Efficacy and safety of pralsetinib in Chinese advanced RET-mutant medullary thyroid cancer patients.

Pralsetinib has demonstrated efficacious activity in various solid tumors, including medullary thyroid cancer (MTC), as observed in the phase 1/2 global ARROW study (BLU-667-1101; NCT03037385). We evaluated the safety and efficacy of pralsetinib in Chinese patients with advanced RET-mutant MTC. In the extension cohort of ARROW, adult patients with advanced MTC, who had not received systemic therapy (except for cytotoxic chemotherapy), were treated with pralsetinib (400 mg once daily, orally). The primary endpoints were blinded independent central-reviewed (BICR) objective response rate (ORR) and safety. Between October 9, 2019, and April 29, 2020, 34 patients were enrolled at 12 centers across China. Among them, 28 patients tested positive for RET mutations in the central laboratory, and 26 of these, with measurable disease at baseline per BICR, were included in the analysis set for tumor response. As of April 12, 2021 (data cutoff), the ORR was 73.1% (95% CI: 52.2-88.4), and the median duration of response was not reached. The most common (≥15%) grade ≥3 treatment-related adverse events (TRAEs) in the 28 patients with RET-mutant MTC were neutrophil count decreased (8/28, 28.6%), blood creatine phosphokinase increased (6/28, 21.4%), and lymphocyte count decreased (5/28, 17.9%). Serious TRAEs were reported by six patients (21.4%), with the most common event being pneumonia (3/28, 10.7%). No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, as well as a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.

More aggressive biological behavior in pediatric than in adult papillary thyroid carcinoma.

OBJECTIVE: Papillary thyroid carcinoma (PTC) remains a common malignancy of the endocrine system in children and adolescents. This study aimed to investigate the differences in clinical characteristics between children and adults with PTC. METHODS: A total of 360 patients [ 308 adults (≥20 years) and 52 children and adolescents (<20 years)] with PTC who underwent thyroid surgery in our center from 2017 to 2022 were retrospectively analyzed. Statistical analysis and comparisons of the clinicopathological data and tumor characteristics between children and adults were performed. RESULTS: Among all enrolled patients, the mean tumor diameter was 26.21 ± 12.72 mm in the pediatric group, while that in the adult group was 11.62 ± 10.21 mm, which was a significant difference (p < 0.001). Pediatric patients were more prone to central lymph node metastasis (90.38% vs. 49.35%, p<0.001), lateral lymph node metastasis (78.85% vs. 45.7%, p<0.001), capsular invasion (90.38% vs. 63.96%, p<0.001) and extrathyroidal extension (61.54% vs. 15.26%, p＜0.001) than adult patients. However, the pediatric group had a lower BRAFV600E mutation rate (54.76% vs. 87.7%, p < 0.001) and lower incidence of Hashimoto's thyroiditis (15.38% vs. 30.84%, p = 0.023) than the adult group. There were no significant differences in clinicopathological factors, such as sex, multifocality and hypothyroidism. CONCLUSIONS: Pediatric patients were more likely to present with advanced disease at diagnosis, including larger tumor volume, more lymph node metastasis, more extensive local invasion, and lower rates of BRAF mutation and concomitant Hashimoto's thyroiditis. Therefore, appropriate surgical management and comprehensive treatment decisions are needed for pediatric patients with PTC.

Lymph node ratio independently associated with postoperative thyroglobulin levels in papillary thyroid cancer.

