晚期甲状腺癌治疗的曙光——靶向和免疫治疗

近年来,甲状腺癌的发病率显著增加,大多数病例以分化型甲状腺癌为主,其特点是预后良好。然而,在初始治疗后仍有15%的患者出现疾病持续或复发,并且局部晚期或转移性癌症患者对既定治疗无效,最终有死亡的风险。国内外对于晚期甲状腺癌的治疗仍有争议,但都倾向于靶向和免疫治疗为主的综合治疗。随着对甲状腺癌分子发病机制的深入理解,临床上已批准了多种新的靶向治疗方法用于晚期甲状腺癌。中国临床肿瘤学会(CSCO)2021年指南和欧洲肿瘤内科学会(ESMO)2022年指南(更新)均将靶向治疗作为晚期甲状腺癌治疗的Ⅰ级推荐。本文将对晚期甲状腺癌临床治疗新进展作一综述。     

甲状腺乳头状癌预后相关因素研究进展

甲状腺乳头状癌的发病率在全球范围内呈上升趋势,因为预后良好,这些患者一度被认为是低风险的。然而,局部晚期以及转移性甲状腺乳头状癌的发病率也在上升,与之相关的死亡率也在增加。因此,如何对甲状腺乳头状癌患者进行预后评估是当下研究的热点,本文将对现阶段甲状腺乳头状癌预后相关因素的研究进行综述。     

CAR-T在甲状腺癌免疫治疗中的研究进展

大多数甲状腺癌患者进行以外科治疗为主的综合治疗可以取得良好的预后,但目前晚期甲状腺癌治疗手段匮乏。采用体外基因编辑技术的嵌合抗原受体T细胞（chimeric antigen receptor T-cell,CAR-T）免疫疗法在血液系统肿瘤中得到应用并取得了良好的治疗效果。以此为基础,CAR-T开始在实体肿瘤中尝试使用,但效果欠佳。CAR-T在晚期甲状腺癌中的研究已有开展,目前仍局限在临床前的基础研究,相关临床试验较少且缺乏试验结果报道。本文将相关报道进行综述,旨在为今后的研究提供参考。     

精确病理诊断在甲状腺癌精准医疗中的意义

甲状腺癌是近年来发病率上升最快的实体恶性肿瘤,其中绝大多数为滤泡细胞来源,以分化型甲状腺癌为主,包括甲状腺乳头状癌（papillary thyroid cancer,PTC）和滤泡癌（follicular thyroid cancer,FTC）。为实现甲状腺癌的精准预防、诊断和治疗,需要以精确病理诊断作为基础。本文分别从评估并降低甲状腺癌发生风险、术前精确诊断、预后和复发风险分层,以及指导晚期患者分子靶向治疗等方面来阐述精确病理诊断在甲状腺癌精准医疗中的意义。      

Advanced thyroid carcinoma: an experience of 385 cases.

AIMS: To report clinical outcomes of a large series of cases with advanced thyroid cancer. STUDY DESIGN: Three hundred and eighty-five patients at the UICC stages III and IV were selected for the study with thyroid cancer. RESULTS: Papillary carcinoma and sclerosing carcinoma have better survival than the Hürthle cell and insular types. Lymphatic metastasis does not appear to worsen the prognosis. All the tumour forms offer the chance of long survival. CONCLUSIONS: Surgical treatment is the primary treatment of thyroid carcinoma. The combined treatments of surgery, metabolic beam therapy, suppressive hormone therapy, radiotherapy and chemotherapy cure a high percentage of patients with the tumour at an advanced stage.     

儿童和青少年甲状腺癌的治疗进展

儿童和青少年甲状腺癌较为罕见。本文通过分析现有数据资料,阐述儿童和青少年甲状腺癌的治疗进展。尽管发现时分期较晚,但该病总体预后较好。手术治疗是最主要的治疗方式,目前无标准的手术处理方式。大部分外科医生赞成甲状腺全切和(或)次全切。对于单侧的低危患者,也可考虑单侧腺叶切除。预防性中央区淋巴结清扫术能够降低局部复发。在特定的患者中行放射性131I治疗能降低复发风险。由于生存期较长,在长期无瘤生存后仍可能再次复发,因此患者需要长期随访。     

