Extent of surgery for unilateral papillary thyroid cancer with nonsuspicious contralateral nodules by ultrasound.

BACKGROUND: The discussion about surgical treatment of patients with papillary thyroid cancer(PTC) has been an ongoing issue, which is mainly focused on characteristics of tumor, but rarely on nonsuspicious contralateral nodules. We aimed to compare recurrence-free survival(RFS)/progression-free survival(PFS) of unilateral PTC patients with nonsuspicious contralateral nodules after different extents of surgery. METHODS: Unilateral PTC patients with nonsuspicious contralateral nodules underwent surgery from 2015 to 2017 were enrolled. The association between surgical extent and RFS/PFS was analyzed by Kaplan-Meier method and Cox proportional hazards model. RESULTS: A total of 1293 PTC patients (595[46.0%]TT,523[40.4%]lobectomy+nodule enucleation(LNE),175[13.5%]lobectomy) were analyzed. Patients with a greater surgical extent were more likely to be older, have a greater multifocality of the tumor and contralateral nodules, larger contralateral nodules and primary tumors, and more micro extrathyroidal extension (P < 0.05). After a median follow-up of 45 months, significant growth(>3 mm) was identified in 24 (4.6%) and 19 (10.9%) patients in the LNE and lobectomy group, 7 (1.2%), 14 (2.7%) and 11 (6.3%) structural recurrences and 7 (1.2%), 11 (2.1%) and 7 (4.0%) progression in disease were identified in the TT, LNE and lobectomy groups, respectively. Unadjusted and adjusted RFS/PFS were significantly worse for patients treated with lobectomy than for those who underwent LNE or TT(3-year RFS, 95.5%, 98.2% vs. 99.0%; 3-year PFS, 97.9%, 98.9% vs. 99.0%, P < 0.05), but difference in PFS between LNE and TT lost statistical significance (unadjusted P = 0.226, adjusted P = 0.150). CONCLUSIONS: Due to subtle changes in nodules and acceptable prognosis, lobectomy is a considerable option for unilateral PTC patients with nonsuspicious nodules, when a similar prognosis to TT is expected, LNE may be an effective alternative to optimize quality of life.

The therapeutic effect of Loranthus parasiticus lignan derivatives on collagen-induced arthritis in rats through the SHBG/NFκB pathway.

Lignan-rich beans, nuts, and various seeds are the main foods with antioxidative and hormone-modulating activities. Although the role of lignans in mediating hormone-dependent cancers and cardiovascular diseases is well characterized, the function of lignans in anti-arthritic activity and its underlying mechanisms remain unknown. Three new lignan derivatives, (-)-nortrachelogenin, trachelogenin, and matairesinol, were extracted from Loranthus parasiticus. After establishing the collagen-induced arthritis (CIA) model by intradermal injection of collagen, rats were treated with three new lignan derivatives ((-)-nortrachelogenin: 37%; trachelogenin: 27%; matairesinol: 25.7%) at a concentration of 50 mg/kg and 100 mg/kg, or methotrexate at 0.3 mg/kg. Mixed lignan derivatives significantly attenuated the immune responses in the joints of CIA rats, leading to lower levels of proinflammatory cytokines (IL-6 and TNF-α) and higher levels of free androgen in the serum compared to the CIA model. The results of molecular docking using AutoDock Vina showed that the lignan derivative (-)-nortrachelogenin was the most effective compound for binding to sex hormone-binding globulin (SHBG), thus inhibiting the activity of NFκB in LPS-stimulated macrophages. In this study, (-)-nortrachelogenin was identified as a novel natural lignan derivative with previously unrecognized anti-inflammatory activity. Its molecular mechanism appears related to the regulation of the NFκB/SHBG pathway. Our findings suggest that further application of sex hormone-like compounds in the treatment of rheumatoid arthritis and the potential clinical applications of (-)-nortrachelogenin are promising.

FGF3 Directs the Pathfinding of Prethalamic GABAergic Axons.

The thalamus plays a crucial role in ensuring the faithful transfer of sensory information, except olfactory signals, to corresponding cortical areas. However, thalamic function is not simply restricted to relaying information to and from the cerebral cortex. The ability to modulate the flow of sensory information is supported by a second abundant neuronal type in the prethalamus, the inhibitory gamma-aminobutyric acid (GABAergic) neurons, which project inhibitory GABAergic axons to dorsal thalamic glutamatergic neurons. Interestingly, during the trajectory of pioneer prethalamic axons, morphogen fibroblast growth factor (FGF)-3 is expressed in the ventral chick hypothalamus. Using in vitro analyses in chick explants, we identify a chemorepellent effect of FGF3 on nearby prethalamic GABAergic axons. Furthermore, inhibition of FGF3 guidance functions indicates that FGF3 signaling is necessary to navigate prethalamic axons correctly. Gene expression analyses and loss of function studies demonstrate that FGF3 mediates prethalamic axonal guidance through the downstream pathway of the FGF receptor (FGFR)-1. Together, these results suggest that FGF3 expressed in the hypothalamus functions as a chemorepellent molecule to direct the pathway selection of neighboring GABAergic axons.

