發(fā)布時間：2019-03-28 16:11

【摘要】：第一部分惡性胸膜間皮瘤基因突變和預(yù)后判斷的初步研究背景與目的:惡性胸膜間皮瘤(malignant pleural mesothelioma,MPM)是一種來源于胸膜間皮細(xì)胞的惡性腫瘤,其以發(fā)病隱匿、早期診斷困難、病情進(jìn)展迅速、預(yù)后差為特點(diǎn)。到目前為止,由于此病的相對少見與可供研究的病例相對缺乏,故人們對其此病的發(fā)病機(jī)理,尤其在其分子、基因?qū)用娴恼J(rèn)知相對匱乏。我們相信通過對MPM驅(qū)動基因的研究有助于我們對此疾病的了解和認(rèn)識。以往的研究揭示出在MPM患者中存在著基因突變現(xiàn)象,包括NF2、BAP1、CDKN2A、P16、CUL1等,但對于后續(xù)的臨床治療的跟蹤描述并不完善。隨著二代測序技術(shù)的出現(xiàn),我們能夠?qū)M織標(biāo)本進(jìn)行進(jìn)一步的大規(guī)模的相關(guān)基因測序,同時還能夠獲得基因突變豐度的數(shù)據(jù)。在我們的研究中,我們收集了18例MPM病理組織切片,進(jìn)行了二代基因測序,并收集了相關(guān)臨床數(shù)據(jù),希望能夠通過基礎(chǔ)技術(shù)與臨床數(shù)據(jù)相結(jié)合,對MPM的基因突變情況及相應(yīng)的臨床特征有更深入的認(rèn)識,并期望能夠最終能轉(zhuǎn)化為對MPM的有效治療手段。方法:我們共收集了從2006.9-2016.3的18例患者的資料,入組標(biāo)準(zhǔn)在為未接受放化療的情況下,手術(shù)切除或CT引導(dǎo)下穿刺獲得標(biāo)本,經(jīng)病理診斷為MPM,并且后續(xù)均接受了4-6個周期標(biāo)準(zhǔn)聯(lián)合化療方案,無其他重大致命性疾病,并剔除了因其他原因致死的患者。我們分別統(tǒng)計了這些病人的性別、初次診斷時的年齡及有無明確的石棉接觸史以及根據(jù)影像學(xué)檢查所做的臨床分期等相關(guān)臨床資料。對于這18例已入組的患者,我們于病理科收集到其病理標(biāo)本,制成石蠟切片,在經(jīng)過基因提取、濃度測定后,對于符合檢測質(zhì)控標(biāo)準(zhǔn)的標(biāo)本基因采用燃石朗康?檢測技術(shù),對56個相關(guān)癌基因進(jìn)行了二代基因測序(附錄1)。檢測的項(xiàng)目包括基因名稱、突變類型、所在染色體編號、突變豐度等。結(jié)果:在本研究中,共收集18例惡性胸膜間皮瘤患者資料。其中,男性11人,女性7人,患者首次確診年齡在48-84歲之間,平均年齡為(63.9±10.0)歲;15例患者訴有明確的石棉接觸暴露史,3例未訴明確的石棉接觸暴露史。然后我們依據(jù)Butchart分期法,根據(jù)患者影像學(xué)資料(包括胸部、腹部增強(qiáng)CT,頭顱核磁和全身骨掃描)對18例患者進(jìn)行臨床分期,其中Ⅰ期患者共6人,Ⅱ期患者共9人,Ⅲ期患者共3人,Ⅳ期患者0人。我們共檢測到發(fā)生基因突變的患者為13人,未檢測到基因突變的共5人。突變的基因共有20種,包括TP53、FGFR2、NF1、IGF1R、KRAS、FGFR3、SMAD4、APC、TSC2、ERBB2、RET、NTRK3、ERBB4、ARAF、NTRK1、ROS1、SMO1、BRCA1、FGFR3、NRAS。突變的類型包括錯義突變、拷貝數(shù)異常等。我們對這18位患者分別進(jìn)行了隨訪,對每一位患者總生存期進(jìn)行了統(tǒng)計。我們發(fā)現(xiàn)基因突變組總生存時間明顯小于未突變組(中位生存期分別為9個月和18個月,p=0.04);在基因突變組中,我們又將TP53基因突變組和TP53野生組進(jìn)行了總生存期分析,同樣發(fā)現(xiàn)TP53突變組總生存期少于野生組(中位生存期分別為4.5個月和11.5個月,p=0.01)。結(jié)論:我們的研究表明,在納入本研究的MPM患者中存在著較高基因突變負(fù)荷,其中TP53基因突變的這部分患者對治療效果反應(yīng)欠佳,預(yù)后較差。但由于可收集病例數(shù)量限制,有待進(jìn)一步病例收集和驗(yàn)證。第二部分肺隔離癥的診斷與外科治療的療效對比目的探討肺隔離癥的診斷方法,并比較傳統(tǒng)開胸手術(shù)與胸腔鏡手術(shù)的療效。方法本文收集了2009-2016年在天津醫(yī)科大學(xué)總醫(yī)院收治并同意行手術(shù)治療的18例患者臨床資料,其中7例行胸腔鏡手術(shù),11例行開胸手術(shù)。比較兩組患者的平均年齡、手術(shù)時長、術(shù)中出血量、術(shù)后引流量、術(shù)后引流天數(shù)、有無術(shù)后并發(fā)癥、術(shù)后住院天數(shù)以及總住院費(fèi)用。結(jié)果胸腔鏡組術(shù)后平均引流時間和住院時間均短于開胸組,差異均有統(tǒng)計學(xué)意義(P0.05)(t值分別為4.553和5.068;P0.05)。但兩組患者的平均年齡、手術(shù)時間、術(shù)中出血量總住院費(fèi)用比較,差異均無統(tǒng)計學(xué)意義(P0.05)。其診斷主要依靠胸部影像學(xué)診斷,特別是胸部增強(qiáng)CT及三維重建血管成像,能夠發(fā)現(xiàn)異常動脈血管影,尤其是多排螺旋CT掃描更能明顯減少三維重建產(chǎn)生的偽影,使圖像更接近于真實(shí),再結(jié)合患者既往病史即可初步診斷。結(jié)論與傳統(tǒng)開胸手術(shù)相比,胸腔鏡手術(shù)的術(shù)后引流時間與術(shù)后住院時間均更短,說明應(yīng)用胸腔鏡治療肺隔離癥同樣安全可靠,而且胸腔鏡治療患者術(shù)后恢復(fù)更快,傷口美觀,值得推廣和應(yīng)用。
