甲状腺髓样癌的超声特征分析

目的:总结甲状腺髓样癌（medullary thyroid cancer, MTC）的超声特征并分析其对MTC诊断的临床价值。方法:回顾性分析2013年4月至2018年11月郑州大学第一附属医院甲状腺外科收治并经手术确诊的91例MTC患者（共103个结节）,其中男36例,女55例,收集其术前超声影像学特征及血清降钙素水...     

Leflunomide suppresses growth in human medullary thyroid cancer cells

Background

Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the calcitonin-secreting parafollicular cells of the thyroid gland. Leflunomide (LFN) is a disease-modifying antirheumatic drug approved for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide has been identified as a potential anticancer drug. In this study we investigated the ability of LFN to similarly act as an anticancer drug by examining the effects of LFN treatment on MTC cells.

Methods

Human MTC-TT cells were treated with LFN (25–150 μmol/L) and Western blotting was performed to measure levels of neuroendocrine markers. MTT assays were used to assess the effect of LFN treatment on cellular proliferation.

Results

LFN treatment downregulated neuroendocrine markers ASCL1 and chromogranin A. Importantly, LFN significantly inhibited the growth of MTC cells in a dose-dependent manner.

Conclusions

Treatment with LFN decreased neuroendocrine tumor marker expression and reduced the cell proliferation in MTC cells. As the safety of LFN in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC may be warranted.     

甲状腺髓样癌临床诊疗方案分析

目的:探讨影响甲状腺髓样癌（medullary thyroid carcinoma,MTC）治疗方案制订与转归的关键要素。方法:回顾性分析2007年4月至2020年3月湖南省人民医院乳甲外科收治的23例MTC患者病例资料、典型病例的临床特点及生存随访结果,结合ATA等指南对MTC治疗方案和转归进行分析。结果:23例MT...     

Influence of lymph node metastases on survival in pediatric medullary thyroid cancer

Purpose

Lymph node metastases (LNM) from medullary thyroid cancer (MTC) are common in adults and are a poor prognostic factor. Less is known about LNM in children, who often have hereditary forms of MTC. Guidelines recommend prophylactic thyroidectomy in early childhood, but randomized prospective trials are not feasible. We hypothesized that LNM is associated with poor prognosis in children.

Methods

Patients with MTC 21 years or younger from the National Cancer Data Base from 1985 to 2007 were studied. Multivariable logistic regression was used to identify factors associated with lymph node evaluation. Survival was estimated using the Kaplan-Meier method.

Results

Of 430 patients, 276 (64.2%) had nodal evaluation with LNM present in 121 (28.1%). Older patients, those with tumors larger than 2 cm, and those with involved margins were more likely to have LNM (all P < .05). Patients undergoing total thyroidectomy, those with involved margins, and older patients were more likely to undergo lymph node evaluation after controlling for patient, tumor, and hospital factors (all P < .05). Over time an increasing number of patients with MTC have undergone total thyroidectomy. Patients 16 to 21 years of age had lower 10-year overall survival compared to patients 0 to 15 years old (88.7% vs 98.1%, P = .005). Lymph node metastases were also associated with decreased 10-year overall survival (84.4% vs 100%, P < .001).

Conclusions

In pediatric MTC, LNM predict poorer overall survival. Adequate lymph node assessment can provide valuable prognostic information for the pediatric MTC patient. Lymph node assessment should be considered for older pediatric patients undergoing surgery for hereditary MTC or biopsy confirmed MTC.     

Increased incidence of medullary thyroid carcinoma in patients treated for Hirschsprung's disease

Background/Purpose

Mutations of the RET proto-oncogene are responsible for the development of inherited multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma (MTC). RET mutations are encountered in patients with Hirschsprung's disease (HD). We hypothesized that the incidence of MTC is increased in patients with HD.

