Abstract
目的
应用超声新技术及Ki67等指标研究与Graves病(GD)患者131I治疗后甲亢未愈或复发的相关因素。
方法
研究2020年1月~2021年11月在我院核医学科接受131I治疗的GD患者89例。随访结局分为甲状腺功能亢进(甲亢)未愈或复发、早发甲状腺功能减退(早发甲减)和甲状腺功能正常或失随访。131I治疗后1个月为随访开始，每位患者最长随访时间为1年。治疗前应用三维超声自动测量技术、剪切波弹性成像技术和超声引导下细针穿刺抽吸技术，获取患者甲状腺容积、腺体剪切波弹性值和滤泡上皮细胞Ki67表达情况。并纳入年龄、病程、用药史、131I治疗剂量、TRAb等因素。应用竞争风险模型分析患者发生甲亢未愈或复发的相关因素并计算其调整风险比(HR)和95%置信区间(95% CI)。
结果
在89例GD患者中，出现甲亢未愈或复发的患者有27例，早发甲减患者有50例，甲状腺功能恢复正常的患者1例，失随访11例。竞争风险模型分析显示Ki67表达、131I治疗剂量及甲状腺容积与治疗后甲亢未愈或复发存在独立关联，其HR(95% CI)分别为0.36(0.15，0.86)、0.81(0.68，0.96)和1.11(1.07，1.15)。
结论
Graves病患者甲状腺滤泡上皮细胞Ki67表达阳性、131I治疗剂量及甲状腺容积与131I治疗后甲亢未愈或复发存在独立关联。超声新技术可以在评估GD患者131I治疗结局中发挥重要作用。
Keywords: Graves病, 131I治疗, Ki67, 竞争风险模型
Abstract
Objective
To analyze factors associated with failure to cure or recurrence of hyperthyroidism in patients with Graves disease (GD) after 131I treatment using ultrasound combined with Ki67 detection.
Methods
Eighty-nine patients with GD receiving 131I treatment in the Department of Nuclear Medicine at our hospital from January, 2020 to November, 2021 were enrolled. Before treatment, thyroid volume, shear wave elastic value and Ki67 expression in the follicular epithelial cells were measured using three-dimensional ultrasonic virtual organ computer-aided analysis, shear-wave elastic imaging and ultrasound-guided fine needle aspiration. The data including age, gender, antithyroid drug (ATD) history, dose of 131I, and TRAb were collected from all the cases. The patients were followed up for up to 1 year, starting at 1 month after 131I treatment, and the follow-up results of the patients were divided into failure to cure or recurrence of hyperthyroidism, premature hypothyroidism and euthyroidism or loss to follow-up. The proportional hazards model and fine-Gray test were used to estimate the adjusted hazard ratio (HR) and 95% confidence interval (95% CI) for patients with failure to cure or recurrence of hyperthyroidism.
Results
Among the 89 patients, 27 patients were found to have failure to cure or recurrence of hyperthyroidism, 50 had premature hypothyroidism, 1 patient had euthyroidism, and 11 patients were lost to follow-up at the end of the 1-year follow-up. Analysis of the competitive risk model showed that status of Ki67 expression, 131I dose and thyroid volume were independently correlated with failure to cure or recurrence of hyperthyroidism after the treatment with HR (95% CI) of 0.36 (0.15, 0.86), 0.81 (0.68, 0.96) and 1.11 (1.07, 1.15), respectively.
Conclusion
In patients with GD, the expression of Ki67 in thyroid follicular epithelial cells, 131I dose and thyroid volume are independently correlated with failure to cure or recurrence of hyperthyroidism after 131I treatment. New ultrasound techniques can play an important role in evaluating the therapeutic outcome of 131I treatment in GD patients.
