本文選題：進展期胃癌 + 腫瘤時空異質(zhì)性�。� 參考：《河北醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:通過觀察進展期胃癌患者不同個體之間及同一個體的化療前與化療后,術(shù)前與術(shù)后以及原發(fā)灶與轉(zhuǎn)移灶,原發(fā)灶的不同區(qū)域之間HER-2的表達狀態(tài),分析腫瘤時空異質(zhì)性對進展期胃癌患者HER-2過表達的影響,為進一步探討胃癌的真正個體化精準(zhǔn)治療提供理論依據(jù)。方法:選取前瞻性、多中心、開放、隨機對照Ⅲ期臨床試驗(NCT01516944)中胃或胃食管結(jié)合部腺癌患者共521例,其中直接手術(shù)患者277例和新輔助化療患者244例,采用免疫組織化學(xué)染色(IHC)法,對直接手術(shù)的277例進展期胃癌患者術(shù)后進行HER-2蛋白表達的檢測(其中2+和3+認(rèn)為是HER-2蛋白過表達),分析腫瘤異質(zhì)性在進展期胃癌患者不同個體之間HER-2蛋白過表達的影響;觀察進展期胃癌患者在術(shù)前與術(shù)后,化療前與化療后HER-2的表達狀態(tài),分析腫瘤時間異質(zhì)性在同一個體中HER-2蛋白的影響;觀察進展期胃癌患者原發(fā)灶與轉(zhuǎn)移灶(淋巴結(jié)轉(zhuǎn)移灶、肝轉(zhuǎn)移灶、腹腔灌洗液脫落細(xì)胞(PLC)陽性,原發(fā)灶的不同區(qū)域HER-2的表達狀態(tài),分析腫瘤空間異質(zhì)性對進展期胃癌患者HER-2過表達的影響。結(jié)果:1不同個體之間,277例直接手術(shù)患者中,HER-2過表達與患者性別、年齡、腫瘤大小、遠(yuǎn)處轉(zhuǎn)移、脈管瘤栓、神經(jīng)受侵無統(tǒng)計學(xué)差異(P0.05),而與患者的分化程度、Lauren分型、浸潤深度、淋巴結(jié)轉(zhuǎn)移、TNM分期具有統(tǒng)計學(xué)差異(P0.05);2同一個體,277例直接手術(shù)患者中,術(shù)前咬檢及術(shù)后標(biāo)本經(jīng)過IHC方法行HER-2蛋白檢測,胃鏡咬檢組織中HER-2過表達率為32.85%,術(shù)后標(biāo)本測得HER-2蛋白過表達率29.60%,兩者無統(tǒng)計學(xué)差異。雖然在術(shù)前標(biāo)本和術(shù)后標(biāo)本兩組中,HER-2評分0/1+和2+/3+兩組比例極其相似,但41例(14.8%)配對標(biāo)本的IHC評分不一致(活檢標(biāo)本評分為0/1+者在手術(shù)標(biāo)本則評分為2+/3+,或活檢標(biāo)本評分為2+/3+者在手術(shù)標(biāo)本則評分為0/1+)。3同一個體,244例接受新輔助化療患者,經(jīng)過新輔助化療后,除去15例患者化療后胃鏡咬檢標(biāo)本病理為炎性組織或異型細(xì)胞,在剩下的229例患者中,104例患者為化療前胃鏡咬檢的HER-2過表達,HER-2的過表達率為45.41%,86例患者為化療后胃鏡咬檢的HER-2過表達,過表達率為37.55%,兩者無統(tǒng)計學(xué)差異。雖然在化療前、后胃鏡咬檢,HER-2評分0/1+和2+/3+兩組比例極其相似,但26例(11.35%)配對標(biāo)本的IHC評分不一致(化療前標(biāo)本評分為0/1+者在化療后標(biāo)本則評分為2+/3+,或化療前標(biāo)本評分為2+/3+者在化療后標(biāo)本則評分為0/1+)。4同一個體,244例接受新輔助化療患者,經(jīng)過新輔助化療后,10例患者術(shù)后標(biāo)本組織中未見殘余癌(化療后出現(xiàn)PCR),在剩下的234例患者中,術(shù)后標(biāo)本HER-2蛋白(+)的約86人,過表達率約36.75%。與化療前胃鏡咬檢45.41%對比,差異不具有統(tǒng)計學(xué)意義(P=0.1660.05)(Table7)。雖然在化療前胃鏡咬檢與術(shù)后標(biāo)本,HER-2評分0/1+和2+/3+兩組比例極其相似,化療前胃鏡咬檢(+)且術(shù)后標(biāo)本HER-2蛋白(+)的共76人,化療前胃鏡咬檢(-)且術(shù)后標(biāo)本HER-2蛋白(-)的共118人,一致性為82.90%。但40例(17.47%)配對標(biāo)本的IHC評分不一致(化療前咬檢評分為0/1+者在化療后標(biāo)本則評分為2+/3+,或化療前咬檢評分為2+/3+者在化療后標(biāo)本則評分為0/1+)。5 30例左鎖骨上淋巴結(jié)轉(zhuǎn)移患者中,原發(fā)灶與淋巴結(jié)HER-2表達一致率為86.67%。不一致率為:13.33%(4/30)。4例蛋白表達不一致病例。其中2例原發(fā)灶陰性,而淋巴結(jié)轉(zhuǎn)移灶HER-2蛋白過表達(陽性轉(zhuǎn)變),陽性轉(zhuǎn)變率為6.67%;其中2例原發(fā)灶陽性,而淋巴結(jié)轉(zhuǎn)移灶HER-2陰性表達(陰性轉(zhuǎn)變),陰性轉(zhuǎn)變率為6.67%。12例肝轉(zhuǎn)移穿刺活檢陽性的患者的初診胃鏡活檢與肝轉(zhuǎn)移標(biāo)本的HER-2蛋白表達一致性為83.34%,不一致率為:16.67%(2/12)。即2例蛋白表達不一致病例。其中1例原發(fā)灶陰性,而肝轉(zhuǎn)移灶HER-2蛋白過表達(陽性轉(zhuǎn)變),陽性轉(zhuǎn)變率為8.34%;其中1例原發(fā)灶陽性,而肝轉(zhuǎn)移灶HER-2蛋白陰性表達(陰性轉(zhuǎn)變),陰性轉(zhuǎn)變率為8.34%。5例腹腔灌洗液脫落細(xì)胞(PLC)陽性的患者中,初診胃鏡活檢與腹腔灌洗液脫落細(xì)胞HER-2蛋白表達一致性為40%,不一致率為:60%(3/5)。即3例蛋白表達不一致病例。3例原發(fā)灶陽性,而腹腔灌洗液脫落細(xì)胞HER-2蛋白陰性表達(陰性轉(zhuǎn)變),沒有陽性轉(zhuǎn)變。6 50例直接手術(shù)患者中,對同一患者原發(fā)灶的不同區(qū)域行粗針穿刺取材并進行IHC方法檢測,賁門側(cè)、中心、幽門側(cè)三個區(qū)域HER-2蛋白表達一致率為:86%(43/50)。其中約14%的的IHC評分不一致。即7例患者中,原發(fā)灶中同時存在陰性區(qū)域及過表達區(qū)域。結(jié)論:1不同的個體間,隨著胃癌浸潤深度、淋巴轉(zhuǎn)移、TNM分期增加,HER-2蛋白過表達率隨之增加,并且HER-2蛋白過表達率在中分化胃癌患者中所占比例較大。2同一個體中,HER-2狀態(tài)存在時間異質(zhì)性,不同的時間節(jié)點,即術(shù)前與術(shù)后,化療前與化療后的HER-2表達狀態(tài)存在不一致狀態(tài),綜合術(shù)前與術(shù)后,化療前與化療后的過陽性患者,可提高HER-2陽性檢出率。3同一個體中,HER-2表達存在明顯的空間異質(zhì)性,HER-2表達在原發(fā)灶和其他轉(zhuǎn)移灶(肝轉(zhuǎn)移灶及淋巴結(jié)轉(zhuǎn)移灶和腹腔灌洗液脫落細(xì)胞)存在差異性表達,若原發(fā)灶HER-2陰性,尤其針對存在轉(zhuǎn)移復(fù)發(fā)的晚期患者,應(yīng)進一步檢測轉(zhuǎn)移灶。4同一原發(fā)灶的不同區(qū)域,HER-2表達狀態(tài)呈差異性表達,說明HER-2陽性率的檢測與取材部位及個數(shù)有關(guān),由于腫瘤空間異質(zhì)性的影響,增加腫瘤檢測區(qū)域,將有助于全面可靠評估HER-2表達。
