Prognostic value of C-reactive protein levels in patients with bone neoplasms: A meta-analysis
Li Z (2018)
Prognostic value of C-reactive protein levels in
patients with bone neoplasms: A meta-analysis.
PLoS ONE 13(4): e0195769. https://doi.org/
Prognostic value of C-reactive protein levels in patients with bone neoplasms: A meta- analysis
Wenyi Li 0 1
Xujun Luo 0 1
Zhongyue Liu 0 1
Yanqiao Chen 1
Zhihong Li 0 1
0 Department of Orthopedic, The Second Xiangya Hospital, Central South University , Changsha, Hunan , China , 2 Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University , Changsha, Hunan , China
1 Editor: Surinder K. Batra, University of Nebraska Medical Center , UNITED STATES
The aim of this study was to conduct a meta-analysis of retrospective studies that investigated the association of preoperative C-reactive protein (CRP) levels with the overall survival (OS) of patients with bone neoplasms. A detailed literature search was performed in the Cochrane Library, Web of Science, Embase and PubMed databases up to August 28, 2017, for related research publications written in English. We extracted the data from these studies and combined the hazard ratios (HR) and 95% confidence intervals (CIs) to assess the correlation between CRP levels and OS in patients with bone neoplasms. Five studies with a total of 816 participants from several countries were enrolled in this current meta-analysis. In a pooled analysis of all the publications, increased serum CRP levels had an adverse prognostic effect on the overall survival of patients with bone neoplasms. However, the combined data showed no significant relationship between the level of CRP and OS in Asian patients (HR = 1.73; 95% CI: 0.86±3.49; P = 0.125). Similar trends were observed in patients with bone neoplasms when stratified by ethnicity, histology, metastasis and study sample size.
☯ These authors contributed equally to this work; * lizhihong@csu; edu; cn
Competing interests: The authors have declared
that no competing interests exist.
The results of this meta-analysis suggest that increased CRP expression indicates a poorer
prognosis in patients with bone neoplasms. More prospective studies are needed to confirm
the prognostic significance of CRP levels in patients with bone neoplasms.
Primary neoplasms of bone, namely osteosarcoma, chondrosarcoma, and the Ewing's sarcoma
family of tumors, are estimated to affect 3240 new patients and to cause 1550 deaths each year
in the U.S. [
]. Osteosarcoma and Ewing's sarcoma occur most commonly in teenagers, while
chondrosarcoma occurs more frequently in older adults. Despite advances in surgical
techniques and continuous efforts to improve therapy regimens, the 5-year relative survival rates
of bone cancers have remained relatively stable since the 1980s. Therefore, multiple studies are
being conducted to determine new markers for prognosis and targets for prospective
treatments for those cancers [
C-reactive protein (CRP) is a common acute phase serum protein. It was first discovered in
the plasma of patients with pneumonia and was named after its reactivity with the C
polysaccharide derived from the pneumococcal cell wall [
]. CRP can interact with multiple ligands
and receptors, including phosphocholine (PC) on pathogenic organism and damaged cell
membranes, nuclear antigens, C1q in the classical complement pathway, and FcγRI and
FcγRII on the surface of leukocytes, allowing it to play an important role in innate immunity
]. CRP is produced by hepatocytes, mainly in response to interleukin-6 (IL-6) secreted by T
cells and macrophages, which regulates CRP production at the transcriptional level [
]. In the
circulating blood of healthy adults, CRP is only present in trace amounts, but its level rapidly
rises within 2 hours of the onset of trauma, infection, and inflammation, and decreases quickly
after the resolution of such conditions. Therefore, it has been used as a common marker for
inflammation. Interestingly, CRP has been proven to be strongly associated with various
cancers, exhibiting diagnostic or prognostic value [6±13]. While multiple studies have been
carried out, the relationship between CRP and the prognosis of bone cancer remains
controversial, with end results varying among studies. To evaluate the significance of the preoperative
level of CRP for the outcome of bone cancer patients, we did a systematic review and
metaanalysis using updated data on individual patients from all available trials.
Compliance with ethical standards
Ethical approval: All procedures performed in studies involving human participants were
performed in accordance with the ethical standards of the institutional and/or the national
research committee and with the 1964 Helsinki declaration and its later amendment.
