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Background The homebox superfamily play an important role in tumorigenesis. HOXC9 and HOXD10 were reported playing critical roles in tumor progression in many malignant tumors. This study aimed to research the expression of HOXC9 and HOXD10 in papillary thyroid cancer, and to verify the prognostic and clinical significance of HOXC9 and HOXD10. Methods Immunohistochemistry was used to determine the expression of HOXC9 and HOXD10 in 98 pairs of papillary thyroid cancer and paracancer tissues. Clinicopathologic data were collected and analyzed to verify the prognostic and clinical significance of HOXC9 and HOXD10. Results The expression of HOXC9 and HOXD10 decreased in papillary thyroid cancer. The low expression of HOXC9 was associated with Hashimoto’s thyroiditis and lymph node metastasis (P

Background Neuregulin 1 (NRG1) is a membrane glycoprotein mediating cell-to-cell signaling and has a crucial role in the growth and development of various organ systems. Our study explored its diagnostic value in distinguishing BRAF V600E mutant status in papillary thyroid cancer (PTC) patients by analyzing multiple glycan patterns of serum NRG1 through lectin assays. Methods We first extracted serum from PTC patients and tested BRAF V600E mutation by immunohistochemical (IHC) staining. Then we applied antibody overlay lectin microarray and lectin blot to detect glycol-alterations of NRG1. Then Aleuria aurantia lectin (AAL) ELISA was performed according to ELISA index to test the protein fucosylation level of NRG1 (Fuc-NRG1). Results We got glycan profiles of 14 lectins, including GNL, GSL2, AAL, BPL, ECL, CAL, NML, HHL, PHA-L, RCA-I, ConA, DBA, PWA and LEL. Six of them, namely, GSL2, BPL, NML, HHL, PHA-L and LEL, had significantly increased binding affinity capacity in BRAF(+) PTC compared with BRAF(-) PTC controls. LEL, BPL and NML tended to bind to NRG1 in BRAF(+) PTC group. Both AAL ELISA and protein ELISA assays showed that the fucosylated structures of NRG1 had a remarkable increase in BRAF V600E mutant PTC patients compared with BRAF wild type PTC controls. Conclusions This study sheds a new light on the role of NRG1 glycosylation in PTC. NRG1 could serve as a supplementary glycobiomarker for BRAF indicator in discrimination of PTC patients with BRAF wild type negative fine needle aspiration results.

Verteporfin, a FDA approved second-generation photosensitizer, has been demonstrated to have anticancer activity in various tumors, but not including papillary thyroid cancer (PTC). In current pre-clinical pilot study, we investigate the effect of verteporfin on proliferation, apoptosis, cell cycle and tumor growth of PTC. Our results indicate verteporfin attenuates cell proliferation, arrests cell cycle in G2/S phase and induces apoptosis of PTC cells. Moreover, treatment of verteporfin dramatically suppresses tumor growth from PTC cells in xenograft mouse model. We further illustrate that exposure to MEK inhibitor U0126 inactivates phosphorylation of ERK1/2 and MEK in verteporfin-treated PTC cells. These data suggest verteporfin exhibits inhibitory effect on PTC cells proliferation and cell cycle partially via ERK1/2 signalling pathway, which strongly encourages the further application of verteporfin in the treatment against PTC.

Warburg found that tumor cells exhibit high-level glycolysis, even under aerobic condition, which is known as the ‘Warburg effect’. As systemic changes in the entire metabolic network are gradually revealed, it is recognized that metabolic reprogramming has gone far beyond the imagination of Warburg. Metabolic reprogramming involves an active change in cancer cells to adapt to their biological characteristics. Thyroid cancer is a common endocrine malignant tumor whose metabolic characteristics have been studied in recent years. Some drugs targeting tumor metabolism are under clinical trial. This article reviews the metabolic changes and mechanisms in thyroid cancer, aiming to find metabolic-related molecules that could be potential markers to predict prognosis and metabolic pathways, or could serve as therapeutic targets. Our review indicates that knowledge in metabolic alteration has potential contributions in the diagnosis, treatment and prognostic evaluation of thyroid cancer, but further studies are needed for verification as well.