OBJECTIVES: To investigate the impact of the lymph node ratio (LNR) on postoperative thyroglobulin (Tg) levels in patients with papillary thyroid carcinoma (PTC). PATIENTS AND METHODS: This was a retrospective, cohort study. The association between clinicopathological variables and postoperative unstimulated Tg (uTg) levels, preablative-stimulated Tg (sTg) levels, and postablative unstimulated Tg levels was analysed. RESULTS: A total of 300 patients with PTC were identified. Multivariate logistic analysis showed that M classification (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.62-3.34), and postoperative thyroid-stimulating hormone levels (OR, 1.01; 95% CI, 1.01-1.02) were independently associated with postoperative uTg levels. One hundred and sixteen patients underwent radioactive iodine (RAI) therapy. Multivariate analysis showed that LNR in the central neck (OR, 1.24; 95% CI, 1.02-1.51), LNR in the lateral neck (OR, 1.73; 95% CI, 1.09-2.77), RAI dose (OR, 1.43; 95% CI, 1.21-1.69), and M classification (OR, 1.79; 95% CI, 1.22-2.61) were independently associated with preablative sTg levels. Tumour size (OR, 1.01; 95% CI, 1.00-1.01), LNR in the central neck (OR, 1.28; 95% CI, 1.08-1.51), LNR in the lateral neck (OR, 1.66; 95% CI, 1.10-2.49), RAI dose (OR, 1.54; 95% CI, 1.34-1.79), and M classification (OR, 1.56; 95% CI, 1.12-2.19) were also independently associated with postablative uTg levels. CONCLUSION: LNR was independently associated with postoperative Tg levels in patients with PTC. Patients with high LNR were more likely to have incomplete biochemical responses after surgery.

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.

Lymph node ratio as a tool to stratify patients with N1b papillary thyroid cancer.

BACKGROUND: The prognostic significance of lymph node ratio (LNR) in N1b papillary thyroid cancer is unclear. Therefore, the impact of LNR on disease-specific mortality (DSM) and overall survival (OS) in patients with N1b papillary thyroid cancer (PTC) needs to be defined. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database of patients who had undergone thyroidectomy and lymph node dissection. Factors associated with DSM and OS were analyzed and identified using univariate and multivariate Cox proportional risk models. X-tile software was used to find the best cutoff value of LNR. Kaplan-Meier estimates for DSM were plotted for LNR and were compared with the log-rank test. The ROC curve evaluated the validity of the model. RESULTS: A total of 3223 patients with N1b PTC were identified in the SEER database between 1975 and 2019. The best cutoff value for LNR was 0.6. The multivariate Cox proportional risk model showed that age, race, T3/T4 classification, distant metastasis, extent of surgery, number of metastatic lymph nodes, and LNR > 0.6 were independent risk factors for DSM (all p < 0.05). Age, sex, T4 classification, distant metastasis, extent of surgery, and LNR > 0.6 were independent risk factors for OS (all p < 0.05). The Kaplan-Meier method plotted a cumulative risk curve and showed that patients with LNR > 0.6 had a significantly higher risk of DSM than patients with LNR ≤ 0.6 (p = 0.002). CONCLUSION: LNR was a powerful predictor of DSM and OS in N1b PTC patients. LNR could be a useful tool for the stratification of PTC patients with lateral neck metastases.

Single BRAFV600E mutation is not associated with aggressive biological behavior in adolescent and pediatric papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma is more likely to show aggressive biological behaviors in the majority of pediatric patients than in adult patients. The aim of this study was to investigate the mutation rate of the BRAFV600E gene in adolescents and children with papillary thyroid carcinoma and to analyze the association between BRAFV600E gene mutation and tumor-aggressive pathological factors. METHODS: A total of 42 pediatric patients with papillary thyroid carcinoma who underwent thyroid surgery from 2017 to 2022 were studied retrospectively. Whether the BRAFV600E gene mutation in papillary thyroid carcinoma was related to aggressive biological behavior was analyzed. RESULTS: Among the 42 pediatric patients with papillary thyroid carcinoma, the median patient age was 15.71 ± 2.51 years (mean ± SD) and the median tumor diameter was 24.95 ± 12.29 mm (mean ± SD). Among all enrolled patients, the mutation rate of the BRAFV600E gene was 54.76% (23 of 42). There were 33 patients with classic papillary thyroid carcinoma, and 22 (66.67%) with classic subtypes were BRAFV600E positive. The BRAFV600E mutation was associated with lower distant metastasis (p = .013) and less Hashimoto's thyroiditis (p = .006). There was no significant difference in clinicopathological factors such as sex, age, tumor size, capsular invasion, multifocality, hypothyroidism, recurrence, lymph node metastasis, and extrathyroidal extension. CONCLUSIONS: The BRAFV600E mutation is not uncommon in pediatric papillary thyroid carcinoma but is not significantly associated with aggressive biological behavior. It is not possible to determine whether to adopt more active diagnosis and treatment measures on the basis of the mutation of a single BRAFV600E gene.

