Rong Liang Shi

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.

The Trend of Age-Group Effect on Prognosis in Differentiated Thyroid Cancer

Age has been included in various prognostic scoring systems for differentiated thyroid cancer (DTC). The aim of this study is to re-examine the relationship between age and prognosis by using Surveillance, Epidemiology, and End Results (SEER) population-based database. We identified 51,061 DTC patients between 2004 and 2012. Patients were separated into 10-year age groups. Cancer cause-specific survival (CSS) and overall survival (OS) data were obtained. Kaplan-Meier and multivariable Cox models were built to analyze the outcomes and risk factors. Increasing age gradient with a 10-year interval was associated with the trend of higher proportions for male gender, grade III/IV and summary stage of distant metastases. Both CSS and OS continued to worsen with increasing age, being poorest in in the oldest age group (≥71); multivariate analysis confirmed that CSS continued to fall with each age decade, significantly starting at 60 years (HR = 7.5, 95% 1.0–54.1, p = 0.047) compared to the young group (≤20). Similarly, multivariate analysis suggested that OS continued worsening with increasing age, but starting at 40 years (HR = 3.7, 95% 1.4–10.1, p = 0.009) compared to the young group. The current study suggests that an age exceeding 60 years itself represents an unfavorable prognostic factor and high risk for cancer-specific death in DTC.

Programmed Death-Ligand 1 Expression in Papillary Thyroid Cancer and Its Correlation with Clinicopathologic Factors and Recurrence.

BACKGROUND Programmed death-ligand 1 (PD-L1) expression has been reported in several malignancies, but the expression of PD-L1 in papillary thyroid cancer (PTC) has been characterized rarely. The aim of this study was to assess the significance of PD-L1 expression and its associations with clinicopathologic factors and disease outcome in PTC. METHODS Immunohistochemistry staining was conducted retrospectively to evaluate the expression of PD-L1 in a total of 260 PTC tumors and corresponding non-tumor tissues. The correlations between PD-L1 expressions with clinicopathologic features and recurrence-free survival (RFS) were analyzed. RESULTS PD-L1 expression was positive in 52.3% (136/260) of PTC tumor tissues, which was significantly higher than in corresponding non-tumor thyroid tissues. In clinicopathologic analyses, this positive staining of PD-L1 was positively linked to multifocality (p = 0.001) and extrathyroidal extension (p = 0.001). In multivariate Cox regression analysis, positive PD-L1 expression in tumor tissue was significantly associated with worse RFS (hazard ratio 2.825 [confidence interval 1.149-6.943], p = 0.024). In subgroup analyses based on clinicopathologic factors, positive PD-L1 staining of tumor tissue was associated with worse RFS in males (p = 0.001), older patients (≥45 years; p = 0.001), and patients with a primary tumor size >4 cm (p = 0.002), multifocal tumors (p = 0.031), extrathyroidal extension (p = 0.012), and lymph node metastasis (p = 0.004). In contrast, positive PD-L1 staining predicted worse RFS in the subgroup of patients without Hashimotos thyroiditis (p = 0.001) and treated with total thyroidectomy (p = 0.019). CONCLUSIONS PD-L1 is important in determining aggressiveness of PTC and could predict the prognosis of patients. Therefore, inhibition of PD-L1 is suggested as a potential strategy for the treatment of advanced PTC with high expression of PD-L1.

The impact of marital status at diagnosis on cancer survival in patients with differentiated thyroid cancer

Previous studies have revealed that marital status influences the prognosis of patients with various types of cancer. We evaluated the influence of marriage on the survival outcomes in differentiated thyroid cancer (DTC). The Surveillance, Epidemiology and End Results (SEER) database between 2002 and 2012 was used to compare cancer‐specific mortality in different marital status, and in each sex, age, and stage stratification by multivariate Cox regression model. In total, 61,077 eligible patients were identified. The widowed group had the highest proportion of women, elderly patients (≥45 years), and advanced stage III/IV tumor (P = 0.001), but the total thyroidectomy (TT) performed and radioisotopes therapy rates were lower than those in the married group. Married patients had a better cancer‐specific survival (CSS) than the unmarried (P < 0.05). Further analysis showed that widowed patients always presented the lowest CSS compared with other groups. Widowed patients had a significant increased risk for CSS compared with married patients in males [hazard ratio (HR) 2.72, 95% confidence interval (CI): 1.59–4.65, P = 0.001], females (HR 2.02, 95% CI: 2.24–4.06, P = 0.001), young patients (<45, HR 28.12, 95% CI: 3.48–227.25, P = 0.002), elderly patients (≥45, HR 28.12, 95% CI: 2.97, 95% CI: 2.30–3.83, P = 0.001), stage I (HR 8.44, 95% CI: 4.05–17.59, P = 0.001), stage II (HR 3.64, 95% CI: 1.30–10.20, P = 0.014), stage III (HR 2.27, 95% CI: 1.08–4.78, P = 0.031), and stage IV (HR 2.63, 95% CI: 1.94–3.57, P = 0.001). These results showed that unmarried status, especially for widowhood, increased the risk of cancer mortality in DTC patients.

