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Abstract

BACKGROUND:

Platelets play a crucial role in cancer progression and metastasis. The aim of the present study was to assess the relationship between platelet indices and non-small cell lung cancer (NSCLC) with brain metastases.

METHODS:

Between January 2015 and December 2017, 232 NSCLC patients with brain metastases and 244 NSCLC patients without metastases were retrospectively analyzed. Patients’ clinicopathological characteristics data were collected.

RESULTS:

Platelet count was increased and mean platelet volume (MPV) was reduced in NSCLC patients with brain metastases compared with NSCLC patients without metastases. In addition, the prevalence of NSCLC decreased as MPV quartiles increased. After adjusting for other risk factors, the ORs (95% CIs) for NSCLC brain metastases according to MPV quartiles were 1.757 (1.024–3.015), 2.097 (1.209–3.635), 1.517 (0.874–2.635), and 1.000, respectively.

CONCLUSIONS:

MPV is reduced in NSCLC patients with brain metastases compared with NSCLC patients without metastases. Moreover, MPV is found to be independently associated with the presence of NSCLC brain metastases.

Keywords

Non-small cell lung cancer mean platelet volume platelet activation

1. Introduction

Lung cancer is the leading cause of cancer deaths and non-small cell lung cancer (NSCLC) accounts for 85% lung cancer cases [1, 2]. Nearly 20–40% NSCLC patients will develop brain metastases [3]. The median survival time of NSCLC brain metastases is only approximately 9.3–19.1 months [4, 5, 6]. Therefore, identification of clinically useful biomarkers in NSCLC brain metastases is urgently needed.

Platelets play a recognized role in various stages of cancer growth and metastasis [7, 8]. Mean platelet volume (MPV) indicates platelets activation and is closely related to different inflammatory conditions [9]. Pla-telet distribution width (PDW) reflects variation in platelet size and differentiates thrombocytopenia [10]. Altered MPV levels were detected in various types of cancer, such as lung cancer, breast cancer, gastric cancer, colorectal cancer, and ovarian cancer [11, 12, 13, 14, 15]. A study reported that decreased MPV predicted worse outcome in NSCLC patients [12]. Moreover, our previous study revealed that elevated PDW predicts a worse prognosis in NSCLC patients [16]. However, little information is available concerning platelet indices in NSCLC patients with metastases.

Table 1
Baseline characteristics of NSCLC patients

Variables	With brain metastases	Without brain metastases	$P$ value
N	232	244
Age (years)	56.3 (9.5)	57.7 (9.5)	0.123
Gender (male, %)	155 (66.8)	142 (58.2)	0.052
BMI (kg/m ${}^{2}$ )	22.4 (3.2)	23.3 (3.1)	0.003
Smoker (n, %)
(Ever/current, %)	128 (55.2)	132 (54.1)	0.814
Alcohol
(Ever/current, %)	64 (27.6)	70 (28.7)	0.789
FPG (mmol/L)	5.20 (4.80–5.70)	5.10 (4.73–5.56)	0.080
Albumin (g/L)	43.1 (5.5)	44.0 (5.6)	0.103
Creatinine (umol/L)	76.4 (19.6)	74.7 (16.0)	0.309
Hypertension (%)	39 (16.8)	49 (20.1)	0.358
Diabetes (%)	16 (6.9)	17 (7.0)	0.976
WBC ( $\times$ 10 ${}^{9}$ /L)	8.1 (3.0)	6.9 (2.4)	$<$ 0.001
Haemoglobin (g/dl)	136.8 (19.2)	138.0 (18.0)	0.493
Platelet count ( $\times$ 10 ${}^{9}$ /L)	278.4 (81.0)	240.4 (69.1)	$<$ 0.001
MPV (fL)	8.4 (1.2)	8.8 (1.4)	0.004
PDW (%)	17.2 (1.0)	17.0 (1.8)	0.229
Histological type			0.009
Adenocarcinoma	113 (48.7)	148 (60.7)
Non-adenocarcinoma	119 (51.3)	96 (39.3)

NSCLC, non-small cell lung cancer; BMI, body mass index; FPG, fasting plasma glucose; WBC, white blood cell; MPV, mean platelet volume; PDW, platelet distribution width.

The aim of the present study was to assess the relationship between platelet indices and NSCLC brain metastases.

2. Patients and methods

2.1 Study population

Two hundred and thirty-two NSCLC patients with brain metastases and 244 NSCLC patients without metastases at the Harbin Medical University Cancer Hospital between January 2015 and December 2017 were enrolled in the retrospective study. The inclusion criteria were as follows: (1) diagnosis of NSCLC was confirmed by histology; (2) brain metastasis was diagnosed by magnetic resonance imaging (MRI); (3) untreated before diagnosis. The Institutional Review Board of Harbin Medical University Cancer Hospital approved this study. Written informed consent was obtained from all patients.

