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术前血小板与白蛋白比值对Ⅰ~Ⅲ期胃癌患者预后的预测价值

2022-04-01施汉飞潘德键

中国医学创新 2022年4期
关键词:胃癌

施汉飞 潘德键

【摘要】 目的:探讨术前血小板与白蛋白比值(platelet-to-albumin ratio,PAR)对Ⅰ~Ⅲ期胃癌患者术后生存的预测价值。方法:回顾性分析2010年1月-2015年9月中国人民解放军联勤保障部队第九〇四医院收治的242例行胃癌根治术治疗的Ⅰ~Ⅲ期胃癌患者的临床资料。采用受试者工作特征(receiver operating character,ROC)曲线确定PAR最佳截断值,根据最佳截断值将患者分为低PAR组和高PAR组。比较两组病理特征及总生存期(overall survival,OS)。通过单因素和多因素Cox比例危险回归模型分析胃癌患者术后OS的影响因素。结果:ROC曲线显示PAR最佳截断值为4.52×109,以此将患者分为低PAR(≤4.52×109)组86例和高PAR(>4.52×109)组156例。低PAR组和高PAR组的年龄、肿瘤最大径、肿瘤浸润深度、淋巴结是否转移及病理分期比较,差异均有统计学意义(P<0.05)。低PAR组术后1、3、5年生存率分别为92.6%、77.2%、60.3%均优于高PAR组的72.5%、36.3%、23.5%,差异均有统计学意义(P<0.01)。单因素分析结果显示:术前PAR、肿瘤最大直径、浸润深度、淋巴结转移、TNM分期均为胃癌患者根治性手术术后OS的影响因素(P<0.05);多因素分析结果显示:TNM分期和术前PAR以及淋巴结转移均为胃癌根治性术后OS的独立危险因素(P<0.05)。结论:术前PAR与胃癌患者的病理特征存在一定联系,是术后OS的独立危险因素之一,可作为判断胃癌患者预后的指标。

【關键词】 胃癌 血小板与白蛋白比值 总生存期

Prognostic Value of Preoperative Platelet-to-albumin Ratio in Patients with Stage Ⅰ-Ⅲ Gastric Cancer/SHI Hanfei, PAN Dejian. //Medical Innovation of China, 2022, 19(04): 0-022

[Abstract] Objective: To explore the predictive value of preoperative platelet-to-albumin ratio (PAR) for postoperative survival of patients with stageⅠ-Ⅲ gastric cancer.Method: From January 2010 to September 2015, the clinical data of 242 patients with stageⅠ-Ⅲ gastric cancer underwent radical gastrectomy were collected retrospectively in the 904th Hospital of the Chinese PLA Joint Logistics Support Force. The receiver operating character (ROC) curve was used to determine the best cut-off value of PAR, and the patients were divided into low PAR group and high PAR group according to the best cut-off value. The pathological features and overall survival (OS) were compared between the two groups. The influencing factors of postoperative OS in patients with gastric cancer were analyzed by univariate and multivariate Cox proportional hazard regression models. Result: ROC curve showed that the best cut-off value of PAR was 4.52×109, which divided the patients into 86 cases with low PAR (≤4.52×109) group and 156 cases with high PAR (>4.52×109) group. There were significant differences in age, greatest tumor diameter, tumor invasion depth, lymph node metastasis and pathological stage between low PAR group and high PAR group (P<0.05). The 1-, 3- and 5-year survival rates of low PAR group were 92.6%, 77.2% and 60.3% respectively, which were better than those of high PAR group, which were 72.5%, 36.3% and 23.5%, the differences were statistically significant (P<0.01). Univariate analysis showed that preoperative PAR, tumor maximum diameter, invasion depth, lymph node metastasis and TNM stage were all influencing factors of OS after radical operation for gastric cancer patients (P<0.05). Multivariate analysis showed that TNM staging, preoperative PAR and lymph node metastasis were independent risk factors for OS after radical gastrectomy (P<0.05). Conclusion: Preoperative PAR is related to the pathological features of patients with gastric cancer, which is one of the independent risk factors of OS after operation, and can be used as an index to judge the prognosis of patients with gastric cancer.gzslib202204011605

[Key words] Gastric cancer PAR OS

First-authors address: Wuxi Clinical College of Anhui Medical University, Wuxi 214044, China