Benefits of subdividing small-differentiated thyroid carcinoma (sDTC) by tumor size are controversial. We conducted a meta-analysis to investigate whether tumor size is associated with prognosis of sDTC. PubMed and Web of Science databases were searched from their inception to September 2018. The identified studies according to the inclusion/exclusion criteria were analyzed using fixed/random-effects models. Data were calculated and results of the meta-analysis were expressed as odd ratio (OR). sDTC was classified as S1 (≤1 cm) and S2 (>1 cm and ≤2 cm). A systematic analysis was performed to compare the difference of recurrence, survival and clinicopathological factors between the two subgroups of sDTC (S1 vs. S2). A total of 21 studies published between 2004 and 2017 enrolling 219,291 patients were included. Findings showed that, S2 was associated with higher recurrence risk compared with S1 (OR=1.575, 95% CI=1.428–1.738; P

The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central lymph node dissection (CLND), remains controversial. This meta-analysis was conducted to investigate the clinicopathologic factors predictive of central compartment lymph node metastasis (CLNM) in patients diagnosed with PTMC.PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library were searched from their inception to September 2013. Published studies that explored the association between clinicopathologic factors and CLNM in PTMC patients were included. From the identified studies, we extracted the number of individuals with or without each risk factor to calculate the CLNM-positive proportions and used fixed/random-effects models for the meta-analyses of overall relative risk (RR). The pooling analysis on the association between CLNM or the different CLNDs and prognosis was also conducted.A total of 19 eligible studies that included 8345 patients were identified. Three studies did therapeutic CLND, while the other 16 studies performed prophylactic CLND in PTMC patients. Meta-analyses revealed that CLNM was associated with male gender (RR = 1.36; 95 % CI 1.22-1.52, p = 0.001), younger age (45 years; RR = 1.15; 95 % CI 1.04-1.27, p = 0.006), larger tumor size (5 mm; RR = 1.51 95 % CI 1.32-1.65, p = 0.001), multifocality (RR = 1.40; 95 % CI 1.27-1.54, p = 0.001), and extrathyroidal extension (RR = 1.81; 95 % CI 1.34-2.43, p = 0.001). Meta-regression analysis indicated that a disparity in the proportion of PTMC patients with CLNM in each study was the main factor resulting in heterogeneity among the 19 studies. In addition, the pooling analyses suggested that CLNM did not significantly predict neck recurrences [hazard ratio (HR) = 0.95, 95 % CI 0.67-1.22, p = 0.054], and the prophylactic CLND group did not improve local control significantly compared to the therapeutic group (RR = 0.96, 95 % CI 0.46-2.01, p = 0.544).Prophylactic CLND may be performed in PTMC patients with clinically uninvolved central lymph nodes but with high risk factors; multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for central nodes in PTMC.

Four single nucleotide polymorphisms (SNPs) have been reported to be associated with thyroid cancer risk in two genome-wide association studies (GWASs) and were validated in a Chinese population. Because of a lack of further clinical and functional evidence, the clinical significances of these SNPs remain unknown. Four GWAS-identified SNPs of papillary thyroid cancer (PTC), rs965513, rs944289, rs966423 and rs2439302, were genotyped in a case-control study of 838 patients with PTC and 501 patients with benign thyroid tumor (BTT) from the Chinese Han population. The associations between these SNPs, clinicopathologic features, and the outcome of the PTC patients were examined. The CT and CT + TT genotypes of rs966423 were more common in PTC patients with extrathyroidal extension and more advanced T stage. The TC and TC + CC genotypes and the C allele of rs944289 were significantly less frequent in patients with multifocal disease. No correlation was observed between GWAS-identified SNPs and disease persistence of PTC after a short-term follow-up. Significantly different allele distributions between the PTC and BTT groups were observed for all four selected SNPs. Individuals with more than five risk alleles were 8.84-fold (95% CI 3.23-24.17) more likely to suffer from PTC compared with those with zero or 1 risk allele. GWAS-identified SNPs affect the individual predisposition to PTC without interacting with existing Hashimoto thyroiditis and BTT lesions. GWAS-identified SNPs were associated with certain clinicopathologic features of PTC, and may contribute to identifying PTC patients with different clinical patterns. Large prospective studies are required to further evaluate the diagnostic and prognostic power of these genetic markers.