PubMed, Cochrane Library, Web of Science and Embase were thoroughly searched up to
August 28, 2017 using the following key words: ªC-reactive proteinº, ªbone neoplasmsº and
ªbone cancerº. All studies identified in this manner were retrieved. The references of the
selected studies were also searched for other relevant studies. The publication language was
limited to English. The titles and abstracts of the selected studies were screened to filter
appropriate studies, and the full texts were evaluated carefully. There were no restrictions on the
number of patients in these published studies. This meta-analysis was registered in
PROSPERO (http://www.crd.york.ac.uk/PROSPERO), and the registration number for this article is
The following inclusion criteria were used: 1) patients included in studies were pathologically
diagnosed as having bone neoplasms; 2) the level of CRP was evaluated before treatment; 3)
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the study provided HRs and 95% CIs for CRP in terms of OS or the data necessary to calculate
them; 4) the publications were written in English. The exclusion criteria were as follows: 1)
articles that were reviews, meeting abstracts, or letters, or lacking the full text in English; 2)
nonhuman studies; 3) studies that did not provide the levels of CRP before treatment. If the
data sets overlapped or were duplicated, only the most recent information was included in this
meta-analysis. All identified studies were investigated independently for eligibility by two
Two independent authors (W, L and X, L) independently extracted information from the
eligible studies, and any disagreement between them was resolved by discussion and consensus.
The following information was recorded from the 5 included studies: the surname of the first
author, the study country, the year of publication, the sample size, the survival data and the
detailed information regarding the bone neoplasms.
The quality assessment of the primary studies was performed according to the
NewcastleOttawa quality assessment scale (NOS). The maximum possible score is 9 points, and studies
scoring 6 points were regarded as high-quality studies (http://www.ohri.ca/programs/
All statistical analysis was carried out by STATA 14.0 (STATA Corp, College Station, TX) .
Statistical heterogeneity among the studies was evaluated with Q and I2 statistics, with the
significance level set at p <0.05 . If there was significant heterogeneity among the studies, the
random effects model was used to calculate the pooled HR and 95% CI . The potential
publication bias was estimated using Begg's test . P< 0.10 was considered statistically
significant. Sensitivity analyses were performed by excluding each study individually from the
The characteristics of the included studies
The flow diagram of the current study is presented in Fig 1. Five relevant studies with a total of
816 patients were selected for initial review by the search strategies described above [18±22].
The sample sizes ranged from 85 to 318 participants. All the enrolled studies were
retrospective. Of these studies, three [18, 19, 22] were carried out in Europe, and the remaining studies
were conducted in Asia. Only two publications [18, 22] involved patients with osteosarcoma
and other kinds of bone neoplasms, and the other three studies focused on osteosarcoma [19±
21]. An elevated level of CRP was defined as 8 mg/l or 75 nmol/l in one study ;
otherwise, a normal level of CRP was defined as less than 10 mg/dl. Among the participants, there
were 671 patients with distant metastasis, and 145 with no distant metastasis. All enrolled
publications defined OS as the time from diagnosis to the day of death or the day of the last
followup. The articles were published between 2011 and 2016, and the NOS scores of the included
studies ranged from 6±9. The detailed information is shown in Table 1.
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Fig 1. Flow chart of the study selection.
Relationship between CRP and OS in bone neoplasms
The five selected studies provided the levels of CRP before treatment and OS in patients
with bone neoplasms. The random effects model showed a significant relationship between
elevated levels of CRP and OS in patients with bone neoplasms (HR: 1.87; 95% CI: 1.28±2.75;
P = 0.001), with heterogeneity (I2 = 62.4%, P = 0.031, Fig 2).
To detect the potential source of heterogeneity, the subgroup analyses were stratified by
ethnicity, histology, metastasis and sample size (Table 2, Fig 3). As presented in Table 2, the
relationship between the level of CRP and OS was not significant in Asian populations (HR = 1.73;
95% CI: 0.86±3.49; P = 0.125) (I2 = 44.4%; P = 0.18). However, the elevated CRP predict poorer
OS in patients in Europe (HR = 1.96; 95% CI: 1.51±3.34; P = 0.013) (I2 = 77.4%; P = 0.01). We
also performed subgroup analyses on histology, metastasis and sample size to further explain
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S,C and R
S and C
S,C and R
Fig 2. Forest plot of the association between the level of CRP and OS in patients with bone neoplasms. Summary of estimated hazard ratios (HRs) and 95% CI
for patients with bone neoplasms.
