發(fā)布時(shí)間：2018-08-15 17:20

【摘要】：第一部分 內(nèi)鏡下黏膜切除術(shù)與內(nèi)鏡黏膜下剝離術(shù)在治療食管胃交界早期病變(Siewert Ⅱ型)的回顧性研究前言：隨著內(nèi)鏡治療技術(shù)的發(fā)展,內(nèi)鏡下治療食管胃交界的早期病變已成為了一種選擇。據(jù)了解,到目前為止尚無(wú)文獻(xiàn)報(bào)道內(nèi)鏡下黏膜切除術(shù)(EMR)和內(nèi)鏡黏膜下剝離術(shù)(ESD)在治療食管胃交界早期病變的單中心臨床對(duì)照研究。為此,我們進(jìn)行了一項(xiàng)回顧性研究,目的就是分析比較EMR與ESD在治療食管胃交界早期病變方面的可行性、安全性和有效性。材料和方法：本項(xiàng)研究包括130例接受內(nèi)鏡治療的食管胃交界早期病變患者,其中52例接受EMR、78例接受ESD。內(nèi)鏡操作時(shí)間、并發(fā)癥、整塊切除率、完整切除率和復(fù)發(fā)率是這項(xiàng)研究的主要指標(biāo)。結(jié)果： EMR組和ESD組在年齡、性別構(gòu)成、病變大小、病理分型、內(nèi)鏡分型和腫瘤浸潤(rùn)深度方面并沒(méi)有明顯的統(tǒng)計(jì)學(xué)差異(P0.05)。ESD組較EMR組手術(shù)操作時(shí)間更長(zhǎng)(64.4±33.9 min vs 22.1±8.0 min;P0.05)。ESD組較EMR組更易發(fā)生并發(fā)癥(16.7% vs 3.8%；P0.05),并發(fā)癥包括出血(7.7% vs 3.8%),穿孔(5.1%vs 0%)和術(shù)后狹窄(5.1% vs 0%)。ESD組較EMR組有更高的整塊切除率和完整切除率(98.7%和92.3% vs 23.1%和23.1%；P0.05)。ESD組較EMR組復(fù)發(fā)率較低(0% vs 7.7%；P0.05)。結(jié)論：在治療食管胃交界早期病變方面,ESD較EMR存在更高的技術(shù)難度,但是ESD在整塊切除率和完整切除率方面明顯高于EMR,同時(shí)ESD隨訪結(jié)果顯示其復(fù)發(fā)率較低。因此,上述試驗(yàn)結(jié)果顯示內(nèi)鏡黏膜下剝離術(shù)和內(nèi)鏡下黏膜切除術(shù)在治療食管胃交界早期病變的明顯不同,內(nèi)鏡黏膜下剝離術(shù)優(yōu)于內(nèi)鏡下黏膜切除術(shù),特別是對(duì)于病變直徑超過(guò)14mm的病變。當(dāng)然,如果內(nèi)鏡下黏膜切除術(shù)可以達(dá)到整塊切除的標(biāo)準(zhǔn),仍不失是治療食管胃交界早期病變的一個(gè)選擇。第二部分海綿拉網(wǎng)膠囊(CytospongeTM)聯(lián)合p53免疫組織化學(xué)染色篩查早期食管癌及癌前病變中的應(yīng)用前言：我國(guó)是食管鱗癌的最高發(fā)的國(guó)家之一,在食管癌的高發(fā)區(qū)已經(jīng)開(kāi)展了應(yīng)用內(nèi)鏡下碘染色進(jìn)行篩查的項(xiàng)目。鑒于在全部高危人群開(kāi)展以?xún)?nèi)鏡為主的篩查項(xiàng)目在成本、技術(shù)和風(fēng)險(xiǎn)上都存在一定的問(wèn)題。因此,我們需要一種簡(jiǎn)單、成本低的方法作為初篩工具。為此,我們?cè)谑彻馨└甙l(fā)區(qū)開(kāi)展了海綿拉網(wǎng)膠囊(CytospongeTM)聯(lián)合p53免疫組織化學(xué)染色篩查早期食管癌及癌前病變這項(xiàng)前瞻性隊(duì)列研究,以判斷其在篩查早期食管癌及癌前病變中的可行性、安全性和有效性。材料和方法：87例受試者年齡的中位數(shù)為58歲(24～70歲),包括52名男性受試者(59.8%)和35名女性受試者(40.2%)。所有受試者先進(jìn)行拉網(wǎng)檢查,填寫(xiě)調(diào)查問(wèn)卷后,進(jìn)行內(nèi)鏡檢查或接受內(nèi)鏡下治療。結(jié)果：根據(jù)活檢或內(nèi)鏡治療術(shù)后的病理診斷,本試驗(yàn)共包括28例正常食管、11例食管炎、12例輕度不典型增生(LGIN)、13例中度不典型增生(MGIN)、14例重度不典型增生(HGIN)和9例早期食管癌(EESCC)。以異型的鱗狀細(xì)胞(Atypia)作為標(biāo)志物,海綿拉網(wǎng)膠囊(CytospongeTM)篩查食管鱗狀上皮輕度不典型增生(LGIN)、中度不典型增生(MGIN)的敏感度均低于10%,但在篩查食管重度不典型增生和早期食管鱗狀細(xì)胞癌方面的敏感度可以達(dá)到約70%、特異度為93.8%。而以p53陽(yáng)性的異型的鱗狀細(xì)胞(p53+ Atypia)作為標(biāo)志物,海綿拉網(wǎng)膠囊篩查篩查食管鱗狀上皮重度不典型增生(HGIN)和早期食管鱗狀細(xì)胞癌(EESCC)的敏感度僅為26.1%、特異度為98.4%。結(jié)論：海綿拉網(wǎng)膠囊(CytospongeTM)是一種簡(jiǎn)單、安全、易于接受的篩查工具,將其應(yīng)用于篩查食管重度不典型增生和早期食管癌的敏感度可以達(dá)到約70%,但是以p53作為生物標(biāo)志物以提高敏感度的預(yù)期沒(méi)有達(dá)到。第三部分頭頸部鱗狀細(xì)胞癌伴發(fā)食管鱗狀細(xì)胞癌的相關(guān)研究前言：頭頸部鱗狀細(xì)胞癌(HNSCC)患者,特別是發(fā)生在口腔、口咽及下咽者,經(jīng)常會(huì)伴發(fā)食管鱗狀細(xì)胞癌(ESCC).HNSCC伴發(fā)ESCC通常用“區(qū)域癌化”進(jìn)行闡釋。多原發(fā)腫瘤需要多種治療措施相結(jié)合,但是對(duì)于異時(shí)多原發(fā)癌,對(duì)先發(fā)的腫瘤的治療措施有可能會(huì)影響第二原發(fā)腫瘤的治療。材料和方法：8例食管癌伴發(fā)早期下咽癌的患者接受了內(nèi)鏡黏膜下剝離術(shù),其中有2例患者下咽部病變?yōu)殡p原發(fā)癌,即共10處病變。3例頭頸部鱗癌患者因既往接受過(guò)放化療或外科手術(shù)造成食管入口或頸段食管狹窄,導(dǎo)致普通內(nèi)鏡無(wú)法通過(guò)。這3例患者接受了經(jīng)腹入路早期食管癌內(nèi)鏡下黏膜切除術(shù)。另外,我們收集了8例頭頸部鱗癌伴發(fā)食管鱗癌患者的腫瘤組織標(biāo)本、配對(duì)癌旁標(biāo)本及血液標(biāo)本進(jìn)行二代基因檢測(cè)。