Epigenetic abnormalities as well as genetic abnormalities may play a vital role in the tumorigenesis of papillary thyroid cancer (PTC). The present study aimed to analyze the function and methylation status of the HOXD10 gene in PTC and aimed to identify relationships between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics of PTC. A total of 152 PTC patients were enrolled in the present study. The methylation status of the HOXD10 promoter was analyzed by quantitative methylation-specific polymerase chain reaction (Q-MSP). BRAFV600E mutation status was analyzed by polymerase chain reaction (PCR) followed by DNA sequencing. HOXD10 mRNA expression level was analyzed by real-time polymerase chain reaction (RT-PCR). 5-Aza-2-deoxycytidine (5-Aza) treatment was performed in 4 PTC cell lines to observe the change in HOXD10 expression. Transwell, cell cycle and apoptosis assays were then performed in an HOXD10-overexpressing PTC cell line. Furthermore, we analyzed the associations between HOXD10 methylation, HOXD10 expression, BRAF mutation and clinicopathological characteristics in PTC. Overexpression of HOXD10 suppressed the migration of PTC cells, and promoted cell apoptosis. Q-MSP showed that methylation levels of the HOXD10 promoter were significantly higher in PTC tissues than levels in the adjacent normal thyroid tissues (P=0.02). In addition, expression of HOXD10 was decreased in the PTC cell lines and PTC tissues compared with that noted in the adjacent normal thyroid tissues (P=0.008). However, BRAFV600E mutation was detected in 42.1% of PTC patients enrolled. In addition, the BRAF mutation status was associated with the methylation and expression level of HOXD10 in PTC. We then observed that 5-Aza treatment could revert the expression of HOXD10 in PTC cell lines. Moreover, the hypermethylation of HOXD10 was associated with invasion of the primary tumor and age >45. In conclusion, the HOXD10 gene may act as a tumor suppressor in PTC. The aberrant hypermethylation and decreased expression of the HOXD10 gene were shown in PTC patients, particularly in those with BRAFV600E mutation. The epigenetic suppression of the HOXD10 gene may play a role in the tumorigenesis of PTC, and it is a prospective biomarker for the diagnosis and prognosis of PTC.

(1) Background: The genetic predisposition to papillary thyroid cancer (PTC) is far from clearly elucidated. Rs2292832 is a genetic polymorphism that located in the precursor of mir-149 and has been studied in diverse cancers. Thus far, the role of rs2292832 in PTC tumorigenesis and progression was unclear, (2) Method: Rs2292832 was genotyped in 838 PTCs, 495 patients with thyroid benign tumors (BNs) and 1006 controls in a Chinese Han population. Clinicopathological data was collected and compared. The expression level of mature mir-149 was examined in 55 normal thyroid tissue samples, (3) Results: The CC genotype of rs2292832 was significantly associated with an increased risk of PTC compared with TT homozygote (OR = 1.60, 95% CI: 1.72–2.20, p = 0.003) and TT/TC combined genotype (OR = 1.54, 95% CI: 1.14–2.09, p = 0.005). Rs2292832 is an independent risk factor correlated with tumor invasion (p = 0.006) and higher T stage in PTC patients (p = 0.007), but uncorrelated with short-term disease persistence of PTC. PTC subjects carrying CC genotype have lower mir-149-5p expression than those with TC genotype (p = 0.002). Twelve predicted target genes have been identified by collaboratively using computational tools, (4) Conclusion: Rs2292832 was possibly involved in the susceptibility and local progression of PTC in Chinese patients, by altering the expression level of mir-149-5p and its target genes.