Treatment of head and neck cancer with twice-a-day fractionation

Fifty patients with locally advanced head and neck cancer were treated with twice-a-day fractionation (1.0-1.5 Gy 2 times daily, 5 days per week). These patients consist of 12 cases of thyroid cancer, 23 of hypopharynx cancer, 7 of cancer of the oral cavity, 6 of oropharynx cancer and 2 of other sites. Total delivered dose was 21-73 Gy in 10-74 days. In respect of thyroid cancer, 2 cases of 3 with papillo-follicular carcinoma, 1 of 1 with small cell carcinoma and 3 of 8 with giant cell carcinoma were locally controlled. Patients of hypopharyngeal carcinoma treated with multifractionated radiotherapy combined with or without surgery revealed good prognosis (91% of T1 + T2, 100% of T3 + T4 at 2 years). Patients with cancer of the oral cavity or oropharynx, however, had poor prognosis.     

分化型甲状腺癌患者的临床特点及预后分析

目的 分析分化型甲状腺癌患者的临床特点及预后影响因素.方法 收集147例分化型甲状腺癌患者的临床资料,包括一般资料、手术方法、术后基本情况及临床特征,采用Logistic回归模型分析分化型甲状腺癌患者预后的影响因素.结果 147例分化型甲状腺癌患者中,单侧发病95例,双侧发病52例;单发59例,多发88例;91.16％...     

乳腺癌患者再发甲状腺癌9例临床分析

目的:探讨乳腺癌患者再发甲状腺癌的潜在关系。方法:对2000-2008年收治9例乳腺癌患者再发甲状腺癌的临床资料进行回顾性分析。结果:9例患者中,乳腺癌雌激素受体(ER)阳性7例,阴性2例;甲状腺癌ER阳性4例,阴性5例。4例ER阳性的甲状腺癌全来自于ER阳性的乳腺癌患者。结论:雌激素很可能对甲状腺癌的发生和发展起重要作用。临床上对激素依赖性乳腺癌患者要常规检查甲状腺。甲状腺癌的治疗原则是手术切除,预后良好。雌激素治疗ER阳性的甲状腺癌有可能成为一种新的手段。     

Locally advanced differentiated thyroid cancer

Although most patients with differentiated thyroid cancer (DTC) of follicular cell origin enjoy a relatively good prognosis, some patients unfortunately present with or develop locally advanced DTC which leads to significant local morbidity and mortality. DTC accounts for 54-94% of all locally advanced thyroid cancers. DTC invasion of the recurrent laryngeal nerve, strap muscles and trachea are the most common followed by invasion of the esophagus, internal jugular vein and carotid artery. Surgical resection is the primary treatment for locally advanced DTC. Although the optimal surgical approach (ranging from conservative shave excision to aggressive en bloc resection of tumor and vital structures) in patients with locally advanced DTC is controversial, a curative resection should be the goal unless complete tumor resection results in unwanted perioperative morbidity and mortality or widely metastatic disease is present. Postoperative radioiodine ablation with TSH suppression is imperative after surgical resection of locally advanced DTC. Patients with microscopic or small gross residual disease, after surgical resection, may benefit from postoperative external radiotherapy for local control of disease.     

乳腺癌患者再发甲状腺癌9例临床分析

目的：探讨乳腺癌患者再发甲状腺癌的潜在关系。方法：对2000-2008年收治9例乳腺癌患者再发甲状腺癌的临床资料进行回顾性分析。结果：9例患者中,乳腺癌雌激素受体（ER）阳性7例,阴性2例;甲状腺癌ER阳性4例,阴性5例。4例ER阳性的甲状腺癌全来自于ER阳性的乳腺癌患者。结论：雌激素很可能对甲状腺癌的发生和发展起重要作用。临床上对激素依赖性乳腺癌患者要常规检查甲状腺。甲状腺癌的治疗原则是手术切除,预后良好。雌激素治疗ER阳性的甲状腺癌有可能成为一种新的手段。     

Understanding the Relationship Between Age and Thyroid Cancer

Unique among malignancies, age is a key prognostic indicator for well‐differentiated thyroid cancer. Patients aged <45 years can have the same degree of disease involvement and a distinctly different prognosis than those aged >45. Although the reason for the association between age and outcome is not entirely clear, it does imply that there is something intrinsic to either the cancer or the treatment that is age dependent. This article explores the characteristics of the normal thyroid and thyroid cancer that are age dependent. It then provides theories for the relationship between advanced age and poor prognosis, in addition to treatment options tailored to age at diagnosis.     