Association between surgical extent and recurrence in unilateral intermediate- to high-risk papillary thyroid cancer.

BACKGROUND: Guidelines recommend total thyroidectomy (TT) to facilitate radioactive ablation and serological follow-up for intermediate- to high-risk papillary thyroid carcinoma (PTC). However, the association between surgical extent and tumor recurrence in these patients has not been well validated. We aimed to examine the association between the extent of surgery and recurrence in patients with completely resected unilateral intermediate- to high-risk PTC. METHODS: Patients with completely resected unilateral PTC from 2000 to 2017 in a single institute were reviewed. Those who had extrathyroidal extension (ETE) or lymph node metastasis (LNM, cN1 or pN1 > 5 lymph nodes involved) were included for analysis. Cox proportional hazards models were applied to measure the association between surgical extent and recurrence-free survival (RFS) while adjusting for patient demographic, clinicopathological and treatment variables. RESULTS: A total of 4550 patients (mean[SD] age, 43.0[11.7] years; 3379 women[74.3%]) were included. Of these patients, 2262(49.7%), 656(14.4%), 1032(22.7%), and 600 (13.2%) underwent lobectomy, TT, lobectomy + neck dissection (ND) and TT + ND, respectively. With a median follow-up period of 68 months, after multivariate adjustment, lobectomy was associated with a compromised RFS compared with other surgical extents (HR[95%CI], TT 0.537[0.333-0.866], P = 0.011, lobectomy + ND 0.531[0.392-0.720] P < 0.0001, TT + ND 0.446[0.286-0.697] P < 0.0001). RFS was similar between the two extents with ND (lobectomy + ND, HR [95%CI], 1.196 [0.759-1.885], P = 0.440). CONCLUSION: Lobectomy alone is associated with an elevated recurrence risk in patients with unilateral intermediate- to high-risk PTC compared with larger surgical extents. However, lobectomy and ND may provide similar tumor control compared with the conventional approach of TT and ND.

Anlotinib in Locally Advanced or Metastatic Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Randomized, Double-Blind, Multicenter Phase II Trial.

PURPOSE: Alhough antiangiogenic agents are the bedrock of treatment for radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC), novel antiangiogenic agents with optimized features like greater target-binding affinities and more favorable pharmacokinetics profile are needed. This phase II randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of anlotinib, a multikinase inhibitor, for RAIR-DTC. PATIENTS AND METHODS: Patients (ages between 18 and 70 years) with pathologically confirmed locally advanced or metastatic RAIR-DTC were enrolled and randomly received 12 mg anlotinib once daily or placebo on day 1 to 14 every 3 weeks. Patients on placebo were allowed to receive open-label anlotinib after disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS) and safety. RESULTS: Between September 2015 and August 2018, 76 and 37 patients randomly received anlotinib and placebo, respectively. Patients receiving anlotinib had a significantly longer median PFS [40.5 months, 95% confidence interval (CI), 28.3-not estimable (NE) versus placebo 8.4 months, 95% CI, 5.6-13.8; HR = 0.21, 95% CI, 0.12-0.37, P < 0.001], meeting the primary endpoint. OS was still immature, with a trend of benefit with anlotinib (HR = 0.57, 95% CI, 0.29-1.12). All patients in the anlotinib group experienced adverse events (AE); 8 (10.5%) discontinued treatment due to AEs. CONCLUSIONS: Anlotinib demonstrated promising efficacy and favorable tolerance in the treatment of locally advanced or metastatic RAIR-DTC, supporting further research to establish its role in the treatment of this serious disease.

Comparison of Lobectomy vs Total Thyroidectomy for Intermediate-Risk Papillary Thyroid Carcinoma With Lymph Node Metastasis.