[Abstract]:Objective: To investigate the effect of HER-2 on the expression of HER-2 in the patients with advanced gastric cancer by observing the expression status of the different regions between pre and post chemotherapy before and after chemotherapy and after chemotherapy, before and after chemotherapy and after chemotherapy, before and after chemotherapy, and after chemotherapy, and after chemotherapy, and after chemotherapy, and after chemotherapy. Methods: 521 patients with gastric or gastroesophageal junction adenocarcinoma were selected in a prospective, multi center, open, randomized controlled clinical trial (NCT01516944), including 277 cases of direct surgery and 244 patients with neoadjuvant chemotherapy, 277 cases of direct operation with immunohistochemical staining (IHC), and 277 cases of direct operation. The expression of HER-2 protein in patients with advanced gastric cancer (of which 2+ and 3+ are considered to be HER-2 protein overexpression), and to analyze the effect of HER-2 protein overexpression between different individuals in advanced gastric cancer patients, and to observe the expression of HER-2 before and after chemotherapy, before and after chemotherapy, and to analyze the tumor in advanced gastric cancer patients. The effect of time heterogeneity on HER-2 protein in the same individual; to observe the primary and metastatic foci (lymph node metastases, liver metastases, PLC) positive and the expression state of HER-2 in different regions of primary gastric cancer, and to analyze the effect of spatial heterogeneity of tumor on the HER-2 overexpression in advanced gastric cancer patients. Fruit: 1 among 277 patients, HER-2 overexpression was significantly different from the patient's sex, age, tumor size, distant metastasis, vascular tumor thrombus, and nerve invasion (P0.05), while the degree of differentiation, Lauren, infiltration, lymph node metastasis, and TNM staging were statistically different from those of the patients (P0.05); 2 of the same individuals and 277 cases were straight. In surgical patients, HER-2 protein was detected by IHC method before and after operation. The rate of HER-2 overexpression in gastroscopy was 32.85%, and the rate of HER-2 protein overexpression was 29.60% after operation. Although there were no statistical differences between the two groups, the HER-2 scores of 0/1+ and 2+/3+ two were very similar in the preoperative and postoperative specimens of two groups. But in 41 cases (14.8%), the IHC score of the paired specimens was inconsistent (the score of the biopsy specimen was 0/1+ in the surgical specimen 2+/3+, or the score of the biopsy specimen was 0/1+).3 in the same individual, and the 244 patients received the neoadjuvant chemotherapy, after the neoadjuvant therapy, the pathology of the gastroscopy specimen after chemotherapy was removed. For the 229 patients with inflammatory tissue or heterotypic cells, in the remaining 229 patients, 104 patients were overexpressed by pre chemotherapy gastroscopy, the overexpression rate of HER-2 was 45.41%, and 86 patients were HER-2 overexpressed by gastroscopy after chemotherapy, and the overexpression rate was 37.55%. There was no statistical difference between the two patients. The HER-2 score was 0/1+ and 2+/ before chemotherapy. The proportion of the 3+ two groups was very similar, but the IHC score of the paired specimens was not consistent in 26 cases (11.35%). The pre chemotherapy specimens were rated as 2+/3+ after chemotherapy, or the pre chemotherapy specimens were 2+/3+ in the specimens after chemotherapy and 0/1+).4 in the same individual, and 244 patients received neoadjuvant chemotherapy, after the neoadjuvant chemotherapy, 10 patients after chemotherapy. There was no residual cancer in the tissue after the operation (PCR after chemotherapy). In the remaining 234 patients, about 86 of the postoperative specimens were HER-2 protein (+), the overexpression rate was about 36.75%. compared with the pre chemotherapy gastroscopy 45.41%, the difference was not statistically significant (P=0.1660.05) (Table7). The HER-2 score was 0/1+ and 2 in the preoperative gastroscopy and postoperative specimens. The proportion of +/3+ two