, including 82 up-regulated DEGs (DEGs) and 73 down-regulated DEGs (dDEGs). A total of 29 important genes were extracted after integrating these two results, GO and KEGG analyses were used to observe the possible mechanisms of action of these DEGs. The PPI network was constructed to observe hub genes. Prognostic analysis further demonstrated the involvement of these genes in the biological processes of PTC. CONCLUSION: This study identified some potential molecular targets and signal pathways, which might help us raise our awareness of the mechanisms of PTC.

The Potential Action of Thomsen-Friedenreich Monoclonal Antibody (A78-G/A7) in Thyroid Cancer.

BACKGROUND: Thomsen-Friedenreich antibody (TF-Ab) is a specific antibody against the Thomsen-Friedenreich antigen (TF-Ag). At present, studies on a number of other tumors have shown that TF-Ab can effectively inhibit metastasis and induce apoptosis in tumor cells. However, the role of TF-Ab in thyroid cancer (TC) remains unclear. MATERIALS AND METHODS: Normal subjects and patients with primary papillary TC with or without lymph node metastasis were tested for TF-Ab expression by enzyme-linked immunosorbent assays (ELISAs). Immunofluorescence was used to assess the expression of TF-Ag in thyroid papillary carcinoma with or without lymph node metastasis and undifferentiated cancer tissues. To evaluate the role of TF-Ab in TC, the effects of TF monoclonal antibody (mAb A78-G/A7) on cell biological function were investigated by MTT assays, flow cytometry, adhesion assays and transwell experiments. RESULTS: Compared with normal individuals, TF-Ab levels in patients with TC were decreased, but no changes were observed with respect to lymph node metastasis. The expression of TF-Ag in TC tissues was relatively higher than that detected in adjacent tissues, but it was not affected by the presence or absence of lymph node metastasis. Upon treatment mAb A78-G/A7 treating, TC cell cycles were affected, meanwhile the abilities to adhere, invade and migrate were also significantly reduced. CONCLUSION: The results of the present study showed that mAb A78-G/A7 could affect the invasion and migration of all assayed TC cell lines. The effects of mAb A78-G/A7 on the cell cycle, adhesion, invasion and migration of TC cells were more significant than those observed for proliferation and apoptosis.

Role of Ca²âº in Inhibiting Ischemia-Induced Apoptosis of Parathyroid Gland Cells in New Zealand White Rabbits.

BACKGROUND Hypoparathyroidism is a common complication after thyroidectomy. Calcium supplementation can relieve these symptoms, but it is not clear whether it can protect the parathyroid glands. This study aimed to verify whether Ca²âº inhibits the apoptosis of parathyroid cells following ischemic injury. MATERIAL AND METHODS A rabbit model of parathyroid gland ischemic injury was established. The blood calcium concentrations were measured by colorimetry. The parathyroid hormone (PTH) levels were measured by enzyme-linked immunosorbent assay (ELISA). The parathyroid tissues were observed by hematoxylin and eosin (H&E) staining and the TdT-mediated dUTP nick-end labeling (TUNEL) assay. Western blotting was used to quantify the levels of the following proteins: caspase-3 and p38 MAP Kinase (p38 MAPK). RESULTS This study demonstrates that apoptosis can be a part of the pathological changes associated with parathyroid ischemic injury. Calcium supplementation inhibited the apoptosis of parathyroid cells following ischemic injury. There were no significant differences among the serum calcium levels from the Sham operation (Sham), the Control group (CG), or the Calcium supplementation group (CSG) after 24 h, 72 h, and 168 h of treatment. PTH levels in the CG were significantly higher than in the CSG at 24 h and 72 h after treatments. The apoptosis rate of parathyroid cells from rabbits in the CSG was significantly lower than that of those from rabbits in the CG at 24 h and 72 h after the treatment. Calcium supplementation inhibited p38 MAPK and caspase-3 expression. CONCLUSIONS This study demonstrates that calcium supplementation inhibited the apoptosis of parathyroid cells following ischemic injury.

Expression of MUC1 and CD176 (Thomsen-Friedenreich antigen) in papillary thyroid carcinomas.