Importance: Surgical treatment of patients with papillary thyroid cancer (PTC) by either lobectomy or total thyroidectomy (TT) has long been a topic of debate, especially for patients with intermediate-risk PTC. Objective: To compare recurrence-free survival (RFS) for patients with PTC and lymph node metastasis after lobectomy vs TT. Design, Setting, and Participants: This retrospective cohort study included a review of patients with PTC treated from January 1, 2000, to December 31, 2017. Propensity score matching (PSM) was performed between patients treated with lobectomy and TT. This study involved a single institute in a cancer referral center. Enrolled were adult patients (aged 18-75 years) with unilateral PTC and ipsilateral clinical lateral neck metastasis (cN1b). Patients with the following characteristics were excluded: a lymph node yield less than 20, primary tumor size greater than 4 cm, gross extrathyroidal extension, metastatic lymph node size greater than 3 cm, and distant metastasis. Data analysis was performed from April 1 to April 30, 2022. Exposures: Lobectomy and TT. Main Outcomes and Measures: The primary outcome was the association between extent of surgery and RFS, assessed using Cox proportional hazards regression models. Results: A total of 946 patients with PTC (mean [SD] age, 37.0 [12.1] years, 630 female individuals [66.6%]) were analyzed. Lobectomy (624 [66.0%]) was negatively correlated with the frequencies of older age (≥65 years, 17 [2.7%]), female sex (393 [63.0%]), multifocality (132 [21.2%]), minor extrathyroidal extension (259 [41.5%]), number of metastatic lymph nodes (median [range], 9 [6-14] nodes), and radioactive iodine ablation (0). After PSM with treatment period and potential prognostic factors (age, sex, primary tumor size, multifocality, minor extrathyroidal extension, number of lymph node metastases and lymph node ratio), 265 pairs of patients were available for analysis. After a median (range) follow-up of 60 (9-150) months in the lobectomy group and 58 (8-161) months in the TT group, 21 (7.9%) and 17 (6.4%) structural recurrences were identified in the lobectomy and TT groups, respectively. Lobectomy was not associated with significantly compromised 5-year RFS rate (lobectomy, 92.3% vs TT, 93.7%; adjusted hazard ratio, 1.10; 95% CI, 0.58-2.11; P = .77). Power analysis indicated that the test had 90% power to detect a more than 4.9% RFS difference. No significant difference in RFS was observed between patients treated with TT and radioactive iodine ablation (n = 75) and their counterparts (adjusted hazard ratio, 0.59; 95% CI, 0.14-2.41; P = .46). Conclusions and Relevance: Results of this cohort study suggest that patients with PTC and lymph node metastasis had a similar RFS after lobectomy vs those who had TT. If radioactive iodine ablation is not going to be performed, lobectomy may be an effective alternative option.

Prognostic value of the preoperative and early trends in postoperative serum thyroglobulin antibody levels among patients with papillary thyroid carcinoma and concomitant Hashimoto's thyroiditis.

BACKGROUND: Thyroglobulin antibody(TgAb) was generally used as a prognostic marker of papillary thyroid cancer(PTC) only after total thyroidectomy, but its value in PTC patients with concomitant Hashimoto's thyroiditis(HT) is unclear. We aimed to assess the prognostic significance of the serum TgAb in these patients. METHODS: This retrospective cohort study included PTC patients and pathologically proven HT from 2007-2016. The Cox proportional hazards model with restricted cubic spline was used to analyze the association between TgAb and structural recurrence, and then survival analysis was performed. RESULTS: Of 839 patients enrolled, 48 recurrences were identified during a median follow-up of 64 months. Macrocarcinoma and lymph node metastasis were significantly associated with higher TgAb (P = 0.006, 0.002), but no significant difference was found for any other characteristics. An increasing preoperative TgAb level up to 2000 IU/ml was associated with shorter recurrence-free survival(RFS) (P < 0.001), and the 5-year RFS rates in patients with TgAb ≤400, 400-800 and >800 IU/ml were 97.3%, 93.2% and 85.8%, respectively (P < 0.05). The difference was found even after adjusting for potential risk factors (P < 0.001). Of 337 PTC patients who were treated with lobectomy and had available TgAb data at the first year after surgery, a significant decrease (≥50%) in postoperative TgAb was achieved in 41.8% patients, who had a favorable prognosis compared with others (5-year RFS rate 98.5% vs. 92.0%, P = 0.008). CONCLUSIONS: The preoperative serum TgAb seem to effectively stratify PTC patients with concomitant HT who had high risk for recurrence, and the early postoperative trends of TgAb was a good prognostic marker for these patients who treated with lobectomy.

Anlotinib in patients with medullary thyroid carcinoma with negative prognostic factors: A sub-analysis based on the ALTER01031 study.