doi:10.3969/j.issn.1674-4985.2022.04.004

胃癌是最常见的消化道恶性肿瘤,其全球发病率在癌症中排名第五,死亡率居第三位[1];我国胃癌的发病率虽然有所下降,但仍处在较高水平[2]。迄今为止,根治性切除术仍被认为是治愈早期胃癌的唯一方法,但数据显示:42.5%的胃癌患者会在术后两年内复发,术后总复发率高达60.8%[3]。肿瘤的复发已经成为胃癌患者死亡的主要原因,而目前预测胃癌预后的主要指标仍是经典的临床病理因素,如病理分期、肿瘤分级、分化程度、淋巴结及远处转移等[4],但这些数据往往在术前难以得到,所以发展一套可用于术前预测胃癌患者术后肿瘤进展程度的指标至关重要。慢性炎症在肿瘤的发生发展中发挥着重要作用,且与恶性肿瘤的不良预后相关[5-7]。目前对于术前炎症标志物和恶性肿瘤之间关系的研究多集中在术前外周血炎症指标与各种恶性肿瘤预后之间的相关性,如C反应蛋白、中性粒细胞、淋巴细胞、血小板、单核细胞、白蛋白等。血小板/白蛋白比值(platelet-to-albumin ratio, PAR)作为一种衍生的指标,已被证明在胰腺导管腺癌、尿路上皮癌等肿瘤的临床病理特征和预后方面有显著价值[8-9],但目前尚无PAR与胃癌预后的相关研究,本研究旨在探讨术前PAR对胃癌根治术的预后是否有预测价值,现报道如下。

1 资料与方法

1.1 一般资料 采用回顾性队列研究方法,收集2010年1月-2015年9月中国人民解放军联勤保障部队第九〇四医院收治242例胃癌患者的病历资料。纳入标准:(1)经胃癌根治术治疗,术后病理学检查证实为胃腺癌;(2)根据美国癌症分期联合委员会(American joint committee on cancer,AJCC)第8版胃癌指南对纳入的病例进行TNM分期,TNM分期为Ⅰ、Ⅱ、Ⅲ期;(3)术前未接受新辅助放化疗;(4)术后生存>1个月;(5)术前1周内的各项检验结果、术后病理资料完整。排除标准:(1)合并同时或异时的其他恶性肿瘤;(2)患有血液系统相关疾病;(3)术前出现严重消化道梗阻、穿孔、感染或大出血等并发症;(4)术前输注血小板或白蛋白制剂。本研究通过中国人民解放军联勤保障部队第九〇四医院医学伦理委员会审批。

1.2 方法 收集患者相关病历资料。术前外周血液指标:血小板数目、白蛋白及癌胚抗原水平等;术后标本主要报告:肿瘤大小、肿瘤浸润深度、肿瘤分化程度、淋巴结转移数目等。随访:通过患者门诊复诊或定期电话等方式进行随访。总生存期(OS)定义为自手术时间至任何原因所致的死亡时间间隔。患者出现死亡事件或术后生存时间≥5年即停止随访。结合ROC曲线和预后信息,获得PAR的最佳截断值,根据最佳截断值将患者分为低PAR组和高PAR组。比较两组性别、年龄、肿瘤最大径、浸润深度、淋巴结转移、TMN分期、分化程度、肿瘤部位和CEA水平,分析PAR与临床病理特征的相关性。

1.3 统计学处理 采用SPSS 21.0软件对所得数据进行统计分析,计数资料以率(%)表示,比较采用字2检验;采用Kaplan-Meier法绘制生存函数曲线,log-rank用于检验生存函数,通过单因素和多因素Cox比例危险回归模型分析独立预后因素。以P<0.05为差异有统计学意义。

2 结果

2.1 临床病理特征 纳入的242例胃癌患者中,男186例(76.9%),女56例(23.1%);年齡25~87岁,平均(63.3±11.66)岁,其中≤65岁125例(51.7%),>65岁117例(48.3%);肿瘤最大径:≤3 cm 125例(51.7%),>3 cm 117例(48.3%);病理浸润深度分期:T1期78例(32.2%),T2期36例(14.9%),T3期59例(24.4%),T4期69例(28.5%);淋巴结分期:N0期121例(50.0%),N1期32例(13.2%),N2期38例(15.7%),N3期51例(21.1%);TNM分期:Ⅰ期92例(38.0%),Ⅱ期74例(30.6%),Ⅲ期76例(31.4%);CEA 0.15~370.11 ng/mL,平均值为7.89 ng/mL,CEA>5 ng/mL 39例(16.1%);手术方式:全胃切除术46例(19.0%),胃大部切除术196例(81.0%)。242例患者的OS为4~60个月,中位OS为51个月,其中143例(59.1%)患者因各种原因出现OS终点。

2.2 PAR最佳分界值的确定及分组情况 所有患者PAR为(1.47~13.64)×109,平均值为(5.48±2.06)×109,以中位OS作为状态变量,PAR作为检验变量,通过PAR的ROC曲线分析可得,PAR曲线下面积(AUC)为0.659[95%CI(0.591,0.727)],当PAR=4.52×109时,约登指数最大,此时敏感度为0.774,特异度为0.492,故以4.52×109作为PAR最佳界值,见图1。将患者分为低PAR(≤4.52×109)组86例和高PAR(>4.52×109)组156例。

2.3 低PAR组和高PAR组临床病理特征比较 低PAR组和高PAR组的年龄、肿瘤最大径、肿瘤浸润深度、淋巴结是否转移及病理分期比较,差异均有统计学意义(P<0.05);而两组性别、肿瘤分化程度,肿瘤发生部位及CEA水平比较,差异均无统计学意义(P>0.05)。见表1。gzslib202204011605

2.4 低PAR組和高PAR组生存情况比较 低PAR组术后1、3、5年生存率分别为92.6%、77.2%、60.3%均优于高PAR组的72.5%、36.3%、23.5%,差异均有统计学意义(P<0.01),见图2。