PGC-1α participates in tumor chemoresistance by regulating glucose metabolism and mitochondrial function.

Chemotherapy resistance is the main reason for the failure of cancer treatment. The mechanism of drug resistance is complex and diverse. In recent years, the role of glucose metabolism and mitochondrial function in cancer resistance has gathered considerable interest. The increase in metabolic plasticity of cancer cells' mitochondria and adaptive changes to the mitochondrial function are some of the mechanisms through which cancer cells resist chemotherapy. As a key molecule regulating the mitochondrial function and glucose metabolism, PGC-1α plays an indispensable role in cancer progression. However, the role of PGC-1α in chemotherapy resistance remains controversial. Here, we discuss the role of PGC-1α in glucose metabolism and mitochondrial function and present a comprehensive overview of PGC-1α in chemotherapy resistance.

High Diagnostic Accuracy of Epigenetic Imprinting Biomarkers in Thyroid Nodules.

PURPOSE: To explore the novel diagnostic value of epigenetic imprinting biomarkers in thyroid nodules. PATIENTS AND METHODS: A total of 550 patients with fine-needle aspiration (FNA)-evaluated and histopathologically confirmed thyroid nodules were consecutively recruited from eight medical centers. Quantitative chromogenic imprinted gene in situ hybridization (QCIGISH) was used to assess the allelic expression of imprinted genes SNRPN and HM13, on the basis of which a diagnostic grading model for thyroid nodules was developed. The model was retrospectively trained on 124 postsurgical thyroid samples, optimized on 32 presurgical FNA samples, and prospectively validated on 394 presurgical FNA samples. Blinded central review-based cytopathologic and histopathologic diagnoses were used as the reference standard. RESULTS: For thyroid malignancy, the QCIGISH test achieved an overall diagnostic sensitivity of 100% (277/277), a specificity of 91.5% (107/117; 95% CI, 86.4 to 96.5), a positive predictive value (PPV) of 96.5% (95% CI, 94.4 to 98.6), and a negative predictive value (NPV) of 100% in the prospective validation, with a diagnostic accuracy of 97.5% (384/394; 95% CI, 95.9 to 99.0). QCIGISH demonstrated a PPV of 97.8% (95% CI, 94.7 to 100) and NPV of 100%, with a diagnostic accuracy of 98.2% (111/113; 95% CI, 95.8 to 100), for indeterminate Bethesda III-V thyroid nodules. QCIGISH demonstrated a PPV of 96.6% (95% CI, 91.9 to 100) and a NPV of 100%, with a diagnostic accuracy of 97.5% (79/81; 95% CI, 94.2 to 100), for Bethesda III-IV. For Bethesda VI, QCIGISH showed a 100% (184/184) accuracy. CONCLUSION: This imprinting biomarker-based test can effectively distinguish malignant from benign thyroid nodules. The high PPV and NPV make the test both an excellent rule-in and rule-out diagnostic tool. With such a diagnostic performance and its technical simplicity, this novel thyroid molecular test is clinically widely applicable.

Preoperative prediction of central neck metastasis in patients with clinical T1-2N0 papillary thyroid carcinoma.

BACKGROUND: Central neck metastasis (CNM) is common in patients with papillary thyroid carcinoma (PTC). However, the prediction of CNM risk remains poorly defined, especially for patients with clinically negative lymph nodes. We developed a preoperative clinical nomogram to predict CNM risk in patients with clinical T1-2N0 (cT1-2N0) PTC. METHODS: Data from 436 patients with unifocal cT1-2N0 PTC were available. We analyzed the association between preoperative variables and CNM using univariate and multivariate logistic regression and developed a clinical nomogram based on the multivariate regression model. The nomogram was validated externally using an independent dataset. RESULTS: The CNM rate was 25.5%. Three clinical variables were associated with CNM, including age, gender, and tumor size. We built a CNM nomogram integrating these three variables. It had a poor index of internal discrimination (C-index, 0.655; 95% CI 0.596-0.715) and a poor index of external discrimination (C-index, 0.690; 95% CI 0.611-0.769). CONCLUSIONS: We developed a preoperative nomogram to quantify the risk of CNM in unifocal cT1-2N0 PTC patients. However, our data showed that preoperative clinical parameters were not able to accurately predict the likelihood of CNM. Other variables need to be investigated to improve the prediction capability of this nomogram.

