131I难治性分化型甲状腺癌分子靶向治疗进展

放射性碘难治性分化型甲状腺癌患者因病灶摄碘功能不佳而无法从131I等传统治疗方法中获益。近年来,甲状腺癌分子病理学研究新成果为甲状腺癌的分子诊断和靶向治疗提供了新的契机,相关分子靶向治疗的临床试验和荟萃分析均取得了可喜的结果。本文从临床角度对放射性碘难治性分化型甲状腺癌分子靶向治疗的最新进展进行综述。     

碘难治性分化型甲状腺癌靶向治疗新进展

近年来，靶向治疗为碘难治性分化型甲状腺癌带来了革命性的突破。新型靶向药物的研发，让更多晚期分化型甲状腺癌患者获得了更好的生存。以索拉非尼和仑伐替尼为代表的多靶点小分子酪氨酸激酶抑制剂显著提升了患者的无进展生存期。与此同时，靶向BRAF及靶向RET的新型酪氨酸激酶抑制剂同样也取得了瞩目的疗效，丰富了甲状腺癌的治疗手段。本文就靶向治疗在碘难治性分化型甲状腺癌中的最新研究进展进行综述。     

碘难治性分化型甲状腺癌诱导再分化治疗研究进展

分化型甲状腺癌（DTC）大多进展缓慢,经手术、促甲状腺素抑制治疗和（或）放射性碘（RAI）等规范化治疗后总体预后好,但仍有部分患者治疗后出现复发或远处转移,并可能在自然病程或治疗过程中丧失摄碘能力,不能从后续RAI治疗中获益,成为碘难治性分化型甲状腺癌（RAIRDTC）。RAIR-DTC患者可选择的治疗方法有限,且效果欠佳。近年来,随着对RAIR-DTC分子机制研究的不断深入,诱导再分化联合RAI治疗在RAIR-DTC中展现出一定的应用前景。本文综述了信号通路抑制剂、组蛋白去乙酰化酶抑制剂（HDACi）、DNA甲基化酶抑制剂、维甲酸类药物及过氧化物酶体增殖物激活受体（PPAR）激动剂在RAIR-DTC诱导再分化治疗中的进展。     

甲状腺癌分子靶向治疗进展

目的：总结近年来国内外甲状腺癌分子靶向治疗方面的进展。方法：应用Medline及CHKD期刊全文数据库，以“甲状腺癌和分子靶向治疗”等为关键词检索2002—01～2007-10相关甲状腺癌分子靶向治疗的文献。对资料进行初选，选择甲状腺癌发病分子机制、分子靶向治疗药物作用机制、治疗效果和毒副反应评价方面的文献。纳入标准：1）甲状腺癌分子病因学研究；2）甲状腺癌分子靶向治疗药物作用机制研究；3）甲状腺癌分子靶向治疗疗效评价的研究；4）甲状腺癌分子靶向治疗发展方向的研究。粗选有近百篇关于甲状腺癌分子靶向治疗方面的文章，根据纳入标准，精选42篇文献，最后纳入分析22篇文献。结果：小分子多靶点酪氨酸激酶抑制剂范得他尼治疗晚期甲状腺髓样癌，索拉非尼治疗晚期甲状腺乳头状癌，羟胺类口服组蛋白去乙酰酶抑制剂SAHA治疗晚期甲状腺癌均取得一定效果，利用选择性COX-2抑制剂塞来昔布治疗晚期分化型甲状腺癌未取得满意疗效。而更多的，1名床实验如AMG706治疗分化型甲状腺癌和甲状腺髓样癌以及利用伊马替尼治疗甲状腺未分化癌的，临床试验正在进行。结论：甲状腺癌分子靶向治疗显示出良好的前景，有望成为治疗的发展方向之一。     

