131 I-metabolizing genes are markers for differentiation of thyroid carcinoma.The loss or down-regulation of these genes represents progression of dedifferentiation,which results in low 131 I uptake and suggests a poor prognosis.The mechanism of dedifferentiation of DTC is important for treatment.This article reviews the mechanism of dedifferentiation from 131I radiation damage,gene mutation,tumor markers and protein.

During 131Ⅰ therapy or the natural course of DTC,2％ to 5％ of them will gradually no longer be sensitive to 131Ⅰ therapy and lead to radioactive iodine-refractory DTC (RAIR-DTC).Recent studies found that alterations of critical molecular targets in main signal transduction pathways could decrease the iodine-trapping function of thyroid carcinoma,such as BRAFV600E mutation,followed by negative 131 Ⅰ-whole body scan (WBS) and discounted efficacy.This article reviews novel diagnostic and therapeutic modalities for RAIR-DTC.

Background and purpose:Thyroglobulin antibody (TgAb) is often positive in papillary thyroid carcinoma (PTC) patients. This study aimed to investigate the effect of TgAb on radioiodine ablation efficacy in PTC patients.Methods:A total number of 329 PTC patients with no distant metastasis were included and classified into 2 groups[G1 group (>115 U/mL,n=84) and G2 group (<115 U/mL,n=245)], G2 group was further divided into 2 subgroups[S1 (>40 U/mL,n=31) and S2 (<40 U/mL,n=214)], before131I ablation. The median follow-up time was 24 months after a total or subtotal thyroidectomy and subsequent131I ablation. The efficacy in terms of131I ablation success rates (IBR) between two groups were compared and the influencing factors were analyzed according to criteria posed by 2015 American Thyroid Association Guidelines, then the effect of131I dose on IBR was also explored.Results:Female and younger age were more prevalent in patients with high TgAb (P<0.05). The G1 group presented lower IBR over the G2 group (35.7%vs 72.7%,P=0.000). Moreover, S1 group also presented lower IBR over S2 group (54.8%vs 75.2%,P=0.017), indicating the adverse effect from high titer TgAb on IBR. No matter high or low dose, the G1 group presented lower IBR (34.1%vs 71.9%, 37.2%vs 73.2%;P=0.000). However, IBR did not differ in G1 or G2 group either with high or low dose131I (P>0.05). TgAb was the only adverse indicator correlating with IBR in multi-logistic regression analysis (P=0.018).Conclusion:TgAb could negatively affect131I ablation efficacy, while increasing the dose of131I failed to improve the success rate in such cases.

Background and purpose:This study aimed to investigate the relationship between lymph node metastatic rate (LR) and response to radioiodine therapy in patients with papillary thyroid carcinoma (PTC).Methods:A total number of 143 PTC patients after radioiodine therapy were included and classified into 4 groups [Ⅰ(0%-10%),Ⅱ(>10%-25%),Ⅲ(>25%-50%),Ⅳ(>50%)] according to the lymph node metastatic rate, and the responses to initial radioiodine therapy after a median follow-up period of 20.7 months were evaluated. They were classiifed into 4 groups [excellent response (ER), indeterminate response (IDR), biochemical incomplete response (BIR), and struc-tural incomplete response (SIR)] according to the guideline proposed by 2015 American Thyroid Association. One-Way analysis of variance,χ2 test and Kruskal-Wallis test were used to evaluate the differences in basic clinicopathological features and clinical responses among the 4 groups. The ROC curve was analyzed to evaluate the clinical value of lymph node metastatic rate for predicting ER and optimal cut-off point.Results:There were no signiifcant differences in gender and T-stage among 4 groups (P>0.05). However,Ⅰ group was signiifcantly older than the other 3 groups (P=0.001). With the increase of lymph node metastatic rate, the number of ER cases decreased, while cases of BIR and SIR generally increased. Compared with the other 3 groups, less cases of ER (27.8%), while more BIR (27.8%) or SIR (11.1%) were observed in groupⅣ (H=18.816,P=0.000). Cut-off value of lymph node involved rate was 52.27%, with a better speciifcity of predicting ER. Area under the ROC curve was 0.668.Conclusion:The higher lymph node metastatic rate in patients with PTC, the worse clinical outcome it could be. A cut-off value of lymph node metastatic rate 52.27% is a speciifc independent predictor for the clinical outcome in PTC patients treated with radioiodine therapy.

