D-Dimer：預測癌症轉移與進展的新指標

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研究顯示，血漿D-Dimer水平顯著升高與乳腺、胃、胰腺、結腸和直腸癌患者的腫瘤分期和轉移密切相關。D-Dimer作為凝血和纖維蛋白溶解系統的指標，或許能預測癌症的進展及轉移風險，成為癌症治療中的潛在輔助工具。

D-dimer as a potential clinical marker for predicting metastasis and progression in cancer

D‑dimer 作為預測癌症轉移與進展的潛在臨床指標

Dai H, Zhou H, Sun Y, et al. D-dimer as a potential clinical marker for predicting metastasis and progression in cancer. Biomed Rep. 2018;9(5):453-457. doi:10.3892/br.2018.1151

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201047/#:~:text=patients%20(30).-,D%2Ddimer%20is%20a%20widely%20used%20biomarker%20for%20indicating%20the,in%20cancer%20metastasis%20(31).

Abstract

D‑dimer is a widely used biomarker for indicating the activation of coagulation and fibrinolysis, and is reported to serve important roles in cancer progression. The aim of the current retrospective study was to investigate the association of D‑dimer plasma level with the development of various cancers. Patients with breast (n=86), gastric (n=317), pancreatic (n=37), colon (n=153) and rectal (n=137) cancers and 92 healthy volunteers were assessed in the present study. Plasma levels of D‑dimer in the patients and healthy controls were measured by immunoturbidimetric assays. The association of D‑dimer levels with the clinicopathological features of patients were also determined. The plasma levels of D‑dimer were significantly higher in patients with breast cancer (P=0.0022), gastric cancer (P<0.0001), pancreatic cancer (P=0.0003), colon cancer (P=0.0001) and rectal cancer (P=0.0028), compared with the healthy controls. It was also determined that the plasma D‑dimer levels were positively associated with clinical cancer stage (P<0.05) and metastasis (P<0.05). These findings suggested that the plasma D‑dimer level may be used as marker for predicting cancer metastasis and progression.

摘要

D‑dimer 是一種廣泛使用的生物標誌，用於指示凝血和纖維溶解的活化，並被報導在癌症進展中扮演重要角色。本回溯性研究的目的是探討 D‑dimer 血漿濃度與各類癌症發展之間的關聯性。本研究評估了患有乳癌（n=86）、胃癌（n=317）、胰臟癌（n=37）、結腸癌（n=153）和直腸癌（n=137）的患者以及92名健康志願者的情況。透過免疫比濁法測量患者與健康對照組的 D‑dimer 血漿濃度，並確定 D‑dimer 水平與患者臨床病理特徵之間的關聯性。與健康對照組相比，乳癌（P=0.0022）、胃癌（P<0.0001）、胰臟癌（P=0.0003）、結腸癌（P=0.0001）和直腸癌（P=0.0028）患者的 D‑dimer 血漿濃度顯著升高。研究還顯示，D‑dimer 血漿濃度與臨床癌症分期（P<0.05）和轉移（P<0.05）呈正相關。這些發現表明，D‑dimer 血漿濃度可能作為預測癌症轉移和進展的標誌物。

引言

D-dimer 是由凝血系統活化形成的交聯纖維蛋白裂解產物，這表示在凝塊活化和纖維蛋白形成過程中出現了纖維溶解過度的情況（1）。在彌散性血管內凝血（2）、鐮刀型細胞病的血管阻塞危機（3）、血栓栓塞事件（4,5）和心肌梗塞（6）患者中，均可檢測到升高的 D-dimer 水平。D-dimer 是一種廣泛使用的生物標誌，用於指示凝血和纖維溶解的活化（7,8）。凝血障礙是癌症患者中最常見的併發症之一（7,9）。在多種實體癌症患者的血漿中，如前列腺癌（10–12）、子宮頸癌（13–15）和食道鱗狀細胞癌（16），均發現 D-dimer 水平升高。然而，D-dimer 水平與癌症進展之間的關聯性仍是研究的重點。