2.5 影响患者预后的因素分析 单因素分析结果显示:术前PAR、肿瘤最大径、浸润深度、淋巴结转移、TNM分期均为胃癌患者根治性手术术后OS的影响因素(P<0.05),见表2。将表2中差异有统计学意义的因素进行多因素分析,结果显示:TNM分期和术前PAR以及淋巴结转移均为胃癌根治性术后OS的独立危险因素[HR=2.288、1.547、2.207,P<0.05],见表3。

3 讨论

许多研究已经证明炎症在实体肿瘤起始、进展和转移过程中都发挥着重要作用。PAR作为衍生的外周血炎症指标之一,在预测一些癌症患者的预后上具有临床价值[8-9],虽然其与肿瘤发生、发展的相关分子机制尚不完全明确,但白蛋白和血小板作为影响肿瘤进展和预后的重要因素,其基础机制已有相应研究。

白蛋白除了能反映机体的营养状况,也可以在一定程度反映机体的炎症程度。恶性肿瘤患者外周血白蛋白水平往往降低,研究表明肿瘤微环境诱导的细胞炎症因子(如肿瘤坏死因子-α,白介素-1和白介素-6)可以抑制肝脏中白蛋白的合成并增加血管通透性,导致血清白蛋白水平降低,而消化道肿瘤导致营养物质吸收障碍,加剧了患者营养不良的状况[10]。有学者指出白蛋白具有抗氧化功能,有助于维持DNA复制和细胞生长的稳定,起到抗癌作用[11],因此,白蛋白降低不仅会影响人体的防御机制,导致免疫功能低下,还可能参与肿瘤的发生发展过程。血清白蛋白降低导致肿瘤患者预后不良的原因除了会损害人体的自然防御机制外,影响抗癌药的分布和药理活性也是重要原因之一[12]。文献[13]的研究结果显示术前白蛋白水平低是胃癌独立的营养预后指标。对于血小板,现有的研究认为其主要从两个方面对癌症的预后产生影响,一方面影响肿瘤相关的静脉血栓栓塞症(venous thromboembolism,VTE)的发展,另一方面影响肿瘤细胞的远处转移,两者最终都会导致肿瘤患者预后不良[14-15]。肿瘤细胞能够吸引和激活血小板,形成纤维蛋白凝块,同时血小板可能通过上调致癌基因直接刺激癌细胞的增殖[16],原因可能是癌症患者的血小板在肿瘤源性刺激的影响下,基因转录物发生了选择性剪接[17-18]。除此之外,癌症患者的血小板被证明可吸收肿瘤成分,有助于增加血小板的黏附倾向,导致血栓形成的风险增加[19]。研究证明VTE的发生与胃癌患者的生存期降低相关,是胃癌患者死亡的独立预测因子[20-21]。实体瘤中,肿瘤细胞在血液循环中存活以及免疫逃逸的主要策略之一是与血小板的相互作用。肿瘤细胞可促进血小板的产生[22],而血小板又可以刺激肿瘤细胞中金属蛋白酶的表达从而促进细胞外基质降解,继而有助于肿瘤细胞侵袭[23-24]。另外,肿瘤细胞可促进血小板聚集速率和血小板P-选择素的表达,经血小板处理的培养基能增强胃癌细胞的增殖和迁移能力[25]。同时,肿瘤的生长离不开血管的生成,肿瘤细胞可以通过分泌ADP等因子来激活血小板[26],进而导致脱颗粒并释放促血管生成和促癌因子[27],肿瘤诱导生成的血小板诱导血管生成的能力和效率更高,可以更有效地递送促血管生成因子[28]。

综上所述,肿瘤患者术前白蛋白和血小板的水平与肿瘤的发生发展及预后存在着密切关系。由于低血清白蛋白和血小板数量升高都表示为癌症患者预后差,则它们的组合可以显示出比各单一标记物更高的预后价值。本研究通过ROC曲线分析确定PAR的最佳界值为4.52×109。Kaplan-Meier生存分析显示低PAR组术后1、3、5年生存率均优于高PAR组(P<0.05)。进一步采用Cox比例风险回归模型分析患者预后的影响因素,结果显示术前PAR水平是胃癌患者预后的独立危险因素之一(P<0.05)。研究数据明确表明术前PAR值的增加是胃癌患者不利的预后因素,且外周血PAR指标成本低、易开展、可重复性好,能够对肿瘤患者生存预后进行有效评估,因此术前血浆PAR水平可与TNM临床分期及其他预后指标一起用于评估胃癌根治术后患者的预后情况,为临床医师治疗决策提供参考,以提高胃癌患者的总体生存率。

然而本研究也存在着一些不足,除肿瘤因素外,许多其他环境和遗传因素也会影响白蛋白和血小板的水平及功能,例如年龄、糖尿病、高血压和性激素等。同时,单中心及样本量的不足可能会对结果产生一定偏倚。另外目前关于PAR在不同肿瘤中的研究不够丰富,PAR能否真正成为预测疗效和预后有价值的因子尚需大量前瞻性研究支持。

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