血清ProGRP、TPS及NSE在小细胞肺癌患者治疗监测中的应用

目的 分析评价血清ProGRP、TPS和NSE在SCLC患者临床诊断和疗效监测中的临床意义.方法 分别采用化学发光法、ELISA法和电化学发光法测定51例SCLC患者(SCLC组,局限期患者36例,广泛期患者15例)、60例肺良性疾病患者(良性疾病对照组)及60名健康人(健康对照组)血清ProGRP、TPS和NSE浓度;分析评价3项指标在SCLC患者治疗前、化疗第1周期和第2周期的变化.结果 局限期SCLC患者治疗前的血清ProGRP、TPS和NSE浓度分别为136.9(22.8～631.7)ng/L、78.2(56.4～114.6)U/L和28.1(20.9～46.1)μg/L;广泛期为1 106.6(41.2～2 161.1)ng/L、230.9(143.5～259.0)U/L和81.1(34.3～140.0)μgL;肺良性疾病组为19.7(9.5～29.1)ng/L、48.7(17.9～95.4)U/L和12.1(1.2～13.9)μg/L;健康对照组为20.3(10.7～30.6)ng/L、50.3(19.5～70.7)U/L和11.7(1.1～13.4)μg/L;经Kruskal-Wallis检验,3项指标在各组间的差异均有统计学意义(x2值分别为51.368、36.532和81.645,P均＜0.01);两个对照组分别与局限期SCLC比较,差异均有统计学意义(U值分别为491、827、609和476、831、585,P均＜0.05);两个对照组分别与广泛期SCLC比较,差异亦有统计学意义(U值分别为314、532、456和302、553、430,P均＜0.01).血清ProGRP诊断SCLC的ROC曲线AUC为0.832±0.029(95%CI:0.774～0.890),以37.7 ng/L为临界值时,其敏感度、特异度、阳性预测值、阴性预测值和约登指数分别为71%(36/51)、97%(116/120)、90%(36/40)、89%(116/131)和67%.联合检测时,ProGRP+TPS+NSE、ProGRP+TPS、ProGRP+NSE和TPS+NSE组合的敏感度分别为92%、86%、92%和88%,特异度分别为77%、77%、92%和77%.经非参数Fridman检验,3项指标在不同治疗阶段的差异均有统计学意义(x2值分别为49.120、10.614和44.392,P均＜0.01).经过连续2个周期化疗后,血清ProGRP浓度持续降低,分别降低至68.0(18.6～158.4)和21.0(14.9～63.5)ng/L,与化疗前组比较,差异均有统计学意义(Z值分别为-4.889、-5.594,P均＜0.01);血清TPS在第1周期化疗结束后升高至105.2(54.1～181.2)U/L,但差异无统计学意义(Z=-1.248,P＞0.05),在第2周期化疗结束后明显降低至79.0(48.7～155.3)U/L,差异有统计学意义(Z=-2.484,P＜0.05);血清NSE在第1周期化疗后迅速降低至11.8(8.0～16.0)μg/L,差异有统计学意义(Z=-5.568,P＜0.01),第2周期化疗后降为10.6(9.0～12.7)μg/L,与第1化疗周期结束后相比,差异无统计学意义(Z=-1.851,P＞0.05).在2个周期化疗后,临床治疗有效的SCLC患者46例(CR 3例,PR 43例),其中3项指标的检测结果全部正常或仅有1项超过临界值的患者为38例(各19例),占83%;3项指标全部异常的患者2例,临床疗效评价均为PD;还有2例临床疗效评价为SD和1例未评价的患者均有2项指标结果异常.结论 血清ProGRP、TPS和NSE均为诊断和监测SCLC治疗疗效的较好的指标,尤其以ProGRP+NSE组合的临床诊断价值最高.联合应用3项指标,有助于SCLC患者的疗效监测和预后判断.