在本回溯性研究中，首先測量了乳癌、胃癌、胰臟癌、結腸癌和直腸癌患者及健康對照組的 D-dimer 血漿濃度。隨後，評估了 D-dimer 水平與臨床特徵之間的關聯性。結果顯示，D-dimer 血漿濃度與癌症患者的腫瘤轉移程度及腫瘤分期有顯著相關性。

材料與方法

本研究納入的患者均於2010年1月至2014年12月期間在中國常州南京醫科大學附屬常州市第二人民醫院被診斷為乳癌（n=86；年齡範圍，35–79歲；全為女性）、胃癌（n=317；年齡範圍，32–83歲；男性：女性，208:109）、胰臟癌（n=37；年齡範圍，34–82歲；男性：女性，22:15）、結腸癌（n=153；年齡範圍，26–90歲；男性：女性，73:80）或直腸癌（n=137；年齡範圍，44–79歲；男性：女性，81:56）。2016年1月在常州市第二人民醫院接受體檢的92名健康志願者（年齡範圍，23–69歲；男性：女性，43:49）也被納入研究。癌症的診斷依據病理結果。其他納入標準包括通過磁共振成像測量病灶。臨床分期（I–IV期）依據國家綜合癌症網絡臨床實踐指南中的系統（17–21）。排除標準包括由中國血液學會（22–24）根據參數診斷出的彌散性血管內凝血。本回溯性研究經常州市第二人民醫院倫理委員會批准，並在充分告知研究目的和程序後，獲得所有參與者的書面知情同意。

在癌症患者中，D-dimer 濃度在治療前後進行檢測。在健康對照組中，D-dimer 濃度於空腹（前8小時）體檢時進行檢測。從每位受試者的肘前靜脈抽取3毫升全血，並收集於3.8%檸檬酸鈉真空採血管（Greiner Bio-One GmbH, 德國弗里肯豪森）。使用 INNOVANCE®D-Dimer 校準器（西門子公司，德國慕尼黑）分析血漿中的 D-dimer 濃度。所有樣本均根據製造商的建議進行重複測試。D-dimer 的交聯區域具有立體對稱結構，這意味著單克隆抗體的表位出現兩次。由於健康志願者的平均值在90%置信區間內的上限為0.55 mg/l，因此 D-dimer 濃度超過0.55 mg/l 被視為升高。腫瘤患者的 D-dimer 濃度可能會受到手術（25,26）、化療（27,28）和輔助治療（29）後的影響。因此，本研究分析的數據為所有患者治療前的 D-dimer 濃度。

D-dimer 濃度以中位數和範圍表示。健康志願者與癌症患者之間的統計顯著性差異使用未配對 Student’s t 檢驗進行比較。根據 D-dimer 中位數的臨界值，將病例分為高濃度組和低濃度組。使用 χ2 檢驗分析 D-dimer 濃度與臨床病理特徵之間的關聯性。P<0.05 被視為具有統計學顯著性。統計分析與數據繪圖使用 GraphPad Prism 7.00 版（GraphPad Software, Inc.，美國加州拉霍亞）進行。

結果

為探討 D-dimer 在癌症發展中的作用，本研究使用 INNOVANCE®D-Dimer 校準器分析乳癌、胃癌、胰臟癌、結腸癌及直腸癌患者與健康對照組的 D-dimer 濃度。結果顯示，與健康志願者相比，乳癌患者（2.61±0.77 mg/l；n=86；P=0.0022）、胃癌患者（2.85±0.21 mg/l；n=317；P<0.0001）、胰臟癌患者（5.65±1.39 mg/l；n=37；P=0.0003）、結腸癌患者（4.48±0.83 mg/l；n=153；P=0.0001）及直腸癌患者（2.00±0.46 mg/l；n=137；P=0.0028）的 D-dimer 水平顯著升高，而健康志願者的 D-dimer 水平為0.29±0.01 mg/l（n=92；圖1）。這些結果表明，D-dimer 在癌症發展過程中呈現高水平表達，可能在其中扮演重要角色。