The incidence of thyroid cancer has appeared as an increasing trend globally, especially in Asian countries. In this study, the expression of mucin-1 (MUC1) and Thomsen-Friedenreich antigen, Galß1-3GalNAcα1-R (CD176) was investigated by immunohistochemistry in papillary thyroid carcinomas (PTCs), which accounts for approximately 80 % of all thyroid cancer. We found that 78 % of PTC overexpressed MUC1. Importantly, we observed firstly that CD176 was expressed in 63 % of PTC, but was faintly or not expressed in normal thyroid tissues and benign thyroid disease tissues, indicating that CD176 is also a tumour-associated antigen for PTCs. Moreover, expression of CD176 was strongly correlated with MUC1 by immunohistochemical staining in PTCs. Furthermore, we used the immunochemical method to confirm that MUC1 is a common and main carrier of CD176 in PTCs. Our data demonstrated that MUC1 and CD176 might be promising biomarkers for thyroid cancer.

[Thyroid lymphography:a new clinical approach for protecting parathyroid in surgery].

OBJECTIVE: To research the role of lymph tracers to protect parathyroid in surgery for papillary thyroid carcinoma. METHODS: Patients with papillary thyroid carcinoma who met selected criteria were enrolled in this study. Patients were divided into carbon nanoparticle group, methylene blue group, and conventional surgery group. RESULTS: No significant complication occurred in the patients of carbon nanoparticle and methylene blue groups. In carbon nanoparticle group, methylene blue group and conventional surgery group, the mean numbers of parathyroid glands detected during surgery were 3.1 ± 0.3, 2.9 ± 0.4 and 2.3 ± 0.3 (F = 3.78, P < 0.01) , the rates that parathyroid was cut mistakenly were 1.37% (2/146) , 2.62% (2/97) and 7.14% (6/84) respectively (χ(2) = 17.372, P < 0.05) ; and the incidence of postoperative hypocalcemia were 10.4% (5/48) , 9.1% (3/33) and 17.5% (7/40,χ(2) = 0.671, P = 0.037) . CONCLUSION: Thyroid lymphography technique is helpful to protect from the injury to the parathyroid glands in surgery.

[A prospective randomized and controlled study on no drainage after surgery for benign thyroid disorders].

OBJECTIVE: To evaluate the necessity of drainage after thyroidectomy for benign thyroid disorders. METHODS: A total of 272 patients who underwent thyroidectomy for benign thyroid disorders were randomly divided into drainage group or non-drainage group. Operating time, postoperative stay time in hospital, comfort of neck assessed by visual analogue scale (VAS) on postoperative day (POD) 0 and POD1 were and the incidence of complications, including post-thyroidectomy bleeding, hematoma, seroma, wound infection, hoarseness, and hypoparathyroidism, were assessed and compared between two groups. RESULTS: Both groups were similar in the mean age, the sex ratio and the underwent procedure types. There was no significant difference in the mean operating time between two groups (87.5 ± 32.0) min and (93.8 ± 30.1) min (t = 0.12, P = 0.45). The mean postoperative hospital stay time of non-drainage group (1.9 ± 0.3) d was significantly shorter than that of drainage group (2.6 ± 0.6) d (t = 1.45, P = 0.02). The mean VAS scores of neck comfort on POD0 and POD1 in non-drainage group were significantly high than those in non-drainage group(t = 2.67, P = 0.03 and t = 0.33, P = 0.006). There were no significant difference in postoperative complications, including permanent hoarseness and hypoparathyroidism, between two groups. CONCLUSIONS: No drainage after thyroidectomy for benign thyroid disorders does not increase postoperative complications, with the increase in postoperative neck comfort, the decrease in hospital stay time and potential wound infections. The routine drainage is not necessary after thyroid surgery for benign disorders.

Expression of CD176 (Thomsen-Friedenreich antigen) on lung, breast and liver cancer-initiating cells.

