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Purpose: Papillary thyroid cancer (PTC) is generally associated with a favorable prognosis. However, some patients have fatal disease, with locally infiltrating tumors or progressive distant metastases; yet few studies have investigated the characteristics of the tumor-progressive gene expression profile in advanced PTC. We conducted this study to clarify the gene expression status in advanced PTC and identify candidate molecules for prognostic biomarkers., Methods: We analyzed 740 tumor-progressive gene expression levels from formalin-fixed paraffin-embedded blocks of samples from six patients with low-risk PTC and six patients with high-risk PTC, using the nCounter PanCancer Progression panel. Then, we investigated the association between the expression levels of focused genes and pathological factors in PTC patients in The Cancer Genome Atlas (TCGA) database., Results: The expression levels of 14 genes in the high-risk PTC specimens were more than two-fold those in the low-risk PTC specimens. In the TCGA database, expression levels of four genes (CCL11, COL6A3, INHBA, and SRPX2) were significantly higher in patients with advanced PTC. Among the patients with advanced PTC, those with high SRPX2 expression levels had poor disease-free survival. Univariate and multivariate analyses revealed that high SRPX2 expression was an independent prognostic factor., Conclusion: Based on the findings of this study, CCL11, COL6A3, INHBA, and SRPX2 are potential biomarkers that indicate advanced PTC. SRPX2, in particular, is considered a prognostic biomarker., (© 2021. Springer Nature Singapore Pte Ltd.)

Background: Age is a prognostic factor for recurrent differentiated thyroid carcinoma (DTC) and may be related to radioactive iodine (RAI) nonavidity. Indications for molecular-targeted drugs (MTDs) are currently limited to RAI-refractory DTC. Demonstrating refractoriness to RAI, mainly indicated by RAI nonavidity, may be a barrier to the introduction of MTDs for elderly patients. The present study was conducted to evaluate the impact of age and histological type on the RAI avidity of recurrent lesions of DTC., Methods: Two hundred fifty-eight patients (189 patients with classic papillary thyroid carcinoma [cPTC], 8 patients with follicular variant of papillary thyroid carcinoma, and 61 patients with follicular thyroid carcinoma), who underwent their first RAI whole-body scanning for recurrent DTC at our institution between 2004 and 2013, were retrospectively studied. Radioactive iodine uptake was determined by visible uptake by metastatic lesion(s) in a diagnostic RAI-whole-body scan., Results: The prevalence of RAI-avid lung metastases in cPTC indicated a significant, inverse correlation with age (<55 years, 36.2%; ≥55 years, 3%; P < 0.001). By contrast, for follicular thyroid carcinoma, the prevalence of RAI avidity was not influenced by age. Similar tendencies were observed for lymph node metastases., Conclusions: Radioactive iodine avidity by metastatic lesions of cPTC in elderly patients, especially those older than 55 years, was seldom demonstrated. Adherence to a strategy of restricting MTD administration after confirmation of RAI refractoriness should be revisited for elderly patients. A strategy of omitting RAI treatment should be taken into account when considering age and histological type.

Purpose: Surgical treatment of local recurrent papillary thyroid carcinoma is still controversial because of the increased morbidity in comparison to primary surgery, and the unclear efficacy. This study analyzed the efficacy and safety of surgery for recurrent disease., Methods: A retrospective cohort analysis of 86 patients who underwent surgery for local recurrent papillary thyroid carcinoma at a single institution during the period 1979-2009., Results: The cause-specific survival rates of all patients at 5, 10, and 20 years were 86 % (95 % CI 77-95 %), 74 % (95 % CI 62-87 %), and 36 % (95 % CI 18-54 %), respectively. A univariate analysis found that gender, age >45 years at reoperation and macroscopic non-curative surgery for recurrence affected the cause-specific survival rates. The latter two features remained significant in a multivariate analysis. Permanent recurrent nerve paralysis and hypoparathyroidism developed in 4 (4.7 %) and 5 (5.8 %) patients, respectively., Conclusions: Surgery for local recurrent papillary thyroid carcinoma could be effective when macroscopic curative dissection was possible, and that the procedure was safe and was associated with minimal morbidity. Therefore, repeat surgery for local recurrent papillary thyroid carcinoma is worthwhile.