Background: Medullary thyroid carcinoma (MTC) is a rare type of thyroid cancer; however, it accounted for 13.4% of the disease-specific mortalities. ALTER01031 (NCT02586350) was a randomised, placebo-controlled phase 2b trial that evaluated the efficacy and safety of anlotinib in locally advanced or metastatic MTC. This post hoc analysis aimed to evaluate the efficacy and safety of anlotinib in older patients and those with bone metastases using ALTER01031. Methods: In ALTER01031, anlotinib significantly prolonged the median progression-free survival (PFS) from 11.1 months to 20.7 months compared with placebo in the whole population. Patients who were older (≥ 50 years) or had bone metastases were selected. PFS and overall survival (OS) were estimated and compared between patients receiving anlotinib or placebo in each subgroup. A sub-analysis of tumour response and safety was also performed. Results: Patients with older age or bone metastases experienced rapid disease progression as the median PFS was 6.8 months and 7.0 months respectively in the placebo group. Anlotinib significantly improved the median PFS to 17.5 months (P = 0.002) and 20.7 months (P = 0.029) with hazard ratio (HR) of 0.31 (95% CI, 0.15-0.68) and 0.44 (95% CI, 0.20-0.94) compared with placebo. Significant benefit in OS was observed in patients with older age after a longer follow-up (HR = 0.47 [95% CI, 0.22-0.99], P = 0.041). The safety profile of these subgroups was similar to that of the entire population. Conclusion: This sub-analysis demonstrated significant survival benefits and favourable safety of anlotinib in patients with MTC who had old age or bone metastases, supporting the feasibility of anlotinib in these patients.

Risk stratification of lateral neck recurrence for patients with pN1a papillary thyroid cancer.

BACKGROUND: Lateral neck is not recommended for dissection in patients with pN1a papillary thyroid cancer (PTC), but its recurrence risk has not been well stratified. We aimed to develop a risk stratification system for lateral neck recurrence in patients with pN1a PTC. METHODS: Patients with pN1a PTC who underwent thyroidectomy and unilateral central compartment dissection from 2000-2016 were enrolled. The association between number of central lymph node metastases (CLNMs) and lateral neck recurrence was comprehensively assessed using a Cox proportional hazards model with restricted cubic spline. Stratification was then performed based on CLNMs and other significant risk factors selected by multivariate analysis. Lateral neck recurrent-free survival (LRFS) rate of each stratification was estimated with Kaplan-Meier curve and comparison was performed using log-rank test. RESULTS: Ninety-six (3.8%) lateral neck recurrences were identified during a median follow-up of 62 months among a total of 2500 admitted cases. An increasing number of CLNMs was associated with compromised LRFS for up to 6 CLNMs (P < 0.001), and CLNMs > 3 indicated significantly worse 5-year LRFS than that of CLNM ≤ 3 (90.6% vs. 98.1%, P < 0.001). When stratification with CLNMs and primary tumor size (selected by multivariate analysis, HR (95%CI) = 4.225(2.460-7.256), P < 0.001), 5-year LRFS rates of high- (CLNMs > 3 and primary tumor size > 2 cm), intermediate- (CLNMs > 3 and primary tumor size 1-2 cm) and low-risk (primary tumor size ≤ 1 cm or CLNMs ≤ 3) groups were 78.5%, 90.0% and 97.9%, respectively (P < 0.05). CONCLUSIONS: The number of CLNMs combined with primary tumor size seems to effectively stratify lateral neck recurrence risk for patients with pN1a PTC.

Isthmectomy is effective and sufficient for selected patients with the isthmus-confined solitary papillary thyroid carcinoma.

BACKGROUND: To retrospectively analyze the outcomes of patients treated with isthmusectomy for a solitary papillary thyroid carcinoma (PTC) confined to the isthmus, and re-assess the role of isthmusectomy in these patients. METHODS: The medical records of 65 patients who underwent isthmusectomy for a solitary PTC confined to the isthmus at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College between 1985 and 2015 were retrospectively reviewed. Demographic data, surgical procedures, pathological characteristics, stages, and outcomes were analyzed. RESULTS: Patients' median age was 39 years (range, 19-63), and the majority were female (86.2% female, 13.8% male). All patients had a solitary PTC confined to the isthmus and were treated with isthmusectomy. Pretracheal lymph node dissection was performed in 34 patients, in which unilateral central neck dissection was performed in 4 patients and bilateral central neck dissection in 2 patients. Microscopic extrathyroidal extension (ETE) was observed in 23 (35.4%) patients, and macroscopic ETE was observed in 3 (4.6%) patients. Thirty-eight (58.5%) patients were stage pT1a, 19 (29.2%) patients were stage pT1b, 5 (7.7%) patients were stage pT2, and 3 (4.6%) patients were stage p3b. Fifteen (23.1%) patients were stage pN1a. Median follow-up time was 78 months (range, 12-274). Two patients experienced a recurrence and both achieved remission after re-operation. The 10-year recurrence-free survival was 92.1%. The 10-year overall survival and disease specific survival were 98.3% and 100%, respectively. CONCLUSIONS: Isthmusectomy is effective and sufficient for select patients with a solitary PTC confined to the isthmus.

