224例分化型甲状腺癌放射性碘治疗分析

目的：对在我科8年来治疗的分化型甲状腺癌（DTC）患者进行回顾性分析,了解DTC发病规律,并证明131碘治疗DTC的疗效。方法：2002至2010年确诊为DTC并有颈部淋巴结转移的患者,进行甲状腺近全切除,并进行颈部淋巴结清扫,术后^131碘治疗。^131碘治疗后,每半年随访一次。随访指标：颈部超声检查;血清TSH、FT4、FT3;血清Tg、TgAb检查;全身放射性碘扫描;胸部CT或MRI。疗效判定：当血清Tg、TgAb阴性,颈部超声未见肿大淋巴结,全身放射性碘扫描未见放射性浓聚时,为DTC治愈。当上述指标为阳性时,则进行再次^131碘治疗。用SPSS软件进行统计学处理。结果：DTC患者数逐年明显增加;乳头癌与滤泡癌的比例约为12（207）：1（17）,女性患者远多于男性,男：女患者患病比例约为1（57）：3（167）;DTC在20-55岁之间为高发年龄段,峰值在25-35岁之间;^131碘治疗对DTC治愈率约达90%,近10%的顽固性DTC患者多次^131碘治疗效果欠佳。结论：分化型甲状腺癌患病率有明显增加趋势,25-35岁为高发年龄,女性多于男性,早期诊断及早期治疗是关键。手术切除甲状腺后进行^131碘治疗对DTC治愈率达90%。近10%的患者^131碘治疗效果欠佳,需寻求更好的治疗方法。     

碘难治性甲状腺癌的诊治进展

多数分化型甲状腺癌(differentiated thyroid cancer,DTC)经过规范的手术、选择性131I治疗及促甲状腺激素抑制治疗后预后良好,然而,仍有部分转移性DTC的患者在早期或131I治疗过程中失去了摄碘能力发展为碘难治性DTC(radioiodine-refractory DTC,RAIR-DTC)。RAIR-DTC病情进展快,死亡率高,为这些患者寻找有效的治疗手段一直是甲状腺癌领域研究的热点。该文对碘难治性甲状腺癌的诊断及治疗进展进行综述,为及早识别这些患者,并为其他可能获益的治疗手段如靶向治疗及放疗等的早期干预争取时间。     

222例分化型甲状腺癌再手术的临床分析

目的 分析分化型甲状腺癌（DTC）再手术的原因,总结减少再次手术的策略。方法 回顾性分析2013年1月至2017年12月于重庆医科大学附属第一医院内分泌乳腺外科行手术治疗分化型甲状腺癌再次手术的患者222例,根据其初次手术前的临床评估情况,将患者分为cN0分化型甲状腺癌（DTC cN0）、cN1分化型甲状腺癌（DTC cN1）、分化型甲状腺癌未评估（DTC unknown）及甲状腺良性病变组,随访统计其再次手术间隔时间、初次手术方式及再次手术区域,分析总结其再次手术的原因及对策。结果 222例中甲状腺乳头状癌（PTC）219例,滤泡状癌（FTC）3例;首次手术术前或术中评估为DTC cN0 63例（284%）,DTC cN148例（216%）,DTC unknown27例（122%）,甲状腺良性肿瘤组84例（378%）。首次手术为良性肿瘤组再次手术均在1年内,DTC cN0组为13个月（15天～132个月）,DTC cN1为12个月（4～18个月）。在DTC cN0组中初次手术方式为甲状腺全切+患侧中央区淋巴结清扫或甲状腺全切有40例（占635%）;在DTC cN1组中初次手术方式为甲状腺全切+患侧中央区及侧区淋巴结清扫有39例（813%）。侧区淋巴结出现转移是DTC再次手术的主要原因,DTC cN0组同侧Ⅲ区出现复发的频率最高为597%;DTC cN1组同侧Ⅱ区复发为500%。结论 首次手术术前及术中对甲状腺肿瘤进行精确的评估能减少再次手术的发生,而对于首次手术术前评估为DTC的患者首次手术前对颈侧区淋巴结转移情况进行准确的评估以及规范的手术切除范围能够减少DTC术后复发。     