Malignant transformation of thyroid cancer; poorly differentiated cancer and anaplastic cancer transformation

The prognosis of thyroid cancer depends largely on histological differentiation and clinical stage. The prognosis in anaplastic cancer is worst, in well differentiated cancer it is best; poorly differentiated cancer takes a middle position. The prognosis of patients with differentiated cancer is generally good, however, there are cases with malignant transformation such as poorly differentiated, anaplastic and squamous-cell cancer transformation. We studied the frequency and the inducement factors of malignant transformation in patients with thyroid cancer. The frequency of poorly differentiated, anaplastic and squamous-cell cancer transformation was 13.6%, 6.4% and 0.7%, respectively. In anaplastic cancer transformation, irradiation is an important factor.     

The clinical behavior of radiation-induced thyroid cancer in patients with prior Hodgkin's disease

Second primary neoplasms are occurring with increasing frequency. Despite growing literature on the incidence and etiology of this phenomenon, very little has been documented about the clinical aspects and biological behavior of these tumors. As our experience has hinted at a worse prognosis for second primaries, we thought it of interest to study this phenomenon for one type of tumor. We reviewed 32 cases of thyroid cancer arising as a second neoplasm in patients with Hodgkin's disease and compared various clinical characteristics to reported series of de novo (non-radiation-induced) thyroid cancer. Thyroid cancer, as a second primary, occurred more frequently in males with a more malignant histology and was diagnosed at a more advanced stage. The survival appears to be worse. The behavior of radiation-induced thyroid cancer in a host with prior malignant neoplasia appears to be more aggressive than that of both de novo (non-radiation-induced) thyroid cancer and radiation-induced thyroid cancer in a host with no prior malignancy. The selected nature of the cases precludes any firm conclusions. This type of information should be collected prospectively for all secondary malignancies as it may have an impact on the clinical management of these patients.     

2型糖尿病合并甲状腺癌的发生率及预后相关影响因素分析

目的 探讨2型糖尿病合并甲状腺癌的发生率及预后的相关影响因素.方法 以534例住院2型糖尿病患者为研究对象,回顾分析其空腹血糖、餐后2 h血糖、胰岛素(FINS)以及甲状腺彩超检查的结果,对2型糖尿病患者的甲状腺癌发生率及预后相关因素进行分析.结果 2型糖尿病患者甲状腺癌的发生率为19.7%,女性的发生率为12.4%,高于男性6.4%,且随年龄的增加甲状腺癌的发病率增加.单因素分析结果表明,影响2型糖尿病合并甲状腺癌患者3年生存率的主要相关因素为性别、年龄、病理类型、淋巴结转移、临床分期、病程和胰岛素依赖.多因素回归分析结果显示,病理类型、临床分期、病程、胰岛素抵抗是影响2型糖尿病合并甲状腺癌患者预后的独立因素(P<0.05).结论 2型糖尿病患者的甲状腺癌的患病率较高,病理类型、临床分期、病程、胰岛素抵抗可能是2型糖尿病患者甲状腺癌预后的独立影响因素.临床实践中,应及时对患者进行甲状腺癌筛查,早发现早治疗,以减少甲状腺癌的发生.     

Palliation of advanced thyroid malignancies

While most thyroid cancers are slow-growing and have an excellent prognosis after appropriate treatment, a subset of thyroid cancers behave aggressively, and approximately 1500 individuals in the US will die of the disease in the year 2007. Advanced thyroid malignancies can cause distressing and life-threatening symptoms by local invasion in the neck, growth of distant metastases in the lung, bone, and other organs, and tumor production of bioactive substances in the case of medullary thyroid cancer. This article will review palliative modalities, including surgery, radioactive iodine, external beam radiation, and chemotherapy, as well as novel targeted therapies, for the treatment of patients with advanced thyroid malignancies.     