Safety and effectiveness of carbon nanoparticles suspension-guided lymph node dissection during thyroidectomy in patients with thyroid papillary cancer: a prospective, multicenter, randomized, blank-controlled trial.

Objective: This study aimed to evaluate the effectiveness and safety of carbon nanoparticles-guided lymph node dissection during thyroidectomy in patients with papillary thyroid cancer(PTC). Methods: Clinical trials consisted of two subgroups: unilateral lobectomy (UL; n=283) and total thyroidectomy (TT; n=286). From each subgroup, the patients were randomly assigned to two groups: the carbon nanoparticle group and control group. Primary endpoints included parathyroid hormone (PTH) levels, number of lymph nodes (LNs) detected, number of tiny lymph nodes detected, and recognition and retention of the parathyroid glands. Secondary endpoint was recognition and protection of the recurrent laryngeal nerve. Results: A total of 569 patients with PTC were recruited. There were no statistically significant differences in demographics between the carbon nanoparticles and control groups (P > 0.05). In the UL subgroup, there were no significant differences in PTH levels between the two groups at preoperative, intraoperative, and postoperative day one, and postoperative month one (P>0.05). There was no significant difference in the serum Ca2+ levels between the two groups preoperatively and at postoperative month one (P>0.05). The number of lymph nodes dissected in the carbon nanoparticles group was significantly higher than that in the control group (P<0.0001). The detection rate of tiny lymph nodes in the carbon nanoparticles group was higher than that in the control group (P=0.0268). In the TT subgroup, there was no significant difference in PTH levels between the two groups at preoperative, intraoperative, and postoperative day one (P>0.05). However, the mean PTH level in the carbon nanoparticles group was significantly higher than that of the control group at postoperative month one (P=0.0368). There was no significant difference in the serum Ca2+ levels between the two groups preoperatively and at postoperative month one (P>0.05). There were no significant differences between the two groups in the number of dissected LNs (P>0.05) or the detection rate of tiny lymph nodes (P>0.05). No drug-related AE and complications due to the injection of carbon nanoparticles were recorded in this study. There were no significant differences between the two groups in terms of parathyroid preserved in situ and recurrent laryngeal nerve injury in the UL and TT subgroups. Conclusions: Carbon nanoparticles demonstrated efficacy and safety in thyroidectomy. The application of carbon nanoparticles could significantly facilitate the identification and clearance of LNs and the optimum preservation of parathyroid function. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2300068502.

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.

Design of new drugs for medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is one of the common malignant endocrine tumors, which seriously affects human health. Although surgical resection offers a potentially curative therapeutic option to some MTC patients, most patients do not benefit from it due to the difficulty to access the tumors and tumor metastasis. The survival rate of MTC patients has improved with the recent advances in the research, which has improved our understanding of the molecular mechanism underlying MTC and enabled the development and approval of novel targeted drugs. In this article, we reviewed the molecular mechanisms related to MTC progression and the principle for the design of molecular targeted drugs, and proposed some future directions for prospective studies exploring targeted drugs for MTC.

Mitoxantrone hydrochloride injection for tracing helps to decrease parathyroid gland resection and increase lymph node yield in thyroid cancer surgery: a randomized clinical trial.

The identification and preservation of parathyroid glands (PGs) during thyroid surgery can be challenging. Many techniques have been developed to help surgeons find PGs. We have developed a novel mitoxantrone hydrochloride injection that can be used for lymphatic targeting. After local application during surgery, mitoxantrone hydrochloride injection for tracing (MHI) helps surgeons better identify and preserve PGs and helps pathologists find more lymph nodes. We conducted an open-label, multicenter, randomized clinical trial (CTR20171137) in six centers in China from 08/2017 to 12/2018. Patients with thyroid carcinoma were randomized to the MHI group or the control group. All patients received total thyroidectomy and bilateral central compartment lymph node dissection. The primary outcomes were the PG resection rate and lymph node staining rate. The full analysis set (FAS) included 461 patients, of which 228 were assigned to the MHI group, and 233 were assigned to the control group. The PG resection rates of the MHI group and the control group were 6.6% (15/228) and 26.6% (62/233), respectively, with a significant difference (P < 0.001). No PGs were stained blue with MHI. The central lymph nodes were stained blue with MHI, and the staining rate was 90.5%±12.0%. More lymph nodes were detected in the MHI group than in the control group (13.0±7.3 vs. 10.1±6.4 nodes/patient, P < 0.001). No adverse events related to MHI were observed. MHI is a safe and effective tracer that may help to preserve PGs and identify more central lymph nodes in patients with thyroid cancer.