Keywords: Graves disease, 131I treatment, Ki67, competing risk model
甲状腺功能亢进(甲亢)的发病率约为1.2%[1, 2]。约有70%~85%的甲亢是由Graves病(GD)所引起[3-5]。放射性131I治疗可以快速缓解患者的甲亢症状，被视为当前治疗GD的有效手段[6-8]。但仍有8%~50%的患者面临治疗后甲亢未愈或复发需要二次治疗的问题[9, 10]。影响GD患者131I治疗结局的相关因素一直受到关注[11-14]。既往研究表明，Ki67可以反映细胞增值的情况[15, 16]。Domoslawski等[17]认为GD患者滤泡上皮细胞Ki67表达水平明显高于结节性甲状腺肿患者，Jessica等[18]的研究表明接受β受体阻滞剂治疗的GD患者Ki67表达减少。然而，GD患者滤泡上皮细胞Ki67表达水平是否与131I治疗结局相关以及能否作为反映治疗反应性的指标，尚未见报道。本研究旨在联合应用超声新技术，分析与甲亢未愈或复发相关的因素，了解甲状腺滤泡上皮细胞Ki67表达与甲亢未愈或复发的关系。
1. 资料和方法
1.1. 研究对象
选取2020年1月~2021年11月在我院核医学科就诊的GD患者112例，年龄18~72岁。研究截止时间为2022年1月24日。
纳入标准：(1)符合GD诊断标准[19]；(2)无放射性131I治疗禁忌证；(3)131I治疗相关资料、病理资料及随访资料完整。排除标准：(1)有甲状腺手术史；(2)非首次接受131I治疗；(3)伴发甲状腺恶性肿瘤者；(4)病理资料不完整，未获得Ki67结果；(5)研究截止时间到，服药后未满1年且未出现相关事件。
排除患者23例，其中12例为非首次接受131I治疗；11例为研究截止时间到，服药后未满1年且未出现相关事件。最终纳入患者89例，男性22例，女性67例，年龄45.0±14.0岁。
所有受试者均知情同意并签署书面同意书。本研究得到福建医科大学附属漳州市医院伦理委员会的批准(No. 2020KYB138)。
1.2. 131I治疗后随访时间及结局事件定义
每位患者最长随访时间为1年，治疗后1个月为随访开始时间。随访终止有以下3种情况：(1)患者每种事件首次出现的时间；(2)随访时间满1年；(3)研究截止时间到。根据随访结果，结局分为甲亢未愈或复发(事件1)、早发甲状腺功能减退(早发甲减)(事件2)及甲状腺功能正常或失随访(删失)3种。
1.3. Ki67结果
甲状腺组织细针抽吸活检术后，穿刺物应用罗氏全自动免疫组化仪进行细胞增殖指数Ki67染色，在显微镜(目镜直径为22 mm)高倍镜(×400)下观察。以每视野中≥200个细胞为合格标本，镜下观察切片：(1)镜下细胞较多或存在明显Ki67热点的切片，选取2~3幅包含阳性率最高区域的视野计数；(2)镜下细胞较少或无明显Ki67热点的切片，选取包含切片中全部滤泡细胞的视野。Ki67增殖指数= Ki67阳性核的滤泡细胞数/滤泡细胞总数×100%。根据Ki67增殖指数分为：Ki67表达阴性(增殖指数 < 1%)、Ki67表达阳性(增殖指数≥1%)。
1.4. 相关因素
1.4.1. 131I治疗剂量
用计算剂量法确定131I给药剂量，即根据甲状腺质量和甲状腺摄131I率(RAIU)进行计算[19]。每克甲状腺组织的剂量范围为80~150 uCi。口服131I活度(uCi) =[计划量(uCi/g)×甲状腺质量(g)]/[最高RAIU或24h RAIU(%)]。摄碘率的计算采用以下公式：RAIU=[甲状腺部位计数率(计数·min-1)-本底(计数· min-1)]/[标准源计数率(计数·min-1)-本底(计数·min-1)]× 100%。
1.4.2. 甲状腺三维容积
使用GE LOGIQ E8的超声诊断仪，三维容积探头RAB-6。由上至下横切扫查甲状腺，选取最大横切面后固定探头，启动三维超声体积自动测量技术对甲状腺进行自动图像采集并存储，设备自动重建甲状腺模拟模型并计算体积(cm3)，从而获得甲状腺的三维容积。
1.4.3. 甲状腺腺体剪切波弹性速度值
使用SEMENS ACUSON Sequoia 512的超声诊断仪，10L4相阵探头。进入弹性成像模式，选取一侧甲状腺最大纵切面，避开血管和结节，待图像稳定后定帧，在腺体中央由距上极5 mm处开始测量，每隔5 mm测一次，总共测3次，平均值为一侧甲状腺剪切波弹性速度值；同样的方法测量另一侧甲状腺，双侧平均值即为该患者甲状腺剪切波弹性速度值。
1.4.4. 游离甲状腺素(FT4)和游离三碘甲状原胺酸(FT3)，血清促甲状腺激素受体抗体(TRAb)水平
使用电化学发光免疫测定法(贝克曼，DXI800，美国)测量患者空腹过夜后静脉血的FT3、FT4及TRAb水平。FT3正常范围为3.10~6.80 pmol/L；FT4正常范围为7.5~ 21.1 pmol/L；TRAb正常范围为 < 1.75 IU/L。
1.4.5. 患者临床资料
记录患者年龄、性别、甲亢病程、131I治疗前是否服用过抗甲亢药物(ATD)。
1.5. 统计学处理
