肾错构瘤TSC1/2基因检测与依维莫司药物干预的研究

郭刚; 蔡伟; 王威; 朱捷; 张旭

doi:10.13201/j.issn.1001-1420.2016.12.012

肾错构瘤TSC1/2基因检测与依维莫司药物干预的研究

- 解放军总医院泌尿外科(北京, 100853)

详细信息

通讯作者: 张旭,E-mail:xuzhang@foxmail.com

中图分类号: R737.11

收稿日期: 2016-04-18

TSC1/2 gene detection and everolimus treatment for renal angiomyolipoma

- Department of Urology, General Hospital of PLA, Beijing, 100853, China

More Information

Corresponding author: ZHANG Xu, E-mail: xuzhang@foxmail.com

Received Date: 18 April 2016

摘要

摘要: 目的:探讨肾错构瘤(AML)患者TSC1/2基因突变情况及依维莫司在结节性硬化(TSC)相关肾错构瘤治疗中的疗效及安全性。方法:2015年1月~2016年3月,对单中心49例肾AML患者进行外周血白细胞基因组TSC1/2基因突变检测。对临床诊断为TSC或存在TSC1/2基因突变的AML患者,如果肿瘤直径超过4 cm且暂时不适应手术者,给予依维莫司(10 mg口服,1次/d)药物治疗,收集患者临床资料及药物治疗的疗效及不良反应,并与未治疗组进行对比。结果:本组患者男15例,女34例,平均年龄35.5(18~56)岁,肾AML平均最大直径9.6(4~30)cm,其中25例患者临床诊断为TSC。基因检测结果示总体突变发生率85.7%(42/49),其中TSC1 29例次,TSC2 22例次,两者同时突变18例,不同外显子突变分布未见明确差异。临床诊断为TSC的患者基因突变率为88.0%(22/25),20例患者仅伴有基因突变而无TSC典型临床表现。共有25例患者接受了依维莫司治疗,1个月疗效评估:客观缓解率88.0%,疾病控制率100%,实体肿瘤直径平均缩小3.6 cm(38.2%);3个月疗效评估:客观缓解率92.0%(23/25),疾病控制率100%,实体瘤直径平均缩小3.8 cm(44.5%)。到达AML最佳缓解的患者比例为36.0%(9/25),未接收药物治疗的对照组为0。而临床诊断者与无症状者疗效差异无统计学意义。伴中心液化坏死或CT强化后CT值仍为负值的瘤体多无显著变化,部分形态已失常的肾脏出现重新塑形表现。主要不良反应包括轻度口腔黏膜炎4例,皮疹3例,泌尿系感染1例。平均随访5.4个月,无患者出现疾病进展。结论:TSC1/2基因的突变已被用于TSC相关肾AML的诊断。尽管部分患者肾AML不具有TSC的典型临床特征,但依维莫司对于临床诊断的TSC患者和单纯依靠基因诊断的患者均显示出良好的临床效果。短期应用安全性良好,可作为TSC相关肾AML的有效非手术治疗选择。
- 错构瘤 /
- 结节性硬化 /
- 突变 /
- 依维莫司
Abstract: Objective: To evaluate the TSC 1/2 gene mutation in renal angiomyolipoma (AML) and the feasibility and safety of everolimus treatment for renal AML.Method: From Jan. 2015 to Mar. 2016, TSC 1/2 gene were detected in 49 renal AML patients. TSC1/2 gene mutation were detected by PCR-SSCP. Twenty-one exon of TSC1 and 41 exon of TSC2 were detected. Twenty-five patients were treated with everolimus (10mg Qd) who had any TSC1/2 mutation or had been diagnosed as tuberous sclerosis complex (TSC), the biggest diameter of tumor was longer than 4 cm and refused operation. Toxicities and tumor responses were monitored.Result: The study included 15 male and 34 female patients, whose average age was 35.5 (range, 18-56) years old. The average max diameter of tumor was 9.6 (range, 4-30) cm and 25 patients were diagnosed with TSC by clinical diagnostic criteria. The result of TSC 1/2 gene detection: mutation rate was 85.7% (42/49) in all and 88.0% (22/25) in TSC group, including TSC1 mutation in 29 cases, TSC2 mutation in 22 cases and TSC1/TSC2 mutation in 18 cases. There was no significant difference in the mutation rate of any exon. Twenty-five patients received everolimus (10mg Qd) treatment. One month result: objective response rate (ORR) was 88.0%, disease control rate was 100%, the average diameter reducing was 3.6 cm (38.2%). Three months result: ORR was 92.0%, disease control rate was 100%, the average diameter reducing was 3.8 cm (44.5%). AML best response rate (total tumor volume shrinkage rate ≥ 50%) was 36.0% (9/25) for everolimus compared with 0% (0/24) for placebo. The change was not obvious in tumor with liquefaction or necrosis in centre and negative CT value. Some abnormal kidney appeared to remodel. The main adverse reaction was oral mucositis in four cases, rash in three cases and urinary[CM(45] system infection in one case. The average follow-up period was 5.4 months, and no tumor progress was found.Conclusion: The TSC 1/2 gene mutation in renal AML had a close correlation with TSC. Everolimus therapy can impact the size and density of the primary tumor and appears safe and feasible in renal AML patients with TSC1/2 mutation, even the patients did not accompanied by TSC. Short-term application security is good, so everolimus is an effective non-surgical treatment option for TSC associated with renal AML.
- angiomyolipoma /
- tuberous sclerosis complex /
- mutation /
- everolimus

