The D-dimer level predicts the postoperative prognosis in patients with non-small cell lung cancer.

BACKGROUND: Carcinoma cells often modulate coagulation and fibrinolysis among cancer patients. Plasma dimerized plasmin fragment D (D-dimer) has been reported as a prognostic marker of various types of malignancies, including non-small cell lung cancer (NSCLC). However, the associations between the plasma D-dimer level and peripheral small NSCLC remain unclear.
METHODS: Three hundred and sixty-two patients with NSCLC who underwent radical surgery were retrospectively reviewed. Patients who received anticoagulation therapy before surgery or who lacked preoperative D-dimer data were excluded. The other 235 patients were divided into a high D-dimer (over 1.0 μg/mL) group (HDD group, n = 47) and a normal D-dimer group (NDD group, n = 188) and investigated for their clinical characteristics, computed tomography (CT) findings, pathological findings, and clinical outcomes.
RESULTS: The mean D-dimer levels was 2.49±2.58 μg/ml in the HDD group and 0.42±0.23 μg/ml in the NDD group. The HDD group was characterized by a predominance of male gender, older age, pure solid appearance on chest CT, vascular invasion in pathology, and a large solid part of the tumor. The HDD group showed a worse overall survival, disease-free survival, and disease-specific survival than the NDD group (p<0.001, <0.001, <0.001, respectively). These survival features were also observed in p-Stage IA disease. There was no marked survival difference when tumors showed ground-glass opacity on CT.
CONCLUSION: In NSCLC patients with a solid tumor appearance on CT, high D-dimer levels predict a poor survival and early recurrence.

Introduction

Carcinoma cells often affect coagulation and fibrinolysis in cancer patients due to their inducing cytokines and coagulation factors. Plasma dimerized plasmin fragment D (D-dimer) has been reported as a prognostic marker of various types of malignancies. Man et al. showed that pretreatment plasma D-dimer, fibrinogen, and platelet levels reflected the prognosis in patients with epithelial ovarian cancer [1]. Several previous studies have reported that, in operable non-small cell lung cancer (NSCLC) patients, the D-dimer levels predict the risk of postoperative early recurrence and a poor prognosis [2, 3]. Little information has been obtained regarding the relationship between the plasma D-dimer level and the detailed clinicopathologic features of NSCLC patients, although multiple overlapping and interacting mechanisms that can explain the increased incidence of thrombosis in patients with malignancies are reported [4-5].

Recently, improvements in and the spread of computed tomography (CT) have increased the chance of detecting small-size peripheral lung cancers. Hattori et al. showed that patients with tumors showing a ground-glass appearance on CT had a better prognosis than those with tumors with a pure solid appearance [6]. Such a radiologic feature is very important when considering surgical management for peripheral small NSCLC, i.e. whether to perform limited resection or conventional lobectomy.

Therefore, in the present study, we investigated the associations between the plasma D-dimer levels and clinicopathologic factors, including the tumor appearances on chest CT.

Materials and methods

Patients

A total of 362 patients with NSCLC who underwent radical surgery at Chiba University Hospital between April 2015 and March 2017 were retrospectively reviewed using a prospectively registered database. Patients who had received anticoagulation therapy that affected the D-dimer level before surgery were excluded. In 235 patients, the plasma D-dimer level was measured within 2 months before surgery for a routine checkup of deep vein thrombosis (n = 78) or for an observational study to monitor postoperative thrombus of pulmonary venous stump (UMIN000017528) (n = 157). We divided the patients into 2 groups: a high D-dimer (over 1.0 μg/mL) group (HDD group, n = 47) and a normal D-dimer (less than 1.0 μg/mL) group (NDD group, n = 188) (Fig 1). The cut off value of D-dimer was decided based on the Japanese guidelines, “Guidelines for Diagnosis, Treatment and Prevention of Pulmonary Thromboembolism and Deep Vein Thrombosis” [7]. The 235 subjects of this study and the 119 patients excluded due to a lack of available D-dimer data showed a similar clinicopathologic profile except for age (S1 Table), and their survival curves were almost perfectly superimposed (S1 Fig).

Fig 1

The flow chart of the patients in this study.

The patients were divided into 2 groups: a high D-dimer (over 1.0 μg/mL) group (HDD group, n = 47) and a normal D-dimer group (NDD group, n = 188).