Figure 1.

The prevalence rate of NSCLC brain metastases (%) according to MPV quartiles.

Table 2

Platelet indices in NSCLC patients

Variables	PLT ( $\times$ 10 ${}^{9}$ /L)	$P$ value	MPV(fL)	$P$ value	PDW(%)	$P$ value
Without brain metastases
Tumor size		0.034		0.011		0.363
$>$ 4 cm	255.4 (70.8)		8.4 (1.2)		17.2 (1.3)
$\leqslant$ 4 cm	234.6 (67.7)		8.9 (1.4)		16.9 (2.0)
Differentiation		0.883		0.316		0.194
Well/moderate	240.8 (69.2)		8.8 (1.4)		17.1 (1.6)
Poor	239.4 (69.3)		8.6 (1.2)		16.8 (2.2)
Histological type		$<$ 0.001		0.324		0.606
Adenocarcinoma	227.3 (58.7)		8.9 (1.4)		17.1 (1.9)
Non-adenocarcinoma	260.6 (78.7)		8.7 (1.3)		16.9 (1.7)
T stage		0.029		0.259		0.106
T1 $+$ T2	236.9 (66.5)		8.8 (1.4)		17.1 (1.7)
T3 $+$ T4	266.7 (82.4)		8.5 (1.1)		16.5 (2.3)
Lymph node metastasis		0.842		0.340		0.597
Present	241.7 (65.1)		8.9 (1.3)		16.9 (2.2)
Absent	239.8 (71.1)		8.7 (1.4)		17.1 (1.6)
Cancer stage		0.236		0.501		0.051
I $+$ II	237.2 (69.6)		8.7 (1.4)		17.2 (1.6)
III	248.9 (67.5)		8.9 (1.4)		16.7 (2.2)
With brain metastases
Histological type		0.060		0.120		0.535
Adenocarcinoma	268.1 (77.7)		8.6 (1.3)		17.2 (1.1)
Non-adenocarcinoma	288.1 (83.2)		8.3 (1.1)		17.1 (0.9)
Number of brain metastases		0.081		0.301		0.525
1–3	290.9 (87.2)		8.3 (1.3)		17.2 (1.1)
$>$ 3	271.5 (76.9)		8.5 (1.2)		17.1 (0.9)
Size of brain metastases		0.722		0.529		0.404
$<$ 3 cm	279.4 (82.5)		8.5 (1.3)		17.3 (0.9)
$\geqslant$ 3 cm	274.7 (76.2)		8.3 (1.0)		17.1 (1.0)
Extracranial metastases		0.946		0.678		0.718
Present	279.1 (72.0)		8.5 (1.0)		17.1 (0.9)
Absent	278.2 (83.2)		8.4 (1.3)		17.2 (1.0)
Karnofsky performance status		0.970		0.768		0.416
$<$ 70	277.9 (88.9)		8.4 (1.6)		17.3 (1.3)
$\geqslant$ 70	278.4 (79.8)		8.4 (1.2)		17.2 (0.9)

PLT, platelet; MPV, mean platelet volume; PDW, platelet distribution width.

2.2 Statistical analysis

Statistical analysis of the differences between two groups was performed using the Student’s t test, Mann-Whitney’s U-test, and $\chi^{2}$ test. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for brain metastasis were calculated after adjusting for confounding variables across MPV quartiles using multivariate logistic regression analysis. All subjects were stratified into quartiles according to their MPV levels. The MPV quartiles were quartile 1 (Q1) ( $\leqslant$ 7.7 fL), quartile 2 (Q2) (7.8–8.4 fL), quartile 3 (Q3) (8.5–9.3 fL), quartile 4 (Q4) ( $\geqslant$ 9.4 fL). $P<$ 0.05 was considered to indicate a statistically significant difference. The statistical analyses were carried out using SPSS Statistics version 22.0 (SPSS Inc., Chicago, IL, USA).

3. Results

The baseline clinicopathological characteristics of NSCLC patients are listed in Table 1. Of the 476 NSCLC patients enrolled, 297 (62.4%) were men and 179 (37.6%) were women. The patients with brain metastasis had lower body mass index and MPV, and higher white blood cell and platelet count. The numbers of patients with adenocarcinoma were 113 and 148 in brain metastasis group and non-brain metastasis group, respectively. However, age, gender, smoking status, drinking status, fasting plasma glucose, albumin, creatinine, haemoglobin, and PDW in the two groups had no difference.

