本文選題：結(jié)節(jié)性硬化癥 + 血管平滑肌脂肪瘤�。� 參考：《北京協(xié)和醫(yī)學(xué)院》2015年博士論文

【摘要】：第一部分 TSC-RAML患者TSC1/TSC2突變位點(diǎn)檢測(cè)與分目的：明確TSC1/TSC2致病性突變?cè)赥SC-RAML患者中的分布,探索基因型與臨床表型之間的關(guān)系。方法：本組研究對(duì)象共24例,其中,TSC確診患者22例,TSC疑似患者2例；22例TSC確診患者中TSC-RAML患者20例。經(jīng)知情同意,取外周靜脈血3m1,通過(guò)微陣列芯片捕獲,在Illumina HiSeq2500平臺(tái)上進(jìn)行高通量測(cè)序,并將檢測(cè)結(jié)果與LOVD數(shù)據(jù)庫(kù)比對(duì)。結(jié)果：22例TSC確診患者中,TSC1突變4例,TSC2突變15例,未檢測(cè)到突變3例。20例TSC-RAML患者中,TSC突變率85%(17/20), TSC1:TSC2約為1：4.7(3vs 14),TSC1/TSC2突變位點(diǎn)的分布均較為彌散,突變類型以無(wú)義突變(41.2%)及框移突變(35.3%)為主。TSC1及TSC2突變患者中,最小年齡分別為14歲及8歲,RAML的最大直徑分別為10.3cm及20cm, RAML最大直徑≥10cm的例數(shù)分別為1例及8例。通過(guò)與LOVD數(shù)據(jù)庫(kù)比對(duì),檢測(cè)出新發(fā)突變位點(diǎn)8例,TSCl突變1例,TSC2突變7例。3例家系中,先證者RAML最大直徑分別為10、10.3及16cm,而家系成員RAML最大直徑分別為0、0及1cm。結(jié)論：TSC-RAML患者基因突變以TSC2為主,突變位點(diǎn)彌散,以無(wú)義突變及框移突變?yōu)橹�；TSC2突變患者RAML發(fā)病年齡相對(duì)更早,病情相對(duì)更重；TSC-RAML臨床表現(xiàn)個(gè)體化差異較大,但與突變位點(diǎn)及突變類型可能無(wú)關(guān)。第二部分 TSC-RAML組織中nTOR信號(hào)通路激活水平研究目的：研究mTOR信號(hào)通路在TSC-RAML組織中的激活水平。方法：研究組5例TSC-RAM IL標(biāo)本,對(duì)照組10例S-RAML標(biāo)本及10例非腎臟腫瘤患者的正常腎組織標(biāo)本,以免疫組織化學(xué)技術(shù)分別檢測(cè)p-mTOR、p-S6K1及p--4EBP1在上述3組標(biāo)本中的表達(dá)。結(jié)果：p-mTOR在TSC-RAML中呈陽(yáng)性或強(qiáng)陽(yáng)性表達(dá),在S-RAML中呈弱陽(yáng)性表達(dá)；p-S6K1在TSC-RAM L中呈陽(yáng)性表達(dá),在S-RAML中呈弱陽(yáng)性或陰性表達(dá)；p-4EBP1在TSC-RAML中呈陽(yáng)性或弱陽(yáng)性表達(dá),在S-RAML中呈弱陽(yáng)性表達(dá)；p-mTOR、p-S6K1及p-4EBP1在正常腎臟組織中均呈陰性表達(dá)。5例TSC-RAML標(biāo)本中,p-mTOR及p-4EBP1在發(fā)生TSC2突變的3例患者標(biāo)本中的表達(dá)水平相對(duì)高于2例發(fā)生TSC1突變患者的標(biāo)本,而p-S6K1在TSC1突變及TSC2突變患者標(biāo)本的表達(dá)無(wú)明顯差別。結(jié)論：與S-RAML及正常腎臟組織相比,mTOR信號(hào)通路在TSC-RAML組織中的激活程度相對(duì)較高；與TSC1突變相比,mTOR信號(hào)通路在TSC2突變患者的RAML組織中激活程度相對(duì)較高。第三部分 mTOR抑制劑治療TSC-RAML的療效及安全性初步研究目的：評(píng)估m(xù)TOR抑制劑everolimus治療TSC-RAML的療效及安全性。方法：?jiǎn)沃行�、開放、非隨機(jī)臨床研究,研究對(duì)象為臨床確診的TSC-RAML患者,按照納入標(biāo)準(zhǔn)及排除標(biāo)準(zhǔn)嚴(yán)格篩選后,符合標(biāo)準(zhǔn)的患者給予everolimus 10mg/d口服,治療時(shí)間為一年,常規(guī)隨訪時(shí)間為開始服藥后第3、6、12及24個(gè)月,治療期間可根據(jù)患者耐受情況調(diào)整藥物用量。詳細(xì)評(píng)估和記錄患者服藥前基線數(shù)據(jù)及服藥后病情變化,以及治療相關(guān)不良事件。結(jié)果：截止目前,已有5例TSC-RAML患者入組并口服everolimus治療3個(gè)月。與基線數(shù)據(jù)相比,每例患者的RAML均有明顯減小,RAML最大直徑平均縮小3.8(1.5-6)cm,最大直徑平均減小百分比28.2%(15.4%-38%)。5例患者的面部血管纖維瘤也明顯變淡變平。2例患者精神癥狀較前明顯好轉(zhuǎn)�？谇谎�、咳嗽、上呼吸道感染、皮疹為最常見不良事件,其中僅1例3級(jí)不良事件,其余均為1～2級(jí)。結(jié)論：mTOR抑制劑everolimus在TSC-RAML治療中療效顯著,TSC-RAML直徑減小明顯,不良事件以1-2級(jí)多見,安全性及患者耐受性良好。
[Abstract]:The first part of TSC-RAML patients TSC1/TSC2 mutation site detection and purpose: to clarify the distribution of TSC1/TSC2 pathogenic mutation in TSC-RAML patients and explore the relationship between genotype and clinical phenotype. Methods: this group of 24 cases, including 22 cases of TSC confirmed patients, 2 cases of suspected TSC patients, 22 cases of TSC confirmed patients 2 TSC-RAML patients 2 0 cases, after informed consent, take the peripheral venous blood 3M1, through microarray capture, high flux sequencing on the Illumina HiSeq2500 platform, and compare the results with the LOVD database. Results: in 22 cases of TSC confirmed patients, 4 cases of TSC1 mutation, 15 cases of TSC2 mutation, and 3 cases of.20 case TSC-RAML, TSC mutation rate 85% (17/20), T. T SC1:TSC2 is about 1:4.7 (3vs 14), and the distribution of TSC1/TSC2 mutation sites is more diffuse. The mutation type is mainly.TSC1 and TSC2 mutations in patients with.TSC1 and TSC2 mutations, with the minimum age of 14 and 8 years, respectively. The maximum diameter of RAML is 10.3cm and 20cm respectively, and the number of RAML maximum diameter > 10cm is 1 cases and 8 cases respectively. Compared with LOVD database, 8 new mutation sites, 1 cases of TSCl mutation, and 7 TSC2 mutations in.3 families were detected. The maximum RAML diameter of RAML was 10,10.3 and 16cm