All patients had undergone thin slice CT (1 mm every 1 mm) prior to surgery, and the CT findings were reviewed by all thoracic surgeons and a board-certified radiologist (AN) at the clinical conference. The two groups were compared for their clinical characteristics, tumor appearance on chest CT, histology and histological subtypes and clinical outcomes. In this study, clinical staging was determined based on preoperative findings for CT, fluorodeoxyglucose-positron emission tomography (PET) and magnetic resonance imaging of the head. Lymph nodes greater than 1.0 cm in the short axis by CT or with a standardized uptake value (SUV) of > 2.5 by Pere considered positive and subjected to a biopsy for precise nodal staging. TNM staging was coded according to the International Association for the Study of Lung Cancer (IASLC) staging system (the 8th edition). In uni/multiple analyses, not pathological TNM staging but clinical staging is used so as to search for predict survival factors prior to surgery. All patients had 0 or 1 ECOG performance status.

This study was approved by the ethics committee of Chiba University, Graduate School of Medicine (No.3093). All patients’ data were fully anonymized before we accessed them and the ethics committee of Chiba University waived the requirement for informed consent.

Statistical analyses

Statistical analyses were performed using the JMP pro software program, ver. 13 (SAS Institute Inc, Tokyo, Japan). Survival curves were estimated using the Kaplan-Meier method. The log-rank statistic was used for the comparison of the overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) distributions. Cox proportional hazards models were used to estimate the hazard ratios for the OS. We considered results to be significant at p < 0.05.

Results

Patients’ characteristics by D-dimer level

The mean D-dimer level was 2.49±2.58 μg/ml in the HDD group and 0.42±0.23 μg/ml in the NDD group. The HDD group was characterized by a predominance of male gender, older age, pure solid appearance on chest CT, a large solid part of the tumor, advanced c-T factor, advanced c-N factor and advanced c-staging compared with the NDD group (Table 1). Regarding pathology and treatment, the HDD group was also characterized by a predominance of advanced p-staging, pathological upstaging, vessel involvement (v+), and undergoing induction therapy than NDD group (Table 2). There were no significant differences in histologic subtypes of adenocarcinomas, surgical procedure, and adjuvant therapy between the two groups.

Table 1

Clinical characteristics of both groups.

		HDD group	NDD group	P value
		n = 47	n = 188
D-dimer	, μg/ml	2.5±2.6	0.4±0.2	-
Age	, years	71.4±7.5	67.0±9.3	0.001
Gender	(%)			0.028
	Male	36 (77)	110 (59)
	Female	11 (23)	78 (41)
Size of the solid part of the tumor (mm)		33.3±25.8	21.9±15.7	0.003
CT appearance				0.020
	Pure solid	40 (85)	123 (65)
	Part solid GGN	7 (15)	52 (28)
	Pure GGN	0 (0)	13 (7)
cT				<0.001
	T1	24(51)	138(73)
	T2	11(23)	42(22)
	T3	5(11)	3(2)
	T4	7(15)	5(3)
cN				0.012
	N0	39(83)	177(94)
	N1-3	8(17)	11(6)
cStage				0.009
	I	163(87)	32(68)
	II	15(8)	8(17)
	III	10(5)	7(15)

D-dimer: plasma dimerized plasmin fragment D, HDD: patients with a high D-dimer level, NDD: patients with a normal D-dimer level, GGN: ground-glass attenuation-dominant nodule, CT: computed tomography

Table 2

Pathological and treatment parameters of both groups.

		HDD group	NDD group	P value
		n = 47	n = 188
p-Stage				0.398
	I	27 (57)	146 (78)
	II	10 (21)	25 (13)
	III	10 (21)	17 (9)
Pathologic upstaging		19(40)	41(20)	0.004
Histology				0.185
	Adenocarcinoma	31 (66)	155 (82)
	Squamous cell carcinoma	14 (30)	41 (22)
	LCNEC	0 (0)	2 (1)
	Large cell carcinoma	1 (2)	1 (1)
	Pleomorphic carcinoma	0 (0)	2 (1)
	Carcinoid	0 (0)	2 (1)
Micropapillary pattern				0.746
	(+)	2 (4)	14 (30)
	(-)	45 (96)	174 (93)
pleural invasion				0.416
	(-)	40 (85)	144 (77)
	(+)	7 (15)	44 (23)
Nodule count				0.700
	Single nodule	46 (98)	184 (98)
	Separate nodule in the same lobe	0 (0)	1 (1)
	Separate nodule in a different ipsilateral lobe	1 (2)	1 (1)
Lymphatic invasion				0.066
	(-)	38 (81)	168 (89)
	(+)	9 (19)	18 (10)
Vascular invasion				0.014
	(-)	28 (60)	148 (79)
	(+)	19 (40)	40 (21)
Surgical procedure				0.433
	Lobectomy or more	12(26)	38(20)
	Sublobar resection	35(75)	150(80)
Induction therapy		6(13)	4(2)	<0.001
	Chemotherapy	2(4)	2(1)
	Chemo-radiation therapy	4(8)	2(1)
Adjuvant therapy		9(19)	38(19)	0.984
	Chemotherapy	6(13)	36(18)
	Radiation therapy	1(2)	1(0)
	Chemo-radiation therapy	2(4)	1(0)