Background Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the world with about 50% survival rate over 5 years. OSCC has a highly invasive potency and frequently metastasizes to the cervical lymph nodes, which is the principle reason leading to poor prognosis. CXCR2, the receptor of CXC chemokines, has been reported to be involved in invasion and metastasis in multiple types of malignancy. However, the accurate role of CXCR2 in OSCC has been little noticed. Methods In this study, we determined the expression of CXCR2 in OSCC using immunohistochemical staining (IHC) and analyzed the association between the expression of CXCR2 and the biobehavior of OSCC. Then, we established stable OSCC cell lines with interference of CXCR2 and observed the effect of CXCR2 knockdown on cell proliferation, migration, invasion, and morphological changes in vitro and in vivo. Results CXCR2 was positively expressed in 55.3% of OSCC patients and was statistically associated with the high cervical lymph node metastasis in OSCC. CXCR2 silencing markedly inhibited migration and invasion of OSCC cells in vitro and in vivo. Moreover, CXCR2 silencing led to morphological changes and decreased lamellipodial structures in OSCC cells. However, CXCR2 silencing showed no effect on proliferation of OSCC cells in vitro and in vivo. Conclusions CXCR2 plays a critical role in the invasion and metastases of OSCC. And it is probably by regulating actin cytoskeletal remodeling that CXCR2 takes part in the invasion and metastases of OSCC.

Objectives/Hypothesis: To find the risk factors of lymph node (LN) metastasis of salivary gland cancer and draw a scheme for LN management. Study Design: Hospital-based retrospective study. Methods: The records of salivary gland cancer patients treated at the Department of Head and Neck Surgery, Cancer Hospital, Fudan University, were entered in a database, and 219 consecutive patients with carcinomas of major salivary glands primarily operated on between January 1998 and January 2011 were chosen for univariate and multivariate analysis to identify risk factors for LN involvement. Results: Fifty-eight (26.5%) patients had LN involvement. Factors associated with cervical LN involvement on univariate analysis included pathologic type, male sex, shorter duration of preoperative course, facial paralysis, advanced T stage, and major nerve, soft tissue, lymphatic/vascular (L/V), neural/perineural, and extracapsular invasion. Multivariate analysis identified major nerve invasion, histologic type, L/V invasion, and extracapsular invasion as significant factors for LN involvement. The proportion of patients with LN involvement with low (105), middle (61), high (34), and super high (19) predictive index scores based on the four risk factors were 3.8%, 27.9%, 55.9%, and 94.7%, respectively. Conclusions: A predictive index using the clinicopathologic factors described in this report can effectively stratify patients into risk groups for nodal metastasis. Comprehensive management based on this risk index should improve treatment outcomes for patients with salivary gland cancer.

Background There are few reviews on the clinical features and prognosis of young patients with papillary thyroid cancer and bilateral cervical metastases. We have investigated the long-term impact of initial surgical and medical therapy on such patients. Methods A retrospective study was performed on 24 young patients (11 females and 13 males) with papillary thyroid cancer and bilateral cervical lymph node metastases, ranging in age from 11 to 20 years (mean age, 16.6 years), who were treated in our institution from 1 January 1970 to 31 December 1985. Results All the patients in this group were followed up for 20 years. The survival of the patients at 20 years was 91.7%. The recurrence of local tumor and distant metastases was 20.8% and 12.5%, respectively. Based on analysis of the clinical data, we determined that the completeness of the surgical excision had a significant correlation with tumor recurrence. Conclusion These young patients with papillary thyroid cancer and cervical metastases have a good prognosis after suitable treatment. Chin Med J 2008;121(1):63-66

Background: Papillary thyroid cancer (PTC) often presents as multifocal. However, the association of multifocality with poor prognosis remains controversial. The aim of this retrospective study was to identify the characteristics of PTC with multiple foci and to evaluate the association between multifocality and prognosis. Methods: We reviewed the medical records of 496 patients who underwent total thyroidectomy for PTC. Patients were classified as G1 (1 tumor focus), G2 (2 foci), and G3 (3 or more foci). We analyzed the clinicopathological features and clinical outcomes in each classification. A Cox regression model was used to assess the relationship between multifocality and recurrence or cancer mortality. Results: The G1, G2 and G3 groups included 287, 141 and 68 patients, respectively. The mean age was 47.1 ± 16.1 yr in G1, 41.1 ± 18.4 yr in G2, and 35.5 ± 15.9 yr in G3 and differed significantly among the 3 groups (p= 0.001). The proportion of extrathyroidal extension, central lymph node metastasis (CLNM), and lateral lymph node metastasis (LLNM) in the G1 to G3 groups increased with increasing number of tumor foci. The Kaplan–Meier curves revealed that G3 had the shortest recurrence-free survival, and differences were significant among the 3 groups (p = 0.001, Log Rank test). Furthermore, cancer-specific survival rates decreased significantly with increasing number of tumor foci (p= 0.041). Independent predictors of recurrence by multivariate Cox analysis included >3 tumor foci [HR 2.60, 95% confidence interval (CI) 1.53-4.39, p= 0.001] and extrathyroidal extension (HR 1.95, CI 1.12-3.38, p= 0.018). Conclusion: An increase in the number of tumors is associated with a tendency toward more aggressive features and predicts poor prognosis in PTC.