统计学分析采用R version 4.0.5(<a href="http://www.rproject.org/" target="_blank">http://www.rproject.org/</a>)。经Kolmogorov-Smirnov正态性检验，本研究中年龄呈正态分布，以“均数±标准差”表示，组间比较采用单因素方差分析；其它连续性变量为非正态分布，以Median[Q25，Q75]”表示，组间比较采用秩和检验；分类变量以“例(率)”表示，组间比较采用卡方检验。对于<italic>P</italic> < 0.05的非正态分布的连续性变量，进一步采用Nemenyi法进行两两组间比较。
用cmprsk包进行竞争风险回归分析。计算甲亢未愈或复发的风险比(HR)及95%置信区间(CI)。随访时间被用作相应的模型中的时间尺度。根据单变量分析的结果(以P < 0.25为具有统计学意义)，多变量模型针对以下变量进行了调整。模型1纳入年龄。为了研究Ki67表达与甲亢未愈或复发之间的关联是否归因于病程、用药史和其它的相关因素，模型2在模型1的基础上进一步纳入了用药史、131I剂量、甲状腺三维容积、甲状腺剪切波速度值及TRAb水平。
2. 结果
2.1. 患者基线特征，甲亢未愈或复发的累积风险边缘概率
最终入组患者有89例，其中甲亢未愈或复发27例，早发甲减50例，甲状腺功能恢复正常1例，失随访11例。患者的基线特征见表 1，结果显示，患者3组间的甲状腺三维容积存在差异，进一步进行两两组间分析显示，甲亢未愈或复发组的甲状腺容积大于其它两组(P均 < 0.05)，而早发甲减组与另一组无明显差异；其余各因素在3组中的分布情况无明显差别(P均>0.05)。累积风险边缘概率分析显示131I治疗300 d后，甲亢未愈或复发的发生概率约25%(图 1)。
1.
89例患者的临床资料
Clinical data of the 89 patients
| Parameter | Non-healing or recurrent hyperthyroidism (n=27) | Premature hypothyroidism (n=50) | Euthyroidism or lost of follow-up (n=12) | P |
| ATD: Anti-thyroid drugs; SWE: Shear wave elastic velocity value; FT3: Free triiodothyronine; FT4: Free thyroxinef; TRAb: Thyrotrophin receptor antibody. | ||||
| Ki67 [n(%)] | 0.082 | |||
| Positive | 14 (0.23) | 37(0.61) | 10 (0.16) | |
| Negative | 13 (0.46) | 13(0.46) | 2(0.07) | |
| Gender [n(%)] | 0.787 | |||
| Male | 8 (0.36) | 11 (0.50) | 3 (0.14) | |
| Female | 19 (0.28) | 39 (0.58) | 9 (0.13) | |
| Age (Mean±SD) | 41.1±13.9 | 46.4±13.6 | 45.2±12.9 | 0.268 |
| Course of GD | 48.0 [12.0;60.0] | 12.5 [3.00;57.0] | 7.00 [4.75;24.2] | 0.098 |
| ATD history [n(%)] | 0.241 | |||
| No | 6 (0.22) | 15 (0.56) | 6 (0.22) | |
| Yes | 21 (0.34) | 35 (0.56) | 6 (0.10) | |
| Dose of 131I (Median[Q25, Q75]) | 6.20 [5.55;8.60] | 6.45 [5.03;7.95] | 6.45 [5.47;7.18] | 0.728 |
| Thyroid volume (Median[Q25, Q75]) | 23.6 [18.7;36.4] | 17.9 [13.5;23.5] | 18.2 [16.6;21.8] | 0.001 |
| SWE (Median[Q25, Q75]) | 1.64 [1.33;1.90] | 1.87 [1.65;2.07] | 1.79 [1.49;2.35] | 0.077 |
| FT3 (Median[Q25, Q75]) | 13.5 [9.28;27.9] | 16.8 [10.7;27.8] | 24.3 [10.8;29.2] | 0.794 |
| FT4 (Median[Q25, Q75]) | 36.3 [23.1;55.5] | 38.2 [27.7;53.3] | 49.2 [30.7;62.7] | 0.554 |
| TRAb (Median[Q25, Q75]) | 3.45 [1.74;9.59] | 13.8 [3.80;21.8] | 13.8 [4.07;18.3] | 0.035 |
1.