結(jié)果：8例食管癌伴發(fā)早期下咽癌的患者(共10處病變),下咽處病變均接受內(nèi)鏡黏膜下剝離術(shù),所有病例均達(dá)到了整塊切除,整塊切除率為100%。在這組病例中,有2例病變側(cè)切緣燒灼處存在重度不典型增生,因此8處病變符合完整切除,完整切除率為80%；所有病例均未發(fā)生并發(fā)癥且隨訪期間無(wú)復(fù)發(fā)發(fā)生。3例頭頸部鱗癌患者因既往接受過(guò)放化療或外科手術(shù)造成食管入口或頸段食管管腔狹窄,導(dǎo)致普通內(nèi)鏡無(wú)法通過(guò),此3例患者均成功接受了經(jīng)腹入路早期食管癌內(nèi)鏡下黏膜切除術(shù)。在這組病例中,除1例發(fā)生術(shù)后食管狹窄,未發(fā)生其他并發(fā)癥且隨訪期間未發(fā)現(xiàn)局部復(fù)發(fā)。8例頭頸部鱗癌合并食管鱗癌標(biāo)本基因檢測(cè)的結(jié)果為：1、腫瘤組織的基因及其相應(yīng)的外周血及血漿的基因顯示出高度的一致性,同時(shí)血漿里游離的基因也顯示出一定的突變位點(diǎn),雖然同相對(duì)應(yīng)的腫瘤組織比起來(lái),這種突變位點(diǎn)要少一些,但是它卻遠(yuǎn)遠(yuǎn)超過(guò)了相應(yīng)外周血細(xì)胞的突變位點(diǎn)；2、5個(gè)突變位點(diǎn)(EGFR 8-p.E330*/13-p.P512L;ERBB212-p.L485/20-p.D821N;NRAS 5- p.K170N;PIK3CA 11-p.V580E,14- p.H701L;RB12- p.R46S/6- p.L199*)僅出現(xiàn)在同一個(gè)患者的頭頸部鱗癌組織中,但未出現(xiàn)在食管癌組織中。結(jié)論：在治療食管癌伴發(fā)早期下咽癌中,內(nèi)鏡黏膜下剝離術(shù)是一項(xiàng)既安全有效又侵入性較小的治療措施。同時(shí),對(duì)于既往因頭頸部鱗癌接受治療導(dǎo)致內(nèi)鏡不能對(duì)早期食管癌進(jìn)行治療的患者可以采用經(jīng)腹入路早期食管癌內(nèi)鏡下黏膜切除術(shù)。通過(guò)對(duì)頭頸部鱗癌伴發(fā)食管鱗癌基因檢測(cè)研究發(fā)現(xiàn),有可能利用個(gè)體血漿中脫落的DNA替代腫瘤組織本身進(jìn)行基因位點(diǎn)突變檢測(cè),另外,食管癌與下咽癌在腫瘤基因突變位點(diǎn)上的存在差異,這可以幫助判斷腫瘤是否為轉(zhuǎn)移或雙原發(fā),同時(shí)指導(dǎo)下一步的精確的靶向治療。
[Abstract]:Part I. Retrospective study of endoscopic mucosal resection and submucosal dissection in the treatment of early esophagogastric junction lesions (Siewert type II). Preface: With the development of endoscopic treatment technology, endoscopic treatment of early esophagogastric junction lesions has become a choice. It is understood that no literature has reported so far. We conducted a retrospective study to compare the feasibility, safety and efficacy of endoscopic submucosal dissection (ESD) and mucosal resection (EMR) in the treatment of early esophagogastric junction lesions. The study included 130 patients with early esophagogastric junction lesions treated with endoscopy, 52 with EMR, 78 with ESD. Endoscopic operation time, complications, block resection rate, complete resection rate and recurrence rate were the main indicators of this study. There was no significant difference between ESD group and EMR group (P 0.05). The operation time of ESD group was longer than that of EMR group (64.4+33.9 min vs 22.1+8.0 min; P 0.05). Complications in ESD group were more likely to occur (16.7% vs 3.8%; P 0.05), including bleeding (7.7% vs 3.8%), perforation (5.1% vs 0%) and postoperative stenosis (5.1% vs 0%). ESD group had a lower recurrence rate than EMR group (0% vs 7.7%; P 0.05). Conclusion: ESD has a higher technical difficulty than EMR in the treatment of early esophagogastric junction lesions, but ESD has a higher overall resection rate and complete resection rate than EMR. The ESD follow-up results also showed a low recurrence rate. Therefore, these results suggest that endoscopic submucosal dissection and endoscopic mucosal resection are significantly