The impact of coexistent Hashimoto's thyroiditis (HT) on lymph node metastasis (LNM) and prognosis in papillary thyroid microcarcinoma (PTMC) remains controversial. We evaluated the association of coexistent HT with clinicopathologic parameters, LNM, and prognosis by retrospectively reviewing a series of consecutive patients treated for PTMC at Fudan University Cancer Center from January 2005 to December 2010. Of all 1,250 patients with complete data for analysis, 364 (29.1 %) had coexistent HT (HT group) and 886 patients (70.9 %) had no evidence of HT (control group). The HT group had higher proportion of female (87.9 vs 70.1 %) patients, higher mean level of thyroid-stimulating hormone (TSH) (2.39 vs 2.00 mIU/L), and lower incidence of extrathyroidal extension (7.4 vs 11.7 %) than those in the control group. However, the incidence of LNM and recurrence was similar between the two groups, and HT was not associated with LNM and recurrence. A series of clinicopathologic factors identified for predicting LNM and recurrence in the control group did not show any prediction in the HT group. In summary, this study suggested that coexistent HT had insignificant protective effect on LNM and prognosis in PTMC, which was inconsistent with prior studies. Further studies aiming to determine novel predictors are recommended in PTMC patients with coexistent HT.

MicroRNAs (miRNAs) are small non-coding RNA molecules that are involved in a variety of cellular functions. Single nucleotide polymorphisms (SNPs) have been identified in mature miRNAs (mmSNPs), some of which have been linked to cancer risk; however, it is unclear which mmSNPs contribute to the susceptibility to thyroid tumors. In the present study, we examined the influence of selected mmSNPs on the risk of thyroid tumor. After systematic in silico screening, seventeen mmSNPs were identified and genotyped in a Chinese population including 828 patients with papillary thyroid cancer (PTC), 488 patients with benign thyroid tumor (BN), and 1038 cancer-free controls. Multivariate logistic regression analyses were conducted to evaluate the association of SNP genotypes and alleles with the risk of developing PTC and BN. Three SNPs (rs67106263 in mir-3144, GA versus GG, OR = 1.35, 1.09–1.68; rs4919510 in mir-608, CC versus GG/GC, OR = 0.76, 0.60–0.97; and rs79402775 in mir-933, AA versus GG/GA, OR = 1.76, 1.00–3.12) were associated with PTC risk. A combined effect of unfavorable genotypes was observed to give increased PTC risk in a dose-dependent manner. In addition, three SNPs (rs10061133 in mir-449b, rs79402775 in mir-933 and rs4919510 in mir-608) showed at least borderline correlations with the risk of BN. False-positive report probability was assessed for significant findings. The rs67106263 SNP was associated with the expression level of mir-3144 in thyroid tissue. These results indicate that mmSNPs may contribute to genetic susceptibility to thyroid tumors. Large validation and functional studies are required to further explore the role of mmSNPs in carcinogenesis.

OBJECTIVE: To analyze the impact of the lymph node ratio (LNR, ratio of metastatic to examined nodes) on the prognosis of hypopharyngeal cancer patients. METHODS: SEER (Surveillance, Epidemiology and End Results)-registered hypopharyngeal cancer patients with lymph node metastasis were evaluated using multivariate Cox regression analysis to identify the prognostic role of the LNR. The categorical LNR was compared with the continuous LNR and pN classifications to predict cause-specific survival (CSS) and overall survival (OS) rates of hypopharyngeal cancer patients. RESULTS: Multivariate analysis of 916 pN+ hypopharyngeal cancer cases identified race, primary site, radiation sequence, T classification, N classification, M classification, the number of regional lymph nodes examined, the continuous LNR (Hazard ratio 2.415, 95% CI 1.707-3.416, P0.30), the Cox regression model for CSS and OS using the R classification had a higher C-index value and lower AIC value than the model using the pN classification. Significant improvements in both CSS and OS were found for R2 and R3 patients with postoperative radiotherapy. CONCLUSIONS: LNR is a significant prognostic factor for the survival of hypopharyngeal cancer patients. Using the cutoff points 0.05/0.30, the R classification was more accurate than the pN classification in predicting survival and can be used to select high risk patients for postoperative treatment.