Abstract：

Objective To evaluate the clinical significance of serum levels of ProGRP, TPS and NSE in diagnosis and therapy monitoring in small cell lung cancer patients. Methods The levels of serum ProGRP, TPS and NSE in 51 SCLC patients (SCLC group), 60 benign pulmonary disease patients (benign disease group ) and 60 healthy people (healthy group ) were determined using chemiluminescent immunoassay, ELISA and electrochemiluminescent immunoassay respectively. Blood samples were collected and detected prior to therapy, before the second course of chemotherapy and the third course of chemotherapy consecutively in all the 51 SCLC patients. Results The serum ProGRP, TPS and NSE concentrations prior to chemotherapy in limited stage SCLC (LSCLC) were 136. 9(22.8-631.7)ng/L, 78. 2(56.4-114.6) U/L and 28.1(20.9-46.1)μg/L, respectively; And in extensive stage SCLC patients (ESCLC) were 1 106.6(41.2-2161.1) ng/L, 230. 9( 143.5-259.0) U/L and 81.1 (34.3-140.0)μg/L, respectively. The serum concentrations of the 3 markers in benign disease group were 19. 7 ( 9. 5-29. 1 )ng/L, 48. 7 ( 17.9-95.4) U/L and 12. 1(1.2-13.9) μg/L; and in healthy group were 20.3(10.7-30.6) ng/L, 50.3(19.5-70.7) U/L and 11.7 (1.1-13.4)μg/L, respectively. The Kruskal-Wallis test showed significantly statistical difference in different groups of the 3 tumor markers, Chi-Square were 51. 368,36. 532 and 81. 645( P ＜0. 01 ). Significant statistically differences showed when the concentrations of the 3 marks of the 2 control group were compared with that of the LSCLC group ( U =491, 827, 609 and 476, 831, 585,respectively, P ＜ 0. 05 ). Differences were also statistically significant when the 2 control group compared with that of the ESCLC group ( U = 314,532,456 and 302,553,430, respectively, P ＜ 0. 01 ). The AUC of ProGRP was 0.832 +0.029(95% CI:0.774-0.890). When cutoff value of ProGRP set as 37.7 ng/L, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value and Youden's index were 71% (36/51), 97% (116/120), 90% (36/40), 89% ( 116/131 ) and 67%, respectively; show good detection performance. The sensitivity increased to 92%, 86%, 92% and 88%, when combination detection of ProGRP + TPS + NSE, ProGRP + TPS, ProGRP + NSE and TPS + NSE were used, and the specificities were 77%, 77% , 92% and 77% accordingly. The Fridman test showed significantly statistical difference in the 3 tumor markers at different stages of treatment, x2 were 49. 120, 10. 614 and 44. 392, P ＜0. 01. After the first chemotherapy course, all the tumor marker levels except TPS decreased significantly in comparison with the pretreatment concentrations. However, only ProGRP levels showed a progressive drop during the two consecutive courses of therapy, and the median concentrations were 68.0 ( 18. 6-158.4 ) and 21.0( 14. 9-63.5) ng/L (compared to the level before therapy,Z=-4. 889 and -5. 594, P ＜0. 01 ). The median of serum TPS increased slightly to 105.2 (54. 1-181.2 ) U/L after the first chemotherapy course (Z=-1.248, P＞0.05), and decreased significantly to 79.0(48.7-155.3) U/L after the second chemotherapy course (Z=-2.484, P＜0. 05 ). As to the NSE, the median concentration decreased to 11.8(8.0-16.0)μg/L after the first chemotherapy course ( Z= - 5. 568, P ＜ 0. 01 ). However, the median was 10. 6(9.0-12.7)μg/L, which showed no significant decrease after the second chemotherapy course (Z=-1.851, P＞0.05).Forty-six SCLC patients evaluated as clinical remission ( 3 CR and 43 PR) after the second chemotherapy course, among them there were 38 patients (83%) with normal serum ProGRP, TPS and NSE level ( 19 patients) or with only 1 abnormal tumor level ( 19 patients). There were only 2 patients with all abnormal serum ProGRP, TPS and NSE level, and both patients were evaluated as clinical PD. Two patients with 2 abnormal tumors results were classified as SD, the only 1 patient without therapy evaluation also had 2 abnormal tumor marker results. Conclusions The serum ProGRP, TPS and NSE are valuable tumor markers for diagnosis and treat monitoring of SCLC, particularly the ProGRP + NSE shows the highest clinical value. Combing detection of the 3 tumor markers are valuable for therapy monitoring and prognosis in SCLC patients.