Graves病患者131I治疗后发生甲亢未愈或复发及甲减的累积风险边缘概率
Cumulative marginal risk probability of unhealed or recurrent hyperthyroidism and hypothyroidism in patients with Graves disease after 131I treatment.
2.2. 甲亢未愈或复发的相关因素
以早发甲减作为治疗结局竞争事件，在单因素分析结果基础上，模型1纳入年龄后，显示Ki67表达阳性组患者甲亢未愈或复发的风险为表达阴性组患者的0.31倍，HR(95% CI)为0.31(0.13，0.73)。模型2在模型1的基础上继续纳入用药史、131I剂量、甲状腺三维容积、甲状腺剪切波速度值、TRAb后，Ki67表达阳性组患者甲亢未愈或复发的风险为表达阴性组患者的0.36倍，HR (95% CI)为0.36(0.15，0.86)，而131I剂量及甲状腺三维容积的HR(95%CI)分别为0.81(0.68，0.96)，1.11(1.07，1.15)，P均 < 0.05(表 2)。
2.
竞争风险模型分析结果
Results of competitive risk model analysis
| Parameter | Univariate analysis | Model 1# | Model 2＄ | ||||||||
| β | HR | P | β | HR | P | β | HR | P | |||
| #: Model 1 was adjusted for age $: Model 2 was adjusted for age, ATD history, dose of131I, thyroid volume, SWE and TRAb. HR: Hazard ratio; ATD: Anti-thyroid drugs; SWE: Shear wave elastic velocity value; FT3: Free triiodothyronine; FT4: Free thyroxinef; TRAb: Thyrotrophin receptor antibody. | |||||||||||
| Ki67 | -0.91 | 0.40 (0.19, 0.85) | 0.017 | -1.17 | 0.31 (0.13, 0.73) | 0.007 | -1.04 | 0.36 (0.15, 0.86) | 0.022 | ||
| Age | -0.02 | 0.98 (0.95, 1.00) | 0.066 | -0.04 | 0.97 (0.93, 1.00) | 0.030 | -0.02 | 0.98 (0.95, 1.01) | 0.240 | ||
| Gender | -0.25 | 0.78 (0.35, 1.75) | 0.550 | - | - | - | - | - | - | ||
| Course of GD | < 0.01 | 1 (1.00, 1.01) | 0.500 | - | - | - | - | - | - | ||
| ATD history | 0.57 | 1.77 (0.74, 4.23) | 0.200 | - | - | - | 0.15 | 1.17 (0.43, 3.15) | 0.760 | ||
| Dose of 131I | 0.11 | 1.12 (0.93, 1.35) | 0.230 | - | - | - | -0.21 | 0.81 (0.68, 0.96) | 0.017 | ||
| Thyroid volume | 0.08 | 1.09 (1.06, 1.11) | < 0.001 | - | - | - | 0.10 | 1.11 (1.07, 1.15) | < 0.001 | ||
| SWE | -1.32 | 0.27 (0.08, 0.84) | 0.025 | - | - | - | -0.93 | 0.40 (0.11, 1.42) | 0.150 | ||
| FT3 | < -0.01 | 1.00 (0.96, 1.03) | 0.810 | - | - | - | - | - | - | ||
| FT4 | < -0.01 | 1.00 (0.97, 1.02) | 0.720 | - | - | - | - | - | - | ||
| TRAb | -0.05 | 0.95 (0.90, 1.00) | 0.054 | - | - | - | -0.02 | 0.98 (0.93, 1.02) | 0.310 | ||
3. 讨论
131I是目前治疗GD的有效手段[20]。然而，GD患者131I治疗后甲亢未愈或复发仍是临床难题。本研究的累积风险边缘概率分析证实131I治疗300天后，甲亢未愈或复发的发生概率约25%(图 1)，这部分患者临床症状及相关并发症未能得到理想的控制。131I治疗GD的主要作用机制与肿瘤放射治疗相似，利用射线破坏滤泡上皮细胞，以减少甲状腺激素生成[21, 22]。既往的研究认为，患者性别、病程、治疗前是否服用ATD药物治疗等均会影响治疗结局，考虑跟患者甲状腺对131I敏感性不同有关[23-25]。能否评估患者对131I治疗的敏感性并制定相应治疗方案一直是临床关注的重点。Ki67是细胞增殖的标志物，细胞核分裂明显，功能越活跃，Ki67表达水平就越高，主要用来评估肿瘤细胞对治疗的敏感性[26, 27]。本研究以接受首次131I治疗的GD患者为研究对象，研究GD患者甲状腺滤泡上皮细胞Ki67表达与甲亢未愈或复发的关系，目前尚未见报道。
早发甲减是131I治疗的重要结局之一，因此本研究应用竞争风险模型进行分析。由于患者给药剂量是基于计划量、摄碘率和有效半衰期等指标计算，因此本研究仅将最终给药剂量纳入分析，以避免相关指标共线性问题。基线资料分析显示甲亢未愈或复发组的甲状腺容积明显较大，提示容积有可能是甲亢未愈或复发的重要因素，应对其进一步分析。与文献报道一致，本研究结果显示131I剂量为甲亢未愈或复发的保护因素，表明治疗剂量越高，患者甲亢未愈或复发发生的危险性越低；而甲状腺容积为危险因素，容积越大，患者甲亢未愈或复发发生的风险越高，提示治疗前有必要应用容积测量技术对甲状腺容积进行准确测量并调整好131I给药剂量[9, 28, 29]。
此外，为了验证Ki67与甲亢未愈或复发的关系，我们构建了不同的模型进行敏感性分析。为了观察人口学特征的影响，模型1首先对年龄进行调整，结果显示，Ki67的HR由0.40下降为0.31，虽然降幅大于10%，但Ki67与甲亢未愈或复发仍具有直接联系(95% CI为0.13，0.73)。为进一步观察结局是否归因于用药史、131I剂量、甲状腺三维容积、甲状腺剪切波速度值和TRAb，模型2在模型1的基础上进一步对上述因素进行调整，分析结果显示，Ki67和甲亢未愈或复发的关联是独立于其他因素的，表明Ki67的表达与甲亢未愈或复发有直接关系。本研究初步证实甲状腺滤泡上皮细胞Ki67阳性表达的GD患者，甲亢未愈或复发发生的危险性较低。考虑可能的机制为：Ki67阳性表达，细胞处于增殖期，对131I越敏感，细胞破坏越明显[30]。Ki67可以作为反映细胞对131I是否敏感的潜在指标。但纳入样本量偏少是本研究的主要不足之处，在接下来的研究中，我们将进一步扩大样本量并进行多中心研究以进一步验证Ki67与131I治疗结局的关联性。