分化型甲状腺癌术后131I治疗17例临床观察

甲状腺癌占全身肿瘤的1.3%～1.5%,是最常见的内分泌肿瘤.甲状腺癌81%～87%属于分化良好的类型（differentiated thyroid carcinoma,DTC）,主要包括乳头状腺癌（papillary thyoid carcinoma,PTC）和滤泡状腺癌（follicular thyoid carcinoma,FTC）,而预后差的未分化癌仅占10%[1].分化型甲状腺癌（DTC）30%终将复发,2/3发生在术后10年内[2].Mazzaferri[3]报道,术后行131I治疗者术后复发和死亡率明显低于仅行甲状腺激素替代治疗或未行任何治疗者.我科自1999至2003年对17例DTC术后患者行^131I治疗,现将治疗过程和随访结果报告如下.     

分化型甲状腺癌术后首次131I治疗时间选择对疗效的影响

目的:探讨分化型甲状腺癌（DTC）术后首次131I治疗时间选择对疗效的影响。方法:回顾性分析2013年5月至2017年2月于中山大学附属第三医院首次接受131I治疗的DTC患者329例。根据2013年国内131I治疗分化型甲状腺癌指南，131I治疗剂量为30~200 mCi，131I治疗后6个月行疗效评估，疗效分为临床治愈、好转、稳定、进展。根据2015版ATA指南将131I治疗前患者分为中危、高危；按手术与131I治疗时间间隔分为四组:A组（＜1个月）、B组（1~3个月）、C组（＞3~6个月）、D组（＞6~12个月）。分析四组不同时间间隔的DTC患者疗效是否有差异。采用χ2检验、Fisher确切概率法分析数据。结果:各组中年龄及性别构成比等无显著性差异。中危DTC患者中不同时间间隔的四组疗效无差异（P=0.937）。高危DTC患者中不同时间间隔的四组疗效有差异（P=0.017），D组的疗效差于其他各组，其余各组间疗效无差异。结论:中危DTC患者手术后12个月内行首次131I治疗时间间隔对疗效影响不大。高危DTC患者中时间间隔＞6~12个月组的疗效较其他组差，建议高危DTC患者宜在手术后6个月内进行首次131I治疗。     

100例分化型甲状腺癌术后131I治疗的疗效及安全性评价

目的：探讨131I在分化型甲状腺癌（differentiated thyroid cancer,DTC）术后清除残留甲状腺组织（清甲）和转移灶（清灶）治疗中的疗效及安全性。方法随机选取100例进行131I清甲及清灶治疗的DTC患者。所有患者治疗前3～4周均停服L-T4,并予以131I（2.96～5.55）×103 MBq清甲治疗;治疗后口服L-T4替代治疗,6个月后复查,根据颈部超声、全身显像及血清甲状腺球蛋白（thyroglobulin,Tg）水平评价131I治疗的效果。结果所有的患者均接受1～3次的131I治疗,共140个疗程,平均每次治疗剂量为4.03×103 MBq,1次131I治疗成功率为67%,2次131I治疗成功率为92%,经131I治疗后患者的Tg转阴率为53.3％;治疗后5例患者出现一过性白细胞下降,治疗前后肝肾功能无明显改变。结论 DTC患者术后尽早进行规范化的131I治疗,具有治疗次数少、清甲成功率高且不良反应少的特点,对预防甲状腺癌的复发有重要的作用。     