groups was very similar, 76 people with pre chemotherapy gastroscopy (+) and postoperative specimens of HER-2 protein (+), 118 people with HER-2 protein (-) before chemotherapy and after the operation, the consistency was 82.90%., but 40 cases (17.47%) matched the IHC score of the paired specimens (the pre chemotherapy bite score was 0/1+ after chemotherapy, the score was 2+/3+, or Before chemotherapy, the score of 2+/3+ was 0/1+ after chemotherapy. In.5 30 cases of left supraclavicular lymph node metastasis, the consistent rate of HER-2 expression in the primary foci and lymph nodes was 86.67%.: 13.33% (4/30).4 case protein expression inconsistency. 2 cases were negative, while HER-2 protein overexpression in lymph node metastasis (positive) was positive. The positive conversion rate was 6.67%, of which 2 cases were positive, and the lymph node metastases HER-2 negative expression (negative transformation). The negative transformation rate was 83.34% for the HER-2 protein expression of the first diagnosed gastroscopy and liver metastasis of 6.67%.12 cases with positive liver metastases, and the inconsistency rate was 16.67% (2/12). That is, 2 cases of protein table. Of these cases, 1 cases were negative, and the liver metastases HER-2 protein overexpression (positive transformation) and positive conversion rate were 8.34%, of which 1 cases were positive, and the negative transformation of HER-2 protein in liver metastases (negative transformation), negative transformation rate was in 8.34%.5 cases of PLC positive of peritoneal lavage fluid (PLC). The concordance of HER-2 protein expression in the exfoliative cells of the peritoneal lavage fluid was 40%, the inconsistency rate was 60% (3/5), that is, 3 cases of protein expression inconsistency in.3 cases were positive, and the negative expression of HER-2 protein (negative transformation) in the exfoliated cells of the peritoneal lavage fluid (negative transformation), and no positive transformation of.6 in 50 cases of direct surgery, the different areas of the same patient's primary focus were performed. HER-2 protein expression in three regions of the cardia side, center and pylorus was 86% (43/50). Among them, about 14% of the IHC scores were inconsistent. That is, there were negative regions and overexpressed regions in the primary foci. Conclusion: 1 different individuals, with the depth of infiltration of gastric cancer, lymphatic metastasis, TNM The over expression rate of HER-2 protein increases with the increase of stages, and the rate of overexpression of HER-2 protein in patients with differentiated gastric cancer is larger in.2, HER-2 state has time heterogeneity. Different time nodes, that is, preoperative and postoperative, the state of HER-2 expression before and after chemotherapy, comprehensive before and after the operation. The positive rate of HER-2 positive in the same individual before and after chemotherapy can improve the positive rate of.3 in the same individual, and the expression of HER-2 has obvious spatial heterogeneity. The expression of HER-2 in the primary and other metastatic foci (liver metastasis and lymph node metastasis and peritoneal lavage exfoliative cells) is differential expression, if the primary focal HER-2 is negative, especially for the survival of the metastasis. In the advanced patients with metastatic recurrence, the different regions of the same primary focus of.4 should be further detected. The expression of HER-2 expression is differential expression, indicating that the detection of HER-2 positive rate is related to the location and number of the material. The increase of the tumor detection area due to the effect of tumor spatial heterogeneity will help to comprehensively and reliably evaluate the expression of HER-2.

