本文關鍵詞：BLCA-1在肌層浸潤性膀胱癌患者血清、尿液中的表達　出處：《承德醫(yī)學院》2016年碩士論文　論文類型：學位論文

  更多相關文章： 膀胱腫瘤 膀胱癌特異性核基質蛋白-1 競爭性酶聯(lián)免疫吸附試驗 腫瘤標志物 診斷

【摘要】：在我國,膀胱癌是最常見的泌尿系惡性腫瘤之一,其逐年上升的發(fā)病率和高復發(fā)率給患者和社會帶來了沉重的經(jīng)濟和醫(yī)療負擔。目前診斷膀胱腫瘤的金標準依然是膀胱鏡檢查加組織活檢,但臨床中這種有創(chuàng)性操作具有潛在并發(fā)癥,不適用于大規(guī)模人群篩查,而傳統(tǒng)的尿脫落細胞學檢查因其敏感性較低,同樣不適用于膀胱癌的早期診斷、術后隨訪。因此尋找方便快捷敏感特異的腫瘤標志物成為了科研工作者們的研究熱點。在腫瘤發(fā)生發(fā)展中,會釋放以酶、激素、抗原等形式存在于患者機體環(huán)境中的腫瘤標記物。據(jù)研究,膀胱癌特異性核基質蛋白(Bladder cancer specific nuclear matrix proteins,BLCAs)家族特異表達于膀胱腫瘤組織,其中BLCA-1顯示出了較高的敏感性和特異性。本研究應用酶聯(lián)免疫吸附實驗(Enzyme linked immunosorbent assay,ELISA),對受試人群血清與尿液中的BLCA-1和膀胱腫瘤相關抗原(Bladder tumor antigen,BTA)進行定量檢測,探討B(tài)LCA-1與膀胱癌生物學特性的內在聯(lián)系,并與FDA認可的腫瘤標志物BTA檢測結果及本課題組王曉鵬等人關于BLCA-4的檢測結果相對比,為開發(fā)在膀胱癌篩查、診斷及術后隨訪中具有高度特異性、敏感性的腫瘤標記物提供實驗依據(jù)。目的:通過實驗觀測BLCA-1在受試人群血清、尿液中的表達水平,探討B(tài)LCA-1在膀胱癌早期篩查、診斷及術后監(jiān)測中的應用價值。方法:受試人群分為實驗組、對照組,選取我院2014年3月~2015年3月22例病理結果確認為肌層浸潤性膀胱尿路上皮癌患者作為實驗組,其中男16例,女6例,年齡范圍45~90歲,平均年齡64±11歲。根據(jù)WHO2004分級法,乳頭狀尿路上皮癌低分級:5例,高分級:17例。根據(jù)2009 TNM分期標準,T2:16例,T3:5例,T4:1例。對照組包括健康體檢者和良性前列腺增生患者共44例,對照組A:選自健康體檢者22例,其中男10例,女12例,年齡范圍21~66歲,平均年齡41±14歲。對照組B:良性前列腺增生癥患者22例,年齡范圍52~81歲,平均年齡64±7歲。三組受試人群一般情況無差異,可以比較。采用elisa法定量檢測22例肌層浸潤性膀胱癌患者、44例對照組患者血清與尿液blca-1和上述人群尿液中bta的表達水平。檢測blca-4在肌層浸潤性膀胱癌中的表達已由本課題組的王曉鵬等人完成,實驗對象與試驗方法與本實驗一致,具有可比性。應用統(tǒng)計學分析實驗數(shù)據(jù)。非正態(tài)性計量資料均用中位數(shù)加減四分位間距(m±qd)表示,非正態(tài)性計量資料兩兩比較采用wilcoxon秩和檢驗,三組間差異進行kruskal-wallish檢驗,多組間兩兩比較采用nemenyi檢驗;blca-1與bta之間比較采用fisher確切概率法檢驗;計數(shù)資料用百分比表示,所有資料均應用spss19.0統(tǒng)計軟件進行處理,以p0.05為差異有統(tǒng)計學意義。結果:實驗組、對照組a、對照組b受試者尿液blca-1含量的中位數(shù)為1.479ng/ml、0.435ng/ml和0.709ng/ml,實驗組患者blca-1表達水平顯著高于其它兩組(p0.01),對照組b患者blca-1表達水平較對照組a升高,差異有統(tǒng)計學意義(p0.05)。當cut-off值取0.946ng/ml時,尿blca-1敏感性、特異性最佳,分別為77%(17/22)和93%(41/44)。實驗組、對照組a、對照組b受試者血清blca-1含量的中位數(shù)分別為6.621ng/ml、3.522ng/ml和5.611ng/ml,實驗組與對照組b血清blca-1表達水平差異無統(tǒng)計學意義(p0.05),明顯高于對照組a(p0.01)。當cut-off值取4.537ng/ml時,血blca-1敏感性、特異性最佳,分別為86%(19/22)和56%(26/44)。實驗組、對照組a和對照組b尿液中bta含量中位數(shù)分別為214.494ng/ml、9.384ng/ml和121.982ng/ml,實驗組數(shù)據(jù)高于兩對照組(p0.05),三組數(shù)據(jù)兩兩比較差異均有統(tǒng)計學意義(p0.05)。當cut-off值取81.01ng/ml時,尿bta敏感性、特異性最佳,分別為77%(17/22)和64%(28/43)。實驗組尿液blca-1表達水平與患者年齡、性別、肌層浸潤性膀胱癌不同分期、分級無相關性,差異無統(tǒng)計學意義(p0.05);實驗組血清blca-1水平在膀胱癌患者高年齡(≥60歲)和高分級中表達較高(p0.05)。應用fisher確切概率法比較elisa檢測患者尿液blca-1和bta在肌層浸潤性膀胱癌患者診斷中的敏感性和特異性,結果顯示:兩者敏感性相近(p0.05),尿blca-1特異性顯著高于尿bta(p0.05)。同時,尿BLCA-1檢測低級別肌層浸潤性膀胱癌患者敏感性顯著高于尿BTA(P0.05),分別為80%(4/5)、20%(1/5),特異性差異無統(tǒng)計學意義(P0.05),分別為88%(15/17)、94%(16/17)。ELISA檢測尿液BLCA-1診斷膀胱癌的準確度、陽性預測值、陰性預測值和Youden指數(shù)均高于尿BTA。本課題組王曉鵬等人實驗顯示ELISA法檢測尿中BLCA-4診斷膀胱癌敏感性為91%(22/24),特異性為100%,但血清BLCA-4的表達無診斷價值。應用Fisher精確概率法分析,尿BLCA-4的敏感性、特異性與本實驗尿BLCA-1結果差異無統(tǒng)計學意義(P0.05)。結論:1、當cut-off值取0.946ng/ml,檢測尿液BLCA-1診斷膀胱癌敏感性特異性最佳,但其表達水平與肌層浸潤性膀胱癌不同分級、分期未顯示出相關性。2、當cut-off值取4.537ng/ml時,檢測血清BLCA-1診斷膀胱癌敏感性特異性最佳。患者血清中BLCA-1水平顯示出了與肌層浸潤性膀胱癌患者年齡和腫瘤分級的相關性,具體機制尚不明確,還需進一步研究。3、與具有代表性的膀胱腫瘤標志物BTA比較,尿BLCA-1顯示出了較高特異性(93%vs 64%)。檢測尿BLCA-1診斷膀胱癌陽性預測值、陰性預測值、Youden指數(shù)及準確性均高于BTA。4、作為新一代膀胱腫瘤標志物,競爭性ELISA法檢測BLCA-1診斷膀胱癌簡便無創(chuàng),具有潛在臨床價值。