The Usefulness of Preoperative Thyroid-Stimulating Hormone for Predicting Differentiated Thyroid Microcarcinoma

Objective Thyroid-stimulating hormone (TSH) is a known thyroid growth factor, but the pathogenic role of TSH in thyroid tumorigenesis is controversial. The aim of this study is to examine the relationship between preoperative TSH and differentiated thyroid microcarcinoma (DTMC). Data Sources We searched PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library from their inception to March 2015 and performed a systematic literature review of original studies. Review Methods Published studies that explored the relationship between preoperative TSH and DTMC were included for the review. We calculated odds ratio referring to different TSH concentrations between DTMC and control groups and used random effects model for the meta-analysis. Results Nine eligible studies that included 6523 patients were identified. Meta-analysis revealed that DTMC was associated with high TSH concentration (odds ratio = 1.23, 95% confidence interval = 1.03-1.46, P = .001). Metaregression analysis indicated that the disparity of control groups was the possible factor resulting in heterogeneity among the studies. Conclusions The risk of DTMC increases significantly in parallel with TSH concentration. These results support the hypothesis that TSH is involved in tumorgenesis of differentiated thyroid cancer.

Yes-associated protein 1 promotes papillary thyroid cancer cell proliferation by activating the ERK/MAPK signaling pathway

Yes-associated protein 1 (YAP1) stimulates cell proliferation, epithelial-to-mesenchymal transition, invasion and metastasis in several cancers. Here, we investigated the involvement of YAP1 in papillary thyroid carcinoma (PTC) by assessing YAP1 mRNA and protein levels in PTC tissues and matched normal thyroid epithelial tissues from 50 patients. YAP1 mRNA and protein levels were higher in PTC tumor tissues than in control tissues, and correlated positively with the levels of proliferation-related genes (KI67 and c-MYC). We also used lentiviral vectors to overexpress or silence YAP1 expression in the K1 PTC cell line so that we could investigate the effects of YAP1 on cancer cell proliferation. YAP1 overexpression enhanced PTC cell proliferation by activating ERK1/2 and AKT, and these effects were impaired by treating the cells with the MEK inhibitor U0126 or the AKT inhibitor GSK690693. Finally, YAP1 overexpression dramatically induced growth of tumors from PTC cells in a xenograft mouse model. These results suggest that YAP1 enhances cell proliferation in PTC, and thus may be a promising target in the treatment of PTC.

Metastatic lymph node ratio can further stratify risk for mortality in medullary thyroid cancer patients: A population-based analysis

Medullary thyroid cancer (MTC) has a propensity to cervical lymph node metastases (LNM). Recent studies have shown that both the number of involved lymph nodes (LNs) and the metastatic lymph node ratio (MLNR) confer prognostic information. This study was to determine the predictive value of MLNR on cancer-specific survival (CSS) in SEER (Surveillance, Epidemiology and End Results)-registered MTC patients treated with thyroidectomy and lymphadenectomy between 1991 and 2012, investigate the cutoff points for MLNR in stratifying risk of mortality and provide evidence for selection of appropriate treatment strategies. X-tile program determined 0.5 as optimal cut-off value for MLNR in terms of CSS in 890 MTC patients. According to multivariate Cox regression analysis, MLNR (0.50–1.00) is a significant independent prognostic factor for CSS (hazard ratio 2.161, 95% confidence interval 1.327–3.519, p=0.002). MLNR (0.50–1.00) has a greater prognostic impact on CSS in female, non-Hispanic white, T3/4, N1b and M1 patients. The lymph node yield (LNY) influences the effect of MLNR on CSS; LNY ≥9 results in MLNR (0.50–1.00) having a higher HR for CSS than MLNR (0.00-0.49). In conclusion, higher MLNRs predict poorer survival in MTC patients. Eradication of involved nodes ensures accurate staging and maximizes the ability of MLNR to predict prognosis.

Prognostic significance and optimal cutoff of age in medullary thyroid cancer

Age has been found to correlate with the prognosis for medullary thyroid cancer (MTC). This study was conducted to investigate whether age can predict long-term unfavorable prognosis and evaluate its predictive accuracy associated with TNM staging, using data of patients diagnosed with MTC between 2000 and 2010 from Surveillance, Epidemiology and End Results database. The relationship between the patients’ age at diagnosis and cancer-specific survival (CSS) was evaluated using multivariate Cox regression analysis. Age stratifications were combined into a nomogram model to predict the CSS of MTC. The X-tile program determined 49 and 69 as optimal age cutoff values for CSS. On multivariate analysis, independent factors for survival were age (50–69 years, HR 2.853, 95% CI 1.631–4.991; ≥70 years, HR 5.804, 95% CI 2.91–11.555), race (white, HR 0.344, 95% CI 0.188–0.630), T (T3/4, HR 3.931, 95% CI 2.093–7.381), N (N1a, HR 3.269, 95% CI 1.386–7.710) and M (M1, HR 3.998, 95% CI 2.419–6.606). The C-index for CSS prediction with TNM, age (cutoff of 45)/sex/race/TNM and age (cutoff of 49 and 69)/sex/race/TNM were 0.832 (95% CI 0.763–0.901), 0.863 (95% CI 0.799–0.928), and 0.876 (95% CI 0.817–0.935), respectively. Subgroup multivariate analyses also showed that age significantly increased the risk for CSS in females, non-Hispanic white patients, and those with stage IV MTC. In conclusion, CSS was independently associated with ages between 49 and 69 years, which might be applied for risk stratification in MTC patients.