【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R735.2

【參考文獻】

相關(guān)期刊論文 前10條

1 展鵬;王學(xué)順;劉新泳;;“精準(zhǔn)醫(yī)療”背景下的分子靶向藥物研究——精準(zhǔn)藥物設(shè)計策略淺析[J];化學(xué)進展;2016年09期

2 王岳君;王娜娜;楊苗苗;韓彪;孟剛;;胃癌中HER-2表達異質(zhì)性的病理學(xué)分析[J];臨床與實驗病理學(xué)雜志;2016年08期

3 季加孚;范彪;步召德;;精準(zhǔn)醫(yī)學(xué)在胃腸腫瘤外科中的內(nèi)涵與臨床實踐[J];中華普外科手術(shù)學(xué)雜志(電子版);2016年03期

4 Victoria A.Forte;Dany K.Barrak;Mostafa Elhodaky;Lily Tung;Anson Snow;Julie E.Lang;;The potential for liquid biopsies in the precision medical treatment of breast cancer[J];Cancer Biology & Medicine;2016年01期

5 涂超峰;綦鵬;李夏雨;莫勇真;李小玲;熊煒;曾朝陽;李桂源;;腫瘤異質(zhì)性:精準(zhǔn)醫(yī)學(xué)需破解的難題[J];生物化學(xué)與生物物理進展;2015年10期

6 張希炯;俞進;郭春君;王有美;嚴(yán)磊;方瑩;;胃癌原發(fā)灶不同區(qū)域HER2的表達及其臨床意義[J];浙江醫(yī)學(xué);2015年15期

7 何明燕;夏景林;王向東;;精準(zhǔn)醫(yī)學(xué)研究進展[J];世界臨床藥物;2015年06期

8 湯立達;徐為人;;精準(zhǔn)醫(yī)療時代下制藥行業(yè)的挑戰(zhàn)和機遇[J];現(xiàn)代藥物與臨床;2015年04期

9 賈士杰;范慧敏;劉偉;謝敏;林路平;艾香英;羅純;高倩;;2002～2011年中國惡性腫瘤死亡率水平及變化趨勢[J];中國腫瘤;2014年12期

10 CHIN Francis Y.L.;LEUNG Henry C.M.;YIU S.M.;;Sequence assembly using next generation sequencing data —challenges and solutions[J];Science China(Life Sciences);2014年11期

，

本文編號：1794684