HDD: patients with a high D-dimer level, NDD: patients with a normal D-dimer level, LCNEC: large cell neuroendocrine carcinoma.

Clinical outcomes

During postoperative follow-up, recurrence was observed in 14 (29.8%) and 28 (13.7%) patients in the HDD and NDD groups, respectively (p = 0.015). The HDD group had more distant recurrences than did the NDD group (p = 0.045) (Table 3). In contrast, there was no significant difference in the local recurrence between the 2 groups (p = 0.218). The HDD group showed a worse OS (p<0.001), DFS, (p<0.001) and DSS (p<0.001) than the NDD group (Fig 2). Even in p-Stage IA patients, the HDD group showed a worse OS (p<0.001), DFS, (p<0.001) and DSS (p<0.001) than the NDD group (Fig 3).

Table 3

Types of recurrence of both groups.

		HDD groupn = 47	NDD groupn = 188	P value
Recurrence
	Local	6(13)	14(7)	0.218
	Distant	8(17)	14(7)	0.045

HDD: patients with a high D-dimer level, NDD: patients with a normal D-dimer level.

Fig 2

Kaplan-Meier survival curves among the total patients.

Kaplan-Meier survival curves of the postoperative overall survival (A), disease-free survival (B) and disease-specific survival (C) by preoperative D-dimer level among the total patients in this study.

Fig 3

Kaplan-Meier survival curves among patients with p-Stage IA disease.

Kaplan-Meier survival curves of the postoperative overall survival (A), disease-free survival (B) and disease-specific survival (C) by preoperative D-dimer level among patients with p-Stage IA disease.

In a multivariate analysis, a high D-dimer level (hazard ratio [HR] 5.75; 95% confidence interval [CI], 2.12–15.56; p<0.001) and c-T (HR: 4.60, 95% CI, 1.42–14.92; p = 0.011) were independent prognostic factors (Table 4). The HR of CT findings could not be calculated due to no events occurring in patients with ground-glass attenuation-dominant nodules. In an analysis of patients with a pure solid appearance, a high D-dimer level (HR: 5.50; 95% CI, 1.67–11.56; p = 0.003) and c-T (HR: 4.30, 95% CI, 1.54–18.09; p = 0.011) were also found to be independent prognostic factors according to a multivariate analysis (S2 Table). Regarding the patients with ground-glass attenuation-dominant nodules (n = 72), only 1 patient in the NDD group showed recurrence of disease. There was no significant difference in the OS, DFS or DSS between the HDD and NDD groups. In patients with a pure solid appearance on CT (n = 163), the HDD group showed a worse OS (p < 0.001), DFS (p = 0.008) and DSS (p = 0.002) than the NDD group (Fig 4).

Table 4

Uni- and multivariate analyses for the OS.

		Univariate analysis		Multivariate analysis
		Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value
Age (years)
	<70	-
	≥70	1.34 (0.54–3.38)	0.522
Gender
	Male	2.34 (0.85–8.21)	0.105
	Female	-
cN
	0	-		-
	1	1.39 (0.08–6.84)	0.760	1.35 (0.07–7.59)	0.788
	2	3.60 (0.57–12.71)	0.147	2.03 (0.30–8.22)	0.412
	3	-		-
cT
	1	-		-
	2	0.89 (0.20–2.91)	0.857	0.69 (0.17–2.86)	0.604
	3	5.48 (0.84–20.91)	0.070	3.00 (0.63–14.36)	0.169
	4	9.29 (2.88–26.29)	< 0.001	4.60 (1.42–14.92)	0.011
CT appearance
	Pure solid		- *		- *
	With GGN
D-dimer (μg/mL)
	≥1	7.54(3.12–19.26)	< 0.001	5.75(2.12–15.56)	< 0.001
	< 1	-		-

GGN: ground-glass attenuation-dominant nodule, CI: confidence interval, CT: computed tomography, OS: overall survival

*The hazard ratio of computed tomography findings could not be calculated because no events occurred in patients with ground-glass attenuation-dominant nodules.