Although postoperative serum thyroglobulin (Tg) is a prognostic indicator for papillary thyroid carcinoma (PTC), it is unreliable when Tg antibody (TgAb) is positive. We evaluated the prognostic significance of changes in serum TgAb levels of pre- and post-total thyroidectomy in TgAb-positive PTC patients. We reviewed our medical charts of 225 TgAb-positive PTC patients in whom TgAb levels were measured before and 1-2 years after total thyroidectomy, performed between April 2002 and March 2007. We divided them into 3 groups based on changes in TgAb levels. Postoperative serum TgAb levels decreased by ≥ 50% in 181 patients (80.4%) (Group 1), by <50% in 22 patients (9.8%) (Group 2), and increased in 22 patients (9.8%) (Group 3). During the follow-up, 3 patients died of the disease and 14 patients had recurrences. All 3 patients who died of PTC were seen only in Groups 2 and 3. Groups 2 and 3 showed similar prognostic outcomes, thus were analyzed together as Group 2+3. Group 1 had significantly better lymph node recurrence-free survival and distant recurrence-free survival than Group 2+3 (96.9% vs. 90.5%, p <0.001, and 98.9% vs. 90.1%, p = 0.004, respectively at 5 years). Multivariate analyses on prognostic factors revealed that classification to Group 2+3 was the strongest indicator for poor prognosis. The present results suggest that changes in TgAb levels following total thyroidectomy can be an important dynamic prognostic factor of PTC patients. Prospective periodical measurements of TgAb are necessary to confirm these findings.

Background: In patients with papillary thyroid carcinoma (PTC), the appropriate extent of lymph node dissection has not yet been established due to lack of accurate patterns of lymph node metastases (LNM). The aim of this study was to clarify the LNM pattern in PTC patients based on our institution's experience with a consistent technique of bilateral neck dissection, and to consider the rational extent of lymph node dissection., Methods: Between 1990 and 1999, 152 consecutive patients with PTC who underwent curative total thyroidectomy and bilateral neck dissection as initial treatment were analyzed. The patterns of LNM according to clinicopathological classification were analyzed using the lymph node ratio (LNR; number of metastatic lymph nodes/number of dissected nodes) and frequency (FLNM; number of patients with LNM/number of dissected patients) in cervical compartments., Results: Regardless of clinicopathological classification, LNR in the central compartment was consistently higher than in other compartments, and FLNM in the ipsilateral lateral compartment was consistently higher than in other compartments except for multifocal tumors. The LNR and FLNM in the contralateral lateral compartment were significantly higher in advanced (≥T3) cases than in cases with smaller tumors (T1) and were comparable to those in the ipsilateral lateral compartment in advanced (≥T3) cases., Conclusions: The pattern of LNR provided a better reflection of the patterns of LNM. In terms of the LNR, central neck dissection is the basic extent of lymph node dissection for all clinically apparent PTC. In advanced patients, it is also advisable to include bilateral lateral neck dissection.

Background: More than 80% of all thyroid cancers, the most common endocrine malignancy, are papillary thyroid cancer (PTC). It is well established that CITED1 (Cbp/p300 Interacting Transactivators with glutamic acid [E] and aspartic acid [D]-rich C-terminal domain) mRNA is characteristically overexpressed in PTC. Our previous study suggested a positive association of BRAF mutation with CITED1 overexpression. However, the mechanism of CITED1 expression in PTC remains to be elucidated. In the present study, we analyzed whether aberrant methylation of CITED1 gene promotes CITED1 overexpression in PTC., Method: CITED1 mRNA expression levels were analyzed by quantitative polymerase chain reaction in three PTC-derived cell lines, TPC1, K1, and KTC-1, and in surgically dissected PTC and surrounding normal tissues from 19 patients. The BRAF mutation status of the cells and clinical specimens was determined by direct sequencing. The methylation status of the deoxycitidine-phosphate-deoxyguanosine dinucleotides (CpGs) in the CITED1 promoter was analyzed by the bisulfite-sequencing method using genomic DNA. Finally, the expression of CITED1 mRNA in TPC1 cells, when subjected to pharmacological inhibition of methylation, was analyzed., Results: CITED1 mRNA was expressed at lower levels in TPC1 than in K1 and KTC-1 cells. A BRAF mutation was present in K1 and KTC-1 cells, but not in TPC1 cells. CITED1 promoter was hypomethylated in K-1 and KTC-1 cells, but not in TPC1 cells. In surgically dissected specimens, the mean expression level of CITED1 mRNA was 30-fold higher in PTC tissues than in normal tissues. CpGs in the CITED1 promoter were more heavily methylated in normal tissues than in PTC tissues. In PTC specimens without a BRAF mutation, two CpGs were more heavily methylated than in PTC specimens with the BRAF V600E mutation. Pharmacological inhibition of methylation in TPC1 cells by 5'-aza-2'-deoxycitidine resulted in increased expression of CITED1 mRNA., Conclusion: Hypomethylation of the CpGs in the promoter region of CITED1 is associated with higher expression of CITED1 mRNA in PTC tissues, consistent with the hypothesis that epigenetic regulation is involved in the overexpression of CITED1. This hypothesis is supported by pharmacologic inhibition studies in TPC1 cells.

