本文選題：CXCR4 + 肺轉(zhuǎn)移�。� 參考：《北京中醫(yī)藥大學(xué)》2015年碩士論文

【摘要】：背景：骨肉瘤(Osteosarcoma)也稱(chēng)成骨肉瘤來(lái)源于原始成骨間充質(zhì)細(xì)胞,是最常見(jiàn)的原發(fā)性骨惡性腫瘤。在原發(fā)性骨腫瘤中骨肉瘤的發(fā)病率位居第二位,僅次于惡性漿細(xì)胞病中最常見(jiàn)的多發(fā)性骨髓瘤。骨肉瘤在不同種族中男女性發(fā)病年齡及95%可信區(qū)間(CI)為0-14歲4.0(3.5-4.6)和0-19歲5.0(4.6-5.6)。在兒童癌癥中,骨肉瘤位于第八位,按照發(fā)病率排列依次是白血病(30%)、大腦和其它神經(jīng)系統(tǒng)腫瘤(22.3%)、神經(jīng)母細(xì)胞瘤(7.3%)、腎母細(xì)胞瘤(5.6%)、非霍奇金淋巴瘤(4.5%)、橫紋肌肉瘤(3.1%)、視網(wǎng)膜母細(xì)胞瘤(2.8%)、骨肉瘤(2.4%)和尤因肉瘤(1.4%)。兒童及青少年骨肉瘤的發(fā)病率為：黑種人6.8/百萬(wàn)/年,拉美裔6.5/百萬(wàn)/年,白種人4.6/百萬(wàn)/年。骨肉瘤發(fā)病年齡呈雙峰狀分布,第一個(gè)峰值在青春期,第二個(gè)峰值在老年期。第一個(gè)高峰出現(xiàn)在10-14歲年齡組,恰逢發(fā)育期的旺盛增長(zhǎng)階段。這表明青春期生長(zhǎng)突增和骨肉瘤之間存在一定關(guān)系。第二個(gè)發(fā)病高峰出現(xiàn)在65歲以上的老年期；其發(fā)生發(fā)展可能與繼發(fā)惡性腫瘤有關(guān),例如佩吉特氏(Paget)病常繼發(fā)骨肉瘤。趨化因子受體-4(chemokine receptor-4, CXCR4)屬趨化因子家族,為G蛋白偶聯(lián)的7次跨膜受體蛋白,基質(zhì)細(xì)胞衍生因子CXCL12是該受體的唯一配體,包括α與β異構(gòu)體,均屬于CXC家族。研究發(fā)現(xiàn),CXCR4是腫瘤細(xì)胞表達(dá)與預(yù)后相關(guān)。CXCR4在各種癌細(xì)胞中高表達(dá)常提示預(yù)后差。雖然以上多方論證CXCR4的表達(dá)與患者的預(yù)后有明顯相關(guān)性,但仍有報(bào)道與其相悖,Ma Q發(fā)現(xiàn)骨肉瘤CXCR4陽(yáng)性表達(dá)與轉(zhuǎn)移無(wú)相關(guān),與腫瘤預(yù)后無(wú)相關(guān)；Mirisola未發(fā)現(xiàn)乳腺癌CXCR4低表達(dá)預(yù)后良好。以上可說(shuō)明,盡管大部分癌細(xì)胞中CXCR4高表達(dá)預(yù)后差,但仍在預(yù)后方面的爭(zhēng)議使得我們繼續(xù)對(duì)CXCR4進(jìn)行深入探索,為提供靶向治療提供依據(jù)。由于至今未得出一個(gè)確切的結(jié)論,為了給予這個(gè)問(wèn)題一個(gè)客觀(guān)的答案,我們?cè)O(shè)計(jì)了本系統(tǒng)評(píng)價(jià)利用符合納入條件的各類(lèi)研究,針對(duì)CXCR4在臨床病理及骨肉瘤患者預(yù)后的臨床應(yīng)用進(jìn)行系統(tǒng)價(jià)。目的：收集國(guó)內(nèi)外有關(guān)應(yīng)用免疫組織化學(xué)方法檢測(cè)CXCR4在骨肉瘤肺轉(zhuǎn)移中表達(dá)以及預(yù)后的文獻(xiàn),通過(guò)Meta分析的方法研究CXCR4高表達(dá)與骨肉瘤肺轉(zhuǎn)移之間是否具有相關(guān)性,以及CXCR4高表達(dá)與骨肉瘤肺轉(zhuǎn)移預(yù)后之間是否存在相關(guān)性,旨在系統(tǒng)評(píng)價(jià)CXCR4與骨肉瘤肺轉(zhuǎn)移的發(fā)生、發(fā)展及預(yù)后等生物學(xué)行為的關(guān)系,為骨肉瘤肺轉(zhuǎn)移早期診斷提供一種新的診斷依據(jù),依次希望能為以后骨肉瘤的靶向治療提供治療依據(jù)。方法：①按系統(tǒng)評(píng)價(jià)要求制定相應(yīng)的詳細(xì)的納入與排除標(biāo)準(zhǔn),包括研究對(duì)象的特征、干預(yù)措施以及結(jié)局指標(biāo)的測(cè)量等。②根據(jù)擬定的標(biāo)準(zhǔn)制定出系統(tǒng)、全面的檢索策略：于北京中醫(yī)藥大學(xué)電子圖書(shū)館全文數(shù)據(jù)庫(kù)進(jìn)行檢索CNKI數(shù)字圖書(shū)館、萬(wàn)方數(shù)據(jù)庫(kù)、維普數(shù)據(jù)庫(kù)、springer, proquest health medical complete (PHMC)、Pubmed、google學(xué)術(shù)、medline、SinoMed檢索1998.1-2014.11公開(kāi)發(fā)表原始文獻(xiàn)、會(huì)議論文、畢業(yè)論文。手工檢索1998.1-2014.11期間中英文發(fā)表或未發(fā)表的文章,包括雜志、學(xué)位論文匯編等。如中華外科雜志、中華醫(yī)學(xué)雜志、中國(guó)矯形外科雜志、中華腫瘤雜志、中國(guó)腫瘤臨床、國(guó)際骨科學(xué)雜志、實(shí)用腫瘤雜志、中華骨科雜志、北京中醫(yī)藥大學(xué)圖書(shū)館館藏學(xué)位論文。③文獻(xiàn)的質(zhì)量評(píng)價(jià)及數(shù)據(jù)信息提�。杭{入的診斷性對(duì)照研究采用由歐洲肺癌工作組(ELCWP)所創(chuàng)建的生物學(xué)預(yù)后因素的質(zhì)量模塊體系來(lái)進(jìn)行文獻(xiàn)評(píng)價(jià)。這個(gè)模塊評(píng)估了科學(xué)的設(shè)計(jì),實(shí)驗(yàn)室研究方法,普遍性以及結(jié)果分析。每個(gè)類(lèi)別最高可達(dá)10分,所以最高分?jǐn)?shù)可達(dá)40分。