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Fig 3. Forest plot of the association between the level of CRP and OS in patients with bone neoplasms stratified by
ethnicity (A), histology (B), metastasis (C) and sample size (D). Summary of estimated hazard ratios (HRs) and 95% CI for
patients stratified by (A) ethnicity, (B) histology, (C) metastasis and (D) sample size.
PLOS ONE | https://doi.org/10.1371/journal.pone.0195769
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Fig 4. Sensitivity analysis of the relationship between CRP level and OS in bone neoplasms. Sensitivity analyses were performed by
excluding each study individually from the meta-analysis.
the results of this meta-analysis. Among patients with osteosarcoma, increased CRP was
correlated with shortened OS (HR = 1.52; 95% CI: 1.10±2.09; P = 0.01) (I2 = 17.8%; P = 0.30), and
the same was true for patients with other kinds of bone cancer (HR = 1.87; 95% CI: 1.28±2.75;
P = 0.02) (I2 = 76.0%; P = 0.04). An increased level of CRP was correlated with decreased
survival in patients regardless of metastasis (Table 2). Similar trends were also observed when
stratified according to sample size (Table 2).
Publication bias and sensitivity analysis
Significant heterogeneity was discovered among all studies (I2 = 62.4%, P = 0.031). The
influence of each individual study on the combined HRs was evaluated by systematically deleting
one included study at a time. The results showed that the pooled HRs for OS were robust in
our study (Fig 4). Moreover, Egger's test showed no evidence of obvious publication bias
(P = 0.473) (Fig 5).
The current meta-analysis summarized the results of five retrospective studies, involving a
total of 816 participants. By combining the HRs and 95% CIs from all studies, we showed the
association between preoperational serum levels of CRP and the overall survival of patients
with bone neoplasms. Our result revealed that higher levels of CRP are associated with shorter
OS, with an HR of 1.87 (95% CI: 1.28±2.75; P = 0.001), indicating that high serum levels of
CRP before treatment may be a negative prognostic factor for patients with bone cancers.
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Fig 5. Begg's funnel plot of the publication bias test for CRP level and OS in bone neoplasms. Summary of funnel
plots of publication bias for the included studies. They are funnel plots of the publication bias for this meta-analysis of
hazard ratios (HRs).
However, stratified analysis by region showed no significant relationship between the level of
CRP and OS in Asia (HR = 1.73; 95% CI: 0.86±3.49; P = 0.125). There might be several reasons
for this result. First, the susceptibility genes for bone neoplasms in Asia are different from
those in Europe, which might lead to different levels of CRP in patients with bone neoplasms.
Second, the use of treatment regimens in Asia was significantly different from that in Europe,
which might explain the lack of a correlation between the level of CRP and OS in Asia. Finally,
the instruments measuring the levels of CRP were not the same in different places, which
might cause the different results in Asia and Europe.
Inflammation has been proven to be closely related to all stages of cancer development. It
may contribute to cancer initiation by supplying reactive oxygen and nitrogen species that
damage DNA directly and it may alter DNA methylation and histone modification, thereby
influencing gene expression . Inflammation also facilitates tumor promotion by producing
growth factors to sustain proliferation, survival factors to limit cell death, and proangiogenic
factors to increase neovascularization . Furthermore, inflammation can assist metastatic
progression by providing inductive signals that activate epithelial±mesenchymal transition
and extracellular matrix-modifying enzymes that aid tumor invasion, as well as by suppressing
anti-tumor immune response . Elevated levels of systemic inflammation have been
indicated as being associated with worse survival in patients with solid tumors [26, 27]. Other
inflammation biomarkers including the NLR (neutrophil to lymphocyte ratio), the PLR
(platelet to lymphocyte ratio) and the mGPS (modified Glasgow prognostic score) could reflect the
cancer-related inflammatory status and have been used as prognostic indicators in other
cancers [28±32]. As an important biomarker of systemic inflammation, CRP is synthesized by
liver cells in response to microbial invasion or tissue injury [
]. CRP is considered a
non-specific but sensitive marker of inflammation. While it is well established that CRP levels rise
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rapidly during acute infection, inflammation, and tissue damage, elevated CRP levels are also
seen as an important risk factor for atherosclerosis [
], stroke [35±37], and myocardial
]. Given that the inflammatory response plays a vital role in cancer, it is not surprising
to find increased CRP levels in various cancers. In fact, the serum CRP level before treatment
has been proven to be an independent prognostic factor in hepatocellular [
], esophageal [
], renal [
], bladder [
], prostate [
], colorectal [
], ovarian [
], pancreatic [
and non-small cell lung cancer [
]. Large prospective studies looking for associations between
circulating concentrations of CRP and cancer risks have produced conflicting results. Positive
relationships were found between serum CRP levels and the increased risk of colorectal and
lung cancers, while other studies indicated no relationship between CRP levels and breast,
prostate or colorectal cancers [
]. Although the exact functional mechanism of CRP in the
development of cancer remains obscure, several hypotheses have been proposed to explain this
relationship. First, a causality model has been proposed wherein chronic inflammation causes
the elevation of CRP levels, which initiates the formation of malignant tumors. Second, a
reverse causality model has been proposed wherein tumor growth and invasion induces tissue
inflammation, leading to the increase in CRP levels. A third proposed mechanism states that
the body's innate and adaptive immune systems may react to tumor antigens by increasing
CRP levels. A fourth proposed mechanism cites the fact that tumor cells can produce CRP
themselves, and they are also able to release cytokines such as IL-6 and IL-8, which contribute
to the increase in CRP levels.