Background and purpose:Radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) is a big challenge in the management of thyroid cancer. Sorafenib and lenvatinib are the 2 tyrosine kinase inhibitors (TKIs) recently approved by FDA, which could not be affordable for most of the Chinese patients. This pilot study aimed to evaluate the short term effcacy and safety of apatinib, a Chinese domestic TKI targeted vascular endothelial growth factor receptor (VEGFR), in advanced RAIR-DTC.Methods:Ten patients who were identiifed as progressive RAIR-DTC were enrolled in this study. Patients received oral apatinib 750 mg once daily. Both thyroglobulin (Tg) and/or Tg antibody (TgAb) levels were monitored every 2 weeks after the treatment. Computed tomography (CT) was per-formed every 4 weeks after apatinib treatment to evaluate the response according to response evaluation criteria in solid tumor version 1.1 (RECIST 1.1). Within 8 weeks after apatinib treatment, therapeutic response was evaluated in terms of Tg, a sensitive biochemical tumor marker for DTC, and RECIST 1.1 assessment. Meanwhile, the adverse events (AE) were monitored during the therapy.Results:The Tg levels declined after the ifrst 2 weeks of apatinib treatment, and a mean decline rate of 68% could be observed in 8 patients with Tg available for evaluation after 8 weeks, which repre-sented a biochemical partial response. Eighteen target lesions (TL) of 10 patients were evaluated and followed up. The diameter of TL began to decrease after 4 weeks, and a mean decline of 40% could be observed after 8 weeks’ apatinib treatment. A total of 9 patients (9/10) achieved partial response according to RECIST 1.1 criteria and 1 patient with stable disease, with 90% objective response rate and 100% disease control rate. The most common AE beyond grade 3 included hand-foot-skin reactions, hypertension and hypocalcemia, which accounted for 50%, 30% and 20% of the cases, respectively. No severe AE related to apatinib was observed during the treatment.Conclusion:A safe and rapid response and high partial response rate in terms of biochemistry, RECIST 1.1 could be observed in RAIR-DTC patients within 8 weeks of apatinib treatment.

Objective To evaluate the impact of low-dose 131I therapy and high-dose 131I therapy on the clinical outcome in PTC patients coexisting with Hashimoto's thyroiditis (HT).Methods A total of 140 non-distant metastatic PTC patients (16 males,124 females,age range:16-66 years) from July 2010 to December 2014 were enrolled in this retrospective study.Patients concurrent with HT (n=84,group A) were divided into low-dose group (1 110 MBq,n=56,group A1) and high-dose group (5 550 MBq,n=28,group A2) according to 131I ablation dose.Patients without HT (n =56) were enrolled as control group (group B),and received 1 110 MBq of 131I.The thyroid remnant ablation outcome was evaluated according to 131I diagnostic whole-body scan (Dx-WBS),neck ultrasonography (US),serum Tg and TgAb level 6-8 months after 131I ablation therapy.The successful ablation rates were compared by x2 test.Kruskal-Wallis rank sum test was also used.Results There were no significant differences among the 3 groups in terms of both clinicopathological features and postoperative remnant thyroid (H:0.203-2.944,x2:0.271-0.970,all P＞0.05).When negative Dx-WBS and US were deemed as successful ablation criterion,complete ablation rate was found significantly more in group B (94.6％,53/56) than that in group A1 (82.1％,46/56;x2=4.264,P＜0.05),but no significant difference was found between group A2 (85.7％,24/28) and group A1 (x2 =0.318,P＞0.05).When combining negative sTg (sTg＜1 μg/L,TgAb＜46 kU/L) with the above 2 criterions to assess remnant ablation outcome,group B also had a higher successful rate to achieve complete ablation (85.7％,48/56) compared with group A1 (75.6％,34/45),but without statistical significance (x2=2.978,P＞0.05),and no difference was observed between group A2 (12/15) and group A1 (x2=1.320,P＞ 0.05).Conclusion Non-distant metastatic PTC patients coexisting with HT has undesirable 131I ablation outcome compared with those without HT,increasing 131I dose is unhelpful to enhance efficiency of remnant ablation for PTC patients with HT.

