CXCR4在骨肉瘤中的表达及临床意义的系统评价

发布时间：2018-05-06 13:24

本文选题：CXCR4 + 肺转移　；参考：《北京中医药大学》2015年硕士论文

【摘要】：背景：骨肉瘤(Osteosarcoma)也称成骨肉瘤来源于原始成骨间充质细胞,是最常见的原发性骨恶性肿瘤。在原发性骨肿瘤中骨肉瘤的发病率位居第二位,仅次于恶性浆细胞病中最常见的多发性骨髓瘤。骨肉瘤在不同种族中男女性发病年龄及95%可信区间(CI)为0-14岁4.0(3.5-4.6)和0-19岁5.0(4.6-5.6)。在儿童癌症中,骨肉瘤位于第八位,按照发病率排列依次是白血病(30%)、大脑和其它神经系统肿瘤(22.3%)、神经母细胞瘤(7.3%)、肾母细胞瘤(5.6%)、非霍奇金淋巴瘤(4.5%)、横纹肌肉瘤(3.1%)、视网膜母细胞瘤(2.8%)、骨肉瘤(2.4%)和尤因肉瘤(1.4%)。儿童及青少年骨肉瘤的发病率为：黑种人6.8/百万/年,拉美裔6.5/百万/年,白种人4.6/百万/年。骨肉瘤发病年龄呈双峰状分布,第一个峰值在青春期,第二个峰值在老年期。第一个高峰出现在10-14岁年龄组,恰逢发育期的旺盛增长阶段。这表明青春期生长突增和骨肉瘤之间存在一定关系。第二个发病高峰出现在65岁以上的老年期；其发生发展可能与继发恶性肿瘤有关,例如佩吉特氏(Paget)病常继发骨肉瘤。趋化因子受体-4(chemokine receptor-4, CXCR4)属趋化因子家族,为G蛋白偶联的7次跨膜受体蛋白,基质细胞衍生因子CXCL12是该受体的唯一配体,包括α与β异构体,均属于CXC家族。研究发现,CXCR4是肿瘤细胞表达与预后相关。CXCR4在各种癌细胞中高表达常提示预后差。虽然以上多方论证CXCR4的表达与患者的预后有明显相关性,但仍有报道与其相悖,Ma Q发现骨肉瘤CXCR4阳性表达与转移无相关,与肿瘤预后无相关；Mirisola未发现乳腺癌CXCR4低表达预后良好。以上可说明,尽管大部分癌细胞中CXCR4高表达预后差,但仍在预后方面的争议使得我们继续对CXCR4进行深入探索,为提供靶向治疗提供依据。由于至今未得出一个确切的结论,为了给予这个问题一个客观的答案,我们设计了本系统评价利用符合纳入条件的各类研究,针对CXCR4在临床病理及骨肉瘤患者预后的临床应用进行系统价。目的：收集国内外有关应用免疫组织化学方法检测CXCR4在骨肉瘤肺转移中表达以及预后的文献,通过Meta分析的方法研究CXCR4高表达与骨肉瘤肺转移之间是否具有相关性,以及CXCR4高表达与骨肉瘤肺转移预后之间是否存在相关性,旨在系统评价CXCR4与骨肉瘤肺转移的发生、发展及预后等生物学行为的关系,为骨肉瘤肺转移早期诊断提供一种新的诊断依据,依次希望能为以后骨肉瘤的靶向治疗提供治疗依据。方法：①按系统评价要求制定相应的详细的纳入与排除标准,包括研究对象的特征、干预措施以及结局指标的测量等。②根据拟定的标准制定出系统、全面的检索策略：于北京中医药大学电子图书馆全文数据库进行检索CNKI数字图书馆、万方数据库、维普数据库、springer, proquest health medical complete (PHMC)、Pubmed、google学术、medline、SinoMed检索1998.1-2014.11公开发表原始文献、会议论文、毕业论文。手工检索1998.1-2014.11期间中英文发表或未发表的文章,包括杂志、学位论文汇编等。如中华外科杂志、中华医学杂志、中国矫形外科杂志、中华肿瘤杂志、中国肿瘤临床、国际骨科学杂志、实用肿瘤杂志、中华骨科杂志、北京中医药大学图书馆馆藏学位论文。③文献的质量评价及数据信息提取：纳入的诊断性对照研究采用由欧洲肺癌工作组(ELCWP)所创建的生物学预后因素的质量模块体系来进行文献评价。这个模块评估了科学的设计,实验室研究方法,普遍性以及结果分析。每个类别最高可达10分,所以最高分数可达40分。研究者比较他们的计算分数,如果产生分歧则共同商讨一并解决达成一致。最终分数以百分比形式表示出,范围从0到100%。由此可知分数越高则代表文献总体质量越高。④资料的统计学处理：应用已设计好的表格提取资料。资料项目主要包括：(1)试验的基本情况、两组标本的基线情况；(2)试验设计、检查方法、结局测量指标、反应研究质量的指标。所有生物数据资料均输入SPSS13.0、Stata version 11.0以进行研究结果的分析和报告。研究间统计学异质性检验采用卡方检验,以α=0.1为检验水准,以判断多个研究结果的总体效应是否一致。若多个研究结果的效应一致,则采用固定效应模型；反之,则用随机效应模型。对可能影响合并效应的不同因素采用敏感性分析,从而判断结果的稳定性和强度。结果：①资料概括14篇原始文献的特征在图表中进行了总结,总共865例病人的平均年龄是20.9岁。其中男性占441例,女性占424。国内研究占大多数,其中有来自国内的原始文献共10篇,其余文献4篇分别来自日本、美国、瑞士、巴西。CXCR4阳性表达率从分别从29.1%到90.5%。风险比(HRs)和95%可信区间(CIs)仅从两篇文献中的卡迈生存曲线(Kaplan-Meier curves)中获得。依据免疫组织化学(IHC)方法检测CXCR4的文章共计13篇,1篇文献中的CXCR4依据组织切片法进行检测,以细胞核或细胞质是否被染色作为CXCR4是否表达的依据,如被染色则为CXCR4阳性表达,反之同理。关于阳性表达的临界值,8篇文献根据强度和染色百分比介绍了染色评分,其它6篇文献单独应用了百分率表示CXCR4是否表达。②含有二分类变量资料的文章揭示了CXCR4在骨肉瘤组织中的高表达而且与年龄(n=5, OR:1.76,95%CI:1.02-3.03; p=0.044),肺转移(n=9, OR:3.69,95%CI:2.33-5.83; p=0.000)相关。因不存在异质性,我们采用固定效应模型进行计算,正如所预期,7篇合并的OR值未显示CXCR4表达与性别(OR：0.91,95%CI：0.61-1.38；p=0.663),肿瘤尺寸(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)具有相关性,以上结果表明,CXCR4在骨肉瘤组织中高表达可以预测肺转移。③在Meta分析中,两篇文章评价了CXCR4高表达与3年内总生存率之间存在密切关系(HR:0.36,95%CI:0.14-0.96; p=0.042),这预示着CXCR4可以有效的进行诊断及判断预后并依此提供骨肉瘤肺转移的治疗依据。结论：(1)骨肉瘤中CXCR4高表达与骨肉瘤转移具有相关性,高表达可提示转移情况；(2)骨肉瘤中CXCR4高表达与3年总生存率存在相关,高表达提示转移情况预后不良；(3)骨肉瘤中CXCR4高表达与年龄存在相关性,表达在低龄组更高。
[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.

【学位授予单位】：北京中医药大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R738.1

【参考文献】