[Abstract]:The first part of the study on the mutation and prognosis of malignant pleural mesothelioma (MPM) is a kind of malignant tumor derived from the pleural mesothelioma. The prognosis is a characteristic. So far, since the relatively rare and available cases of this disease are relatively scarce, the pathogenesis of the disease, in particular its molecular and genetic level, is relatively scarce. We believe that the study of the MPM-driven gene will help us to understand and understand this disease. The previous studies have revealed that there is a gene mutation in MPM patients, including NF2, BAP1, CDKN2A, P16, CUL1, etc., but the following description of follow-up clinical treatment is not perfect. With the advent of the second generation sequencing technology, we can carry out a further large-scale related gene sequencing on the tissue specimen, and also can obtain the data of the gene mutation abundance. In our study, we collected 18 MPM pathological tissue sections, carried out second-generation gene sequencing, and collected relevant clinical data. It was hoped to be able to combine the basic technology with clinical data, and to have a better understanding of the gene mutation of the MPM and the corresponding clinical features. And it is desirable to be able to eventually be transformed into an effective means of treatment for mpm. Methods: We collected the data from 18 patients from 2006.9 to 2016.3. The enrollment criteria were obtained by surgical resection or CT-guided puncture under the condition of not receiving the radiotherapy and chemotherapy. The pathological diagnosis was MPM, and 4-6 cycle-standard combined chemotherapy was received in the follow-up. There were no other major fatal diseases and excluded patients who died from other causes. We respectively count on the sex of these patients, the age at the time of the initial diagnosis, the history of exposure to asbestos, and the clinical stage and other relevant clinical data according to the imaging examination. For the 18 enrolled patients, we collected the pathological specimen from the Pathology Section to make the paraffin section. After the gene extraction and concentration measurement, the specimen gene in accordance with the test quality control standard was used to be fired. The second-generation gene sequencing of 56 associated oncogenes was performed using the detection technique (Appendix 1). The items to be tested include gene name, type of mutation, chromosome number, mutation abundance, etc. Results: In this study,18 patients with malignant pleural mesothelioma were collected. Of these,11 males and 7 females, the first diagnosis was between 48 and 84 years, with a mean age of (63.9-10.0) years;15 patients had a clear history of asbestos exposure exposure and 3 did not have a clear history of exposure to asbestos exposure. Then we performed the clinical stage of 18 patients according to the image data of the patient (including the chest, the abdomen enhanced CT, the head core magnetic and the whole body bone scan) according to the Butchart stage method, including 6 patients in stage I,9 in phase II,3 in stage III and 0 in stage 鈪，

本文編號：2449025