Optimal Serum Thyrotropin Level for Patients with Papillary Thyroid Carcinoma After Lobectomy.

Background: The optimal serum thyrotropin (TSH) level for postlobectomy papillary thyroid carcinoma (PTC) patients is unclear. The objective of this study was to examine the association of TSH and recurrence in postlobectomy patients. Methods: Patients who underwent lobectomy for PTC in a single tertiary hospital from January 2000 to December 2014 were enrolled. The mean TSH of a patient was calculated based on each serum TSH value during follow-up. The reference range of serum TSH was 0.5-4.0 mU/L. Univariate and multivariable analyses were performed with Cox proportional hazards models. Restricted cubic spline (RCS) functions were used to model relationships between mean TSH and recurrence-free survival (RFS). Results: A total of 2297 patients (median age 42 years; 1750 (76.2%) female) were analyzed. Mean TSH below (≤0.5mU/L), in the lower half (0.6-2 mU/L), in the upper half (2.1-4 mU/L), and above (>4 mU/L) the reference range were observed in 668 (29.1%), 1162 (50.6%), 345 (15.0%), and 122 (5.3%) patients, respectively. According to the Cox model and RCS, no association was observed between mean TSH and RFS in the whole cohort, low-risk group and intermediate- to high-risk groups (adjusted p = 0.4737, 0.9314, 0.1859, adjusted p for nonlinear = 0.4589, 0.8622, 0.3010). The only RFS difference observed in the stratified univariate analysis was between patients with mean TSH in the lower half (0.6-2 mU/L, n = 659) and above the reference range (>4 mU/L, n = 68) in the intermediate- to high-risk group (10-year RFS by Kaplan-Meier 84.4% vs. 69.4%, log rank p = 0.011). Conclusions: Mean serum TSH levels are not associated with recurrence. A normal TSH reference range is recommended for postlobectomy PTC patients.

Organ preservation surgery for pyriform sinus carcinoma with vocal cord fixation: functional and oncological outcomes.

BACKGROUND: Pyriform sinus carcinoma with vocal cord fixation is stratified as stage T3 and above, and non-surgical treatment is generally preferred according to the guidelines, aiming to preserve laryngeal function. However, long-term survival is often compromised by deep infiltration of the tumor. Vertical hemipharyngolaryngectomy (VHPL) was previously reported to be a feasible surgical approach for organ preservation. The aim of this study was to evaluate the functional and oncological outcomes of VHPL in patients. METHODS: Patients who underwent VHPL type II (total VHPL, which includes the removal of a vertical section of the thyroid cartilage through the anterior commissure to the upper border of the cricoid cartilage) for pyriform sinus cancer with vocal cord fixation at the authors' institute between 1999 and 2015 were retrospectively analyzed. Functional outcomes concerning swallowing and decannulation were evaluated. Successful functional preservation was defined as laryngeal preservation as well as oral realimentation and decannulation within 6 months after surgery. The oncological outcomes were measured by overall survival (OS) and disease-free survival (DFS) with Kaplan-Meier curves and comparisons were performed between the VHPL-treated patients and patients who underwent non-surgical treatment within the same period. RESULTS: A total of 23 patients (stage T3, 17 patients; stage T4, 6 patients) whose initial treatment was VHPL type II were studied, and a cohort of 123 patients was selected as the control group. Pedicle and free flap reconstructions were performed on 12 and 11 patients, respectively. Postoperative radiation and chemoradiation was performed on 14 and 3 patients, respectively. Flap failure and pharyngeal fistula were detected in 2 and 5 patients, respectively. Oral realimentation and decannulation within 6 months were achieved in 82.6% (19 patients) and 87.0% (20 patients) of patients, respectively, and the total functional preservation rate of the study cohort at 6 months was similar to that of the control cohort. (78.3% vs. 82.9%, p = 0.28). After a median follow-up period of 49 months, 9 recurrences and 8 deaths had occurred in the study cohort. According to the Kaplan-Meier analysis, the study cohort had superior DFS (5-year DFS 60.3% vs. 44.6%, p = 0.04) and similar OS (5-year OS 63.8% vs 57.0% p = 0.28) compared with those in the control group. CONCLUSION: VHPL yielded favorable oncological and functional outcomes in patients with unilateral pyriform sinus carcinoma and vocal cord fixation.