HTML全文

参考文献(13)

[1]	Curatolo P,Bombardieri R,Jozwiak S.Tuberous sclerosis[J].Lancet,2008,372(9639):657-668.
[2]	Henry J,Baskin Jr.The pathogenesis and imaging of the tuberous sclerosis complex[J].Pediatr Radiol,2008,38(9):936-952.
[3]	郭刚,蔡伟,高江平,等.新辅助分子靶向治疗在肾细胞癌患者治疗中的临床应用研究[J].微创泌尿外科杂志,2013,2(5):347-350.
[4]	Therasse P,Arbuck S G,Elizabeth E A,et al,New guidelines to evaluate the response to treatment in solid tumors.European Organization for Research and Treatment of Cancer,National Cancer Institute of the United States,National Cancer Institute of Canada[J].J Natl Cancer Inst,2000,92(3):205-216.
[5]	Halpenny D,Snow A,McNeill G,et al.The radiological diagnosis and treatment of renal angiomyolipomacurrent status[J].Clin Radiol,2010,65(2):99-108.
[6]	Nelson C P,Sanda M G.Contemporary diagnosis and management of renal angiomyolipoma[J].J Urol,2002,168(4 Pt 1):1315-1325.
[7]	Soulen M C,Faykus M H Jr,Shlansky-Goldberg R D,et al.Elective embolization for prevention of hemorrhage from renal angiomyolipomas[J].J Vasc Interv Radiol,1994,5(4):587-591.
[8]	Yamakado K,Tanaka N,Nakagawa T,et al.Renal angiomyolipoma:relationships between tumor size,aneurysm formation,and rupture[J].Radiology,2002,225(1):78-82.
[9]	Siroky B J,Yin H,Bissler J J.Clinical and molecular insights into tuberous sclerosis complex renal disease[J].Pediatr Nephrol,2011,26(6):839-852.
[10]	Huang J,Manning B D.The TSC1-TSC2 complex:a molecular switchboard controlling cell growth[J].Biochem J,2008,412(2):179-190.
[11]	Staehler M,Sauter M,Helek A,et al.Nephron-sparing resection of angiomyolipoma after sirolimus pretreatment in patients with tuberous sclerosis[J].Int Urol Nephrol,2012,44(6):1657-1661.
[12]	Bissler J J,Kingswood J C,Radzikowska E,et al.Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis(EXIST-2):a multicentre,randomised,double-blind,placebo-controlled trial[J].Lancet,2013,381(9869):817-824.
[13]	Krueger D A,Northrup H.Tuberous selerosis complex surveillance and management:recommendations of the 2012international tuberous sclerosis complex consensus conference[J].Pediatr Neurol,2013,49(4):255-226.