Fig 4

Kaplan-Meier survival curves among patients with solid CT appearance.

Kaplan-Meier survival curves of postoperative overall survival (A), disease free survival (B), and disease specific survival (C) by preoperative D-dimer level, among patients with solid CT appearance.

Discussion

Peripheral small-size lung cancer is basically treated by lobectomy if possible, with the role of segmentectomy for such tumors still controversial [8-10]. Even among peripheral early-stage lung cancers, micropapillary- or solid predominant-type adenocarcinoma has been reported to have a poor prognosis [11, 12], and anatomical lobectomy is recommended over segmentectomy because of the increased frequency of local recurrence [13]. NSCLC with ground-glass opacity on CT has shown favor clinical outcomes; however, the preoperative projection of the prognosis is difficult in NSCLC with a pure solid appearance.

We focused on the serum D-dimer level and CT findings to identify new predictors of postoperative outcomes in peripheral small NSCLC. While no correlation was noted between the histology or histological subtypes and the D-dimer level, surgical pathology revealed a relationship between the D-dimer level and vessel involvement of tumors. However, we also found that the patients with ground-glass opacity had favor prognoses despite their serum level of D-dimer. Hattori et al. recently showed that the presence of a ground-glass nodule component is a significant prognostic factor in early-stage NSCLC and that patients with ground-grass opacity tumors had an excellent prognosis (≥90%) irrespective of clinical T factors [6, 14]. Given the results of this study, the preoperative serum D-dimer level did not affect in NSCLC patients with ground-glass opacity tumor.

Previous studies have reported the utility of several coagulation parameters, such as D-dimer, fibrinogen or platelet count, as prognostic markers in patients with several types of malignancies, including lung cancer. Ma et al. showed that high serum D-dimer levels were associated with a poor prognosis in lung cancer patients in a meta-analysis of 11 studies [15]. Zhu et al. showed that D-dimer and fibrinogen could be used to predict the chemotherapy efficacy and prognosis in patients with small cell lung cancer [16]. Inal et al. showed that the D-dimer levels were decreased in chemotherapy responders but increased in non-responders among lung cancer patients [17]. Several recent studies have described the association of a poor prognosis with high D-dimer levels in operable NSCLC patients [2-3]. Gao et al. revealed that the D-dimer level is useful for predicting lymph node metastasis [18]. Several prospective studies of other organs have shown that the association of high coagulation parameters with a poor prognosis was independent of venous thromboembolism [19-20]. The D-dimer level might thus affect the prognosis solely through an important role in tumorigenesis separately from the venous thromboembolism pathway.

Several reports have shown that tumor-mediated coagulation activation is associated with tumor growth, angiogenesis promotion and metastasis [21]. Platelets are reported to increase the metastatic success via multiple mechanisms, including direct shielding of tumor cells and protection of tumor cells from cytokines [22-23]. The fibrinolytic system has been reported to promote tumor growth through several different mechanisms, including angiogenesis, suppressing apoptosis, proliferation of tumor cells and degradation of the extracellular matrix [24]. These previous findings may explain why the HDD group had more distant metastasis in the present study than NDD group did. However, the mechanism underlying the association between the serum D-dimer level and the aggressiveness of NSCLC remains unclear. Regarding the pathology in the present study, tumors in the HDD group frequently invaded vessels. Some studies have found that thrombin increased the invasiveness of cancer [25-26], although no report has mentioned the coagulation system and vessel invasion. Although increased D-dimer levels might be a result of vessel injury due to tumor invasion, the association between the D-dimer levels and vessel invasion is unclear and more detailed studies are required.

One limitation of this study was the retrospective nature of the analysis and its performance at a single center. Most of the patients in this study were subjects of an observational study to monitor pulmonary venous thrombosis, as described in the Materials and Methods section; however, there were no marked differences in the clinicopathologic profiles and survival outcomes between the 235 subjects of this study and the 119 patients who were excluded due to a lack of available D-dimer data. A prospective study will be needed to confirm the existence of a relationship between the D-dimer level and tumor aggressiveness as well as the clinical outcome in NSCLC, especially in peripheral small disease. Another limitation was that no aberrant driver genes were assessed in the study. A certain proportion of patients with adenocarcinoma have driver gene alterations. For example, the existence of epidermal growth factor receptor (EGFR) gene mutations and the use of EGFR tyrosine kinase inhibitors contributes to a better survival.

