Duan Shu Li

Risk Factors for Neck Nodal Metastasis in Papillary Thyroid Microcarcinoma: A Study of 1066 Patients

CONTEXT The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central lymph node dissection, remains controversial. OBJECTIVE The objective of the study was to describe the clinicopathological features of PTMC and to identify the risk factors for central lymph node metastasis (CLNM) that can guide surgical strategies for patients with PTMC. DESIGN In this retrospective cross-sectional study, risk factors and outcome variables were assessed at the time of surgery for the primary tumor. SETTING The study was conducted at a university-based tertiary care cancer hospital. PATIENTS Data from the medical records of 1066 consecutive patients diagnosed with PTMC over a 5-yr period were analyzed. RESULTS Our multivariate logistic regression analysis found male gender, younger age (≤45 yr of age), multifocal lesions, extrathyroidal extension, and larger size of the primary tumor (>6 mm) to be associated with CLNM; multifocal lesions were associated with the highest risk (odds ratio 4.476, 95% confidence interval 2.975-6.735). Extrathyroidal extension, multifocal lesions, and CLNM were associated with lateral neck lymph node metastasis (LLNM). In patients with a solitary primary tumor, tumor location in the upper third of the thyroid lobe was associated with a lower risk of CLNM and a higher risk of LLNM. CONCLUSIONS Prophylactic central lymph node dissection need be considered in PTMC patients presenting with risk factors. In PTMC patients with a solitary primary tumor, tumor location can assist in the evaluation of LLNM. We recommend multicenter research and long-term follow-up to better understand the risk factors and surgical management of PTMC.

Confirmation of papillary thyroid cancer susceptibility loci identified by genome-wide association studies of chromosomes 14q13, 9q22, 2q35 and 8p12 in a Chinese population

Background Five single nucleotide polymorphisms (SNPs) were previously reported to be associated with thyroid cancer in European populations in two genome-wide association studies (GWAS): rs965513 (9q22.33), rs944289 (14q13.3), rs116909374 (14q13.3), rs966423 (2q35) and rs2439302 (8p12). Only the first two SNPs have been validated in independent populations and none were replicated in Chinese populations. Methods The above five SNPs were genotyped in 845 papillary thyroid cancer (PTC) and 503 benign thyroid tumour (BN) patients and 1005 controls in a Chinese population using the SNaPshot multiplex single nucleotide extension system. Results Significant associations were detected among PTC and rs944289 (p=8.007e-11), rs965513 (p=1.013e-4), rs966423 (p=1.688e-3) and rs2439302 (p=1.096e-4) in a dominant model, while the rs116909374 SNP was not detected in the Chinese population. The PTC risk increased with rise in accumulative numbers of risk alleles carried by individuals (p=5.929e-13). The PTC OR of carriers of six risk alleles (1.4% of the control population) was 23.587 compared with non-risk homozygotes (1.0% of the control population, with zero risk alleles). No individuals were homozygous for all the four SNPs (carriers of eight risk alleles) and only three PTC cases were carriers of seven risk alleles. A significant association between 14q13.3 SNP rs944289T and BN was also found (p=0.0014). Conclusions Four candidate loci, rs965513 (9q22.33), rs944289 (14q13.3), rs966423 (2q35) and rs2439302 (8p12), identified by GWAS for PTC risk were confirmed in a Chinese population. The PTC risk of accumulative risk allele carriers increased with the number of risk alleles.

Association between the rs2910164 Polymorphism in Pre-Mir-146a Sequence and Thyroid Carcinogenesis

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<0.001), lower serum thyrotropin levels (1.82±1.42 vs. 2.21±1.74, P = 0.04), and lower rates of level VI lymph node metastasis (20.8% vs. 52.7%, P<0.001) and lateral neck lymph node metastasis (11.5% vs. 23.0%, P = 0.011) compared with PTC only. Then we supposed a possible progression from BN to PTC which may involve rs2910164 in and performed a multivariate logistic regression analysis of PTC/BN and BN cases to determine risk factors of this progression. Results showed that the rs2910164 GG homozygote (OR = 2.25, 95% CI 1.22–4.14, P = 0.01) was the only risk factor in this study. Conclusion Rs2910164 was not associated with increased risk of PTC and BN in Chinese patients, but may play a latent role in the transformation from BN to PTC.

Impact of lymph node ratio on the survival of patients with hypopharyngeal squamous cell carcinoma: a population-based analysis.

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, P<0.001) and age as prognostic variables that were associated with CSS in hypopharyngeal cancer. The categorical LNR showed a higher C-index and lower Akaike information criterion (AIC) value than the continuous LNR. When patients (n = 1152) were classified into four risk groups according to LNR, R0 (LNR = 0), R1 (LNR ≤0.05), R2 (LNR 0.05–0.30) and R3 (LNR >0.30), 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.