Methods

Patients treated for HD at the Children's Hospital, University of Helsinki, during 1939 and 1986 were surveyed for cancer using the population-based countrywide Finnish Cancer Registry from 1967 to 2000. The number of observed cancer cases and that of person-years at risk were counted. The expected number of cancer cases was extrapolated from national cancer incidence rates. To calculate the standardized incidence ratios (SIRs), the observed number of cancer cases was divided by the expected number of cancer cases.

Results

One hundred fifty-six patients (132 males) with HD were identified. The mean length of patient follow-up was 30.9 years. Seven cases of cancer were observed (SIR, 3.5; 95% CI, 1.4-7.3). Two patients developed MTC (SIR, 550; 95% CI, 67-2000). The cases of MTC occurred in male patients at the ages of 34 and 37 years. No patient developed pheochromocytoma.

Conclusions

In this study, we report for the first time an increased risk of MTC occurring in patients treated for HD. The increased risk may be attributed to mutations of the RET proto-oncogene shared by MTC and HD. These findings warrant further studies concerning screening for MTC-type RET mutations in patients with HD.     

Synchronous multifocal medullary and papillary thyroid microcarcinoma detected by elastography

INTRODUCTION

A few cases of concomitant medullary and papillary carcinoma in the same thyroid nodule have been described in the literature. However, the presence of multiple foci of both types of malignancy in the same gland is very rare.

PRESENTATION OF CASE

A 39 year-old female with multiple thyroid nodules, elevated serum calcitonin levels and elastographic findings suggestive of thyroid malignancy, underwent total thyroidectomy and central neck dissection. Histology revealed the presence of one focus of medullary and one focus of papillary carcinoma on each thyroid lobe. Subsequently, the patient underwent treatment with radioactive iodine.

DISCUSSION

This is the third case of synchronous multifocal medullary and papillary thyroid carcinoma reported in the literature. Several theories for the simultaneous development of these malignant entities have been proposed.

CONCLUSION

Ultrasound elastography can be a useful, noninvasive tool in the assessment of thyroid nodules.     

Measures of survival benefit in cancer drug development and their limitations

BackgroundA variety of measures of survival benefit are available to an investigator comparing outcomes across the various arms of a drug development trial. In this article, we systematically review the most common measures of comparative survival used in published studies.MaterialsWe distinguish between relative and absolute survival differences, and measures of instantaneous and cumulative risk. We consider settings in which the end point is overall survival as well as those in which disease-specific end points are of primary interest.ResultsWe note that different measures capture different aspects of benefit, and some may be more reliable than others or more representative of clinically relevant benefit.ConclusionsRather than simply using procedures that have become standard, analyses should identify the most clinically relevant measures of effect and apply procedures that reliably estimate these.     

甲状腺髓样癌的诊断与治疗

甲状腺髓样癌(MTC)来源于滤泡旁C细胞,占甲状腺癌的5%～10%,其中25%具有遗传性.MTC能够较早的出现淋巴结及远处转移,故早期诊断及治疗尤为重要.本文描述了MTC实验室及影像学等方面的主要表现,并对最新的治疗手段及预防性措施进行了阐述.     

Medullary carcinoma of the thyroid: Prognostic factors and treatment recommendations

Background: Because medullary thyroid carcinoma accounts for only 7% of all thyroid malignancies, data to support treatment strategies are scarce. Methods: We retrospectively reviewed treatment and outcome in 34 patients with MTC treated at Roswell Park between 1961 and 1995. Univariate analysis was performed using the variables age, sex, tumor size, N stage, and M stage. Results: Median survival was 4.7 years, with 51% and 32% of patients alive at 5 and 15 years, respectively. Nodal metastases were seen in 76% and distant metastases in 67% of all patients. More than 60% of the patients with nodal metastases survived longer than 10 years. Once diagnosed with distant metastases, 90% of the patients died within 5 years. Local failure rate with lobectomy was 44%, compared to 10% after total thyroidectomy (P<.02). Age, extrathyroid extension, and M stage portend a poor outcome. Nodal status had no statistically significant impact on survival. Conclusion: Survival with tumors confined to the thyroid gland is independent of nodal status. Long-term survival in patients with distant metastases is rare. This study underscores the role of total thyroidectomy in the initial treatment and the need to develop effective adjuvant therapy for MTC.Presented at the 50th Annual Cancer Symposium of The Society of Surgical Oncology, Chicago, Illinois, March 20–23, 1997.     

