Abstract Papillary thyroid carcinoma is the most common type of thyroid cancer worldwide, but its underlying mechanisms remain unclear. This study aimed to develop a non-targeted, metabolism-based tissue metabolomic analysis method and comprehensively identify the papillary thyroid carcinoma metabolic network in clinical samples based on ultra-high-performance liquid chromatography and quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOFMS). UPLC-Q-TOFMS was used to analyze metabolic changes in matched papillary thyroid carcinoma and paracancerous thyroid tissues obtained from patients. Principal component analysis, partial least square discriminant analysis, and orthogonal partial least square discriminant analysis models were used to separate paracancerous human thyroid and papillary thyroid carcinoma samples. In papillary thyroid carcinoma samples, the levels of L-α-amino acids, leucine, β-amino acids, valine, alanine, methionine, and their derivatives, as well as those of polypeptides, were significantly lower than those in paracancerous tissue. In contrast, the levels of dibucaine, propyzamide, tyrosine, pidotimod, deoxysappanone B 7,4′-dimethyl ether, hippurate, and emodic acid were significantly increased. In addition, metabolites with significant differences in expression were mainly involved in amino acid biosynthesis and metabolism and the mammalian target of rapamycin (mTOR) metabolic pathway. According to the results of our metabolomic and bioinformatics analyses, various metabolites may regulate the synthesis and expression of proteins in papillary thyroid carcinoma by regulating amino acid metabolism and mTOR-related pathways, which may be related to papillary thyroid carcinoma pathogenesis. This study provides novel insights into the metabolic abnormalities of papillary thyroid carcinoma and presents a potential method for its treatment.

BackgroundIn recent years, papillary thyroid carcinoma is considered to be one of the fastest increaseing cancer. NDRG family member 3 (NDRG3) has been proposed as a molecular marker of tumor, and is expected to be used in clinic.MethodsEnzyme-linked immunosorbent assay was used to detect the serum NDRG3 expression in 81 papillary thyroid carcinoma cases, 75 benign thyroid nodules cases and 77 healthy control cases, respectively. Electrochemiluminescence method was applied to measure the levels of triiodothyronine, tetraiodothyronine, thyrotropin, thyroglobulin antibody and thyroid peroxidase antibody. Immunohistochemical staining was used to detect the expression of NDRG3 in papillary thyroid carcinoma, benign thyroid nodules and normal tissues adjacent to cancer.ResultsThe expression of serum triiodothyronine, tetraiodothyronine, thyrotropin, thyroglobulin antibody and thyroid peroxidase antibody and NDRG3 were significantly different among benign thyroid nodules, papillary thyroid carcinoma cases and healthy control groups (P <0.001). Only the expression of serum NDRG3 was significantly different between benign thyroid nodules and papillary thyroid carcinoma groups (P <0.001). Immunohistochemistry showed that NDRG3 was expressed in all three groups, the lowest in papillary thyroid carcinoma, the second in benign thyroid nodules, and the highest in normal tissues adjacent to cancer. Logistic regression analysis showed that serum NDRG3 was an independent protective factor for papillary thyroid carcinoma (OR =0.964, 95%CI =0.953 to 0.974, P <0.001). The ROC curve of non-papillary thyroid carcinoma diagnosed by serum NDRG3 showed the optimal cut-off value of 481.38 pg/ml, sensitivity of 72.4%, specificity of 90.1%, and the maximum area under the curve (AUC =0.902, 95%CI =0.863 to 0.940, P <0.001). The ROC curve of benign thyroid nodules diagnosed by serum NDRG3 showed the optimal critical value of 459.28 pg/ml, sensitivity of 81.3%, and specificity of 74.1% (AUC =0.863, 95%CI =0.808 to 0.919, P <0.001). The expression level of serum NDRG3 was significantly correlated with extrathyroid extensionand (P =0.007) and lymphatic metastasis of papillary thyroid carcinoma (P =0.019).ConclusionsThe decrease of NDRG3 expression can not only differential diagnosis benign thyroid nodules and papillary thyroid carcinoma, but also serve as a molecular marker for the diagnosis of papillary thyroid carcinoma.

Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) are high grade malignant small round cell tumors presenting in both skeletal and extraskeletal anatomic locations. Actually, they are the same entity showing varying degrees of neuroectodermal differentiation. Very few cases of peripheral PNET (pPNET) of the tongue was reported in medical literature. Here, we first report a case of primary extraskeletal ES/pPNET in the tongue of a 9-years old girl. The result of immunohistochemical analysis showed the membranous positive for CD99 and Vimentin. The girl underwent radical surgical treatment and received six cycles of OPEC regimen adjuvantchemotherapy without radiotherapy, and now she is remaining tumor-free survival. The individual comprehensive therapy shows a good curative effect.