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。     

甲状腺球蛋白抗体测定在分化型甲状腺癌131I治疗中的临床意义

甲状腺球蛋白（thyroglobulin，Tg）是分化型甲状腺癌（differentiated thyroid carcinoma，DTC）患者治疗后随访的主要血清标志物，Tg的测定会受到甲状腺球蛋白抗体（thyroglobulin antibody，TgAb）的影响，限制了Tg作为肿瘤标志物在DTC随访中的作用。因此，有关TgAb阳性患者的随访一直是临床工作中的难题，有研究指出TgAb可以作为替补肿瘤标志物用于DTC的监测，但有关TgAb与DTC治疗后疾病状态与预后间的关系尚存争议。主要就TgAb在DTC患者¹³¹I治疗中的临床意义进行综述，以期为TgAb阳性患者的临床决策提供更多依据。     

全反式维甲酸诱导再分化在16例甲状腺癌治疗中的应用

目的：探讨全反式维甲酸（ATRA）在分化型甲状腺癌（DTC）放射性碘治疗过程中的临床应用。方法：16例分化型甲状腺癌转移患者,131I治疗中转移灶不摄取或轻度摄取131I,服ATRA2个月后再行131I治疗,7天后SPECT显像,对转移灶部位进行感兴趣区（ROI）计数,并和ATRA治疗前SPECT显像进行比较,评价ATRA治疗前后131I摄取变化情况。结果：16例患者服用ATRA后,其中7例131I摄取增加,治疗有效率43.7%。结论：ATRA治疗能促进部分失分化DTC细胞的再分化。     

血清TgAb对分化型甲状腺癌消除甲状腺后Tg水平的影响

血清甲状腺球蛋白（thyroglobulin,Tg）测定是判断分化型甲状腺癌（differentiated thyroid carcinoma,DTC）术后和^131 I治疗后有无复发的重要指标,而Tg测定均受到甲状腺球蛋白抗体（TgAb）的干扰。本研究对98例DTC患者在消除甲状腺后进行血清Tg、TgAb的检测检查,结果报道如下。     

Different clinical impact of estradiol receptor determination according to the analytical method: a study on 1940 breast cancer patients over a period of 16 consecutive years

SummaryBackground The persistence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with poor prognosis. Preliminary studies indicated that these patients might benefit from secondary adjuvant targeted therapy. HER2 protein is suggested as one of the most promising targets. The aims of this study were (1) to determine the HER2 status of DTC in BM of breast cancer patients and (2) to compare the HER2 status of DTC and corresponding primary tumors.Methods BM aspirates from 137 primary breast cancer patients were included into the study. A double staining procedure was used for the identification of cytokeratin-positive (CK)/HER2 positive cells. HER2 status of the primary tumor was immunohistochemically assessed by the HERCEP-test™.Results In 46 of 137 (34%) breast cancer patients CK-positive cells were detectable in BM. DTC with HER2 positivity were found in 20 (43%) of these patients. The HER2 expression on DTC was heterogeneous in 7 of 17 (41%) patients. Concordance rate of HER2 status between primary tumor and DTC was 62%. In 12 of 20 patients with HER2 negative tumors HER2 positive DTC were detected.Conclusions HER2 positive DTC can be detected in patients with HER2 negative primary tumors. Therefore, the antigenic profile of DTC may be considered for treatment decision since these patients might actually benefit from trastuzumab. However, the HER2 overexpression on DTC is heterogeneous in individual patients which may reduce the efficacy of an immunotherapy based strategy directed against HER2-antigen only.     

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.     

Identification of genomic features associated with immunotherapy response in gastrointestinal cancers

Gastrointestinal (GI) cancers prevail and account for an extremely high number of cancer deaths worldwide. The traditional treatment strategies, including surgery, chemotherapy, radiotherapy, and targeted therapy, have a limited therapeutic effect for advanced GI cancers. Recently, immunotherapy has shown promise in treating various refractory malignancies, including the GI cancers with mismatch repair deficiency (dMMR) or microsatellite instability (MSI). Thus, immunotherapy could be a promising treatment approach for GI cancers. Unfortunately, only a small proportion of GI cancer patients currently respond to immunotherapy. Therefore, it is important to discover predictive biomarkers for stratifying GI cancer patients response to immunotherapy. Certain genomic features, such as dMMR/MSI, tumor mutation burden (TMB), and tumor aneuploidy have been associated with tumor immunity and im-munotherapy response and may serve as predictive biomarkers for cancer immunotherapy. In this review, we examined the correlations between tumor immunity and three genomic features: dMMR/MSI, TMB, and tumor aneuploidy. We also explored their correlations using The Cancer Genome Atlas data and confirmed that the dMMR/MSI status, high TMB, and low tumor aneuploidy are associated with elevated tumor immunity in GI cancers. To improve the immunotherapeutic potential in GI cancers, more genetic or genomic features associated with tumor immune response need to be identified. Furthermore, it is worth exploring the combination of different immunotherapeutic methods and the combination of immunotherapy with other therapeutic approaches for cancer therapy.     