131I难治性分化型甲状腺癌的再分化治疗

¹³¹I难治性分化型甲状腺癌(radioiodine-refractory differentiated thyroid cancer,RR-DTC)是目前甲状腺癌临床治疗领域的一大难题。维甲酸类药物、过氧化物酶体增殖物激活受体激动剂、DNA甲基化酶抑制剂及组蛋白脱乙酰化酶抑制剂都曾被用于诱导RR-DTC再分化并与¹³¹I联合治疗,但疗效并不显著。近年来,随着对RR-DTC分子机制认识的不断深入,靶向治疗等新的再分化治疗策略越来越多地被尝试用于治疗RRDTC。相比之下,分子靶向药物用于诱导RR-DTC重摄碘及介导¹³¹I治疗效果较好,可能具有良好的应用前景。     

放射性~(131)I照射与分化型甲状腺癌细胞摄碘(~(125)I)率关系的实验研究

目的:探讨分化型甲状腺癌培养细胞接受放射性碘(131I)照射剂量与摄取放射性碘间的相关性,为放射性碘去除治疗甲状腺癌提供新的思路。方法:设两个实验组,对分化型甲状腺癌细胞进行培养,其一应用同一活度(20μCi)的放射性131I对培养细胞进行不同时间的照射,另组应用不同活度的放射性131I对培养细胞进行相同时间(12h)的照射,分别测定两组甲状腺癌细胞摄取放射性125I水平。结果:不同活度或不同时间的放射性131I照射使甲状腺癌细胞摄取碘的水平降低,受照射组与未照射对照组细胞摄碘率比较有显著性差异(P<0.01)。结论:放射性131I照射可以使分化型甲状腺癌细胞摄碘率显著降低。     

放射性131Ⅰ照射与分化型甲状腺癌细胞摄碘(125Ⅰ)率关系的实验研究

目的:探讨分化型甲状腺癌培养细胞接受放射性碘(131I)照射剂量与摄取放射性碘间的相关性,为放射性碘去除治疗甲状腺癌提供新的思路.方法:设两个实验组,对分化型甲状腺癌细胞进行培养,其一应用同一活度(20μCi)的放射性131I对培养细胞进行不同时间的照射,另组应用不同活度的放射性131I对培养细胞进行相同时间(12h)的照射,分别测定两组甲状腺癌细胞摄取放射性125I水平.结果:不同活度或不同时间的放射性131I照射使甲状腺癌细胞摄取碘的水平降低,受照射组与未照射对照组细胞摄碘率比较有显著性差异(P＜0.01).结论:放射性131I照射可以使分化型甲状腺癌细胞摄碘率显著降低.     

肿瘤的基因靶向检测和治疗

 随着分子靶向药物和个体化治疗的研发和临床使用,肿瘤的基因靶向检测和治疗已成为肿瘤治疗的热点。尤其是针对表皮生长因子受体（EGFR）信号通路相关基因、DNA复制相关基因、纺锤体形成相关基因、细胞代谢过程相关基因等分子靶向检测和治疗,靶点分子的基因多态性决定了靶向药物治疗的有效性。     

放射性^131I照射与分化型甲状腺癌细胞摄碘（^125I）率关系的实验研究

目的：探讨分化型甲状腺癌培养细胞接受放射性碘（^131I）照射剂量与摄取放射性碘间的相关性,为放射性碘去除治疗甲状腺癌提供新的思路.方法：设两个实验组,对分化型甲状腺癌细胞进行培养,其一应用同一活度（20μCi）的放射性^131I对培养细胞进行不同时间的照射,另组应用不同活度的放射性^131I对培养细胞进行相同时间（12h）的照射,分别测定两组甲状腺癌细胞摄取放射性^125I水平.结果：不同活度或不同时间的放射性^131I照射使甲状腺癌细胞摄取碘的水平降低,受照射组与未照射对照组细胞摄碘率比较有显著性差异（P＜0.01）.结论：放射性^131I照射可以使分化型甲状腺癌细胞摄碘率显著降低.     