Papillary thyroid carcinoma (PTC) is characterized by extensive lymph node metastases. A considerably high frequency of lymph node metastases in the upper mediastinal compartment (UMC) has been reported. However, the significance of prophylactic upper mediastinal lymph node dissection (UMLND) by sternotomy as an appropriate therapeutic option has not yet been clarified. Thirty-three patients who underwent prophylactic UMLND by sternotomy for PTC at our institution between 1980 and 1987 (group A) were analyzed. One hundred and fifty-one consecutive patients with PTC who underwent curative total thyroidectomy, bilateral modified radical neck dissection, and UMLND by collar incision as initial treatment between 1990 and 1999 (group B) were analyzed as controls. The patterns of lymph node metastases in the cervical compartment of these two groups were comparable; distribution of lymph node metastases in UMC was considerably less frequent than in other compartments. Clinical relapse in UMC was not observed in both groups. No significant difference in disease specific survival or relapse free survival between group A and B was observed. The lack of clinical relapse in UMC in group B indicates that most of the lymph node metastases in this compartment could be resected by the conventional collar incision or most microscopic lymphatic metastases could remain dormant as with lateral microscopic node metastases. Thus, upper mediastinal lymph node metastases requiring sternotomy to resect in curable patients with PTC could be less frequent. Prophylactic UMLND by sternotomy for PTC is discouraged from a clinical view point.

There is no established chemotherapy for anaplastic thyroid cancer. We conducted a prospective feasibility study at a single center to explore the antitumor activity of docetaxel against anaplastic thyroid cancer. Docetaxel was administered intravenously at a dose of 60 mg/m(2) over the course of 1 h every 3 weeks in patients with anaplastic thyroid cancer who had received no prior chemotherapy. A total of seven patients with anaplastic thyroid cancer were enrolled over the course of 30 months and received docetaxel. The treatment response was complete response in one patient, stable disease in two and progressive disease in four. The response rate was 14%, and the disease control rate (complete response plus stable disease) was 43%. The median time to progression was 6 weeks (range, 1-50). Toxicity was tolerable. Docetaxel could be an effective drug for the treatment of anaplastic thyroid cancer, with tolerable toxicity.

Somatic mutations in BRAF, especially BRAFV600E, are frequently identified in papillary thyroid cancer (PTC) tumors. It has been established that expression levels of numbers of genes are characteristically altered in PTC, however, the link between BRAF mutation and gene expression patterns are still elusive. In the present study, we analyzed relative expression levels of the wild type BRAF and BRAFV600E mRNA by using quantitative PCR (qPCR) and cDNAPCR- RFLP in 19 PTC specimens and adjacent normal thyroid tissues. BRAFV600E mRNA was detected in 17 out of 19 PTC specimens, and the expression levels were valuable among the specimens, suggesting alternative expression of BRAFV600E in each cell and/or alternative population of BRAFV600E-positive clones in the tumor. We then analyzed expression levels of 20 genes by qPCR, and analyzed for possible correlation with expression levels of BRAFV600E mRNA. Expression levels of fibronectin, vimentin and CITED1 (Cbp/p300 interacting protein with glutamic acid and aspartic acid rich carboxyl terminal domain) were positively correlated with those of BRAFV600E, suggesting pathophysiological links between activated BRAF and overexpression of these genes. Among these genes expression of vimentin was decreased by inhibiting BRAF expression in NPA cells that express BRAFV600E by means of siRNA, suggesting activated BRAF positively regulate expression of vimentin. Collectively, our analyses illustrated the possibilities that variable expression of BRAFV600E may modify characters of PTC through its effects on gene expression.