Objective To investigate the relationships among cerebellar mutism (CM), relapsed medulloblastoma (MB) and the primary tumor location.MethodsA retrospective analysis was conducted in 114 children over 3 years old with MB from November 2011 to April 2015.ResultsThe median onset age was 84.7 months (36.4 to 184.7 months) in 114 children with MB (77 boys and 37 girls), of whom there were 48 cases of recurrence. There were twenty two cases of CM and the overall incidence of CM was 19.3% (22/114). The incidence of CM was 19.7% (13/66) in non-recurrent cases and 18.8% (9/48) in recur-rent cases, and there was no signiifcant difference between two groups (P=0.899). The incidence of CM was 17.6% (9/51) in cas-es with primary tumor in the fourth ventricle, 7.1% (1/14) in cases with primary tumor in the cerebellar vermis, 21.4% (3/14) in cases with primary tumor in both fourth ventricle and cerebellar vermis, 45.5% (5/11) in cases with primary tumor in fourth ven-tricle and other parts of the brain, and 50.0% (4/8) in cases with primary tumor in cerebellar vermis and other parts of the brain. No CM incidence was observed in cases with primary tumor in central nerve system except for the fourth ventricle and cerebellar vermis. The incidence of CM between the cases with fourth ventricle/cerebellar vermis involvement and those without fourth ventricle/ cerebellar vermis involvement had signiifcant difference (P=0.039). ConclusionsThere is no relationship between CM and relapsed MB. Children with MB whose primary tumor is located in the fourth ventricle and/or the cerebellar vermis is susceptible to CM.

Background and purpose: Neck lymph node metastasis, most of which presents in central neck compartment, is common in patients with papillary thyroid carcinoma (PTC). The objective of this study was to investigate the relationship between the number of dissected central neck lymph nodes and clinical outcome after radioactive iodine (RAI) ablation in pN1a PTC with no more than 5 lymph nodes involvement. Methods: A total of 167 PTC patients who had 1-5 proven metastatic lymph nodes according to postoperative pathological diagnosis were retrospectively analyzed, all of whom underwent total or near total thyroidectomy and central lymph node dissection. After a median follow-up period of 26 months, the clinical outcome of each patient was evaluated as excellent response (ER), indeterminate response (IDR), bio-chemical incomplete response (BIR), or structural incomplete response (SIR) according to the new American Thyroid As-sociation guidelines. The accumulative ER rate (ERn) was calculated in patients with different numbers of dissected lymph nodes (ERn was defined as the proportion of patients who achieved ER with the dissected lymph node number of ≤n). The relationship between the number of dissected central neck lymph nodes and ERn were investigated. Results: As the increase in the number of dissected central neck lymph nodes,there was also an overall increase in ERn, especially when n rose from 1 to 10. The values of ER1, ER5, ER10 and ER30 were 25.0%, 66.7%, 74.7% and 79.1%, respectively. Besides, the proportion of patients who achieved ER was higher in those with 10 or more dissected lymph nodes than in those with less than 10 (85.7% vs 73.3%, P=0.05). In the multivariate logistic regression analysis, both the dissected central lymph node number of ≥10 (OR=2.720, 95%CI: 1.052-7.033, P=0.039) and the level of preablation stimulated thyroglobulin (OR=0.955, 95%CI: 0.926-0.984, P=0.003) were shown to contribute independently to ER. Conclusion: As the increas-ing number of dissected central neck lymph nodes, the percentage of pN1a PTC patients that achieved ER after RAI ablation generally rises. In pN1a PTC patients with no more than 5 lymph nodes involvement, a central compartment dissection with 10 or more lymph nodes might help them achieve ER after RAI ablation.