The results of this meta-analysis support increased levels of CRP as a prognostic factor for
OS in bone cancer, which agrees with the results of most studies [18±20, 22]. We noticed that
the previous study carried out by Yi, J. H. also evaluated whether the level of CRP was
correlated with the outcome of patients with osteosarcoma [
]. The literature enrolled in that
study only included studies published by 2013, and only two studies were included. Unlike
that previous study, we had stricter inclusion criteria and enrolled 3 articles published in 2015
and 2016, including a relatively larger number of participants with detailed information. In
addition, the research conducted by Yi, J. H. did not evaluate the association between CRP
level and OS stratified by ethnicity, histology, metastasis or sample size, as we did. In addition,
we concluded that there was no significant relationship between the CRP level and OS in
Asian populations based on data from only two studies; therefore, the results should be
interpreted with caution. Furthermore, three of the enrolled studies only included patients with
osteosarcoma [19±21], although the remaining studies included patients with other kinds of
bone cancer [18, 22]. As we know, different kinds of bone cancer might have different overall
survival times, which may have contributed to the high heterogeneity in this meta-analysis. An
elevated CRP level was defined as less than 10 mg/dl in all studies except one , which
might also explain the high degree of heterogeneity. All survival data were extracted from
multi-factor analyses adjusted for potential confounding factors, including gender, age, stage,
treatment and other biomarkers. However, due to the limited information presented in the
studies, it was not possible to perform a subgroup analysis according to all cofounding factors.
This research does have several limitations. First, obvious heterogeneity existed in this
meta-analysis. Although the sensitivity analysis and the publication bias test indicated the
credibility of the results, we could not rule out the cofounding factors or the study criteria that
may have resulted in discrepancies between the studies. Second, all the studies included were
retrospective studies instead of prospective ones, and therefore the result may represent
reverse causation, survival bias or confounding. Third, this study only focused on the CRP
level before treatment, and to further investigate its prognostic value, the levels of CRP after
surgery and at recurrence should also be taken into consideration.
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Generally, our meta-analysis demonstrated the prognostic value of increased preoperative
levels of CRP for poorer OS in patients with bone cancer in Europe but not in Asia. However,
given the limitations mentioned above, these findings should be treated with caution when
applied to clinical practice. More prospective cohort studies are warranted to confirm our
S1 Table. Search strategy for meta-analysis of prognostic value of C-reactive protein levels
in patients with bone neoplasms.
S1 Checklist. PRISMA checklist for meta-analysis of prognostic value of C-reactive protein
levels in patients with bone neoplasms.
This study was funded by the National Natural Science Foundation of China (No.81372180).
Conceptualization: Wenyi Li, Zhihong Li.
Data curation: Wenyi Li, Xujun Luo.
Formal analysis: Wenyi Li.
Methodology: Xujun Luo, Zhongyue Liu, Yanqiao Chen.
Project administration: Zhongyue Liu.
Writing ± original draft: Wenyi Li, Xujun Luo, Zhongyue Liu, Yanqiao Chen, Zhihong Li.
Writing ± review & editing: Wenyi Li, Xujun Luo, Zhongyue Liu, Yanqiao Chen, Zhihong Li.
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Eggers H, Seidel C, Schrader AJ, Lehmann R, Wegener G, Kuczyk MA, et al. Serum C-reactive protein:
a prognostic factor in metastatic urothelial cancer of the bladder. Med Oncol. 2013; 30(4):705. https://
doi.org/10.1007/s12032-013-0705-6 PMID: 24005810.