Tumor size interpretation for predicting cervical lymph node metastasis using a differentiated thyroid cancer risk model

Lymph node metastasis (LNM) is common in differentiated thyroid cancer (DTC), but management of clinically negative DTC is controversial. This study evaluated primary tumor size as a predictor of LNM. Multivariate logistic regression analysis was used for DTC patients who were treated with surgery between 2002 and 2012 in the Surveillance, Epidemiology, and End Results (SEER) database, to determine the association of tumor size at 10 mm increments with LNM. A predictive model was then developed to estimate the risk of LNM in DTC, using tumor size and other clinicopathological characteristics identified from the multivariate analysis. We identified 80,565 eligible patients with DTC in the SEER database. Final histology confirmed 9,896 (12.3%) cases affected with N1a disease and 8,194 (10.2%) cases with N1b disease. After the patients were classified into subgroups by tumor size, we found that the percentages of male sex, white race, follicular histology, gross extrathyroidal extension, lateral lymph node metastasis, and distant metastasis gradually increased with size. In multivariate analysis, tumor size was a significant independent prognostic factor for LNM; in particular, the odds ratio for lateral lymph node metastasis continued to increase by size relative to a 1–10 mm baseline. The coefficient for tumor size in the LNM predictive model waŝ0.20, indicating extra change in log(odds ratio) for LNM as 0.2 per unit increment in size relative to baseline. In conclusion, larger tumors are likely to have aggressive features and metastasize to a cervical compartment. Multistratification by size could provide more precise estimates of the likelihood of LNM before surgery.

The Prediction of Sonographic features and BRAF Mutation for Central Lymph Node Metastasis in Papillary Thyroid Microcarcinoma: Reply

We appreciate the thoughtful and valuable comments by Dr. Coskun Ali from Turkey for our manuscript. Although papillary thyroid microcarcinoma (PTMC) has an indolent course, the central lymph node metastasis (CLNM) has been found with a high incidence in PTMCs at the time of diagnosis [1–3]. The role of therapeutic central lymph node dissection (CLND) for treatment of CLNM in PTMC is well accepted for cN1 disease by The American Thyroid Association (ATA) guidelines for differentiated thyroid cancer and 2014 updating version [4, 5]. However, given the undetermined effect on long-term survival and related morbidity in PTMC patients, the value of routinely prophylactic CLND for cN0 disease remains unclear. Therefore, we conducted a meta-analysis to investigate the clinicopathologic factors predictive of CLNM for guiding prophylactic CLND in PTMCs with risk factors. As noted from comments, the accurate preoperative imaging doesenable complete clearance of the primary tumor and affected lymph node in PTMC patients. Recently, Yeh et al. have published ‘‘American Thyroid Association Statement on Preoperative Imaging for Thyroid Cancer Surgery’’ and highlighted that ultrasonography (US) remained the most important imaging modality in the assessment for both the primary tumor and all associated cervical lymph node basins preoperatively [6]. Positive lymph nodes may be distinguished from normal nodes based upon size, shape, echogenicity, hypervascularity, loss of hilar architecture, and the presence of calcifications in US examination [6]. Actually, we had reviewed the clinicopathologic and imaging features in a total of 163 patients with thyroid micro-nodules, diagnosed as Bethesda classification V (44/163, 27.0 %) and VI (119/163, 73.0 %) for papillary carcinoma by preoperative cytology. All of them had received thyroidectomy, and PTMC was confirmed in 162 patients on histology. In the multivariate analysis, the US suspicious images for nodal metastasis (Figs. 1 and 2), as mentioned above, we reproved to be independent predictors for CLNM in PTMCs [7]. In addition, recent advances in research on thyroid carcinogenesis have yielded applications of diagnostic molecular biomarkers in the management of thyroid nodules [8]. Molecular markers have been reported to enhance the diagnostic sensitivity of fine-needle aspiration (FNA) cytology in detecting malignancy preoperatively [9], such as genetic alterations occur in the MAP kinase (MAPK) and PI3 K/AKT pathways, including BRAF and RAS point mutations, as well as translocations in the RET/PTC and PAX8/PPARc genes [8, 10]. In the latest 2014 ATA guidelines [5], it is pointed out that studies of the BRAF mutation have suggested an association between presence of the mutation and the risk of nodal disease [11–13]. However, BRAF mutation has a limited positive predictive value for recurrence and therefore BRAF mutation status in the primary tumor is not recommended on the decision for prophylactic CLND in the new guidelines [5]. We have reviewed the related studies and found that results across all patients on association between BRAF mutation status and the risk of & Qing-hai Ji jonathan_qn@163.com