Lenvatinib: Role in thyroid cancer and other solid tumors

Despite recent breakthroughs in treatment of advanced thyroid cancers, prognoses remain poor. Treatment of advanced, progressive disease remains challenging, with limited treatment options. Small-molecule tyrosine kinase inhibitors, including vandetanib, cabozantinib, sorafenib, and lenvatinib, which are now FDA-approved for thyroid cancer, have shown clinical benefit in advanced thyroid cancer. Lenvatinib is approved for treatment of locally recurrent or metastatic, progressive, radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). It has been studied in phase II and III trials for treatment of advanced RAI-refractory DTC, and in a phase II trial for medullary thyroid cancer (MTC). Lenvatinib targets vascular endothelial growth factor receptors 1–3 (VEGFR1–3), fibroblast growth factor receptors 1–4 (FGFR-1–4), RET, c-kit, and platelet-derived growth factor receptor α (PDGFRα). Its antitumor activity may be due to antiangiogenic properties and direct antitumor effects. Lenvatinib has demonstrated antitumor activity in a variety of solid tumors, including MTC, in phase I and II clinical trials. In a phase II study in advanced RAI-refractory DTC, lenvatinib-treated patients achieved a 50% response rate (RR), with median progression-free survival (PFS) of 12.6 months. In a phase III trial in RAI-refractory DTC, median PFS in lenvatinib-treated patients was 18.3 months, with a 65% overall RR, versus 3.6 months in placebo-treated patients, with a 2% RR. Adverse events occurring in >50% of patients included hypertension, diarrhea, fatigue/asthenia, and decreased appetite. Lenvatinib is a promising new agent for treatment of patients with advanced thyroid cancer.     

Microsatellite instability in thyroid cancer: hot spots, clinicopathological implications, and prognostic significance.

PURPOSE: To determine whether microsatellite instability (MSI) in particular loci has clinicopathological significance in thyroid cancer. EXPERIMENTAL DESIGN: Seventy-six cases of surgically resected thyroid cancer were screened for MSI at nine microsatellites: THRA1, TSHR, D2S123, D11S912, D2S115, D2S399, p53, RET, or BAT-26. Multivariate analysis was performed to test for links between MSI and the clinical parameters of gender, age, histology, stage, nodal involvement, and prognosis. RESULTS: THRA1, residing in the thyroid hormone receptor alpha gene, displayed the highest levels of MSI at 36.5%. MSI in TSHR, located within the thyroid-stimulating hormone receptor gene, was found to be linked to cancer in the elderly (>70 years of age) and with high-grade (N 3, 4) nodal involvement. In follicular cancer, MSI in D2S123 occurred at a frequency of 100% (7/7) with no (0%) occurrence of MSI at the nearby D2S115, D2S399, or BAT-26 loci. Regarding prognosis, patients with MSI-positive cancer showed better long-term survival. BAT-26, which is an important marker in colorectal cancer, displayed the lowest frequency of MSI in our panel of thyroid tumors. CONCLUSION: Whereas patients with MSI-positive cancer showed better long-term survival, as is the case for colorectal cancer, our finding of the low frequency of MSI in BAT-26 suggests that the biochemical defects governing the spectrum of MSI in thyroid and colorectal cancer are different. MSI in THRA1, TSHR, and D2S123 appears to be an integral part of thyroid carcinogenesis, as evidenced by the high frequency of MSI and significant correlation to clinical data.     