different in the treatment of early lesions at the esophagogastric junction. Endoscopic submucosal dissection is superior to endoscopic mucosal resection, especially for lesions larger than 14 mm in diameter. Endoscopic mucosal resection can reach the standard of block resection, but it is still a choice for the treatment of early esophagogastric junction lesions. Part II: Application of CytospongeTM combined with p53 immunohistochemical staining in screening early esophageal cancer and precancerous lesions. Foreword: China is one of the countries with the highest incidence of esophageal squamous cell carcinoma. Endoscopic iodine staining screening has been carried out in high-risk areas of esophageal cancer. In view of the cost, technical and risk problems of endoscopic-based screening in all high-risk groups, we need a simple, low-cost method as a primary screening tool. A prospective cohort study was conducted to determine the feasibility, safety and efficacy of CytospongeTM combined with p53 immunohistochemical staining in screening early esophageal cancer and precancerous lesions. Materials and Methods: The median age of 87 subjects was 58 years (24-70 years). Fifty-two male subjects (59.8%) and 35 female subjects (40.2%) were enrolled in the study. All subjects underwent screening, completed questionnaires, and underwent endoscopy or endoscopic treatment. Results: According to the pathological diagnosis after biopsy or endoscopic treatment, 28 normal esophagus, 11 esophagitis and 12 mild SARS were included in the study. Type I hyperplasia (LGIN), moderate atypical hyperplasia (MGIN) in 13 cases, severe atypical hyperplasia (HGIN) in 14 cases and early esophageal carcinoma (EESCC) in 9 cases. The sensitivity of CytospongeTM to detect mild atypical hyperplasia (LGIN) and moderate atypical hyperplasia (MGIN) in esophageal squamous epithelium was lower than 10% with atypia as a marker. The sensitivity and specificity for screening severe atypical hyperplasia and early esophageal squamous cell carcinoma were 70% and 93.8% respectively, while p53 positive atypical squamous cells (p53 + Atypia) were used as markers for screening severe atypical hyperplasia (HGIN) and early esophageal squamous cell carcinoma (EESC). Conclusion: CytospongeTM is a simple, safe and easy-to-accept screening tool. The sensitivity of CytospongeTM in screening for severe atypical esophageal hyperplasia and early esophageal cancer can reach about 70%, but it is not expected to increase the sensitivity by using p53 as a biomarker. Part III. Preface: Head and neck squamous cell carcinoma (HNSCC) patients, especially in the oral cavity, oropharynx and hypopharynx, often accompanied by esophageal squamous cell carcinoma (ESCC). HNSCC accompanied by ESCC is usually explained by "regional carcinogenesis". Multiple primary tumors need more. Materials and Methods: