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Application Value of Serum Kreb Von Den Lungen-6 in the Adjuvant Treatment of Lung Injury after Non-small Cell Lung Cancer Surgery
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摘要:目的 探讨血清涎液化糖链抗原-6(kreb von den lungen-6，KL-6)在非小细胞肺癌(non-small cell lung cancer，NSCLC)术后辅助治疗性肺损伤中的诊断价值。方法 回顾性收集2017年11月—2020年7月中国医科大学附属盛京医院诊治的NSCLC患者(包括术后采用辅助治疗者和仅手术者)资料，以药物诱导性肺损伤(drug induced lung injury, DILI)、放射性肺损伤(radiation induced lung injury, RILI)诊断共识为判断NSCLC术后辅助治疗性肺损伤的诊断标准，将NSCLC术后辅助治疗患者分为肺损伤组和无肺损伤组，仅手术者为NSCLC手术组；以年龄和性别匹配同期体检中心的健康成人为健康对照组。肺损伤组于肺损伤确诊当日，无肺损伤组于辅助治疗的第3~4个月，NSCLC手术组分别于术前、术后7~10 d，健康对照组于体检当日，空腹采集静脉血检测血清KL-6。比较各组血清KL-6差异，并以无肺损伤组为对照，采用受试者工作特征(receiver operating characteristic，ROC)曲线评估血清KL-6诊断NSCLC术后辅助治疗性肺损伤的效能。结果 共206例符合纳入和排除标准的患者入选本研究，其中肺损伤组51例，无肺损伤组52例，NSCLC手术组103例；健康对照组103例，基线资料均衡可比。血清KL-6水平由高至低依次为肺损伤组[512.40(322.30，819.20)kU/L]、NSCLC手术组(术前) [204.40(162.70，283.20)kU/L]、健康对照组[177.70(154.20，206.40)kU/L]、无肺损伤组[147.80(114.25，229.80)kU/L]和NSCLC手术组(术后) [143.80(111.90，247.80)kU/L]。除无肺损伤组与NSCLC手术组术后血清KL-6无统计学差异(P=0.879)外，其余两两比较差异均有统计学意义(P均＜0.05)。ROC曲线分析显示，血清KL-6诊断NSCLC术后辅助治疗性肺损伤的曲线下面积(area under the curve，AUC)为0.972(95%CI：0.948~0.997)，灵敏度、特异度、阳性似然比、阴性似然比分别为86.3%(95% CI：73.0%~94.1%)、96.2%(95% CI：86.2%~98.7%)、22.43(95% CI：5.74~87.69)、0.14(95% CI：0.07~0.28)，最佳诊断临界值为310.15 kU/L。结论 NSCLC术后辅助治疗性肺损伤患者血清KL-6显著升高，其在NSCLC术后辅助治疗性肺损伤中具有较高的诊断价值，但仍需大样本前瞻性研究进一步验证。Abstract:Objective To investigate the diagnostic value of serum kreb von den lungen-6 (KL-6) in lung injury from postoperative adjuvant treatment in non-small cell lung cancer (NSCLC).Methods This study is a retrospective analysis including NSCLC with postoperative adjuvant treatment and NSCLC with merely surgical treatment patients diagnosed and treated in Shengjing Hospital of China Medical University from November 2017 to July 2020. Consensus on the diagnosis of drug induced lung injury and radiation induced lung injury was used as the diagnostic criteria for lung injury from postoperative adjuvant treatment. NSCLC patients with postoperative adjuvant treatment were divided into the lung-injury group and the non lung-injury group. those only with surgery were as NSCLC-surgery group. Match the healthy adults of the physical examination center at the same period as the healthy control group based on the age and gender. Fasting venous blood was collected from NSCLC patients and healthy adults for detection of serum KL-6. The time of venous blood collection was on the day of lung-injury diagnosis for the lung-injury group, after 3 to 4 months of adjuvant treatment for the non lung-injury group, before and 7 to 10 days after surgery for NSCLC-surgery group, and on the day of physical examination for the healthy control group. The levels of serum KL-6 in each group were compared, and the non lung-injury group was used as the control, the diagnostic threshold value of serum KL-6 for adjuvant therapeutic lung injury was preliminarily established based on the receiver operating characteristic(ROC) curve.Results A total of 206 NSCLC patients who met the selection and exclusion criteria were enrolled, of which 51 cases were in lung-injury group, 52 cases were in non lung-injury group, and 103 cases were in NSCLC-surgery group. Meanwhile, 103 cases in healthy control group were enrolled. There was no significant difference among the basic clinical data of the four groups. The levels of serum KL-6 in the descending order were lung-injury group [512.40 (322.30, 819.20)kU/L], pre-operation of the NSCLC-surgery group [204.40 (162.70, 283.20)kU/L], healthy control group [177.70 (154.20, 206.40)kU/L], non lung-injury group [147.80 (114.25, 229.80)kU/L], and post-operation of the NSCLC-surgery group [143.80 (111.90, 247.80)kU/L]. There was no significant difference in serum KL-6 between the non lung-injury group and post-operation of the NSCLC-surgery group (P=0.879), while the difference between other groups were statistically significant (all P < 0.05). The ROC curve analysis showed that the area under the curve (AUC) of serum KL-6 for the diagnosis of lung injury from NSCLC postoperative adjuvant treatment was 0.972 (95% CI: 0.948-0.997), and the diagnostic sensitivity, specificity, the positive and negative likelihood ratio were 86.3% (95% CI: 73.0%-94.1%), 96.2% (95% CI: 86.2%-98.7%), 22.43 (95% CI: 5.74-87.69), 0.14 (95% CI: 0.07-0.28), respectively. The best diagnostic cut-off value was 310.15 kU/L.Conclusions Serum KL-6 is significantly increased in the patients with lung injury from NSCLC postoperative adjuvant treatment, and it has high application value in the diagnosis of lung injury from postoperative adjuvant treatment in NSCLC, but it still needs further verification by prospective studies with large samples.