Objective:To evaluate the biochemical and structural changes of apatinib in patients with progressive radioactive iodine-re-fractory differentiated thyroid cancer (RAIR-DTC). Methods:The participants (n=10) were followed up since March 2016. Treatment ef-fect was evaluated in using both biochemical [thyroglobulin (Tg) and thyroglobulin antibody (Tg-Ab)] and structural responses (target lesions, TL). Adverse events were also recorded over time. Results:The median follow-up was 7.9 months. The Tg level declined rapid-ly within 6 weeks after apatinib treatment, and the average decline ranged from 60%to 90%, indicating the immediate biochemical re-sponse of apatinib in progressive RAIR-DTC. The Tg level tended to stabilize thereafter. However, the Tg level rebounded by 4%–135%when withdrawal was performed for 3–14 days. The number of TLs decreased rapidly within 8 weeks, and the average decreased ranged from 40%to 60%, indicating the presence of rapid structural responses. Thereafter, the number of TLs continued to stabilize. TLs, in contrast to Tg, were not significantly affected by drug withdrawal. The rate of change in Tg (Tgvn) was positively correlated with the rate of change in TL (TLvn) [TLvn=0.17×Tgvn+0.50 (r=0.56, P<0.05)]. The apatinib dose was adjusted due to adverse events, which could be relieved after 3 to 14 days of withdrawal. Apatinib can effectively control the disease even at a reduced dose of 250 mg/d. Conclusion:Apatinib treatment showed a fast and sustainable biochemical and structural responses. Tg could be regarded as an objec-tive indicator. Tgvn is positively correlated with TLvn, and the response of Tg is more sensitive than that of TLs.

Objective To investigate the relationship between V-raf murine sarcoma viral oncogene homolog B1 (BRAF)v600E mutation and radioactive iodine (RAI) uptake in distant metastases from papillary thyroid cancer(PTC).Methods From January 2011 to December 2012,40 PTC patients (21 males,19 females,average age 39.8 years) with distant metastases were recruited and divided into mutation group and wild group according to the BRAFv600E mutation in primary lesions.The clinical,pathological and serological differences were compared between the two groups.The relationship between BRAFv600E mutation and RAI uptake capability in distant metastases from PTC,as well as its relationship with Tg change after 131I treatment were investigated.Statistical analysis was performed with two-sample t test,x2 test or Fisher exact test.Results The BRAFv600E mutation rate was 30.0％ (12/40) in patients with metastases from PTC.There was no significant difference in clinical,pathological and serological features between mutation group (n =12) and wild group (n=28; t:from-0.533 to 1.728,x2:from-1.951 to 1.088,all P＞0.05).Twelve PTC patients had no RAI uptake in the distant metastases,of which 10 belonged to mutation group (83.3％,10/12) and 2 belonged to wild group (7.1％,2/28; x2=19.734,P＜0.05).BRAFv600E mutation group was more likely to have no RAI uptake in the distant metastases.Tg change after 131I treatment in 30 patients were analyzed.In the wild group,Tg level decreased in 66.7％ (14/21) patients,stabilized in 19.0％ (4/21)and increased in 14.3％ (3/21)patients.While there was no decrease of Tg in the mutation group (0/9).Two patients had increased Tg level and 7 patients (with no RAI uptake) kept stable in mutation group.Conclusions Due to poor RAI uptake capability in PTC patients with BRAFv600E mutation,both primary and metastatic sites may have poor response to 131I treatment.Molecular detection of BRAFv600E mutation might be helpful for choosing PTC with distant metastases and predicting the effect of 131 I treatment.