respectively, while the largest RAML diameter of family members was 0,0 and 1cm. conclusion: TSC-RAML patient gene mutation was mainly TSC2, the mutation site dispersed, with nonsense mutation and frame shift mutation. The age of RAML in TSC2 mutation is relatively early and the condition is relatively heavier; the individual difference of TSC-RAML clinical manifestation is larger, but it may not be related to the mutation site and mutation type. The purpose of the study on the activation level of nTOR signaling pathway in the second part of TSC-RAML tissue is to study the activation level of mTOR signaling pathway in the TSC-RAML tissue. Method: 5 specimens of TSC-RAM IL in the study group, 10 cases of S-RAML specimens in the control group and 10 normal renal tissue specimens of non renal tumor patients, the expression of p-mTOR, p-S6K1 and p--4EBP1 in the above 3 specimens were detected by immunohistochemistry. Results: p-mTOR was positive or strongly positive in TSC-RAML, and was weakly positive in S-RAML. P-S6K1 was positive in TSC-RAM L and expressed weakly positive or negative in S-RAML; p-4EBP1 was positive or weakly positive in TSC-RAML, and expressed weakly positive in S-RAML; p-mTOR, p-S6K1 and p-4EBP1 were negative expression in.5 TSC-RAML specimens in normal kidney tissues, and 3 cases suffered from mutation The expression level in the specimens was higher than that of the 2 cases with TSC1 mutation, while there was no significant difference in the expression of p-S6K1 in TSC1 and TSC2 mutations. Conclusion: compared with S-RAML and normal renal tissue, the activation degree of mTOR signaling pathway in TSC-RAML tissues is relatively higher; mTOR signaling pathway is in T compared with TSC1 mutation. The degree of activation in RAML tissues of patients with SC2 mutation is relatively high. Third the efficacy and safety of mTOR inhibitors for the treatment of TSC-RAML. Objective: To evaluate the efficacy and safety of mTOR inhibitor everolimus in the treatment of TSC-RAML. Methods: single center, open, non randomized clinical study, and clinical diagnosis of TSC-RAML patients. After the inclusion criteria and exclusion criteria were strictly screened, the patients in accordance with the standard were given everolimus 10mg/d oral administration for one year. The routine follow-up time was 3,6,12 and 24 months after the beginning of the medicine. The dosage of the drug could be adjusted according to the patient's tolerance. Results: up to now, 5 patients with TSC-RAML were enrolled and treated with everolimus for 3 months. Compared with the baseline data, the RAML of each case decreased significantly, the maximum diameter of RAML decreased by 3.8 (1.5-6) cm, the maximum diameter decreased by 28.2% (15.4%-38%).5 patient's facial blood. The mental symptoms of.2 patients were obviously better than before. Stomatitis, cough, upper respiratory tract infection, and rash were the most common adverse events, of which only 1 cases were grade 3 and the rest were 1~2. Conclusion: mTOR inhibitor everolimus has a significant effect in the treatment of TSC-RAML, the diameter of TSC-RAML decreases obviously, and the adverse event is obvious. It is more common in class 1-2, safety and patient tolerance.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R737.11

【參考文獻(xiàn)】

相關(guān)期刊論文 前3條

1 李書強(qiáng);李漢忠;張玉石;;結(jié)節(jié)性硬化癥相關(guān)腎錯(cuò)構(gòu)瘤自發(fā)性破裂出血臨床診治分析[J];臨床泌尿外科雜志;2014年12期

2 宿恒川;孫�？�;;PI3K/Akt/mTOR信號(hào)通路及mTOR抑制劑在泌尿系統(tǒng)腫瘤中的研究進(jìn)展[J];上海交通大學(xué)學(xué)報(bào)(醫(yī)學(xué)版);2012年05期

3 朱優(yōu)龍;姜波健;俞繼衛(wèi);;mTOR信號(hào)通路與胃癌復(fù)發(fā)轉(zhuǎn)移關(guān)系的研究進(jìn)展[J];中國(guó)普通外科雜志;2013年04期

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本文編號(hào)：1825803