MARCH6 promotes Papillary Thyroid Cancer development by destabilizing DHX9.

Membrane-associated ring-CH-type finger (MARCH) proteins belong to the E3 ubiquitin ligase family, which regulates protein stability by increasing ubiquitination. Recent evidence has shown that some MARCH proteins play important roles in cancer development. However, the role of MARCH6 in tumorigenesis, including thyroid tumorigenesis, remains unknown. In this study, we determined that MARCH6 was upregulated in the majority of primary papillary thyroid cancers (PTCs) at both the mRNA and protein levels. Gain-of-function and loss-of-function studies demonstrated that MARCH6 suppressed apoptosis and promoted cell cycle progression, cell proliferation, growth, migration and tumorigenesis in thyroid cancer cells. Mechanistically, MARCH6 interacted with and downregulated DHX9. Knockdown of DHX9 enhanced the proliferative and migratory abilities of thyroid cancer cells. The inhibitory effect of MARCH6 knockdown on thyroid cancer cell growth and migration was also reversed by DHX9 silencing. In addition, MARCH6 activated the AKT/mTOR signaling pathway in a manner dependent on the downregulation of DHX9. Overall, MARCH6 functions as a potential oncogene in thyroid cancer by destabilizing DHX9 and activating AKT/mTOR signaling.

Predictive Value of Serum Thyroglobulin for Structural Recurrence Following Lobectomy for Papillary Thyroid Carcinoma.

Background: The value of serum thyroglobulin/antithyroglobulin (Tg/antithyroglobulin antibody [ATg]) for papillary thyroid carcinoma (PTC) surveillance after lobectomy was investigated. We aimed to examine the association between postlobectomy serum Tg/ATg and PTC structural recurrence and define applicable values for stratification. Methods: PTC patients who underwent lobectomy with adequate serum Tg/ATg data during 2000-2014 were selected. Predictive classifiers of recurrence using random forest were established combining different variables related to serum Tg (ATg-negative patients) or ATg (ATg-positive patients). Cutoff values were determined with receiver operating characteristic curves when applicable. Kaplan-Meier curve and Cox regression were performed to examine the predictive value of elevated Tg/ATg. Results: Of 1451 patients enrolled, 66 (6.3%) and 26 (6.5%) patients in the ATg-negative group (n = 1050) and ATg-positive group (n = 401) developed recurrence. The established classifier of serum Tg (n = 1050) showed a favorable association with recurrence (AUC = 0.81), while serum ATg did not (AUC = 0.72). The optimal cutoff values of the first Tg (FTg, measured 6-12 months after lobectomy) and last Tg (LTg, measured most recently) were 5.3 and 11.0 ng/mL, respectively. Elevated LTg patients had significantly higher recurrence rates than normal LTg patients (23.5% vs. 4.4%, p < 0.05). Patients with elevated FTg had significantly lower recurrence-free survival rates than patients with normal FTg in all ATg-negative patients, low-risk patients, and intermediate- to high-risk patients (according to the American Thyroid Association initial risk stratification) (n = 1050, 583, and 467, all p < 0.05). Multivariate analysis indicated patients with elevated FTg had twice the recurrent risk compared with those with normal FTg (hazard ratio = 2.052). Conclusions: Postlobectomy serum Tg has favorable value for predicting recurrence in PTC patients, and reasonable thresholds could identify patients at higher risk for recurrence during follow-up.

Prevalence of Hashimoto Thyroiditis in Adults With Papillary Thyroid Cancer and Its Association With Cancer Recurrence and Outcomes.