Background Rs2910164, a Single nucleotide polymorphism (SNP) located in the precursor microRNA sequence of miR-146a, is the only MicroRNA sequence SNP studied in papillary thyroid cancer (PTC). Association studies had been performed in US and UK-Northern European populations, but results were inconsistence. This study evaluated the association between rs2910164 and the risk of PTC as well as benign thyroid tumor (BN), and examined the clinicopathological characteristics of PTC and BN for different genotypes. Methods This case-control study genotyped rs2910164 in 753 PTCs, 484 BNs and 760 controls in a Chinese Han population. Clinicopathological and genetic data were collected and compared. Multivariate logistic regression was performed to calculate adjusted odds ratios (ORs). Results There were no differences in rs2910164 genotype distributions between the three groups. PTC cases with three genotypes (CC, CG, GG) had similar clinicopathological characteristics except the existence of “para-cancer” BN (PTC/BN, P = 0.006). PTC/BN patients were older (P = 0.009), and had smaller cancer lesions (P

Background The goal of this study was to identify the clinicopathological factors of co-existing papillary thyroid cancer (PTC) in patients with Hashimoto’s thyroiditis (HT) and provide information to aid in the diagnosis of such patients. Methods This study included 6109 patients treated in a university-based tertiary care cancer hospital over a 3-year period. All of the patients were categorised based on their final diagnosis. Several clinicopathological factors, such as age, gender, nodular size, invasive status, central compartment lymph node metastasis (CLNM) and serum thyroid-stimulating hormone (TSH) level, were compared between the various groups of patients. Results There were 653 patients with a final diagnosis of HT. More PTC was found in those with HT (58.3%; 381 of 653) than those without HT (2416 of 5456; 44.3%; p < 0.05). The HT patients with co-occurring PTC were more likely to be younger, be female, have smaller nodules and have higher TSH levels than those without PTC. A multivariate analysis indicated that the presence of HT and higher TSH levels were risk factors for a diagnosis of PTC. In the PTC patients, the presence of HT or another benign nodule was a protective factor for CLNM, whereas no significant association was found for TSH levels. Conclusion PTC and HT have a close relationship in this region of highly prevalent HT disease. Based on the results of our study, we hypothesise that long-term HT leads to elevated serum TSH, which is the real risk factor for thyroid cancer.

Background To assess the outcome of and determine prognostic factors for neck residue or recurrence of nasopharyngeal carcinoma (NPC) in patients treated with a salvage neck dissection. Materials and Methods Over a 10-year period (from January 1998 through December 2007) in a tertiary hospital, we systematically reviewed the clinical charts of 355 patients with NPC who were diagnosed with neck residue or recurrence of nasopharyngeal carcinoma, after radical definitive radiotherapy with or without chemotherapy. Results The group with recurrent nodal disease consisted of 285 patients (80.3%), while the group with residual nodal disease included 70 patients (19.7%). There were no patients died of the surgery complications. Overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) were 54.11, 35.01, and 55.59%, respectively, at 3-year, and 26.03, 22.65, and 27.84%, respectively, at 5-year. The local control rate in the neck was 70.92% at 3 years and 60.98% at 5 years. For all the 3 survival outcomes (OS, DFS, and DSS) and the local control rate of disease in the neck, there were significant differences between the “residue group” and “recurrence group.” Conclusions Radical neck dissection is proven to be safe and effective in the treatment of the neck failure. Our study has demonstrated that it may be possible to choose the selective lymph node dissection for patients of the residue group. Electronic supplementary material The online version of this article (doi:10.1245/s10434-010-1292-9) contains supplementary material, which is available to authorized users.