Kinoshita A, Onoda H, Takano K, Imai N, Saeki C, Fushiya N, et al. Pretreatment serum C-reactive
protein level predicts poor prognosis in patients with hepatocellular carcinoma. Med Oncol. 2012; 29
(4):2800±8. https://doi.org/10.1007/s12032-012-0220-1 PMID: 22460836.
Li YJ, Li ZM, Xia Y, Huang JJ, Huang HQ, Xia ZJ, et al. Serum C-reactive protein (CRP) as a simple and
independent prognostic factor in extranodal natural killer/T-cell lymphoma, nasal type. PLoS One.
2013; 8(5):e64158. https://doi.org/10.1371/journal.pone.0064158
Oh BS, Jang JW, Kwon JH, You CR, Chung KW, Kay CS, et al. Prognostic value of C-reactive protein
and neutrophil-to-lymphocyte ratio in patients with hepatocellular carcinoma. BMC Cancer. 2013;
Shao N, Cai Q. High pretreatment serum C-reactive protein level predicts a poor prognosis for
combined small-cell lung cancer. Tumor Biology. 2015; 36(11):1±6.
Tomita M, Shimizu T, Ayabe T, Nakamura K, Onitsuka T. Elevated preoperative inflammatory markers
based on neutrophil-to-lymphocyte ratio and C-reactive protein predict poor survival in resected
nonsmall cell lung cancer. Anticancer Research. 2012; 32(8):3535±8. PMID: 22843942
Higgins JP, Green S. Cochrane Handbook For Systematic Reviews Of Interventions Version 5.0.0.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. British
Medical Journal. 2003; 327(7414):557±60. https://doi.org/10.1136/bmj.327.7414.557 PMID: 12958120
O'Rourke K, Shea B, Wells GA. Meta-Analysis of Clinical Trials: Springer New York; 2001. 397±424 p.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias.
Biometrics. 1994; 50(4):1088±101. Epub 1994/12/01. PMID: 7786990.
11 / 13
12 / 13
1. Howlader N , Noone AM , Krapcho M , Miller D , Bishop K , Kosary CL , et al. SEER Cancer Statistics Review , 1975 ±2014 National Cancer Institute2017 [cited 2017 August 28] . https://seer.cancer.gov/csr/ 1975_2014/.
2. Evola FR , Costarella L , Pavone V , Caff G , Cannavò L , Sessa A , et al. Biomarkers of Osteosarcoma , Chondrosarcoma, and Ewing Sarcoma . Frontiers in pharmacology. 2017; 8.
3. Tillett WS , Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus . Journal of Experimental Medicine . 1930 ; 52 ( 4 ): 561 ± 71 . PMID: 19869788
4. Marnell L , Mold C , Du Clos TW. C-reactive protein: Ligands, receptors and role in inflammation . Clinical Immunology . 2005 ; 117 ( 2 ): 104 ± 11 . https://doi.org/10.1016/j.clim. 2005 . 08 .004 PMID: 16214080
5. Castell JV , GoÂmez-lechoÂn MJ , David M , Fabra R , Trullenque R , Heinrich PC . Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6 . Hepatology. 1990 ; 12 ( 5 ): 1179 ± 86 . PMID: 1699862
6. Allin KH , Nordestgaard BG . Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Critical reviews in clinical laboratory sciences . 2011 ; 48 ( 4 ): 155 ± 70 . Epub 2011/11/01. https://doi. org/10.3109/10408363. 2011 .599831 PMID: 22035340 .
7. Alifano M , Falcoz PE , Seegers V , Roche N , Schussler O , Younes M , et al. Preresection serum C-reactive protein measurement and survival among patients with resectable non-small cell lung cancer . J Thorac Cardiovasc Surg . 2011 ; 142 ( 5 ): 1161 ±7. https://doi.org/10.1016/j.jtcvs. 2011 . 07 .021 PMID: 21872279 .
Aggerholm-Pedersen N , Maretty-Kongstad K , Keller J , Baerentzen S , Safwat A . The prognostic value of serum biomarkers in localized bone sarcoma . Translational Oncology . 2016 ; 9(4):322±8 . https://doi.
org/10 .1016/j.tranon. 2016 . 05 .006 PMID: 27567955 Funovics PT , Edelhauser G , Funovics MA , Laux C , Berzaczy D , Kubista B , et al. Pre-operative serum C-reactive protein as independent prognostic factor for survival but not infection in patients with highgrade osteosarcoma . International orthopaedics . 2011 ; 35 ( 10 ): 1529 ± 36 . Epub 2011/01/21. https://doi.
org/10.1007/s00264-011-1208-8 PMID: 21249357.