甲状腺滤泡上皮细胞Ki67表达阳性、131I给药剂量及甲状腺容积与131I治疗后甲亢未愈或复发存在独立关联。超声引导下甲状腺细针穿刺技术及三维容积测量技术可以在GD患者131I治疗中发挥重要作用。
Biography
王月桂，在读硕士研究生，E-mail: 1146911855@qq.com
Funding Statement
国家自然科学基金(82071943)；福建省自然科学基金(2020J011306)
Supported by National Natural Science Foundation of China (82071943)
Contributor Information
王 月桂 (Yuegui WANG), Email: 1146911855@qq.com.
沈 浩霖 (Haolin SHEN), Email: holin3344@163.com.
References
- 1.Li YZ, Teng D, Ba JM, et al. Efficacy and safety of long-term universal salt iodization on thyroid disorders: epidemiological evidence from 31 provinces of mainland China. Thyroid. 2020;30(4):568–79. doi: 10.1089/thy.2019.0067. [Li YZ, Teng D, Ba JM, et al. Efficacy and safety of long-term universal salt iodization on thyroid disorders: epidemiological evidence from 31 provinces of mainland China[J]. Thyroid, 2020, 30 (4): 568-79.] [DOI] [PubMed] [Google Scholar]
- 2.de Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016;388(10047):906–18. doi: 10.1016/S0140-6736(16)00278-6. [de Leo S, Lee SY, Braverman LE. Hyperthyroidism[J]. Lancet, 2016, 388(10047): 906-18.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Doubleday AR, Sippel RS. Hyperthyroidism. Gland Surg. 2020;9(1):124–35. doi: 10.21037/gs.2019.11.01. [Doubleday AR, Sippel RS. Hyperthyroidism[J]. Gland Surg, 2020, 9 (1): 124-35.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.郑 薇, 王 萱, 李 宁, et al. 格雷夫斯病及格雷夫斯眼病靶向TSHR及IGF-1R治疗策略展望. 中华核医学与分子影像杂志. 2020;40(7):434–9. doi: 10.3760/cma.j.cn321828-20190730-00153. [郑薇, 王萱, 李宁, 等. 格雷夫斯病及格雷夫斯眼病靶向TSHR及IGF-1R治疗策略展望[J]. 中华核医学与分子影像杂志, 2020, 40(7): 434-9.] [DOI] [Google Scholar]
- 5.Sharma P. The unlikely suspect: a case report of new-onset hyperthyroidism due to Graves' disease in an 89-year-old gentleman and review of literature. Cureus. 2022;14(1):e21546. doi: 10.7759/cureus.21546. [Sharma P. The unlikely suspect: a case report of new-onset hyperthyroidism due to Graves' disease in an 89-year-old gentleman and review of literature[J]. Cureus, 2022, 14(1): e21546.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.陈 薏帆, 朱 玉春, 周 伟, et al. 甲状腺摄碘率和(99)Tc(m)显像对Graves甲亢(131)I治疗疗效的分析. 中国医师杂志. 2021;(10):1528-32, 1537. doi: 10.3760/cma.j.cn431274-20200630-00897. [陈薏帆, 朱玉春, 周伟, 等. 甲状腺摄碘率和(99)Tc(m)显像对Graves甲亢(131)I治疗疗效的分析[J]. 中国医师杂志, 2021(10): 1528-32, 1537.] [DOI] [Google Scholar]
- 7.Kahaly GJ, Bartalena L, Hegedüs L, et al. 2018 European thyroid association guideline for the management of Graves' hyperthyroidism. Eur Thyroid J. 2018;7(4):167–86. doi: 10.1159/000490384. [Kahaly GJ, Bartalena L, Hegedüs L, et al. 2018 European thyroid association guideline for the management of Graves' hyperthyroidism[J]. Eur Thyroid J, 2018, 7(4): 167-86.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.吴 彬彬, 王 瑞华, 闫 志华, et al. 影响碳酸锂延长甲亢患者131I有效半衰期的临床因素研究. 中华核医学与分子影像杂志. 2021;41(5):286–90. doi: 10.3760/cma.j.cn321828-20200108-00013. [吴彬彬, 王瑞华, 闫志华, 等. 影响碳酸锂延长甲亢患者131I有效半衰期的临床因素研究[J]. 中华核医学与分子影像杂志, 2021, 41(5): 286-90.] [DOI] [Google Scholar]