Impact of older age on the long-term survival in living-donor liver transplantation: A propensity score matching analysis

BackgroundPrevalence of the end-stage liver disease in the elderly patients indicating a liver transplantation (LT) has been increasing. There is no universally accepted upper age limit for LT candidates but the functional status of older patients is important in pre-LT evaluation. This study aimed to examine the impact of older age on survival after living donor liver transplantation (LDLT).MethodA total of 171 LDLT recipients were assessed in two groups: age ≥65 and < 65. To eliminate selection bias propensity score matching (PSM) was performed, and 56 of 171 recipients were included in this study.ResultsThere were 20 recipients in the older group and 36 in the younger. The 1-, 3-, and 5-year survival rates were 65.0%, 60.0%, and 60.0% in group 1; 88.9%, 84.7%, and 71.4% in group 2, respectively. The 1-year survival was significantly lower in the older recipients; however, overall survival rates were similar between the groups. Of the 56 recipients, 15 (27%) deaths were observed in overall, and 11 (20%) in 1-year follow-up. The univariate regression analysis after PSM revealed that MELD score affected 1- year survival and the multivariate analysis revealed that age ≥65 years and MELD score were the predictors of 1-year survival.ConclusionAt first sight, before PSM, survival appeared to be worse for older recipients. However, we have shown that there were confounding effects of clinical variables in the preliminary evaluation. After the elimination of this bias with PSM, This study highlights that older recipients have similar outcomes as youngers in LDLT for long-term survival.     

Repeat mediastinal lymph-node dissection for palliation in advanced medullary thyroid carcinoma

Background: In medullary thyroid carcinoma (MTC), the effectiveness of repeat mediastinal lymph-node dissection for palliation of specific symptoms caused by discrete mediastinal lesions is unclear in non-bulky tumor disease. Methods: Between November 1994 and August 1998, five symptomatic MTC patients with radiologic evidence of mediastinal tumor and elevated calcitonin levels were subjected to repeat mediastinal lymph-node dissection. Results: At reoperation, an average of 7 of 25 (28%) removed cervical and 5 of 9 (56%) dissected mediastinal lymph-nodes were positive on histopathology. A substantial fraction of these were excised from anatomical regions inaccessible through a purely cervical or partial sternotomy approach. Clinical symptoms were effectively palliated in all five patients. Basal serum calcitonin levels fell only moderately, suggesting distant micrometastases. Mortality was nil. Morbidity encompassed two cases of hypoparathyroidism and a lymphatic fistula that closed spontaneously on total parenteral nutrition. One patient later required cervical reoperation deferred at secondary surgery. All five patients have since remained free of cervical and mediastinal tumor at a mean follow-up of 15 months. Conclusions: In mediastinal lymph-node metastases, repeat lymph-node dissection is warranted for palliation of discrete anatomic lesions inaccessible through a cervical approach. Received: 30 September 1998 in revised form: 15 January 1999 Accepted: 8 February 1999     