Application of serum levels of pro-gastrin releasing peptide, tissue polypeptide specific antigen and neuron specific enolase in therapy monitoring in small cell lung cancer patients

Objective To evaluate the clinical significance of serum levels of ProGRP, TPS and NSE in diagnosis and therapy monitoring in small cell lung cancer patients. Methods The levels of serum ProGRP, TPS and NSE in 51 SCLC patients (SCLC group), 60 benign pulmonary disease patients (benign disease group ) and 60 healthy people (healthy group ) were determined using chemiluminescent immunoassay, ELISA and electrochemiluminescent immunoassay respectively. Blood samples were collected and detected prior to therapy, before the second course of chemotherapy and the third course of chemotherapy consecutively in all the 51 SCLC patients. Results The serum ProGRP, TPS and NSE concentrations prior to chemotherapy in limited stage SCLC (LSCLC) were 136. 9(22.8-631.7)ng/L, 78. 2(56.4-114.6) U/L and 28.1(20.9-46.1)μg/L, respectively; And in extensive stage SCLC patients (ESCLC) were 1 106.6(41.2-2161.1) ng/L, 230. 9( 143.5-259.0) U/L and 81.1 (34.3-140.0)μg/L, respectively. The serum concentrations of the 3 markers in benign disease group were 19. 7 ( 9. 5-29. 1 )ng/L, 48. 7 ( 17.9-95.4) U/L and 12. 1(1.2-13.9) μg/L; and in healthy group were 20.3(10.7-30.6) ng/L, 50.3(19.5-70.7) U/L and 11.7 (1.1-13.4)μg/L, respectively. The Kruskal-Wallis test showed significantly statistical difference in different groups of the 3 tumor markers, Chi-Square were 51. 368,36. 532 and 81. 645( P ＜0. 01 ). Significant statistically differences showed when the concentrations of the 3 marks of the 2 control group were compared with that of the LSCLC group ( U =491, 827, 609 and 476, 831, 585,respectively, P ＜ 0. 05 ). Differences were also statistically significant when the 2 control group compared with that of the ESCLC group ( U = 314,532,456 and 302,553,430, respectively, P ＜ 0. 01 ). The AUC of ProGRP was 0.832 +0.029(95% CI:0.774-0.890). When cutoff value of ProGRP set as 37.7 ng/L, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value and Youden's index were 71% (36/51), 97% (116/120), 90% (36/40), 89% ( 116/131 ) and 67%, respectively; show good detection performance. The sensitivity increased to 92%, 86%, 92% and 88%, when combination detection of ProGRP + TPS + NSE, ProGRP + TPS, ProGRP + NSE and TPS + NSE were used, and the specificities were 77%, 77% , 92% and 77% accordingly. The Fridman test showed significantly statistical difference in the 3 tumor markers at different stages of treatment, x2 were 49. 120, 10. 614 and 44. 392, P ＜0. 01. After the first chemotherapy course, all the tumor marker levels except TPS decreased significantly in comparison with the pretreatment concentrations. However, only ProGRP levels showed a progressive drop during the two consecutive courses of therapy, and the median concentrations were 68.0 ( 18. 6-158.4 ) and 21.0( 14. 9-63.5) ng/L (compared to the level before therapy,Z=-4. 889 and -5. 594, P ＜0. 01 ). The median of serum TPS increased slightly to 105.2 (54. 1-181.2 ) U/L after the first chemotherapy course (Z=-1.248, P＞0.05), and decreased significantly to 79.0(48.7-155.3) U/L after the second chemotherapy course (Z=-2.484, P＜0. 05 ). As to the NSE, the median concentration decreased to 11.8(8.0-16.0)μg/L after the first chemotherapy course ( Z= - 5. 568, P ＜ 0. 01 ). However, the median was 10. 6(9.0-12.7)μg/L, which showed no significant decrease after the second chemotherapy course (Z=-1.851, P＞0.05).Forty-six SCLC patients evaluated as clinical remission ( 3 CR and 43 PR) after the second chemotherapy course, among them there were 38 patients (83%) with normal serum ProGRP, TPS and NSE level ( 19 patients) or with only 1 abnormal tumor level ( 19 patients). There were only 2 patients with all abnormal serum ProGRP, TPS and NSE level, and both patients were evaluated as clinical PD. Two patients with 2 abnormal tumors results were classified as SD, the only 1 patient without therapy evaluation also had 2 abnormal tumor marker results. Conclusions The serum ProGRP, TPS and NSE are valuable tumor markers for diagnosis and treat monitoring of SCLC, particularly the ProGRP + NSE shows the highest clinical value. Combing detection of the 3 tumor markers are valuable for therapy monitoring and prognosis in SCLC patients.