血清甲状腺激素在胃癌中的变化及其临床意义

研究60例胃癌血清甲状腺激素水平的变化.所有患者中出现低T_3占57%,低T_4占17%.早期胃癌血清T_3、T_4均无变化,进展期胃病以血清T_3降低为主,其降低程度与肿瘤浸润深度、淋巴结受累、远处转移相一致,晚期胃癌、病情危重者血清T_4降低.表明这种变化能较好地反映胃癌生物学特性,可作为判断病情及临床分期、监视病情、预报复发转移的参考指标.     

Biomarkers for the diagnosis of thyroid cancer

Thyroid tumor contributes 1% of the total tumor but 90% of the endocrine related tumors. Majority of the thyroid cancers are being diagnosed by Fine needle aspiration cytology (FNAC) and histology. Although histology is considered as gold standard, it has some limitations, like variants of papillary and follicular cancer creates confusion among pathologists, where the morphological features are indistinguishable. Conventional histology and FNAC fails to provide any prognostic and therapeutic information. To address this problem, several immunohistochemical markers are proposed and their efficiency in thyroid cancer diagnosis, treatment and prognosis are being evaluated. Among the discussed immunohistochemical markers, few have potential in accurate diagnosis and prognosis of thyroid carcinoma. Hector battifora mesothelial antigen-1 (HBME-1) and Galectin-3 (GAL-3) shows highest specificity and sensitivity in the diagnosis of thyroid cancer respectively. Overexpression of EGFR in thyroid cancer is in proportionate with the severity of the advanced thyroid carcinoma, which required further evaluation and validation. Surgery and radio-iodine therapy is the main treatment modality, however; combined targeted therapeutic approach against different thyroid cancer receptor and biomarkers can reduce the side effect, and improve therapeutic efficiency. This review is oriented towards the finding of the potent thyroid cancer receptor having enhanced sensitivity and specificity, with diagnostic, prognostic and therapeutic efficiency.     

乐伐替尼靶向调节VEGFR/PI3K/AKT治疗晚期甲状腺癌的作用机制

目的探讨乐伐替尼靶向调节VEGFR/PI3K/AKT治疗晚期甲状腺癌的作用机制。方法选取100例晚期分化型甲状腺癌患者,采用口服乐伐替尼,剂量为24 mg/d,直到出现无法耐受的副作用和疾病恶化。评价药物使用疗效;观察患者甲状腺癌血清标志物Tg水平变化;采用免疫组织化学法检测甲状腺癌患者癌组织中VEGFR2蛋白的表达;采用Western Blot法和Real-Time PCR法检测甲状腺癌癌组织中PI3K、AKT的磷酸化蛋白和基因水平;采用Caspase 3试剂盒测定凋亡蛋白Caspase 3表达。结果乐伐替尼治疗晚期分化型甲状腺癌的有效率为60.00%,患者血清TgAb浓度较治疗前明显下降(P<0.05)。与癌旁组织相比,甲状腺癌组织内Caspase 3活性、VEGFR2蛋白表达含量、p-PI3K和p-AKT蛋白含量及PI3K和AKT mRNA表达明显上升(P<0.05)。晚期分化型甲状腺癌患者应用乐伐替尼治疗后,Caspase 3活性、VEGFR2蛋白表达含量、p-PI3K和p-AKT蛋白含量及PI3K和AKT mRNA表达较治疗前显著降低,差异具有统计学意义(P<0.05)。结论乐伐替尼可以有效治疗晚期分化型甲状腺癌,并调控VEGFR靶向途径抑制PI3K/AKT信号通路,诱导甲状腺癌细胞凋亡。     

BRAF V600E突变对甲状腺乳头状癌发生及预后的影响

甲状腺乳头状癌(papillary thyroid cancer,PTC)是甲状腺癌最常见的病理类型.PTC通常预后良好,但近年来甲状腺癌的发病率逐年攀升.随着患病人数的不断增多,中晚期难治性甲状腺癌患者不再少见.因此,越发庞大的甲状腺癌患者群体的管理与诊治已成为巨大的考验.BRAF V600E基因突变是乳头状癌经典DNA相关标志物,目前已被广泛应用于甲状腺癌的术前诊断和预后评估,并且作为潜在的治疗靶点受到越来越多的关注.因此,正确全面的了解BRAF V600E基因突变可以帮助我们对PTC的发生、发展及生物学行为有更进一步的了解,并为PTC患者管理方式与治疗策略提供新的方向.