血管内皮细胞生长因子受体在甲状腺髓样癌中的高表达

目的:评估血管内皮细胞生长因子受体1(VEGFR-1)和VEGFR-2在甲状腺髓样癌(medullary thyroidcarcinoma,MTC)组织的表达,探讨其与MTC病人临床数据间的关系。方法:用免疫组化技术评估24例MTC病人的石蜡包埋组织VEGFR-1和VEGFR-2的表达,回顾收集病人的临床数据。结果:24例病人平均年龄(44.9±14.1)岁,8例(33.3%)为遗传性,其中6例为多发性内分泌肿瘤(multiple endocrine neoplasia,MEN)-2A,2例为MEN-2B。VEG-FR-1免疫组化染色阳性率为91.7%(22/24),VEGFR-2为87.5%(21/24)。年龄与VEGFR-2染色强度为正相关(r=0.609,P=0.002)。VEGFR-2与肿瘤分期(肿瘤淋巴结转移)、肿瘤大小、病人血清CEA及降钙素在手术前后的相对降幅间没有关联。然而,VEGFR-1与肿瘤分期呈负相关(r=-0.660,P=0.0005),而与MTC病人血清CEA及降钙素在手术前后的相对降幅之间均呈正相关(CEA:r=0.869,降钙素:r=0.849,P0.05)。结论:VEGFR-1和VEGFR-2在MTC病人中高表达,且可能参与肿瘤的进展。     

A novel Czech kindred with familial medullary thyroid carcinoma and Hirschsprung's disease

Purpose

The RET proto-oncogene is involved in neural crest disorders. Activating germline mutations in the RET proto-oncogene cause the development of familial medullary thyroid carcinoma (FMTC) or medullary thyroid carcinoma (MTC) as a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. Inactivating germline mutations in the RET proto-oncogene are detected in Hirschsprung's disease (HSCR). Only in a very small number of families are these 2 diseases expressed together.

Methods

This study presents a novel Czech kindred with FMTC-HSCR phenotype. Two family members (mother and daughter) were tested for RET germline mutations in exons 10, 11, 13, 14, 15, and 16.

Results

Direct fluorescent sequencing of genomic DNA revealed a heterozygous mutation in the RET proto-oncogene in exon 10 at codon C609Y in both persons tested. This family was reclassified, thanks to genetic screening from the apparently sporadic MTC-HSCR to FMTC-HSCR.

Conclusion

The germline mutation was detected because of the systematic genetic screening of the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR and MTC in other family members. This family could be added to the small worldwide cohort of families with MEN2A/FMTC-HSCR.     

甲状旁腺素对人甲状腺髓样癌细胞增殖和凋亡的影响

目的探讨甲状旁腺素对人甲状腺髓样癌细胞体外增殖抑制及凋亡作用。方法体外培养甲状腺髓样癌细胞株,经甲状旁腺素和甲状旁腺素受体单抗干预处理后,倒置相差显微镜下观察细胞生长状况,流式细胞仪检测细胞凋亡。结果倒置相差显微镜下细胞变化明显,各浓度的甲状旁腺素和甲状旁腺素受体单抗均分别能有效地抑制甲状腺髓样癌细胞增殖、诱导细胞凋亡,凋亡作用呈时间和浓度依赖。当甲状旁腺素浓度为2．0μmol／L、甲状旁腺素受体单抗浓度为1．0μmol／L时,对细胞凋亡作用显著（P〈0．05）,凋亡率分别为13．24％及20．78％。结论甲状旁腺素对人甲状腺髓样癌细胞增殖有抑制作用并能诱导其凋亡。     

Role of RET codonic mutations in the surgical management of medullary thyroid carcinoma in pediatric age multiple endocrine neoplasm type 2 syndromes

Purpose

Hereditary medullary thyroid carcinoma (MTC) therapy is surgical resection. Because the genetic screening was available, the early diagnosis of the disease has been possible. The purpose of this study was to evaluate the role of the genetic test in the management of these children and to draw some information about the surgical timing.

Methods

Thirteen patients underwent total thyroidectomy at our institute between 1995 and 2007. Seven patients underwent a curative thyroidectomy, and 6 patients underwent a prophylactic thyroidectomy. Two patients were operated with a minimally invasive video-assisted technique. We studied the following parameters: age, risk level associated to the RET gene mutations, aim of surgery (curative or prophylactic), tumor histopathologic features, lymph node involvement, and distal metastases.