Eight patients with esophageal carcinoma complicated with early hypopharyngeal carcinoma underwent endoscopic submucosal dissection. Among them, 2 patients with hypopharyngeal lesions were double primary carcinoma, i.e. 10 lesions. Three patients underwent endoscopic mucosal resection via abdominal approach for early esophageal cancer. In addition, tumor specimens from 8 patients with head and neck squamous cell carcinoma complicated with esophageal squamous cell carcinoma were collected. Results: Eight patients with esophageal carcinoma complicated with early hypopharyngeal carcinoma (10 lesions) underwent endoscopic submucosal dissection. All patients achieved total resection, with a total resection rate of 100%. Because of atypical hyperplasia, 8 lesions accorded with complete resection, and the complete resection rate was 80%. All cases had no complications and no recurrence occurred during follow-up. Three patients with head and neck squamous cell carcinoma had stenosis of the esophageal entrance or cervical esophagus caused by previous radiotherapy, chemotherapy or surgery, which resulted in the failure of general endoscopy. Endoscopic mucosal resection of early esophageal carcinoma via abdominal approach was successfully performed. In this group of patients, no complications occurred except one case of postoperative esophageal stricture, and no local recurrence was found during the follow-up period. The results of gene detection in 8 cases of head and neck squamous cell carcinoma complicated with esophageal squamous cell carcinoma were as follows: 1. The plasma gene showed a high degree of consistency, and the plasma free gene also showed a certain mutation site, although compared with the corresponding tumor tissue, this mutation site is less, but it is far more than the corresponding peripheral blood cell mutation site; 2,5 mutation sites (EGFR 8-p.E330*/13-p.P512L; ERBB212; -p.L485/20-p.D821N; NRAS 5-p.K170N; PIK3CA 11-p.V580E, 14-p.H701L; RB12-p.R46S/6-p.L199*) only appeared in head and neck squamous cell carcinoma of the same patient, but did not appear in esophageal carcinoma. Conclusion: Endoscopic submucosal dissection is safe, effective and less invasive in the treatment of esophageal carcinoma with early hypopharyngeal carcinoma. Meanwhile, endoscopic mucosal resection of early esophageal cancer through abdominal approach may be used in patients who were previously unable to be treated by endoscopy for head and neck squamous cell carcinoma. In addition, there are differences between esophageal cancer and hypopharyngeal cancer in gene mutation sites, which can help to determine whether the tumor is metastatic or dual primary, and guide the next step of accurate targeted therapy.
【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】：2016
【分類(lèi)號(hào)】：R735;R739.91

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