研究者比較他們的計(jì)算分?jǐn)?shù),如果產(chǎn)生分歧則共同商討一并解決達(dá)成一致。最終分?jǐn)?shù)以百分比形式表示出,范圍從0到100%。由此可知分?jǐn)?shù)越高則代表文獻(xiàn)總體質(zhì)量越高。④資料的統(tǒng)計(jì)學(xué)處理：應(yīng)用已設(shè)計(jì)好的表格提取資料。資料項(xiàng)目主要包括：(1)試驗(yàn)的基本情況、兩組標(biāo)本的基線(xiàn)情況；(2)試驗(yàn)設(shè)計(jì)、檢查方法、結(jié)局測(cè)量指標(biāo)、反應(yīng)研究質(zhì)量的指標(biāo)。所有生物數(shù)據(jù)資料均輸入SPSS13.0、Stata version 11.0以進(jìn)行研究結(jié)果的分析和報(bào)告。研究間統(tǒng)計(jì)學(xué)異質(zhì)性檢驗(yàn)采用卡方檢驗(yàn),以α=0.1為檢驗(yàn)水準(zhǔn),以判斷多個(gè)研究結(jié)果的總體效應(yīng)是否一致。若多個(gè)研究結(jié)果的效應(yīng)一致,則采用固定效應(yīng)模型；反之,則用隨機(jī)效應(yīng)模型。對(duì)可能影響合并效應(yīng)的不同因素采用敏感性分析,從而判斷結(jié)果的穩(wěn)定性和強(qiáng)度。結(jié)果：①資料概括14篇原始文獻(xiàn)的特征在圖表中進(jìn)行了總結(jié),總共865例病人的平均年齡是20.9歲。其中男性占441例,女性占424。國(guó)內(nèi)研究占大多數(shù),其中有來(lái)自國(guó)內(nèi)的原始文獻(xiàn)共10篇,其余文獻(xiàn)4篇分別來(lái)自日本、美國(guó)、瑞士、巴西。CXCR4陽(yáng)性表達(dá)率從分別從29.1%到90.5%。風(fēng)險(xiǎn)比(HRs)和95%可信區(qū)間(CIs)僅從兩篇文獻(xiàn)中的卡邁生存曲線(xiàn)(Kaplan-Meier curves)中獲得。依據(jù)免疫組織化學(xué)(IHC)方法檢測(cè)CXCR4的文章共計(jì)13篇,1篇文獻(xiàn)中的CXCR4依據(jù)組織切片法進(jìn)行檢測(cè),以細(xì)胞核或細(xì)胞質(zhì)是否被染色作為CXCR4是否表達(dá)的依據(jù),如被染色則為CXCR4陽(yáng)性表達(dá),反之同理。關(guān)于陽(yáng)性表達(dá)的臨界值,8篇文獻(xiàn)根據(jù)強(qiáng)度和染色百分比介紹了染色評(píng)分,其它6篇文獻(xiàn)單獨(dú)應(yīng)用了百分率表示CXCR4是否表達(dá)。②含有二分類(lèi)變量資料的文章揭示了CXCR4在骨肉瘤組織中的高表達(dá)而且與年齡(n=5, OR:1.76,95%CI:1.02-3.03; p=0.044),肺轉(zhuǎn)移(n=9, OR:3.69,95%CI:2.33-5.83; p=0.000)相關(guān)。因不存在異質(zhì)性,我們采用固定效應(yīng)模型進(jìn)行計(jì)算,正如所預(yù)期,7篇合并的OR值未顯示CXCR4表達(dá)與性別(OR：0.91,95%CI：0.61-1.38；p=0.663),腫瘤尺寸(OR:0.76,95%CI:0.40-1.42; p=0.389),分期(OR:0.81,95%CI:0.19-3.38; p=0.795)具有相關(guān)性,以上結(jié)果表明,CXCR4在骨肉瘤組織中高表達(dá)可以預(yù)測(cè)肺轉(zhuǎn)移。③在Meta分析中,兩篇文章評(píng)價(jià)了CXCR4高表達(dá)與3年內(nèi)總生存率之間存在密切關(guān)系(HR:0.36,95%CI:0.14-0.96; p=0.042),這預(yù)示著CXCR4可以有效的進(jìn)行診斷及判斷預(yù)后并依此提供骨肉瘤肺轉(zhuǎn)移的治療依據(jù)。結(jié)論：(1)骨肉瘤中CXCR4高表達(dá)與骨肉瘤轉(zhuǎn)移具有相關(guān)性,高表達(dá)可提示轉(zhuǎn)移情況；(2)骨肉瘤中CXCR4高表達(dá)與3年總生存率存在相關(guān),高表達(dá)提示轉(zhuǎn)移情況預(yù)后不良；(3)骨肉瘤中CXCR4高表達(dá)與年齡存在相關(guān)性,表達(dá)在低齡組更高。
[Abstract]:Background: osteosarcoma (Osteosarcoma), also known as osteosarcoma derived from primitive mesenchymal cells, is the most common primary bone malignant tumor. The incidence of osteosarcoma in primary bone tumors is the second largest, second only to the most common multiple myeloma in malignant plasma cell disease. The age of osteosarcoma in different races is the age of male and female. And 95% confidence interval (CI) of 0-14 years and 4 (3.5-4.6) and 0-19 year 5 (4.6-5.6). In children's cancer, osteosarcoma is located in eighth, according to the incidence of leukemia (30%), brain and other nervous system tumors (22.3%), neuroblastoma (7.3%), nephroblastoma (5.6%), non Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), visual