[Abstract]:Bladder cancer is one of the most common urological malignancies in China. Its yearly rising incidence and high recurrence rate bring heavy economic and medical burden to patients and society. The current gold standard for diagnosis of bladder cancer is still the cystoscopy and biopsy, but the clinical invasive operation with potential complications, not suitable for large-scale screening, and conventional cytology due to its low sensitivity, early diagnosis and postoperative follow-up were also not suitable for bladder cancer. Therefore, it has become a hot spot for researchers to find the convenient and sensitive and specific tumor markers. In the development of tumor, the tumor markers that exist in the environment of the patient are released in the form of enzymes, hormones, antigens and other forms. According to the research, the Bladder cancer specific nuclear matrix proteins (BLCAs) family is specifically expressed in bladder tumor tissues, and BLCA-1 shows high sensitivity and specificity. The research and application of enzyme linked immunosorbent assay (Enzyme linked immunosorbent assay, ELISA), on the subject of BLCA-1 and bladder tumor associated antigens in serum and urine in the crowd (Bladder tumor, antigen, BTA) were detected, the relation of BLCA-1 and the biological characteristics of bladder cancer, and the detection results of BTA markers and the research group Wang Xiaopeng et al. Detection of BLCA-4 on the results compared with the FDA approved for the development of tumor in bladder cancer screening, diagnosis and postoperative follow-up with high specificity and sensitivity of tumor markers to provide experimental basis for. Objective: To observe the expression level of BLCA-1 in the serum and urine of subjects, and to explore the value of BLCA-1 in early screening, diagnosis and postoperative monitoring of bladder cancer. Methods: the subjects were divided into experimental group and control group. 22 cases of myometrial invasive bladder urothelial carcinoma confirmed by pathology in our hospital in March March 2014 ~2015 were selected as the experimental group, including 16 males and 6 females, with an age range of 45~90 years, with an average age of 64 + 11 years. According to the WHO2004 classification, the low grade of papillary urothelial carcinoma: 5 cases, high grade: 17 cases. According to the 2009 TNM staging criteria, T2:16 cases, T3:5 cases, and T4:1 cases. The control group consisted of 44 healthy subjects and 22 patients with benign prostatic hyperplasia. In the control group, A: was selected from 22 healthy subjects, including 10 males and 12 females. The age range was 21~66 years old, with an average age of 41 + 14 years. In the control group, there were 22 cases of B: benign prostatic hyperplasia (BPH), the age range of 52~81 years, the average age of 64 + 7 years. The general situation of the three groups was not different, and could be compared. The levels of serum and urine blca-1 and the expression level of BTA in urine of 22 cases of muscle invasive bladder cancer and 44 cases of control group were detected by ELISA. The detection of BLCA-4 expression in muscle invasive bladder cancer has been completed by Wang Xiaopeng, our research group. The experimental objects and experimental methods are consistent with this experiment. Statistical analysis of experimental data. The non normality of measurement data uses the median plus or minus four points spacing (M + QD) said that the non normality of measurement data of 22 compared with the Wilcoxon rank sum test, the difference between the three groups by kruskal-wallish test, multiple comparison between the 22 groups using nemenyi test; between blca-1 and BTA were compared by Fisher exact test; count data expressed as a percentage, all the data are