儿童及青少年分化型甲状腺癌核医学诊治中国专家共识（2022年版）

儿童及青少年分化型甲状腺癌（differentiated thyroid carcinoma in children and adolescents,caDTC）与成人存在较大差异,用于指导成人甲状腺癌的指南及治疗策略不完全适用于儿童及青少年。因此,来自核医学科、甲状腺外科、内分泌科、超声科、病理科及分子生物等甲状腺领域的专家组成编委会共同参与针对儿童及青少年人群的分化型甲状腺癌诊治共识的编撰。本共识的制定基于实用性、本土性及治疗手段可及性的原则,内容包括caDTC的流行病学、检查手段、治疗策略（手术、放射性碘、靶向及内分泌治疗）及随访等,基本涵盖caDTC的常见临床管理。     

Prognostic molecular marker and molecular targeted-therapy in pediatric malignancies

Recent progress in molecular biology has led to an increase of prognostic markers and development of molecular-targeted therapy in pediatric malignancies. Previous treatment including stem cell transplantation showed a remarkable cure rate, however, some patients are resistant to such therapy. Recently, all-trans retinoic acid (ATRA) for acute promyeloblastic leukemia, imatinib for chronic myeloid leukemia, and rituximab for B-cell malignant lymphoma serve to improve the clinical outcome of these patients. Furthermore, molecular-targeted therapies including tyrosine kinase inhibitor, farnesyl transferase inhibitor, methylation inhibitor, and histone deacetyl enzyme inhibitor, were applied for clinical study. For pediatric malignancies, in addition to molecular-targeted therapy against leukemia, molecular-targeted therapies, mainly tyrosin kinase inhibitors, were applied to neuroblastoma and various types of sarcomas. Recent progress in prognostic molecular marker and molecular-targeted therapy against pediatric malignancies was here reviewed.     

Molecular-targeted therapy

This article reviews the concept of molecular-targeted therapy and the current development status of molecular-targeted agents for lung cancer. Epidermal growth factor receptor inhibitors have shown promising antitumor activity against cisplatin-resistant non-small cell lung cancer in phase II trials. Appropriate clinical evaluation of these agents and collaboration with basic researchers are essential for further development.     

Targeting SHP2 sensitizes differentiated thyroid carcinoma to the MEK inhibitor

Pharmacologic targeting of components of the MAPK/ERK pathway in differentiated thyroid carcinoma (DTC) is often limited due to the development of adaptive resistance. However, the detailed mechanism of MEK inhibitor (MEKi) resistance is not fully understood. Here, MEKi-resistant models were constructed successfully, in which multiple receptor tyrosine kinases (RTKs) signaling pathways and Src-homology 2 domain-containing phosphatase 2 (SHP2) were activated in MEKi-resistant cells. Given the physiological role of SHP2 as the downstream target of many RTKs, we first found blockade of SHP2 enhanced the sensitivity to MEKi in constructed MEKi-resistant models. Interestingly, we also found that compared with MEKi treatment alone, MEKi in combination with an SHP2 inhibitor markedly suppressed the reactivation of the MEK/ERK pathway; thus, the addition of the SHP2 inhibitor significantly improved the antitumor effects of MEKi. The synergistic suppression of DTC upon treatment with both inhibitors was further confirmed in xenograft models and transgenic models. Thus, our data suggest that RTKs activation leads to reactivation of the MAPK pathway and resistance to MEKi in DTC, which is reversed by SHP2 blockade. As a novel active inhibitor of SHP2, SHP099 in combination with MEKi is a promising therapeutic approach for advanced DTC and MEKi-resistant one.     

The realisation of targeted antitumour therapy

Better understanding of the pathways regulating proliferation and metastasis of cancer cells has led to the development of novel molecular-targeted therapies. The number of molecular-targeted agents approved for use in the clinic is growing, with many more in clinical trials. Most of these compounds can be broadly classified into two main categories: monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The pathological processes targeted include vascular endothelial growth factor-dependent tumour angiogenesis and epidermal growth factor receptor-dependent tumour cell proliferation and survival. Unlike conventional chemotherapy, molecular-targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. Recent progress in targeted antitumour therapy is discussed, with a focus on antiangiogenesis.     

