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Objective:To investigate the significance of B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation in the prediction of response to apatinib treatment in advanced radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Methods:Twenty patients (10 males, 10 females, age: 51.5(46.3, 65.0) years) with advanced RAIR-DTC from Peking Union Medical College Hospital between March 2016 and March 2023 were retrospectively enrolled, and all patients were treated with apatinib and underwent genetic sequencing (including BRAF V600E and telomerase reverse transcriptase (TERT) promoter). The serological and imaging data, progression-free survival (PFS) and overall survival (OS) data were collected during apatinib treatment. The Kaplan-Meier survival analysis (log-rank test) was performed, and Mann-Whitney U test were used to analyze the differences of duration of response (DOR) between mutation group and wild-type group. Then univariate and multivariate Cox regression analyses were conducted. Results:The PFS (35.3 vs 9.2 months, χ2=7.53, P=0.006) and DOR (25.8(7.4, 35.2) vs 8.2(2.5, 13.4) months, U=23.00, P=0.046) of the BRAF V600E mutation group were longer than those of the wild-type group. Univariate Cox regression analysis showed that the BRAF V600E mutation group had better PFS benefit (hazard ratio ( HR)=0.22 (95% CI: 0.06-0.72), P=0.013), and the risk of disease progression or death in patients with lung metastasis and bone or brain metastasis was 3.06(95% CI: 1.10-8.54, P=0.033) times higher than that in patients with lung metastasis alone. Further, multivariate cox regression analysis showed that only BRAF V600E mutation was an independent predictor of PFS ( HR=0.23 (95% CI: 0.07-0.80), P=0.021), suggesting that RAIR-DTC patients with BRAF V600E mutation might have better efficacy of apatinib. There was no significant difference in PFS ( χ2=1.34, P=0.247) and OS ( χ2=0.19, P=0.664) between TERT promoter mutation group and wild-type group. Conclusion:RAIR-DTC patients with BRAF V600E mutation have longer PFS and DOR after apatinib treatment than those with BRAF V600E wild-type, suggesting that BRAF V600E may be a potential biomarker to guide tyrosine kinase inhibitor (TKI) therapy and help to refine TKI treatment indications.
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Objective:To explore the significance of serum thyroglobulin (Tg) in the decision-making of response to 131I therapy and subsequent treatment for distant metastatic differentiated thyroid cancer (DM-DTC). Methods:Between January 2018 and December 2019, a total of 62 papillary thyroid cancer (PTC) patients (20 males and 42 females, age: (38.1±15.9) years) with pulmonary metastasis from Peking Union Medical College Hospital were retrospectively analyzed. Patients were divided into two groups (non-radioactive iodine (RAI)-avid group and RAI-avid group) according to the post-treatment whole body scan (Rx-WBS). The serum Tg response to 131I therapy including Tg change and Tg change speed was compared between two groups, and the relationship between serum Tg change speed and structural progression was explored by binary logistic regression analysis. The Tg response to different treatment schemes ( 131I treatment or follow-up) was compared in non-RAI-avid group. χ2 test and Mann-Whitney U test were used to compare data between different groups. Receiver operating characteristic (ROC) curve analysis was used to find the best threshold of Tg change speed to predict the structural progress. Results:After 131I treatment, increased Tg level was found in 60.0% (15/25) patients in non-RAI-avid group ( n=25), while only 21.6%(8/37) patients in RAI-avid group ( n=37; χ2=9.417, P=0.002). Non-RAI-avid group showed an overall increased Tg trend, with a speed of 0.05(-0.16, 0.15) μg·L -1·month -1, while RAI-avid group showed a general decreased Tg trend, with a speed of -0.18(-1.95, 0.01) μg·L -1·month -1 ( U=265.000, P=0.005). A significant correlation between Tg change speed and structural response (odds ratio ( OR)=53.005, P<0.001) was found. When Tg change speed was more than 0.135 μg·L -1·month -1, structural progression could be well predicted with the sensitivity of 87.5% and specificity of 97.1%. In comparison to non-RAI-avid patients with merely follow-up, further 131I treatment for such patients did not yield significant benefit in terms of Tg change and Tg change speed ( χ2=0.071, U=394.000; both P>0.05). Conclusions:The serum Tg monitoring can be more sensitive in evaluating the therapeutic response to 131I for DM-DTC patients in whom response evaluation criteria in solid tumors (RECIST) might not be sensitive enough to reflect the minor change. For patients with non-RAI-avidity, Tg evaluation will offer more sensitive evidence to tailor the necessity of further 131I treatment.
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The retained functionality of the sodium iodide symporter (NIS) expressed in differentiated thyroid cancer (DTC) cells allows the further utilization of post-surgical radioactive iodine (RAI) therapy, which is an effective treatment for reducing the risk of recurrence, and even the mortality, of DTC. Whereas, the dedifferentiation of DTC could influence the expression of functional NIS, thereby reducing the efficacy of RAI therapy in advanced DTC. Genetic alternations (such as BRAF and the rearranged during transfection [RET]/papillary thyroid cancer [PTC] rearrangement) have been widely reported to be prominently responsible for the onset, progression, and dedifferentiation of PTC, mainly through activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling cascades. These genetic alternations have been suggested to associate with the reduced expression of iodide-handling genes in thyroid cancer, especially the NIS gene, disabling iodine uptake and causing resistance to RAI therapy. Recently, novel and promising approaches aiming at various targets have been attempted to restore the expression of these iodine-metabolizing genes and enhance iodine uptake through in vitro studies and studies of RAI-refractory (RAIR)-DTC patients. In this review, we discuss the regulation of NIS, known mechanisms of dedifferentiation including the MAPK and PI3K pathways, and the current status of redifferentiation therapy for RAIR-DTC patients.