Omentomomoma (2.8%), osteosarcoma (2.4%) and Ewing's sarcoma (1.4%). The incidence of osteosarcoma in children and adolescents is 6.8/ million / year, 6.5/ million / year of Hispanics and 4.6/ million per year in white people. The age of osteosarcoma is Shuangfeng like, the first peak in adolescence, second peak in the old age. The first peak appears in the age. The 10-14 year old age group coincides with the vigorous growth stage of the development period. This indicates a certain relationship between the sudden growth of puberty and osteosarcoma. Second peaks appear in the aged over 65 years old; the development may be associated with secondary malignant tumors, such as Paget S (Paget) disease often secondary osteosarcoma. Chemokine receptor -4 (CHEM) Okine receptor-4, CXCR4) belongs to the chemokine family, which is the 7 transmembrane receptor protein coupled with G protein. Matrix derived factor CXCL12 is the only ligand of the receptor, including the alpha and beta isomers, all belong to the CXC family. The study found that CXCR4 is a tumor cell expression and the prognosis of the high expression of.CXCR4 in various cancer cells often suggests poor prognosis. Although there was a significant correlation between the expression of CXCR4 and the prognosis of the patients, it was reported that the expression of CXCR4 was not related to the metastasis of osteosarcoma and was not related to the prognosis of the tumor. Mirisola did not find the low expression of CXCR4 in the breast cancer was not well. The above indicated that the high expression of CXCR4 in most of the cancer cells was predisposed to the high expression of CXCR4 in most of the cancer cells. The disputation, but still in the prognosis, makes us continue to explore CXCR4 in order to provide the basis for targeting therapy. Since no exact conclusion has been reached so far, in order to give an objective answer to this problem, we have designed this system to evaluate the use of all kinds of studies that conform to the conditions that are included in the clinical disease and to address the clinical disease of CXCR4. Systematic price for the clinical application of the prognosis of osteosarcoma. Objective: to collect literature on the expression and prognosis of CXCR4 in the pulmonary metastases of osteosarcoma by using immunohistochemical methods at home and abroad. The correlation between high expression of CXCR4 and pulmonary metastasis of osteosarcoma and the high expression of CXCR4 were studied by Meta analysis. Whether there is a correlation between the prognosis of osteosarcoma lung metastasis and the relationship between CXCR4 and the occurrence, development and prognosis of