The cancer-initiating capacity of most malignant tumours is considered to reside in a small subpopulation of cells. Therapeutical interventions should target these cells rather than the tumour mass. Numerous studies have shown that the carbohydrate antigen structure CD176 (Thomsen-Friedenreich antigen, core-1) is present in many types of cancer and absent in normal adult human tissues. In this study, we assessed whether CD176 is co-expressed with CD44 or CD133 [markers of cancer-initiating cells (CIC)] in human lung, breast and liver carcinoma. A variety of human cancer cell lines and surgical specimens of these malignancies were examined. It was found that in most cases the majority of tumour cells stained strongly for CD44 by immunohistochemistry and flow cytometry, whereas CD133 expression was found on a smaller, but varying proportion of cells. Co-expression of CD176 with CD44 was found at a surprisingly high percentage of cancer cells in vitro and in vivo. Co-expression of CD176 with CD133 was also detected, although at a lower rate. Tamoxifen treatment of MDA-435 breast cancer cells enhanced the CD44(+) /CD176(+) phenotype. Evidence is provided through a new sandwich solid-phase enzyme-linked immunosorbent assay (ELISA) suggesting that CD44 is a carrier molecule for CD176 not only in colorectal cancer as previously reported, but also in lung, breast and liver cancer. The expression of CD176 in CIC suggests that it may represent an effective target for tumour therapies.

Co-expression of CD173 (H2) and CD174 (Lewis Y) with CD44 suggests that fucosylated histo-blood group antigens are markers of breast cancer-initiating cells.

Histo-blood group antigens CD173 (H2) and CD174 (Lewis Y) are known to be developmentally regulated carbohydrate antigens which are expressed to a varying degree on many human carcinomas. We hypothesized that they might represent markers of cancer-initiating cells (or cancer stem cells, CSC). In order to test this hypothesis, we examined the co-expression of CD173 and CD174 with stem cell markers CD44 and CD133 by flow cytometry analysis, immunocytochemistry, and immunohistochemistry on cell lines and tissue sections from breast cancer. In three breast cancer cell lines, the percentage of CD173(+)/CD44(+) cells ranged from 17% to >60% and of CD174(+)/CD44(+) from 21% to 57%. In breast cancer tissue sections from 15 patients, up to 50% of tumor cells simultaneously expressed CD173, CD174, and CD44 antigens. Co-expression of CD173 and CD174 with CD133 was also observed, but to a lesser percentage. Co-immunoprecipitation and sandwich ELISA experiments on breast cancer cell lines suggested that CD173 and CD174 are carried on the CD44 molecule. The results show that in these tissues CD173 (H2) and CD174 (LeY) are associated with CD44 expression, suggesting that these carbohydrate antigens are markers of cancer-initiating cells or of early progenitors of breast carcinomas.

[Clinical observation of XELOX (Capecitabine puls Oxaliplatin): an adjuvant chemotherapy regimen used in stage III colorectal cancer].

OBJECTIVE: To evaluate the efficacy and safety of an adjuvant chemotherapy regimen: XELOX (Capecitabine puls Oxaliplatin) used after curative resection for stage III colorectal cancer. METHODS: From Jan. 1998 to Jan. 2004, 256 cases with stage III colorectal cancer randomized received de Gramont, modified FOLFOX4 (mFOLFOX4) and XELOX regimens. The 3-year disease-free survival (DFS) and overall survival (OS) were compared within the three groups and relative prognosis factors within mFOLFOX4 and XELOX groups. Therapeutic adverse events were recorded and analyzed with Kaplan-Meier test. RESULTS: 98, 87 and 71 cases were respectively enrolled in the de Gramont, mFOLFOX4 and XELOX groups, mFOLFOX4 and XELOX had superior efficacy compared with de Gramont regimen. The two former could significantly improve 3-year DFS (79.7% vs. 66.2%, P = 0.015; 81.5% vs. 66.2%, P = 0.004) and medium survival time (40.2 mon vs. 37.8 mon, P = 0.024; 41.4 mon vs. 37.8 mon, P = 0.014). Meanwhile they could respectively decrease the ratio of recurrence risk by 18.0% (P = 0.024) and 21.0% (P = 0.003). The relative benefit of mFOLFOX4 versus XELOX didn't differ for 3-year DFS [hazard ratio (HR): 0.84, 95% confidence interval (CI): 0.79-1.12, P = 0.13] and OS (HR: 0.87, 95% CI: 0.84-1.06, P = 0.54). In the analysis of DFS in relative prognosis factors, XELOX had a better trend of survival advantage. mFOLFOX4 had higher adverse events within these regimens, especially in grade 3 or 4 neutropenia and peripheral neurologic adverse events. CONCLUSION: XELOX maintains its efficacy and safety ratio in advanced colorectal cancer. Patients have good tolerance and compliance. The regiment is deserves to be applied in clinical treatment. Oxaliplatin;