Importance: Hashimoto thyroiditis (HT) has been suggested to be associated with papillary thyroid cancer (PTC) development. However, its association with PTC progression remains unclear. Objective: To examine the association between HT and PTC presentation and outcomes. Design, Setting, and Participants: This retrospective cohort study included a review of patients aged 18 to 75 years who had pathologically confirmed PTC treated at a single center in China from January 1, 2001, to December 31, 2014. Data analysis was performed from November 1 to December 31, 2020. Exposures: Coexistent HT was defined according to evaluation of postoperative paraffin sections. Main Outcomes and Measures: The primary outcome was the association of HT with PTC-related mortality, assessed using Cox proportional hazards regression models. The secondary outcome was the association of HT with aggressive characteristics and structural recurrence of PTC, assessed using logistic regression and Cox proportional hazards regression with and without adjustment for related factors. Results: Of 9210 patients with PTC (mean [SD] age, 43.6 [12.0] years; 6872 [75%] women) included in the analysis, 1751 (19%) had HT. In the logistic regression model, HT was negatively associated with frequencies of primary tumor size of 4 cm or greater (adjusted odds ratio [aOR], 0.20; 95% CI, 0.12-0.33; P < .001), gross extrathyroidal extension (aOR, 0.44; 95% CI, 0.36-0.54; P < .001), extranodal extension (aOR, 0.66; 95% CI, 0.55-0.80; P < .001), and distant metastasis (aOR, 0.17; 95% CI, 0.04-0.71; P = .02). After a median follow-up of 85 months (range, 12-144 months), 131 PTC-related deaths were identified in the cohort; 2 patients who died had HT. Patients with HT had significantly superior outcomes compared with patients without HT in terms of unadjusted 10-year disease-specific survival (99.9% vs 96.6%; log-rank P < .001) and recurrence-free survival (92.0% vs 87.6%; log-rank P = .001). After adjusting for sex, age, primary tumor size, extrathyroidal extension, lymph node metastasis, distant metastasis, extent of surgery, and radioactive iodine ablation, HT was associated with decreased PTC-related mortality (hazard ratio [HR], 0.19; 95% CI, 0.05-0.76; P = .02). Stratified analysis showed that HT was associated with less frequent structural recurrence in patients with extrathyroidal extension (HR, 0.52; 95% CI, 0.38-0.71; P < .001; P = .002 for interaction) or after total thyroidectomy (HR, 0.50; 95% CI, 0.35-0.69; P < .001; P = .009 for interaction). Conclusions and Relevance: In this cohort study, patients with coexistent HT had less aggressive characteristics at presentation and better outcomes of PTC than did patients without HT. The findings suggest that autoimmune thyroiditis has a protective role in association with thyroid cancer.

A Randomized, Phase III Study of Lenvatinib in Chinese Patients with Radioiodine-Refractory Differentiated Thyroid Cancer.

PURPOSE: Lenvatinib has shown efficacy in treating radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the multinational phase III SELECT study; however, it has not been tested in Chinese patients with RR-DTC. PATIENTS AND METHODS: Chinese patients with confirmed RR-DTC (n = 151) were randomly assigned 2:1 to receive lenvatinib 24 mg/day or placebo in 28-day cycles. The primary endpoint was progression-free survival, and key secondary endpoints included objective response rate and safety. Analyses for progression-free survival and objective response rate were conducted using Response Evaluation Criteria in Solid Tumors v1.1 and confirmed by independent imaging review. All adverse events were assessed and monitored. RESULTS: Progression-free survival was significantly longer with lenvatinib treatment [n = 103; median 23.9 months; 95% confidence interval (CI), 12.9-not estimable] versus placebo (n = 48; median 3.7 months; 95% CI, 1.9-5.6; hazard ratio = 0.16; 95% CI, 0.10-0.26; P < 0.0001). The objective response rate was 69.9% (95% CI, 61.0-78.8) in the lenvatinib arm and 0% (95% CI, 0-0) in the placebo arm. At data cutoff, 60.2% of patients receiving lenvatinib remained on treatment; treatment-emergent adverse events led to lenvatinib discontinuation in 8.7% of patients. Overall, treatment-emergent adverse events of grade ≥3 occurred in 87.4% of patients in the lenvatinib arm, the most common being hypertension (62.1%) and proteinuria (23.3%). CONCLUSIONS: Lenvatinib at a starting dose of 24 mg/day significantly improved progression-free survival and objective response rate in Chinese patients with RR-DTC versus placebo. There were no new or unexpected toxicities. Results are consistent with those from SELECT involving patients with RR-DTC.

α-Enolase Lies Downstream of mTOR/HIF1α and Promotes Thyroid Carcinoma Progression by Regulating CST1.

Novel therapy strategies are crucial for thyroid carcinoma treatment. It is increasingly important to clarify the mechanism of thyroid carcinoma progression. Several studies demonstrate that α-Enolase (ENO1) participates in cancer development; nevertheless, the role of ENO1 in thyroid carcinoma progression remains unclear. In the present study, we found that the expression of ENO1 was upregulated in thyroid carcinoma samples. Proliferation and migration of thyroid carcinoma cells were suppressed by depletion of ENO1; conversely, ENO1 overexpression promoted thyroid carcinoma cell growth and invasion. To elucidate the mechanisms, we found that the hypoxia-related mTOR/HIF1 pathway regulated ENO1 expression. ENO1 regulated the expression of CST1; knockdown of CST1 reversed the tumorigenicity enhanced by ENO1 overexpression. Taken together, our findings provide a theoretical foundation for thyroid carcinoma treatment.