Lymph node ratio in lateral neck is an independent risk factor for recurrence-free survival in papillary thyroid cancer patients with positive lymph nodes.

BACKGROUND: The purpose of this study was to explore the impact of the lymph node ratio on prognosis in papillary thyroid cancer patients with lymph node metastasis. METHODS: Data from papillary thyroid cancer patients with positive nodes who were initially treated at our institution during 2015-2016 were analysed. Univariate and multivariate Cox proportional hazard models were adopted to predict prognostic factors. A receiver operating characteristic (ROC) curve was used to find the best cut-off value of the lymph node ratio (LNR). Kaplan-Meier curves were used to show the relationship between the LNR in the lateral neck and recurrence-free survival. RESULTS: The median follow-up time was 64.6 months, and recurrence occurred in 16 of 662 patients (2.27%). Univariate analysis showed that male sex, primary tumour size (>17 mm), visible extrathyroidal extension, LNR in the central neck (>0.5), LNR in the lateral neck (>0.10), and visible extranodal extension were significantly correlated with recurrence-free survival (RFS) (p < 0.05). Multivariate analysis using the Cox proportional hazards model showed that the LNR in the lateral neck was an independent risk factor for RFS (p = 0.039; HR 14.76). CONCLUSION: The LNR in the lateral neck was an independent risk factor for recurrence-free survival. For patients with a high lymph node ratio in the lateral neck, more frequent follow-up might be needed.

Macroscopic extranodal extension is an independent predictor of lung metastasis in papillary thyroid cancer.

PURPOSE: Lymph node metastasis is common in patients with papillary thyroid cancer (PTC). Some metastatic lymph nodes may present extranodal extension (ENE). The clinical role of ENE in PTC has yet to be clearly identified. We evaluated macroscopic ENE as a potential prognostic indicator of lung metastasis in PTC. PATIENTS AND METHODS: We identified 1140 consecutive patients who had PTC initially resected at our cancer center. Clinical data and pathological results were reviewed. Univariate and multivariate logistic regression analyses were used to figure out the association between clinicopathological variables and lung metastasis. RESULTS: In this cohort, 51.7% of PTC patients had lymph node metastasis; 10.4% had macroscopic ENE positive nodes; 2.3% had lung metastasis. In patients with lymph node metastasis, the average number of positive nodes was 5.10 ± 4.91. Multivariable analysis of clinicopathological factors revealed that extrathyroidal extension (odds ratio [OR], 3.57; 95% CI, 1.41-9.04), macroscopic ENE (OR, 7.08; 95% CI, 2.54-19.74), and number of positive nodes were significantly associated with lung metastasis. Compared with 0-3 positive nodes, 7-9 positive nodes denoted a moderate risk of lung metastasis (OR, 4.53; 95% CI, 1.03-19.85). And 10 positive nodes or more indicated a high risk of lung metastasis (OR, 9.63; 95% CI, 2.65-35.02). CONCLUSION: Macroscopic ENE could serve as a strong independent prognostic factor of lungmetastasis in PTC. More attention should be paid to patients with ENE positive nodes duringfollow-up.

Extranodal extension is an independent predictor of extensive nodal metastasis in T1 papillary thyroid cancer.