”圖

此外，本研究評估了 D-dimer 水平與患者臨床病理特徵之間的關聯性。根據 D-dimer 的表達水平（≤ 或 >0.55 mg/l），樣本被分為兩組。數據顯示，乳癌患者的 D-dimer 血漿濃度在轉移（P=0.0181）和 TNM 分期（P=0.0101）方面存在顯著差異（表 I）；胃癌患者在轉移（P<0.0001）和 TNM 分期（P=0.0063）方面存在顯著差異（表 II）；胰臟癌患者在 TNM 分期（P=0.0395）方面存在顯著差異（表 III）；結腸癌患者在轉移（P=0.0120）、TNM 分期（P=0.0039）和性別（P=0.0145）方面存在顯著差異（表 IV）；直腸癌患者在轉移（P=0.0104）和 TNM 分期（P=0.0002）方面存在顯著差異（表 V）。在 D-dimer 水平與其他臨床特徵之間未發現差異（表 I–V）。這些數據表明，D-dimer 血漿濃度可能作為癌症進展的標誌物。

表 I. - D-dimer 水平與乳癌患者臨床病理變數之間的臨床相關性。 表 II. - D-dimer 水平與胃癌患者臨床病理變數之間的臨床相關性。 表 III. - D-dimer 水平與胰臟癌患者臨床病理變數之間的臨床相關性。 表 IV. - D-dimer 水平與結腸癌患者臨床病理變數之間的臨床相關性。 表 V. - D-dimer 水平與直腸癌患者臨床病理變數之間的臨床相關性。

討論

本研究顯示，乳癌、胃癌、結腸癌及直腸癌患者的 D-dimer 血漿濃度升高與臨床癌症分期和轉移有關。此外，胰臟癌患者的 D-dimer 血漿濃度與癌症分期相關，而結腸癌患者的 D-dimer 水平則與性別相關。這些發現表明，D-dimer 濃度在預測多種癌症的轉移和進展方面具有潛在應用價值。

遠端轉移是癌症患者預後不良的主要原因，並導致治療效果不佳（30）。D-dimer 是一種廣泛使用的生物標誌，用於指示凝血和纖維溶解的活化。已知在惡性腫瘤中常見的凝血活化在癌症轉移中扮演重要角色（31）。癌症患者的凝血/纖維溶解系統被激活，可能促進癌症的進展（14）。因此，與腫瘤相關的凝血和纖維溶解系統的降解產物被提出可用於預測腫瘤負荷和預後（14,32）。血漿 D-dimer 是一種促凝血因子，可能反映微轉移或循環腫瘤細胞的存在，這些細胞可能導致腫瘤復發（30,33,34）。近期研究報告顯示，轉移性乳癌患者的循環腫瘤細胞與血漿 D-dimer 水平呈正相關（35,36）。Diao 等人（37）觀察到遠端轉移的胃癌患者，尤其是內臟轉移患者的血漿 D-dimer 水平顯著升高。事實上，他們建議 D-dimer 是胃癌患者臨床分期的有前景的預測指標（37）。Lee 等人（38）報告說，在結直腸癌患者中，血漿 D-dimer 和纖維蛋白原降解產物水平的升高與 TNM 分期顯著相關。此外，結直腸癌患者的術前血漿 D-dimer 水平與較大的腫瘤大小和淋巴結轉移相關（39）。其他近期研究顯示，血漿 D-dimer 值可能預測胰臟癌患者的總生存期和無進展生存期（40,41）。與上述研究一致，本研究證實了 D-dimer 水平與腫瘤發生之間的正相關性。進一步發現，D-dimer 水平與胰臟癌患者的癌症分期相關，但與轉移無關。在胰臟癌患者中，多數患者（34/37）已出現轉移，並且與無轉移癌症患者相比，轉移性胰臟癌患者的纖維蛋白原和糖類抗原 19-9（CA19-9）顯著升高（數據未顯示），這表明 D-dimer、纖維蛋白原和 CA19-9 的組合可用於預測胰臟癌的轉移。

總之，本回溯性研究顯示癌症患者的 D-dimer 血漿濃度顯著升高，並與臨床分期和轉移相關。目前的研究僅限於發現 D-dimer 與腫瘤分期和轉移之間的關聯性。我們將進一步探討 D-dimer 作為腫瘤發生指標的靈敏度和特異性，以及 D-dimer 與癌症患者生存和預後之間的關聯性，以確定 D-dimer 濃度是否可以被認為是癌症患者預後中的重要因素。

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