The platelet indices in NSCLC patients were shown in Table 2. In the group of non-brain metastasis, platelet count was significantly associated with histological type, tumor size and T stage. MPV was associated with tumor size. In the group of brain metastasis, there were no differences of platelet indices observed in histological type, number of brain metastases, size of brain metastases, extracranial metastases, and Karnofsky performance status.

The prevalence of brain metastasis was calculated by the quartiles of MPV levels (Fig. 1). The prevalence rate of brain metastasis in Q1, Q2, Q3, and Q4 was 51.6% (65/126), 56.7% (68/120), 48.3% (57/118), and 37.5% (42/112), respectively. The results indicated that the prevalence of brain metastasis reduced as MPV quartiles increased ( $p<$ 0.001).

The risks of brain metastasis according to MPV quartiles are shown in Table 3. After adjusting for age, gender, BMI, smoking status, drinking status, hypertension, diabetes, and white blood cell, the prevalence risk of brain metastasis for the lowest quartile of MPV was 1.757 (1.024–3.015).

Table 3
The risks of brain metastases in NSCLC patients according to MPV quartiles

	Cases	Controls	OR (95% CI)	$p$ -value
Q1 ( $\leqslant$ 7.7 fL)	65	61	1.757 (1.024–3.015)	0.041
Q2 (7.8–8.4 fL)	68	52	2.097 (1.209-3.635)	0.008
Q3 (8.5–9.3 fL)	57	61	1.517 (0.874–2.635)	0.139
Q4 ( $\geqslant$ 9.4 fL)	42	70	1 (reference)

Logistic regression analysis adjusted for age, gender, BMI, smoking status, drinking status, hypertension, diabetes, albumin, creatinine, and WBC. MPV, mean platelet volume; CI, confidence interval.

4. Discussion

Our study demonstrated that the NSCLC patients with brain metastases have lower MPV levels compared to the NSCLC patients without metastases. Furthermore, MPV was found to be independently associated with the presence of brain metastases. Our results indicted the potential role of anti-platelet treatment in NSCLC brain metastases.

Emerging evidence revealed the pivotal role of platelets in cancer progression [17]. Thrombocytosis is associated with reduced survival in various types of cancers, including brain, lung, breast, stomach, pancreas, rectum, ovary, endometrium, kidney cancer [18, 19]. Increased platelet count was associated with metastases to lymph node, bone, soft tissue, and malignant pleural effusion in lung cancer [20]. Moreover, platelet-derived growth factor (PDGF) beta-receptor expression was significantly higher in rare sarcomatoid NSCLC compared with non-sarcomatoid NSCLC controls [21]. Platelet factor 4 was found to modulate the tumor microenvironment to accelerate tumor outgrowth [22]. In addition, the PDGF pathway may also boost tumor growth directly through activation of downstream signaling pathway [23]. A recent study confirmed that a PDGF receptor inhibitor inhibited cell migration and invasion by suppressing the PDGFR downstream signaling cascades in NSCLC cells [24].

The mechanism underlying the association of decreased MPV with NSCLC brain metastases remains unknown. Cancer-associated inflammation may be a common mechanism for reduced MPV. MPV is an early marker of activated platelets. Decreased MPV could be regarded as an enhanced consumption of large platelets in inflammatory states [9]. Recent reports revealed that MPV were reduced in high-grade inflammatory diseases, which could be reversed in the course of anti-inflammatory therapy [9]. Some reports confirmed the change of MPV in NSCLC patients [12, 25]. Our study further verified the key role of MPV in NSCLC patients with brain metastases. These data are also aligned with the current concept that anti-platelet is considered to be a part of cancer adjuvant therapy [26]. Moreover, elevated MPV suggests us to further evaluate whether there are brain metastases for NSCLC patients.

Our current study included several limitations. First, this was a single-center retrospective study. Second, the exact mechanism of MPV in NSCLC brain metastases is needed to clarify. Third, the application to other ethnic groups needs further investigation because the patients in our study were composed of Chinese. Therefore, additional larger prospective studies with multiethnic groups are needed to confirm our results.

In summary, MPV is reduced in NSCLC patients with brain metastases compared with NSCLC patients without metastases. Moreover, MPV is found to be independently associated with the presence of NSCLC brain metastases. Further studies are warranted to clarify the exact role of MPV in NSCLC brain metastases.

Footnotes

Acknowledgments

This work was supported by grants from the Harbin Medical University Cancer Hospital (JJZD2017-05).

Conflict of interest

None.

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Platelet indices in non-small cell lung cancer patients with brain metastases

Abstract

BACKGROUND:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

Table 1 Baseline characteristics of NSCLC patients

2.1 Study population

3. Results

Table 3 The risks of brain metastases in NSCLC patients according to MPV quartiles

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Baseline characteristics of NSCLC patients

Table 3
The risks of brain metastases in NSCLC patients according to MPV quartiles