BRAF-activated LncRNA functions as a tumor suppressor in papillary thyroid cancer

Long non-coding RNAs (lncRNAs) participate in cancer cell tumorigenesis, cell cycle control, migration, proliferation, apoptosis, metastasis and drug resistance. The BRAF-activated non-coding RNA (BANCR) functions as both an oncogene and a tumor suppressor. Here, we investigated BANCRs role in papillary thyroid carcinoma (PTC) by assessing BANCR levels in PTC and matched normal thyroid epithelial tissues from 92 patients using qRT-PCR. We also used lentiviral vectors to establish PTC cell lines to investigate the effects of BANCR overexpression on cancer cell proliferation, apoptosis, migration and invasion. Our results indicate BANCR levels are lower in PTC tumor tissues than control tissues. Decreased BANCR levels correlate with tumor size, the presence of multifocal lesions and advanced PTC stage. BANCR overexpression reduced PTC cell proliferation and promoted apoptosis, which inhibited metastasis. It also inactivated ERK1/2 and p38, and this effect was enhanced by treatment with the MEK inhibitor U0126. Finally, BANCR overexpression dramatically inhibited tumor growth from PTC cells in xenograft mouse models. These results suggest BANCR inhibits tumorigenesis in PTC and that BANCR levels may be used as a novel prognostic marker.

Association of the miR-149 Rs2292832 Polymorphism with Papillary Thyroid Cancer Risk and Clinicopathologic Characteristics in a Chinese Population

(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.

Incidentally simultaneous occurrence of RET/PTC, H4–PTEN and BRAF mutation in papillary thyroid carcinoma

Because interaction existed between PTEN and RET-RAS-RAF-MAPK pathway, H4-PTEN (a newly identified gene rearrangement), RET/PTC and BRAF mutation were scanned in 125 Chinese patients with papillary thyroid carcinoma (PTC). H4-PTEN were detected in 9.6% of PTC and the frequency of the occurrence of BRAF mutation and/or RET/PTC in H4-PTEN positive tumors was extremely high (75%). On the other hand, age has an important effect on the aberration formation and young age renders more prone to multi-genetic events. A combinational scanning of these involved changes will improve the predictive value of molecular aberrations in the treatment of PTC.

Predictive index for lymph node management of major salivary gland cancer

To find the risk factors of lymph node (LN) metastasis of salivary gland cancer and draw a scheme for LN management.

miR-584 Suppresses Invasion and Cell Migration of Thyroid Carcinoma by Regulating the Target Oncogene ROCK1

Background: Uncovering the target gene of miR-584 to control thyroid carcinoma (TC) invasion and migration is of central importance in the diagnosis, treatment, and prognosis of TC. To validate whether miR-584 has a tumor-suppressive role in thyroid cancer cells by targeting ROCK1, a series of experiments were conducted to figure out the mechanism of action of miR-584. Material and Methods: Migration analyses and cell proliferation assays were performed using miR-584-transfected cells. The expression levels of miR-584 in TC were detected by using real-time polymerase chain reaction (PCR). Western blot analyses were conducted to find out the relationship between the tumor suppressor miR-584 and the target oncogene ROCK1 protein expression levels. Wound healing experiments were used to examine the relationships between miR-584 and the migration of thyroid cancer K1 cells and the effects of ROCK1 knockdown on K1 cell motility. Results: Our results demonstrate that altering the miR-584 levels affects human thyroid cancer cell migration, but has no effect on cell proliferation. The relative ROCK-1 expression levels were 1 and 0.54 in the scrambled-sequence control group and the miR-584 group, respectively. K1 cells transfected with siRNA-ROCK-1 showed weaker cell migration than cells transfected with siRNA-NC (negative control); the cell motility ratios were 18% and 27%, respectively. Conclusion: These results indicate that miR-584 could inhibit the expression of ROCK1, and ROCK1 knockdown would further affect the migration ability of K1 cells.

Lymph node ratio for postoperative staging of laryngeal squamous cell carcinoma with lymph node metastasis

Background Lymph node metastasis has a significant impact on laryngeal cancer prognosis. The role of lymph node ratio (LNR, ratio of metastatic to examined nodes) in the staging of laryngeal cancer was not reported. Patients and Methods Records of laryngeal cancer patients with lymph node involvement from Surveillance, Epidemiology, and End Results database (SEER, training set, N = 1963) and Fudan University Shanghai Cancer Center (FDSCC, validating set, N = 27) were analyzed for the prognostic value of LNR. Kaplan–Meier survival estimates, the Log-rank χ2 test and Cox proportional hazards model were used for univariate and multivariate analysis. Optimal LNR cutoff points were identified by X-tile. Results Optimal LNR cutoff points classified patients into three risk groups R1 (≤0.09), R2 (0.09–0.20) and R3 (>0.20), corresponding to 5-year cause-specific survival and overall survival in SEER patients of 55.1%, 40.2%, 28.8% and 43.1%, 31.5%, 21.8%, 2-year disease free survival and disease specific survival in FDSCC patients of 74.1%, 62.5%, 50.0%, and 67.7%, 43.2%, 25.0%, respectively. R3 stratified more high risk patients than N3 with the same survival rate, and R classification clearly separated N2 patients to 3 risk groups and N1 patients to 2 risk groups (R1–2 and R3). Conclusions R classification is a significant prognostic factor of laryngeal cancer and should be used as a complementary staging system of N classification.