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多发性硬化(multiple sclerosis，MS)是中枢神经系统炎性脱髓鞘性疾病，一氧化氮(nitric oxide，NO)及其氧化物———过氧亚硝酸(peroxynitrite，PN)在其发生发展中具有重要作用[1-3]。尿酸(uric acid，UA)因其可抑制PN而被认为对MS具有一定保护作用[4]。动物研究显示UA具有治疗效应[5-6]; 临床研究发现高尿酸血症患者很少患MS[6]，而MS患者血清UA水平明显低于健康人[6-11]。但是，这一结论仍有争议[12-17]，而且血清UA水平可能随疾病所处阶段不同而有不同变化[9]。有学者指出UA可能具有双重作用:神经保护作用和破坏作用[12]。
目前，疾病调节治疗(disease-modifying therapy，DMT)是MS的一线治疗方法，药物包括β干扰素-1b、β干扰素-1a和醋酸格列默。有研究显示DMT可影响MS患者血清UA水平，但结论不一[11, 17-19]。有关β干扰素-1b对血清UA水平作用的研究至今鲜有报道。
本开放性前瞻性疗效观察研究旨在探讨β干扰素-1b对中国经典型MS (classical MS，CMS)患者血清UA水平的影响及血清UA水平与患者残疾程度、复发情况和颅内磁共振(magnetic resonance imaging，MRI)病灶数目间的关系。
对象和方法
对象
本研究共纳入2007年1月至2008年12月在北京协和医院神经科就诊并接受β干扰素-1b治疗的确诊CMS患者12例，其中女10例，男2例。CMS诊断依据2005年McDonald标准[20]。所有患者入组前未接受过DMT或免疫抑制剂治疗; 均处于缓解期，且至少3个月内未接受过激素治疗; 无肾脏疾病、痛风或糖尿病。12例患者中，复发缓解型10例，继发进展型2例。所有患者治疗前后均进行扩展残疾状态评分(Expanded Disability Status Scale，EDSS)。
β干扰素-1b治疗
β干扰素-1b (倍泰龙，中国北京拜耳先灵公司)的使用方法为将其溶解于0. 54%的盐水中，250 μg皮下注射，隔日1次。在接受β干扰素-1b治疗的6个月期间，所有患者无任何饮食习惯改变，且未服用任何影响UA水平的药物。
MRI检查
MRI检查在1. 5T MRI机器上(GE，Sigma，Milwaukii，USA)进行，增强扫描采用国际标准程序，在注射0. 1 mmol/kg钆喷酸葡胺后5 min进行扫描。收集颅内增强病灶(contrast-enhancing lesions，CELs)数目。
血清UA水平检测
行MRI检查当天，完成血液标本采集。患者隔夜空腹，从肘静脉采集血液标本。血清UA水平用试剂盒(Olympus Diagnostica GmbH，Hamburg，Germany)检测，方法为酶学法，步骤严格参照说明书进行。实验室血清UA正常值女性为140 ~390 μmol/L，男性为200 ~ 500 μmol/L。
统计学处理
所有统计分析均采用SPSS统计学软件(version 11. 0，Chicago，IL，USA)完成。结果用x ± s或中位数表示。配对t检验用于比较治疗前后的数据变化。变量间的相关性则用Spearman线性回归进行分析。以P＜0. 05为差异有统计学意义。
结 果
基线临床资料
12例患者的平均年龄为(33. 4 ± 8. 0)岁(24 ~ 54岁)，平均发病年龄为(27. 4 ± 9. 8)岁(7. 8 ~ 46. 0岁); 治疗开始前患者病程中位数为2. 3年(1. 0 ~ 28. 3年)，中位复发次数为2次(1 ~ 8次)，入组前1年内中位复发次数为1次(1 ~ 2次)。
β干扰素-1b可减少患者年复发次数和颅内CELs数目，但不能降低EDSS评分
本研究无患者脱落。与治疗前相比，治疗后的年复发次数和CELs数目均显著降低(P＜0. 05); EDSS评分有降低趋势，但差异无统计学意义(P = 0. 064) (表 1)。
表 1 β干扰素-1b对患者EDSS、年复发次数、颅内增强病灶数目及血清尿酸水平的影响时间 EDSS (中位数) 年复发次数(中位数) 颅内增强病灶数目(中位数) 尿酸(μmol/L，x ± s) 治疗前(缓解期) 2.8 0.9 1.5 222. 2 ± 28. 9 治疗后6个月 2.0 0.0 0.0 239. 4 ± 48. 7 P值 0.064 0.011 0.007 0.213 EDSS:扩展残疾状态评分 药物不良反应