Anlotinib in Locally Advanced or Metastatic Medullary Thyroid Carcinoma: A Randomized, Double-Blind Phase IIB Trial.

PURPOSE: Medullary thyroid cancer (MTC) accounts for about 2% of all thyroid cancer, but has a relatively poor prognosis compared with differentiated thyroid cancer. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This multicenter, randomized, double-blind, placebo-controlled phase IIB study (ALTER 01031 and NCT02586350) was conducted to investigate the efficacy and safety of anlotinib in MTC. PATIENTS AND METHODS: Patients with histopathologically confirmed, unresectable locally advanced or metastatic MTC were enrolled and randomly assigned in a 2:1 ratio to receive anlotinib (12 mg once daily from day 1 to 14 every 3 weeks) or placebo. Patients in placebo group were allowed to receive open-label anlotinib after disease progression. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). RESULTS: Ninety-one patients were enrolled. At data cutoff date, the median PFS was significantly prolonged in the anlotinib group than in the placebo group (20.7 months vs. 11.1 months, P = 0.029; HR, 0.53; 95% confidence interval, 0.30-0.95). The ORR of anlotinib treatment was 48.4%. The incidence of treatment-related adverse events (TRAE) was 100% and 89.7% in the anlotinib and placebo groups, respectively. The most common TRAEs of all grades in the anlotinib group were palmar-plantar erythrodysesthesia syndrome (62.9%), proteinuria (61.3%), and hypertriglyceridemia (48.4%). CONCLUSIONS: Anlotinib demonstrates its efficacy and safety in this phase IIB trial for the treatment of MTC and may become a new choice for this rare disease, especially for Chinese patients.

Predictive Nomogram for the Necessity of Tracheotomy During Oral and Oropharyngeal Cancer Surgery.

OBJECTIVES/HYPOTHESIS: The individualized risk of airway obstruction after head and neck cancer surgery is unclear, especially oral and oropharyngeal cancer. The study aimed to establish an individualized predictive model for the necessity of temporary tracheotomy in these patients. METHODS: Patients who underwent oral and oropharyngeal cancer surgery from 1999 to 2019 were retrospectively reviewed. A nomogram was developed and validated in patients treated from 1999 to 2009 and 2010 to 2019, respectively. RESULTS: In total, 1551 patients were included. Oropharyngeal cancer, large tumor, midline crossing, preoperative radiation, mandibulectomy, flap reconstruction, and neck dissection were independent risk factors of postoperative airway obstruction in the training group (n = 707). A nomogram incorporating these factors had a C-index of 0.931 and was validated in the testing group (n = 844) (C-index, 0.918). Good calibration curves were observed in both groups. CONCLUSIONS: The nomogram successfully predicted the individual risk of postoperative airway obstruction for patients with oral and oropharyngeal cancer. LEVEL OF EVIDENCE: 4. Laryngoscope, 131:E1489-E1495, 2021.

Long-term outcomes of patients with papillary thyroid cancer who did not undergo prophylactic central neck dissection.

AIMS: The role of prophylactic central neck dissection (CND) in the management of papillary thyroid carcinoma (PTC) is controversial. This study reports outcomes of an observational approach in PTC patients without clinical evidence of lymph node metastasis. MATERIALS AND METHODS: Patients with PTC who had surgery (without prophylactic CND) between January 2000 and December 2008 were included in this study. Recurrence-free survival (RFS) and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. Cox regression was used in multivariable models. RESULTS: Out of 625 patients, 486 (77.8%) were female, 144 (23%) were aged 55 years or more, 73 (11.7%) had macroscopic extrathyroidal extension, and 79 (12.7%) had pT3 or pT4 disease. Samples were collected from 12 (1.9%) patients with lymph node metastasis in the perithyroidal tissue and 2 (0.3%) patients with lymph node metastasis in the lateral neck lymph tissue for frozen section examination. After a median follow-up of 104 months, the 10-year DSS and RFS rates were 99.7% and 90.2%, respectively. The 10-year lymph node recurrence rate in the central compartment was 2.7%. pT3/4 stage was an independent predictive factor for RFS (P < 0.001, hazard ratio 1.966, 95% confidence interval 1.446-2.673). CONCLUSION: The outcomes of patients with clinically negative lymph nodes in the central compartment were favorable without prophylactic CND.