- 9.王 芸, 张 强, 凌 雁, et al. Graves'病(GD)放射性碘治疗效果的影响因素. 复旦学报: 医学版. 2018;45(6):830–4. doi: 10.3969/j.issn.1672-8467.2018.06.012. [王芸, 张强, 凌雁, 等. Graves'病(GD)放射性碘治疗效果的影响因素[J]. 复旦学报: 医学版, 2018, 45(6): 830-4.] [DOI] [Google Scholar]
- 10.Bogazzi F, Giovannetti C, Fessehatsion R, et al. Impact of lithium on efficacy of radioactive iodine therapy for Graves' disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal. J Clin Endocrinol Metab. 2010;95(1):201–8. doi: 10.1210/jc.2009-1655. [Bogazzi F, Giovannetti C, Fessehatsion R, et al. Impact of lithium on efficacy of radioactive iodine therapy for Graves' disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal[J]. J Clin Endocrinol Metab, 2010, 95(1): 201-8.] [DOI] [PubMed] [Google Scholar]
- 11.Yang DR, Xue JJ, Ma WX, et al. Prognostic factor analysis in 325 patients with Graves' disease treated with radioiodine therapy. Nucl Med Commun. 2018;39(1):16–21. doi: 10.1097/MNM.0000000000000770. [Yang DR, Xue JJ, Ma WX, et al. Prognostic factor analysis in 325 patients with Graves' disease treated with radioiodine therapy[J]. Nucl Med Commun, 2018, 39(1): 16-21.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Sapienza MT, Coura-Filho GB, Willegaignon J, et al. Clinical and dosimetric variables related to outcome after treatment of Graves' disease with 550 and 1110 MBq of 131I: results of a prospective randomized trial. Clin Nucl Med. 2015;40(9):715–9. doi: 10.1097/RLU.0000000000000840. [Sapienza MT, Coura-Filho GB, Willegaignon J, et al. Clinical and dosimetric variables related to outcome after treatment of Graves' disease with 550 and 1110 MBq of 131I: results of a prospective randomized trial[J]. Clin Nucl Med, 2015, 40(9): 715-9.] [DOI] [PubMed] [Google Scholar]
- 13.Šfiligoj D, Gaberš\u010dek S, Mekjavi\u010d PJ, et al. Factors influencing the success of radioiodine therapy in patients with Graves' disease. Nucl Med Commun. 2015;36(6):560–5. doi: 10.1097/MNM.0000000000000285. [Šfiligoj D, Gaberš\u010dek S, Mekjavi\u010d PJ, et al. Factors influencing the success of radioiodine therapy in patients with Graves' disease[J]. Nucl Med Commun, 2015, 36(6): 560-5.] [DOI] [PubMed] [Google Scholar]
- 14.Park H, Kim HI, Park J, et al. The success rate of radioactive iodine therapy for Graves' disease in iodine-replete area and affecting factors: a single-center study. Nucl Med Commun. 2020;41(3):212–8. doi: 10.1097/MNM.0000000000001138. [Park H, Kim HI, Park J, et al. The success rate of radioactive iodine therapy for Graves' disease in iodine-replete area and affecting factors: a single-center study[J]. Nucl Med Commun, 2020, 41(3): 212-8.] [DOI] [PubMed] [Google Scholar]