processed by spss19.0 statistical software, using P0.05 as the difference was statistically significant. Results: the experimental group and the control group, the control group a median B subjects urine blca-1 content for 1.479ng/ml, 0.435ng/ml and 0.709ng/ml, the expression level of blca-1 in experimental group were significantly higher than the other two groups (P0.01), the control group B expression level of blca-1 in patients with a increased compared with the control group, the difference was statistically significant (P0.05). When the cut-off value was 0.946ng/ml, the sensitivity and specificity of urine blca-1 were the best, 77% (17/22) and 93% (41/44), respectively. The median level of serum blca-1 in experimental group, control group A and control group B was 6.621ng/ml, 3.522ng/ml and 5.611ng/ml, respectively. There was no significant difference in serum blca-1 expression level between experimental group and control group (P0.05), which was significantly higher than that of control group (P0.01). When the cut-off value was 4.537ng/ml, the sensitivity and specificity of blood blca-1 were the best, 86% (19/22) and 56% (26/44), respectively. The median BTA content of B urine in experimental group and control group A and control group were 214.494ng/ml, 9.384ng/ml and 121.982ng/ml, respectively. The data in experimental group were higher than those in two control group (P0.05), and the difference between three groups was statistically significant (P0.05). The difference between 22 groups was statistically significant (P0.05). When the cut-off value was 81.01ng/ml, the sensitivity and specificity of urine BTA were the best, 77% (17/22) and 64% (28/43), respectively. The experimental group of urine blca-1 expression and patient age, gender, muscle invasive bladder cancer in different stage and grade of no correlation, there was no significant difference between the experimental group (P0.05); the level of serum blca-1 in aged patients with bladder cancer (over 60 years) and high grade high expression (P0.05). The sensitivity and specificity of blca-1 and BTA in patients with myometrial invasive bladder cancer were compared by using the Fisher exact probability method. The results showed that the sensitivity of ELISA was similar (P0.05), and the specificity of urine blca-1 was significantly higher than that of urine BTA (P0.05). Meanwhile, the sensitivity of urine BLCA-1 to detect low grade muscle invasive bladder cancer was significantly higher than that of urine BTA (P0.05), which was 80% (4/5) and 20% (1/5), respectively, and the specificity difference was not statistically significant (P0.05), which was 88% (15/17) and 94% (16/17), respectively. The accuracy, positive predictive value, negative predictive value and Youden index of urine BLCA-1 for the diagnosis of bladder cancer were higher than that of urinary BTA. Wang Xiaopeng and others showed that the sensitivity of ELISA to detect BLCA-4 in bladder was 91% (22/24) and specificity was 100%, but the expression of BLCA-4 in serum was of no diagnostic value. The sensitivity and specificity of urinary BLCA-4 were analyzed by Fisher accurate probability method.
【學位授予單位】：承德醫(yī)學院
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R737.14

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1 李紅陽;BLCA-1在肌層浸潤性膀胱癌患者血清、尿液中的表達[D];承德醫(yī)學院;2016年

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