用药期间，6例(50%)患者出现流感样症状，4例(31%)患者出现注射局部反应，2例(17%)患者甲状腺激素刺激素降低，1例(8%)患者谷丙氨酸转移酶升高。所有上述不良反应均为轻到中度，且为一过性。
血清UA水平
治疗前，仅1例男性患者血清UA水平(186 μmol/L)低于正常。治疗后，所有患者血清UA水平均在正常范围内，平均血清UA水平由(222. 2 ± 28. 9) μmol/L升高至(239. 4 ± 48. 7) μmol/L，但差异未达到统计学意义(P = 0. 213) (表 1)。进一步相关性分析显示，治疗后血清UA浓度变化与CELs数目变化呈显著负相关(r =- 0. 716，P = 0. 009) (图 1)。
讨 论
本研究显示，经6个月β干扰素-1b治疗后，CMS患者年复发次数与CELs数目显著降低，提示β干扰素-1b对中国初治CMS患者，在临床复发性和MRI活动性方面的疗效与白种人相当[21-26]。至今，有关β干扰素1b对EDSS评分影响的报道尚存争议，一些研究显示长期β干扰素1b治疗可改善MS患者EDSS评分[21-23]，而其他一些研究未能证明这一获益[27-31]。本研究观察到CMS患者EDSS评分在6个月治疗后有改善趋势，但差异未达到统计学意义，可能与本研究随访时期较短有关。
值得一提的是，本研究观察到CMS患者经β干扰素-1b治疗后血清UA水平有升高趋势，且血清UA水平的升高与治疗后患者CELs数目的降低显著相关，笔者推测这可能与血脑屏障破坏的减少有关。血脑屏障破坏是MS的特点之一，通常用CELs来评估[32]。在健康人中，UA并不穿过血脑屏障，血清中UA水平至少比脑脊液中高10倍[7]; 在血脑屏障破坏的MS患者，血清UA水平较血脑屏障正常者显著降低[9]; 在MS动物模型中，血脑屏障破坏可以导致脑脊液UA水平升高[5]; 这些均提示血清UA水平高低与血脑屏障破坏程度相关，本研究中发现的血清UA水平升高和血脑屏障破坏减少之间的相关性与上述研究结果一致。因此，笔者推测，相比价格昂贵的MRI检查，血清UA水平的变化也许可以成为评价MS患者血脑屏障功能更经济的指标。
已有研究证实，MS患者血脑屏障破坏与内皮细胞功能障碍有关。正常情况下，脑内皮细胞的紧密连接可限制激活的白细胞穿过血脑屏障进入脑组织。在MS的病理状态下，前炎症细胞因子通过上调黏附分子、破坏紧密连接的完整性和释放内皮微粒导致血脑屏障破坏[33]。有研究证实β干扰素-1b可改善内皮功能，从而抑制血脑屏障开放。这些机制包括抑制紧密连接完整性的破坏[34]，抑制内皮细胞表达黏附分子等[35-37]。由此，笔者推测β干扰素-1b对血脑屏障开放的抑制作用可能是其导致MS患者血清UA水平有升高趋势的机制之一。尽管这一结果没有达到统计学意义，这可能与本研究患者病例数较少有关。因此，为进一步验证β干扰素-1b对血清UA水平的影响，还需进行大规模的研究。
本研究尚存一些不足之处，如:样本量较小，为开放性研究，缺乏安慰剂对照等。因此，为了证实上述结果，以及证实UA能否作为评估血脑屏障功能和评价患者对β干扰素-1b反应性的更简单、经济的指标，还需进行更大规模的双盲安慰剂对照研究。
作者贡献：吴丽娜、秦晓松负责研究设计、数据分析、论文撰写；高弋、李沃松负责标本留取及临床资料收集；刘勇指导研究设计、数据分析及修改论文。利益冲突：无 -
表 1 患者一般资料比较
指标 肺损伤组(n=51) 无肺损伤组(n=52) NSCLC手术组(n=103) 健康对照组(n=103) P值 年龄(x±s, 岁) 58.51±7.14 53.06±8.70 59.26±7.08 54.61±8.90 ＜0.001 性别(男/女，n) 33/18 32/20 66/37 62/41 0.926 病理类型(腺癌/鳞癌，n) 43/8 40/12 82/21 - 0.634 TNM分期(Ⅱ/Ⅲ期，n) 23/28 27/25 48/55 - 0.756 术后辅助治疗方式(单纯放疗/同步放化疗，n) 18/33 17/35 - - 0.780 合并慢性阻塞性肺疾病[n(%)] 4(7.84) 1(1.92) 3(2.91) 0(0) 0.037 合并结缔组织病[n(%)] 1(1.96) 0(0) 0(0) 0(0) 0.166 NSCLC：同图 1；-：不适用 
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期刊类型引用(2)
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