Results

We found a statistical association between cancer maximum diameter and some parameters analyzed: age of patients, aim of surgery, single or multifocal MTC, and number of organs involved by distal metastases. Cancer diameter at the moment of diagnosis seems to increase according to the aggressiveness of RET gene mutation found.

Conclusions

The best strategy to cure MTC is to prevent it. Genetic screening could be a fundamental tool in the management of multiple endocrine neoplasm type 2 children. An improvement of scientific knowledge regarding RET gene alterations and an early and appropriate use of genetic tests could allow a better understanding of the correct surgical timing and a wider use of less aggressive surgical procedures.     

Can the early reduction of tumour markers predict outcome in surgically treated sporadic medullary thyroid carcinoma?

BACKGROUND AND AIMS: Patients with sporadic medullary thyroid carcinoma (MTC) have a variable clinical course. Our aim was to analyse the reduction of tumour markers after thyroidectomy with meticulous dissection and relate it to clinical outcome. MATERIALS AND METHODS: Twenty consecutive patients with palpable sporadic MTC underwent thyroidectomy with central and uni- or bilateral modified radical neck dissection; three were subjected to mediastinal dissection. Basal (b-) and stimulated (s-) calcitonin (CT) and carcinoembryonic antigen (CEA)-levels were measured before and 6-8 weeks after primary surgery, and the reduction of these tumour markers was determined. RESULTS: Median CT (b- and s-) were markedly reduced after surgery (98.5% and 99.1%, respectively), and CEA decreased 11 times. CT (b-) fell >99% in seven patients after surgery; in these and four additional patients, CT (s-) showed a similar reduction. During follow-up (median 52.5 months), two patients (stages IV B and C) died of MTC; they had <95% reduction of CT. Four patients (stage IV A) are alive with verified metastases. Eight patients (one stage III, seven stage IV A) are alive with hypercalcitoninemia. Five stages I-III patients and one stage IV A patient are disease-free. CONCLUSIONS: Thyroidectomy and meticulous dissection caused a pronounced reduction of tumour markers. A postoperative reduction of CT (s-) >/=97% seems to be associated with less aggressive clinical course, while CEA had lower predictive value.     

血清癌胚抗原预测可手术甲状腺髓样癌淋巴结转移的临床价值

目的探讨血清癌胚抗原(carcinoembryonic antigen,CEA)在预测可手术甲状腺髓样癌(medullary thyroid carcinoma,MTC)淋巴结转移中的临床应用价值。方法选取2009年1月至2019年2月在中国科学院大学附属肿瘤医院(浙江省肿瘤医院)头颈肿瘤外科和杭州市第一人民医院肿瘤外科接受手术的140例MTC,回顾性分析血清CEA和140例可手术MTC淋巴结转移的相关性,计算血清CEA预测可手术MTC总体、中央区、侧颈和上纵隔淋巴结转移的受试者工作特征曲线下面积(area under the curve,AUC)、敏感性、特异性,以评估血清CEA表达水平预测可手术MTC淋巴结转移的临床价值。结果140例可手术MTC中有108例血清CEA呈阳性表达,阳性率77.14%。伴淋巴结转移的MTC患者血清CEA显著高于无淋巴结转移者(P<0.001),且血清CEA与淋巴结转移数目正相关(P<0.001)。血清CEA预测可手术MTC总体、中央区、侧颈和上纵隔淋巴结转移的AUC分别为0.773、0.768、0.827及0.847。以约登指数最大时,分别取界值为6.58、11.43、15.74、30.45 ng/ml,血清CEA预测总体、中央区、侧颈和上纵隔淋巴结转移的敏感性分别为88.46%、81.43%、85.00%、95.00%,特异性分别为56.45%、60.00%、71.25%、69.17%。结论血清CEA在可手术MTC中有较高的阳性率,其表达水平在评估MTC淋巴结转移方面具有重要的临床价值。