Anticancer drug therapy for patients with renal dysfunction

International Journal of Clinical Oncology - Anticancer drug therapy for cancer is developing rapidly, including molecular-targeted drugs and immune checkpoint inhibitors that are used in clinical...     

Epidermal growth factor receptor: a promising target in solid tumours

The epidermal growth factor receptor (EGFR) is expressed in a wide variety of solid tumours. It has been demonstrated that the EGFR-associated signaling pathway plays an important role in carcinogenesis and cancer progression. In the new therapeutic paradigm of molecular-targeted cancer therapy, interference with intracellular signaling cascades is an appealing treatment approach. Inhibitory strategies under study include monoclonal antibodies, tyrosine kinase inhibitors, EGFR-ligand conjugates, EGFR immunoconjugates, and antisense oligonucleotides. Many of these strategies have demonstrated efficacy against EGFR-expressing tumour cells in preclinical studies, prompting a large number of clinical trials. In particular, clinical studies using monoclonal antibody blockade and EGFR tyrosine kinase inhibitors have suggested that EGFR blockade is a well-tolerated and effective treatment strategy; however, more trials are needed to precisely define how these agents will fit into modern cancer care.     

Some lessons learned from imatinib mesylate clinical development in gastrointestinal stromal tumors

Imatinib mesylate is a molecular-targeted agent, shown to be effective in chronic myeloid leukemia and gastrointestinal stromal tumors (GIST). The latter may currently serve as a model on which speculating how the future of molecular-targeted therapy in solid tumors will be. So far, some lessons have been learnt. 1) Molecular-targeted therapy can be effective in the advanced disease setting, resulting in major tumor responses. 2) Patterns of tumor responses may be peculiar, radiologically and pathologically. 3) Anti-tumor activity may be highly predictable by assessing tumor molecular biology. 4) The methodology of clinical development of molecular-targeted agents may differ from standard chemotherapy in some respects, because, say, the preclinical rationale may be stronger, thus increasing the Bayesian prior probability of efficacy, or the optimal dose cannot be determined separately from the assessment of activity and efficacy. 5) Molecular-targeted agents will hardly remain "orphan drugs", if effective. 6) While an obvious impact on survival in the advanced disease setting has been clearly demonstrated, the biologic and clinical impact of molecular-targeted therapy still needs to be elucidated. Its eradicating capabilities, as well as the implications of secondary resistance, are to be understood. 7) Integrated, multimodality approaches, including surgery, may still be of value in the molecular-targeted therapy era.     

EGFR-TKI治疗非小细胞肺癌的耐药机制进展研究

肺癌的发病率和死亡率已居我国恶性肿瘤的第一位。以表皮生长因子受体,酪氨酸激酶为靶点的酪氨酸激酶抑制剂(EGFR-TKI)治疗肺癌已广泛引起关注。但部分患者在服用EGFR-TKI初期即出现原发耐药,有些患者在服用EGFR-TKI一段时间后产生继发性耐药,本文综述EGFR-TKl分子耐药机制的研究现状,探讨EGFR-TKl分子耐药机制重要的临床意义。      

PARP抑制剂用于铂敏感复发卵巢癌患者维持治疗的血液学毒性概述

卵巢癌是威胁女性健康和生命的重大疾病之一。近年来,聚腺苷二磷酸核糖聚合酶抑制剂[poly (ADP-ribose)polymerase inhibitors,PARPi]作为一类新型的靶向治疗药物为卵巢癌患者带来获益,并被国内外多项临床指南、规范推荐用于铂敏感复发卵巢癌患者的维持治疗及术后的维持治疗。但与此同时带来的安全性问题,尤其是血液学毒性值得关注。从作用机制、药代动力学出发,对比目前已上市的3种PARPi的特征及其血液学毒性差异,以期为复发性卵巢癌患者临床用药提供参考。