Series Research On The Impact Of Thyroglobulin Antibody On Efficacy Of Radioactive Iodine Therapy In Patients With Papillary Thyroid Carcinoma

Differentiated thyroid carcinoma（DTC）is the most common endocrine malignant tumor.Papillary thyroid carcinoma（PTC）is the most common pathological type.In recent years,the prevalence of PTC showed an upward trend with an increasing mortality rate.Therefore,the follow-up of PTCs after treatment is particularly important.Thyroglobulin（Tg）is a major tumor marker used to monitor the disease status of PTCs after treatment.Thyroglobulin antibody（TgAb）is an inhibitory autoimmune antibody against Tg,which interfere the accuracy of Tg measurement,especially at high titers,limiting the predictive value of Tg.Thus,the follow-up of PTCs with positive TgAb remains a clinical puzzlement.Some studies proposed that TgAb could serve as a surrogate tumor marker for PTC patients with high TgAb level,and the trend in TgAb concentration is more significant than any single TgAb concentration per se.The current researches focus on whether TgAb could predict the occurrence and recurrence of PTC and its impact on the detection of Tg.However,the relationship between TgAb and the efficacy of ¹³¹I in PTC patients is still unclear.As the most frequent genetic alteration which has been confirmed to be associated with PTC,BRAFV600E mutation acts as a vital role in the tumorigenesis of PTC through activating the mitogen-activated protein kinase（MAPK）signal pathway and is closely related to the disease recurrence and death.In this study,we selected TgAb as the main research object,included three factors of TgAb level,positive TgAb combined with BRAFV600E mutant and the trend of TgAb,explored the association between them with the clinical outcome after ¹³¹I therapy in order to provide further evidence-based basis for clinical decision-making of ¹³¹I therapy and predict the clinical prognosis of this part of patients.Here are the three parts as follows:Part 1:The impact of TgAb on efficacy of ¹³¹I ablation in patients with papillary thyroid carcinomaObjective: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 IU/mL,n=84）and G2 group（<115 IU/mL,n=245）],G2 group was further divided into 2 subgroups[S1（≥40 IU/mL,n=31）and S2（<40 IU/mL,n=214）],before ¹³¹I ablation.The median follow-up time was 24 months after a total or subtotal thyroidectomy and subsequent ¹³¹I ablation.The efficacy in terms of ¹³¹I ablation success rates（IBR）between two groups were compared and the influencing factors were analyzed according to criteria posed by 2015 American Thyroid Association guideline,then the effect of ¹³¹I 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 presents lower IBR（34.1%vs 71.9%,37.2%vs 73.2%;P=0.000）;but IBR did not differ in G1 or G2 group either with high or low dose ¹³¹I（P>0.05）.TgAb was the only adverse indicator correlating with IBR in Multi-Logistic Regression Analysis（P=0.018）.Conclusion:TgAb could negatively affect ¹³¹I ablation efficacy,while increasing the dose of ¹³¹I failed to improve the success rate in such cases.Part 2:Changes in TgAb after ¹³¹I ablation in patients with papillary thyroid carcinoma and its relationship with efficacyObjective:To investigate the changes in TgAb and its relationship with radioiodine ablation efficacy in PTC patients.Methods:A total number of 223 PTC patients with no distant metastasis were included and classified into 2 groups according to the TgAb levels at 6 months after ablation[G1group（≥40 IU/mL,n=48）and G2 group（<40 IU/mL,n=175）],G1 group was further divided into 2 subgroups[S1 group（TgAb level decreased more than or equal to 50%,n=25）,S2 group（TgAb level decreased less than 50%or increased,n=23）].The differences between different groups were evaluated with Student’s t test,chi-square test and Mann-Whitney U test.The efficacy in terms of ¹³¹I ablation success rates（IBR）between different groups were compared according to criteria posed by 2015 American Thyroid Association guideline.The two subgroups were followed up to a median time of24 months and observed the changes in TgAb levels and persistence or recurrence in PTC patients.Results:Patients with high TgAb levels at the time of ablation and 6 months thereafter were 39.5%,21.5%,respectively（P=0.000）.Younger female and bigger tumor size were more prevalent in G1 group patients（P=0.022,P=0.016,P=0.017,respectively）.The G1group presented lower IBR over the G2 group[52.1%vs 83.4%,P=0.000]with a higher radioiodine dose（P=0.035）.The clinicopathological features did not differ between the two subgroups（all P>0.05）except the BRAF mutation,S2 possessed a higher mutation[40.0%vs 69.6%,P=0.040],the IBRs had significant differences（P=0.021）,S2 presented the lower efficacy.The persistence or recurrence rates in S1,S2 group were 16.0%,43.5%（P=0.036）.Conclusions:TgAb changes was associated with the ¹³¹I ablation efficacy,dynamically monitoring the changes could provide evidence for predicting the clinical outcome of PTC patients.Part 3:Unfavorable efficacy to ¹³¹I ablation in BRAFV600E mutant papillary thyroid carcinoma with positive TgAbObjective:To explore the cooperative effect of BRAFV600E mutation and positive TgAb on efficacy to radioiodine remnant ablation（RRA）in PTCs.Methods:We included 298 consecutive PTC patients without distant metastases who underwent surgery and RRA from June 2012 to June 2016.The TgAb level and BRAFV600E status were measured and patients were divided into four groups according to the combined status,TgAb was considered“negative”or“positive”based on the specific assay cutoff value in our hospital（negative<115IU/ml;positive≥115IU/ml）,Group 1（both positive in TgAb and BRAF）;Group 2（TgAb positive only）;Group 3（BRAF mutant only）;Group 4（both negative）.The imaging information was collected at6 months after RRA and used to assess ablative efficacy in terms of success or failure.The change of TgAb levels was followed up to 24 months in TgAb positive patients.Results:Older age,more males,extracapsular invasiveness and advanced TNM stage were more likely to harbor BRAFV600E mutation.TgAb positive were more prevalent in younger females with less bilateral tumour lesions.The characteristics had significant differences among the four groups in sex,age（all P=0.000）,Group 2 presented more younger females.The success rates were statistically different among four groups（P=0.009）,Group 1 presented the lowest efficacy.The combined status was associated with the poor efficacy to RRA in the multivariate analysis（P=0.029）.The effect of RRA in reducing TgAb level might be weakened in BRAF mutant status.Conclusion:The combined status of BRAF mutation and positive TgAb predicts low efficacy to RRA and might be served as an independent unfavorable prognostic factor for PTC.BRAF mutant might weaken the effect of RRA in reducing TgAb levels in PTCs.