Background: Head and neck squamous cell carcinoma (HNSCC) is the most leading incident tumor worldwide. Genetic factors act crucial role in the HNSCC progression. Our study is intent to explore the correlation of LINC-PINT polymorphism with the risk of HNSCC in Chinese population.Methods: The case-control study (including 537 HNSCC cases and 533 controls) was performed to determine the relationship between LINC-PINT polymorphisms and HNSCC susceptibility. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine the associations.Results: The current study indicated that rs157916 and rs7781295 in the LINC-PINT gene have a strong significant correlation with HNSCC risk (OR 1.32, p = 0.042; OR 1.31, p = 0.016). Stratification analyses showed that rs157916 is related to the increased risk of HNSCC in age ≤ 46 years (OR 1.56, p = 0.029). Rs157916, rs16873842, rs7801029, and rs7781295 exhibited an enhanced risk of HNSCC in men (OR 1.82, p = 0.004; OR 1.61, p = 0.028; OR 1.53, p = 0.047; OR 1.62, p = 0.021). Besides, we found that rs16873842 significantly increased the risk of Nasopharyngeal SCC (OR 4.04, p = 0.015). Rs157916 (OR 1.39, p = 0.028) and rs7781295 (OR 1.30, p = 0.028) had a high susceptibility to Thyroid SCC.Conclusions: This research indicated that polymorphisms in the LINC-PINT gene are significantly associated with an increased susceptibility to HNSCC, which suggest that LINC-PINT polymorphisms have a significant role in prevention and diagnosis of HNSCC.

Abstract 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.

6019 Background: Anlotinib (AL3818) is a novel multi-target TKI, inhibiting tumor angiogenesis and proliferative signaling. Our previous single-arm phase 2 ALTN/MTC trial (NCT01874873) has demonstrated that anlotinib has a durable antitumor activity with a manageable adverse event profile in locally advanced or metastatic medullary thyroid carcinoma (MTC). Here we report results of the phase IIB trial (ALTER01031, NCT02586350) of anlotinib for locally advanced or metastatic MTC with a larger samples. Methods: Between September 2015 and September 2018, 91 patients were enrolled in China. Eligible patients have diagnosed as phase IV MTC with relapsed and measurable disease and without antiangiogenetic target therapy. The patients were randomly assigned in a 2:1 ratio to receive anlotinib or a matched placebo (12 mg QD from day 1 to 14 of a 21-day cycle). Patients who have been diagnosed with disease progression by the Independent Imaging Committee could be unblinded and crossed to the treatment group if the patient previous treated by placebo. The primary endpoint was progression-free survival (PFS). Results: 91 patients were randomized 62 to anlotinib arm and 29 to placebo arm. Until the data cutoff date (1 Feb 2019), median PFS was 20.67 months (95%CI, 14.03-34.63) in anlotinib arm vs 11.07 (95%CI, 5.82-14.32) months in placebo arm (HR 0.53, p = 0.0289). The OS data were not sufficiently mature for analysis. Considerable improvement in ORR was observed over the two arms (48.39% vs 3.45%, p < 0.0001). The adverse events (AEs) were 100% in anlotinib arm and 89.66% in placebo arm. The most common AEs in anlotinib arm were hand-foot syndrome, hypertension, hypertriglyceridemia and diarrhea. Conclusion: ALTER01031 met its primary endpoint of PFS shows that anlotinib treatment is effective and well tolerated. The safety profile was consistent and no new adverse events were identified. These data potentially extend the role of anlotinib monotherapy as a new therapy strategy for MTC patients. Clinical trial information: NCT02586350.

6015 Background: Medullary thyroid carcinoma (MTC) is a rare disease with no standard therapies available in China for unresectable, advanced or relapsed MTC patients. Anlotinib is a multi-target RTK inhibitor, with inhibition activities to VEGFR1/2/3, FGFR1/2/3, PDGFRα/β, c-Kit, Ret etc in nanomole level. Recommended dose in phase I study is 12mg daily, 2 weeks on/one week off. We conducted a single-arm, multi-center phase 2 study (NCT01874873) to assess efficacy and safety of anlotinib in advanced MTC patients. Methods: Pathology-confirmed advanced or relapsed MTC patients, who cannot receive radical surgery and have measurable indicators (RECIST1.1), were treated with anlotinib. Assess efficacy every 6 weeks. The primary endpoint is PFS. This study used Simon's Two-Stage design, assuming DCR of anlotinib can achieve 70%. Results: From Sept. 2013, we recruited 58 patients in 8 centers in China, including 34 male patients and 24 female patients. Average age is 48 (22-71). One patient dropped after one cycle treatment, 2 patients without measurable lesions, 55 patients are assessable for efficacy. As of May 2015, average PFS is 12.8 months and median PFS is still not reached. 7 patients achieved PR at second treatment cycle, and 31 patients achieved PR over time (28 patients confirmed), overall ORR is 48.28% (FAS). DCR is 92.16% at week 24, and 84.53% at week 48. 58 patients are assessable for safety. Common grade III/IV AEs are: hand-foot-skin reaction (n=5), hypertension (n=3), mucositis (n=2), stomachache (n=1), diarrhea (n=1), fatigue (n=1), cholesterol increase (n=2), triglyceride increase (n=2), amylase increase (n=2), lipase increase (n=2), ALT increase (n=1), and proteinuria (n=1). 12 patients (20.7%) have dose adjustment during treatment, reducing to 10mg daily, 2 weeks on / 1 week off. Conclusions: Anlotinib has a high ORR (48.28%) for treatment of MTC, average PFS is 12.8 months and median PFS is still not reached. The disease can be controlled for long term (DCR is 92.16% at week 24). The primary endpoint of this study has been met. Meanwhile, anlotinib is well tolerated. The randomized, controlled clinical trial is ongoing. Sun Yongkun and Yihebali Chi contributed equally to this work. Clinical trial information: NCT01874873.