PURPOSE: Extensive lymph node metastasis (ELM) can occur in some patients with T1 papillary thyroid cancer (PTC). However, the risk factors for ELM in patients with T1 PTC have not been fully explored. In this study, we aimed to examine the association between extranodal extension (ENE) and ELM in patients with T1 PTC. PATIENTS AND METHODS: We identified 645 consecutive patients who had T1 PTC initially resected at our centre. Clinical and pathological data were reviewed. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for ELM. RESULTS: ELM was identified in 3.9% of T1 PTC patients, and ENE was identified in 8.1% of patients. ENE was associated with male sex, large tumour size, more positive nodes, and comprehensive surgical treatment. In multivariate analysis, three variables were independently associated with ELM, including ENE (odds ratio [OR], 11.15; 95% confidence interval [CI], 4.54 to 27.30; P < 0.001), age (OR, 0.96; 95% CI, 0.93 to 0.99; P = 0.022), and tumour size (OR, 1.18; 95% CI, 1.06 to 1.31; P = 0.002). Bilateral multifocality and sex were not independently associated with ELM. CONCLUSION: ENE is a strong independent predictor of ELM in patients with T1 PTC. Patients with ENE-positive nodes might need extensive neck dissection.

Male patients with papillary thyroid cancer have a higher risk of extranodal extension.

BACKGROUND: There is a sex disparity in papillary thyroid cancer (PTC). Male sex is associated with a higher likelihood of advanced stage disease. This study aimed to examine the significance of sex for extranodal extension (ENE) in PTC. METHODS: We reviewed the data of PTC patients who had undergone initial surgical resection from July 2012 to December 2014 (N = 1531). The effects of sex and other clinicopathological factors on ENE were investigated. RESULTS: Of 1531 patients identified, 377 (24.6%) were male, 816 (53.3%) had positive nodes, and 256 (16.7%) had ENE. Compared with female patients, male patients had a higher risk of ENE (P < 0.001). Multivariable analysis of clinicopathological factors revealed that male sex (odds ratio [OR], 1.98; 95% confidence interval [CI], 1.37-2.87; P < 0.001), age older than 60 years (OR, 1.93; 95% CI, 1.08-3.35; P = 0.023), extrathyroidal extension (OR, 3.52; 95% CI, 2.42-5.14; P < 0.001), bilateral multifocality (OR, 2.18; 95% CI, 1.53-3.13; P < 0.001), and more positive nodes were significantly associated with increased risk of ENE. Patients with 6-10 positive nodes were 16.45-fold higher to have ENE than patients with 5 positive nodes or less (95% CI, 11.07-24.68; P < 0.001). CONCLUSION: Male PTC patients had a higher risk of ENE than female. Sex was an independent predictor of ENE. The underlying mechanism needs to be investigated further.

Analysis of Risk Factors of Level V Lymphatic Metastasis for Papillary Thyroid Carcinoma with pN1b.

OBJECTIVE: To explore the risk factors of level V lymphatic metastasis in papillary thyroid carcinoma (PTC) patients with pN1b. METHODS: Patients were selected if they presented with a suspicious level III or IV lymph node metastasis and underwent surgery by hemi or total thyroidectomy with a lymph node dissection (levels III, IV, VI, and VII). For these patients, if frozen section showed a positive level III or IV node, then levels II and V nodes were resected. Univariate analysis was performed using the chi-square test for some factors, including age, sex, tumor location, multifocal lesions, tumor size, local invasion of primary focus, status of cervical lymphatic metastasis, TNM staging, tumor deposits (independent tumor nodules), and the metastasis to more than 5 central lymph nodes. Then, the factors with statistical significance indicated by the above univariate analysis underwent multivariate analysis. RESULTS: Univariate analysis indicated that the level V lymphatic metastasis was significantly associated with simultaneous metastases to levels II, III, and IV, simultaneous metastases to levels III and IV, and tumor deposits (all p < 0.05), but it was not significantly associated with age, sex, tumor location, multifocal lesions, tumor size, local invasion of primary focus, other cervical lymphatic metastasis, TNM staging, and the metastases to more than 5 central lymph nodes (all p > 0.05). Multivariate analysis suggested that the simultaneous metastases to levels III and IV and tumor deposits were the risk factors of level V lymphatic metastasis. CONCLUSION: The simultaneous metastases to levels III and IV and tumor deposits are independent risk factors of level V lymphatic metastasis. The patients with pN1b PTC who have simultaneous metastases to levels III and IV or/and tumor deposits may have the risk of level V lymph node metastasis.

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.

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.