- 15.Domoslawski P, Pula B, Olbromski M, et al. Expression of metallothionein I/Ⅱ and ki-67 antigen in Graves' disease. Anticancer Res. 2018;38(12):6847–53. doi: 10.21873/anticanres.13059. [Domoslawski P, Pula B, Olbromski M, et al. Expression of metallothionein I/Ⅱ and ki-67 antigen in Graves' disease[J]. Anticancer Res, 2018, 38(12): 6847-53.] [DOI] [PubMed] [Google Scholar]
- 16.Seo SH, Kim KH, Oh SH, et al. Ki-67 labeling index as a prognostic marker in advanced stomach cancer. Ann Surg Treat Res. 2019;96(1):27–33. doi: 10.4174/astr.2019.96.1.27. [Seo SH, Kim KH, Oh SH, et al. Ki-67 labeling index as a prognostic marker in advanced stomach cancer[J]. Ann Surg Treat Res, 2019, 96 (1): 27-33.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Domoslawski P, Podhorska-Okolow M, Pula B, et al. Expression of estrogen and progesterone receptors and Ki-67 antigen in Graves' disease and nodular goiter. Folia Histochem Cytobiol. 2013;51(2):135–40. doi: 10.5603/FHC.2013.0021. [Domoslawski P, Podhorska-Okolow M, Pula B, et al. Expression of estrogen and progesterone receptors and Ki-67 antigen in Graves' disease and nodular goiter[J]. Folia Histochem Cytobiol, 2013, 51 (2): 135-40.] [DOI] [PubMed] [Google Scholar]
- 18.de Vasconcelos JC, Barreto IS, Matos PS, et al. Value of apoptotic, antiapoptotic, and cell proliferation markers in the treatment of Graves' disease. Int J Endocrinol. 2018;2018:3171280. doi: 10.1155/2018/3171280. [de Vasconcelos JC, Barreto IS, Matos PS, et al. Value of apoptotic, antiapoptotic, and cell proliferation markers in the treatment of Graves' disease[J]. Int J Endocrinol, 2018, 2018: 3171280.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.中华医学会核医学分会 131I治疗格雷夫斯甲亢指南(2021版. 中华核医学与分子影像杂志. 2021;41(4):242–53. doi: 10.3760/cma.j.cn321828-20201109-00405. [中华医学会核医学分会. 131I治疗格雷夫斯甲亢指南(2021版[) J]. 中华核医学与分子影像杂志, 2021, 41(4): 242-53.] [DOI] [Google Scholar]
- 20.Subekti I, Pramono LA. Current diagnosis and management of Graves' disease. Acta Med Indones. 2018;50(2):177–82. [Subekti I, Pramono LA. Current diagnosis and management of Graves' disease[J]. Acta Med Indones, 2018, 50(2): 177-82.] [PubMed] [Google Scholar]
- 21.Riley AS, McKenzie GAG, Green V, et al. The effect of radioiodine treatment on the diseased thyroid gland. Int J Radiat Biol. 2019;95(12):1718–27. doi: 10.1080/09553002.2019.1665206. [Riley AS, McKenzie GAG, Green V, et al. The effect of radioiodine treatment on the diseased thyroid gland[J]. Int J Radiat Biol, 2019, 95 (12): 1718-27.] [DOI] [PubMed] [Google Scholar]
- 22.Han XR, Wen X, Wang S, et al. Correlations of CTLA-4 exon-1 49 A/ G and promoter region 318C/T polymorphisms with the therapeutic efficacy of 131I radionuclide in Graves' disease in Chinese Han population. J Cell Biochem. 2018;119(8):6383–90. doi: 10.1002/jcb.26327. [Han XR, Wen X, Wang S, et al. Correlations of CTLA-4 exon-1 49 A/ G and promoter region 318C/T polymorphisms with the therapeutic efficacy of 131I radionuclide in Graves' disease in Chinese Han population[J]. J Cell Biochem, 2018, 119(8): 6383-90.] [DOI] [PubMed] [Google Scholar]