Conclusions

In NSCLC patients with a solid tumor appearance on CT, high D-dimer levels predict a poor survival and early recurrence. The type of surgery as well as careful post-operative follow-up should be considered in this population.

Survival curves of the subject of this study and excluded patients.

For the 235 subjects of this study and 119 excluded patients due to no available D-dimer data, Kaplan-Meier curves of postoperative overall survival (A), disease free survival (B) and disease specific survival (C) were compared.

(TIF)

Click here for additional data file.

Clinicopathologic profiles of the subjects of this study and patients excluded from the study.

(DOCX)

Click here for additional data file.

Uni- and multivariate analyses for the OS in patients with a pure solid appearance.

(DOCX)

Click here for additional data file.

The data of patients used in this study.

(XLS)

Click here for additional data file.

23 Jul 2019

PONE-D-19-18111

The D-dimer level predicts the postoperative prognosis in patients with non-small cell lung cancer

PLOS ONE

Dear Dr. Nakajima,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

(1) Description of a normal range of D-dimer

(2) Discussion about therapeutic intervention for patients with non-small cell lung cancer (NSCLC) who underwent radical surgery

(3) Discussion about the effects of surgical procedure, if any

(4) Discussion related to vascular invasion and distant metastasis

(5) Discussion related to venous thromboembolism (VTE) and prognosis

(6) Other issues pointed out by Reviewers

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Ichiro Yoshino received honorarium from Pfizer Inc., SHIONOGI＆CO., LTD., Astellas Pharma Inc., Nippon Boehringer Ingelheim CO., Ltd., DAIICHI SANKYO COMPANY, LIMITED., Chugai Pharmaceutical Co., Ltd., ONO PHARMACEUTICAL CO., LTD., TEIJIN PHARMA LIMITED.

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Reviewer #1: The authors investigated whether D-dimer was a prognostic impactor for patients with non-small cell lung cancers. Although not that novel, the study was reliable and the analysis was appropriate.

1. What's the normal range of D-dimer in the institution?

2. Why ten patients received induction therapy?

3. Since the small number of patients in each cN group, I wonder if it would be integrated into with or without lymph node metastasis.

4. As for HDD group, any further examination or intervention has been used?

5. Did surgical procedure (Lobectomy vs sublobar resection) impact the prognosis?

Reviewer #2: This is an interesting original work, and the only necessary thing to do is to have more appropriate references, shaping a bit different discussion, and thus making more profound and comprehensive explanations for your findings. Just to mention, vascular invasion should be in this context adequately discussed, as well as the tendency of more distant metastasis in the HDD group than in the NDD group although not significant difference in the type of recurrence, as well as NSCLC with a solid tumor appearance on CT in the context of the poorer prognosis. More recent references should be used - there are several large scaled prospective studies that found that the association of high D-dimer levels with poor prognosis was independent of VTE in hematologic malignancies and solid tumors, which raised the question that D-dimer might be able to affect prognosis through a VTE independent pathway, thus pointing that D-dimer may play an important role in the tumorigenesis.

Some suggested references, among necessary to add and comment:

-Lyman GH, Khorana AA. Cancer, clots and consensus: new understanding of an old problem. J Clin Oncol. 2009; 27:4821-4826.

-Zhao J, Zhao M, Jin B, et al. Tumor response and survival in patients with advanced non-small-cell lung cancer: the predictive value of chemotherapy-induced changes in fibrinogen. BMC Cancer 2012; 12:330.

-Zhu L, Liu B, Zhao Y, Liu L, Yang C, Yang Y, Zhong H. High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab. J Cancer Res Ther. 2014; 10:246-251.

-Chen Y, Yu H, Wu C, Li J, Jiao S, Hu Y, Tao H, Wu B, Li A. Prognostic value of plasma D-dimer levels in patients with small-cell lung cancer. Biomed Pharmacother. 2016; 81:210-217.

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11 Aug 2019

Dear editor

We wish to express our appreciation to the Reviewers for their insightful comments, which have helped us to significantly improve the paper.

Response to Reviewers

Reviewer #1: The authors investigated whether D-dimer was a prognostic impactor for patients with non-small cell lung cancers. Although not that novel, the study was reliable and the analysis was appropriate.

1. What's the normal range of D-dimer in the institution?

Answer: The normal range of D-dimer was less than 1.0µg/ml. We have added the following sentence.