osteosarcoma, provide a new diagnostic basis for the early diagnosis of osteosarcoma and lung metastasis, and hope to provide the therapeutic basis for the target treatment of osteosarcoma in turn. The unified evaluation requires the formulation of detailed inclusion and exclusion criteria, including the characteristics of the research object, the intervention measures and the measurement of the outcome indicators. Secondly, the system is formulated and the comprehensive retrieval strategy is formulated according to the proposed standards: the CNKI digital library, the Wanfang database, is retrieved from the full text database of the electronic library of Beijing University of Chinese Medicine. VP database, Springer, ProQuest health medical complete (PHMC), Pubmed, Google academic, MEDLINE, SinoMed search 1998.1-2014.11 publicly published original documents, conference papers, graduation papers. Articles published or unpublished in Chinese and English, including magazines, theses compilation, etc. during the manual retrieval of 1998.1-2014.11, such as the Chinese Journal of surgery, etc. Chinese Journal of medicine, Chinese Journal of orthopedics, Chinese Journal of cancer, Chinese Journal of cancer clinical, international bone science, Journal of practical cancer, Journal of China Department of orthopedics, and academic papers of the library of Beijing University of Chinese Medicine. 3. Quality evaluation and data extraction of literature: a diagnostic control study was adopted by the European Working Group on lung cancer (ELCWP) the quality module system of the biological prognostic factors was created to evaluate the literature. This module assesses scientific design, laboratory research methods, universality, and results analysis. Each category can reach a maximum of up to 10 points, so the highest score can reach 40 points. The final score is expressed in percentage form. The higher the range from 0 to 100%. is the higher the overall quality of the literature. 4. Statistical processing of the data: using a well designed table to extract data. The data items mainly include: (1) the basic situation of testing, the baseline of the two groups of specimens; (2) Test design, inspection method, outcome measure index, index of quality of response research. All biological data data are entered into SPSS13.0, Stata version 11 for the analysis and report of research results. The statistical heterogeneity test in the study is based on the chi square test, and the alpha =0.1 is used as the test level to determine the overall effect of multiple research results. Consistent. If the effects of multiple results are consistent, a fixed effect model is used; conversely, a random