非小细胞肺癌免疫治疗生物标志物研究进展

非小细胞肺癌约占所有肺癌类型的75%~80%,5年生存率仅为15%。近年来人们对肺癌精准治疗的认识明显提高,但非小细胞肺癌的治疗仍面临挑战,驱动基因阴性患者的治疗方式十分有限,晚期患者的预后仍较差。免疫治疗药物可以通过阻断免疫检查点使抗肿瘤T细胞免疫反应恢复或增强,或者T细胞受体转导的T细胞免疫疗法靶向大部分的肿瘤特异性抗原从而起到抗肿瘤作用。目前,仅免疫检查点治疗的临床试验表明,非小细胞肺癌中非选择性人群的客观缓解率为10%~20%,仍有大部分患者不能从免疫治疗中获益,故优势人群的筛选仍十分重要。PD-L1是目前最常用的免疫治疗的疗效预测标志物,但仍存在一定的局限性,不能作为常规标志物应用于临床。另有相关研究表明：肿瘤突变负荷、肿瘤浸润淋巴细胞、微卫星不稳定等都是预测免疫治疗疗效的重要生物标志物。本文将对目前临床研究中关于免疫治疗的相关生物标志物新进展作系统综述。     

Prognosis in DNA Mismatch Repair Deficient Colorectal Cancer: are all MSI Tumours Equivalent?

Microsatellite instability (MSI) in colorectal tumours is the hallmark of defective DNA mismatch repair (MMR) and high level MSI can be detected in up to 15% of incident colorectal cancers. MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1 while MSI is almost universal in tumours from HNPCC family members due to germline MMR gene mutation with loss or mutational inactivation of the second copy as a somatic event. There is evidence that tumour MSI is associated with a better outcome than the generality of large bowel malignancy. However, although MSI occurs in both sporadic colorectal cancer and in tumours arising in patients with germline MMR gene mutations, cancer survival should not be considered to be equivalent for these two groups with MSI tumours simply because both exhibit similarities in molecular phenotype. Here, we review the evidence on prognosis in patients with sporadic MSI tumours compared to those who have inherited a germline DNA MMR repair gene defect. In addition, we explore whether there are variables that afford opportunity to distinguish three groups on the basis of MSI status, namely: sporadic MSI tumours; MSI tumours in carriers of germline MMR gene defects; microsatellite stable (MSS) tumours. Differences in prognosis between these three groups is important because it underpins the rationale for surveillance and early identification of tumours in MMR gene carriers, as well as refining understanding of the influence of MSI on cancer progression. Furthermore, we discuss the effect of MSI on the effectiveness of chemotherapy regimens.     

晚期非小细胞肺癌免疫治疗与消融治疗的研究进展

肺癌为原发性支气管肺癌的简称,是起源于气管、支气管黏膜或腺体的最常见的肺部原发性恶性肿瘤。根据组织病理学特点分为非小细胞肺癌（non-small cell lung cancer,NSCLC）和小细胞肺癌。其中,NSCLC又包括鳞癌和腺癌。肺癌发病率高,早诊率低,预后较差。2018年全球统计数据显示,肺癌发病率高居所有癌症发病率的第一位（总病例数的11.6%）,是导致癌症死亡的主要原因（占癌症总死亡人数的18.4%）。高达55%的NSCLC患者诊断时已处于Ⅳ期,无法手术。目前全身治疗仍然是晚期NSCLC的主要治疗方式,免疫治疗俨然成为全身治疗中最重要的一环。但是越来越多的证据表明,对原发肿瘤部位进行局部消融治疗同样可以提高生存率,激活全身免疫系统,助力免疫治疗。自然而然,个体化微创消融治疗结合免疫治疗就成为了一种新兴的治疗策略。本文综述了NSCLC的免疫治疗、消融治疗以及两种方式联合治疗的研究进展。