“a normal D-dimer (less than 1.0 µg/mL) group”, to Page 4, Line 70

2. Why ten patients received induction therapy?

Answer: Ten patients had mediastinal lymph node metastasis which was diagnosed as N2, stage IIIA lung cancer. The multidisciplinary team conference which was consisted of thoracic surgeons, respirologists, medical oncologists, and radiologists decided to perform multidisciplinary treatment including induction chemo-radiotherapy following surgery for these patients.

3. Since the small number of patients in each cN group, I wonder if it would be integrated into with or without lymph node metastasis.

Answer: Thank you very much for your suggestion. We have changed the table 1.

4. As for HDD group, any further examination or intervention has been used?

Answer: almost all patients in this study, both for HDD group and NDD group, underwent contrasted CT scan in order to exclude pulmonary artery embolism prior to thoracotomy.

5. Did surgical procedure (Lobectomy vs sublobar resection) impact the prognosis?

Answer: Thank you very much for your suggestion. There was no prognostic difference between the patients who underwent lobectomy or more and the patients with sublobar resection.

Reviewer #2: This is an interesting original work, and the only necessary thing to do is to have more appropriate references, shaping a bit different discussion, and thus making more profound and comprehensive explanations for your findings. Just to mention, vascular invasion should be in this context adequately discussed, as well as the tendency of more distant metastasis in the HDD group than in the NDD group although not significant difference in the type of recurrence, as well as NSCLC with a solid tumor appearance on CT in the context of the poorer prognosis. More recent references should be used - there are several large scaled prospective studies that found that the association of high D-dimer levels with poor prognosis was independent of VTE in hematologic malignancies and solid tumors, which raised the question that D-dimer might be able to affect prognosis through a VTE independent pathway, thus pointing that D-dimer may play an important role in the tumorigenesis.

Some suggested references, among necessary to add and comment:

-Lyman GH, Khorana AA. Cancer, clots and consensus: new understanding of an old problem. J Clin Oncol. 2009; 27:4821-4826.

-Zhao J, Zhao M, Jin B, et al. Tumor response and survival in patients with advanced non-small-cell lung cancer: the predictive value of chemotherapy-induced changes in fibrinogen. BMC Cancer 2012; 12:330.

-Zhu L, Liu B, Zhao Y, Liu L, Yang C, Yang Y, Zhong H. High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab. J Cancer Res Ther. 2014; 10:246-251.

-Chen Y, Yu H, Wu C, Li J, Jiao S, Hu Y, Tao H, Wu B, Li A. Prognostic value of plasma D-dimer levels in patients with small-cell lung cancer. Biomed Pharmacother. 2016; 81:210-217.

Answer: Thank you very much for your very important comments and suggestions. As the reviewer suggested, recent publications suggested the correlation between D-dimer level and poor prognosis. We have added the suggested reference.

We have added the following sentences.

“Several prospective studies of other organs have shown that the association of high coagulation parameters with a poor prognosis was independent of venous thromboembolism [19] [20]. The D-dimer level might thus affect the prognosis solely through an important role in tumorigenesis separately from the venous thromboembolism pathway.” , to Page 15, Line 201

“Several reports have shown that tumor-mediated coagulation activation is associated with tumor growth, angiogenesis promotion and metastasis [21]. Platelets are reported to increase the metastatic success via multiple mechanisms, including direct shielding of tumor cells and protection of tumor cells from cytokines [22] [23]. The fibrinolytic system has been reported to promote tumor growth through several different mechanisms, including angiogenesis, suppressing apoptosis, proliferation of tumor cells and degradation of the extracellular matrix [24]. These previous findings may explain why the HDD group had more distant metastasis in the present study than NDD group did.”, to Page 15, Line 206

“Some studies have found that thrombin increased the invasiveness of cancer [25] [26], although no report has mentioned the coagulation system and vessel invasion. Although increased D-dimer levels might be a result of vessel injury due to tumor invasion, the association between the D-dimer levels and vessel invasion is unclear and more detailed studies are required” , to Page 15, Line 216

As the reviewer suggested, we reanalyze the recurrences, dividing the recurrences into local and distance recurrences. We have also added the following sentences, and modified the table 3.

“The HDD group had more distant recurrences than did the NDD group (p=0.045) (Table 3). In contrast, there was no significant difference in the local recurrence between the 2 groups (p=0.218).”, to Page 10, line 130

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21 Aug 2019

The D-dimer level predicts the postoperative prognosis in patients with non-small cell lung cancer

PONE-D-19-18111R1

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11 Dec 2019

PONE-D-19-18111R1

The D-dimer level predicts the postoperative prognosis in patients with non-small cell lung cancer

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