effect model is used to determine the stability and intensity of the results with different factors that may affect the combination effect. Results: (1) the characteristics of the 14 original articles are summarized in the chart, a total of 865 The average age of the patients was 20.9 years, of which 441 were male and 424. of the domestic research accounted for 424., of which 10 were from the domestic original literature, and the other 4 articles were from Japan, the United States, Switzerland, and Brazil from 29.1% to 90.5%. (HRs) and 95% confidence interval (CIs) from two. A total of 13 articles on the detection of CXCR4 based on the immunohistochemistry (IHC) method were obtained in a total of 13 articles based on the immunohistochemical (IHC) method to detect CXCR4. The CXCR4 in 1 literature was detected by tissue section method, and whether the nucleus or cytoplasm was stained as the basis for the expression of CXCR4, if stained, was CXCR4 positive, and vice versa. With regard to the critical value of positive expression, 8 articles introduced the staining score based on the intensity and percentage of dyed. The other 6 articles used percentages to express the expression of CXCR4 alone. 2. The article containing two classified variables revealed the high expression of CXCR4 in osteosarcoma and was associated with age (n=5, OR:1.76,95%CI:1.02-3.03; p=0.044). Pulmonary metastasis (n=9, OR:3.69,95%CI:2.33-5.83; p=0.000) related. Because of the absence of heterogeneity, we used a fixed effect model to calculate, as expected, 7 combined OR values did not show CXCR4 expression and sex (OR:0.91,95%CI:0.61-1.38; p=0.663), tumor size (OR:0.76,95%CI:0.40-1.42; p=0.389), staging (OR:0.81,95%CI:0.19-3.3). 8; p=0.795) has relevance. The above results show that high expression of CXCR4 in osteosarcoma can predict lung metastasis. (3) in Meta analysis, two articles evaluated the close relationship between high expression of CXCR4 and total survival rate within 3 years (HR:0.36,95%CI:0.14-0.96; p=0.042), which indicates that CXCR4 can be used to diagnose and judge prognosis effectively. And provide the basis for the treatment of osteosarcoma pulmonary metastasis. Conclusion: (1) high expression of CXCR4 in osteosarcoma is associated with osteosarcoma metastasis, high expression may suggest metastasis; (2) high expression of CXCR4 in osteosarcoma is associated with 3 years' total survival, high expression suggests poor prognosis, and (3) high expression of CXCR4 and age in osteosarcoma. In the correlation, the expression is higher in the lower age group.

【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R738.1

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