- 23.Xing YZ, Zhang K, Jin G. Predictive factors for the outcomes of Graves' disease patients with radioactive iodine (131I) treatment. Biosci Rep. 2020;40(1):BSR20191609. doi: 10.1042/BSR20191609. [Xing YZ, Zhang K, Jin G. Predictive factors for the outcomes of Graves' disease patients with radioactive iodine (131I) treatment[J]. Biosci Rep, 2020, 40(1): BSR20191609.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.吕 进泰, 尹 雅芙. Graves病131I治疗的预后因素分析. 国际放射医学核医学杂志. 2019;42(3):268–73. doi: 10.3760/cma.j.issn.1673-4114.2019.03.012. [吕进泰, 尹雅芙. Graves病131I治疗的预后因素分析[J]. 国际放射医学核医学杂志, 2019 42(3): 268-73.] [DOI] [Google Scholar]
- 25.Schneider DF, Sonderman PE, Jones MF, et al. Failure of radioactive iodine in the treatment of hyperthyroidism. Ann Surg Oncol. 2014;21(13):4174–80. doi: 10.1245/s10434-014-3858-4. [Schneider DF, Sonderman PE, Jones MF, et al. Failure of radioactive iodine in the treatment of hyperthyroidism[J]. Ann Surg Oncol, 2014, 21(13): 4174-80.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Li LT, Jiang G, Chen Q, et al. Ki67 is a promising molecular target in the diagnosis of cancer (review) Mol Med Rep. 2015;11(3):1566–72. doi: 10.3892/mmr.2014.2914. [Li LT, Jiang G, Chen Q, et al. Ki67 is a promising molecular target in the diagnosis of cancer (review)[J]. Mol Med Rep, 2015, 11(3): 1566-72.] [DOI] [PubMed] [Google Scholar]
- 27.Honma S, Hisamori S, Nishiuchi A, et al. F-box/WD repeat domaincontaining 7 induces chemotherapy resistance in colorectal cancer stem cells. Cancers. 2019;11(5):635. doi: 10.3390/cancers11050635. [Honma S, Hisamori S, Nishiuchi A, et al. F-box/WD repeat domaincontaining 7 induces chemotherapy resistance in colorectal cancer stem cells[J]. Cancers, 2019, 11(5): 635.] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.祝 林, 冯 雪凤, 邵 飞, et al. 放射性碘治疗497例格雷夫斯病的疗效及影响因素分析. 重庆医科大学学报. 2018;43(12):1566–71. doi: 10.13406/j.cnki.cyxb.001862. [祝林, 冯雪凤, 邵飞, 等. 放射性碘治疗497例格雷夫斯病的疗效及影响因素分析[J]. 重庆医科大学学报, 2018, 43(12): 1566-71.] [DOI] [Google Scholar]
- 29.Mohamadien NR, Sayed MH. Effectiveness of radioactive iodine (131I) in the treatment of Graves' disease: single center experience in Assiut University hospital. Am J Nucl Med Mol Imaging. 2020;10(5):235–42. [Mohamadien NR, Sayed MH. Effectiveness of radioactive iodine (131I) in the treatment of Graves' disease: single center experience in Assiut University hospital[J]. Am J Nucl Med Mol Imaging, 2020, 10(5): 235-42.] [PMC free article] [PubMed] [Google Scholar]
- 30.Luo Y, Deng L, Deng QJ, et al. Comparative study of the chitooligosaccharides effect on the proliferation inhibition and radiosensitization of three types of human gastric cancer cell line. Asian Pac J Trop Med. 2016;9(6):601–5. doi: 10.1016/j.apjtm.2016.04.014. [Luo Y, Deng L, Deng QJ, et al. Comparative study of the chitooligosaccharides effect on the proliferation inhibition and radiosensitization of three types of human gastric cancer cell line[J]. Asian Pac J Trop Med, 2016, 9(6): 601-5.] [DOI] [PubMed] [Google Scholar]