According to our previous data on papillary thyroid cancer (PTC), recurrences are related to lymph node ratio (number of metastatic lymph nodes/number of dissected nodes) and lymphatic spread of PTC is more symmetrical than previously thought. Therefore, neck dissection should be performed symmetrically. Our basic procedure for clinically evident PTC is total thyroidectomy with central neck dissection. For the cases with jugular chain adenopathy and/or T3, T4 tumor, bilateral lateral neck dissection should be added. Surgical clearance of malignant tissue is important for curability. For micro PTC (T<1 cm), lobectomy with ipsilateral central neck dissection or careful observation are proposed. Meticulous maneuver of parathyroid glands and recurrent laryngeal nerves is essential for above-mentioned procedure.

Total thyroidectomy was performed in 455 patients with differentiated thyroid carcinoma between 1978 and 1999. Serum calcitonin (CT) was determined preoperatively in all patients using polyclonal antibodies. Among the subjects, 25 patients showed elevated serum calcitonin levels preoperatively. Pathological diagnoses of 18 patients were confirmed as medullary thyroid carcinoma (MTC) postoperatively. Eight patients were diagnosed as papillary thyroid carcinoma (PTC) in the final pathological diagnosis without evidence of minimal foci of MTC or C cell hyperplasia, and they showed elevated CT levels preoperatively. Hypercalcitoninemia in 8 patients with PTC continued through out the 24 follow-up months with normal CEA levels. Extrathyroidal CT-producing diseases were all neglected, and precise pathological examination showed negative evidence of minute MTC or C cell hyperplasia in these 8 patients. Serum CT levels were simultaneously determined by a different CT assay kit using the same blood samples in 7 of 8 patients. Serum CT levels were all within normal values in another CT kit applying a different polyclonal antibody, although elevated CT values continued in the routine CT kit. The recognition of polymeric or fragmented CT by polyclonal antibody was thought to be the causative factor for the hypercalcitoninemia after total thyroidectomy in the patients with PTC. Knowledge of the false positive CT determination makes it important to employ different CT assay kits, especially the new generation of two-site immunoassays using two monoclonal antibodies against distinct epitopes of human CT, although the new generation kits are not clinically available in Japan.

Background: Permanent hypoparathyroidism is a major complication of thyroidectomy. Autotransplantation of parathyroid glands has been attempted to prevent this complication. However, no direct data have been available to assess grafted parathyroid function after long-term follow-up in terms of the serum intact parathyroid hormone (PTH) concentration., Methods: Eighty-four consecutive patients with differentiated thyroid carcinoma who underwent total thyroidectomy and bilateral modified neck dissection from 1992 to 1996 were enrolled. They concomitantly underwent total parathyroidectomy and autotransplantation of all parathyroid glands to the pectoralis major muscle. The serum intact PTH concentration was periodically measured as an index of grafted parathyroid function., Results: The mean follow-up was 34 months. In all autotransplanted patients serum intact PTH concentrations fell below detectable limits immediately after surgery. They were restored to the normal range within 1 month postoperatively and were maintained during observation in 80 (95%) of 84 patients. Seventy-eight of 80 patients with normal intact PTH values were normocalcemic without any treatment and the remainder were normocalcemic with 1 microgram of 1 alpha-vitamin D3. Four hypoparathyroid patients were normocalcemic with 2 micrograms of 1 alpha-vitamin D3. The postoperative average serum intact PTH concentration of patients having more than 2 autotransplanted parathyroid glands was almost equal to that of patients with preservation of the parathyroid glands in situ. The incidence of permanent hypoparathyroidism was inversely correlated with the number of autotransplanted parathyroid glands., Conclusions: The recovery patterns of the intact PTH concentration indicate that the glands were grafted successfully and functioned for a long period. This feasible method of parathyroid autotransplantation bears comparison with the previous reports in terms of the incidence of permanent postoperative hypoparathyroidism, and it can be performed simply and is reproducible.