Tumor Biology . 2015 ; 36 ( 7 ): 5663 ±6. https://doi.org/10.1007/s13277-015-3240-6 PMID: 25986475 Liu B, Huang Y , Sun Y , Zhang J , Yao Y , Shen Z , et al. Prognostic value of inflammation-based scores in patients with osteosarcoma . Scientific reports . 2016 ; 6 : 39862 . Epub 2016/12/23. https://doi.org/10.
1038 /srep39862 PMID: 28008988 .
Nakamura T , Grimer RJ , Gaston CL , Watanuki M , Sudo A , Jeys L . The prognostic value of the serum level of Creactive protein for the survival of patients with a primary sarcoma of bone . Journal of Bone and Joint SurgeryÐSeries B . 2013 ; 95 B(3):411±8 .
Elinav E , Nowarski R , Thaiss CA , Hu B , Jin C , Flavell RA . Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms . Nature reviews Cancer . 2013 ; 13 ( 11 ): 759 ± 71 .
Epub 2013 /10/25. https://doi.org/10.1038/nrc3611 PMID: 24154716 .
Mantovani A , Allavena P , Sica A , Balkwill F . Cancer-related inflammation . Nature . 2008 ; 454 ( 7203 ): 436 . https://doi.org/10.1038/nature07205 PMID: 18650914 Qian BZ . Inflammation fires up cancer metastasis . Seminars in cancer biology . 2017 ; 47 : 170 ±6. https:// doi.org/10.1016/j.semcancer. 2017 . 08 .006 PMID: 28838845 .
European journal of cancer . 2011 ; 47 ( 17 ): 2633 ± 41 . https://doi.org/10.1016/j.ejca. 2011 . 03 .028 PMID: 21724383 .
Roxburgh CS , McMillan DC . Role of systemic inflammatory response in predicting survival in patients with primary operable cancer . Future oncology . 2010 ; 6 ( 1 ): 149 ± 63 . https://doi.org/10.2217/fon.09.136 PMID: 20021215 .
Su K , Wang X , Chi L , Liu Y , Jin L , Li W. High glasgow prognostic score associates with a poor survival in Chinese advanced non-small cell lung cancer patients treated with platinum-based first-line chemotherapy . International Journal of Clinical and Experimental Medicine . 2016 ; 9 ( 8 ): 16353 ± 9 .
Wang X , Teng F , Kong L , Yu J . Pretreatment neutrophil -to-lymphocyte ratio as a survival predictor for small-cell lung cancer . Onco Targets Ther . 2016 ; 9 : 5761 ± 70 . https://doi.org/10.2147/OTT.S106296 PMID: 27703374 .
30. Lan H , Zhou L , Chi D , Zhou Q , Tang X , Zhu D , et al. Preoperative platelet to lymphocyte and neutrophil to lymphocyte ratios are independent prognostic factors for patients undergoing lung cancer radical surgery: A single institutional cohort study . Oncotarget . 2017 ; 8 ( 21 ): 35301 ± 10 . Epub 2016/11/16. https:// doi.org/10.18632/oncotarget.13312 PMID: 27845912 .
31. Sanchez-Salcedo P , de-Torres JP , Martinez-Urbistondo D , Gonzalez-Gutierrez J , Berto J , Campo A , et al. The neutrophil to lymphocyte and platelet to lymphocyte ratios as biomarkers for lung cancer development . Lung Cancer . 2016 ; 97 : 28 ± 34 . https://doi.org/10.1016/j.lungcan. 2016 . 04 .010 PMID: 27237024 .
32. Kos M , Hocazade C , Kos FT , Uncu D , Karakas E , Dogan M , et al. Prognostic role of pretreatment platelet/lymphocyte ratio in patients with non-small cell lung cancer . Wien Klin Wochenschr . 2016 ; 128 ( 17 ± 18): 635 ± 40 . https://doi.org/10.1007/s00508-015-0724-8 PMID: 25720573 .
33. Morris-Stiff G , Gomez D , Prasad KR . C-reactive protein in liver cancer surgery . European Journal of Surgical Oncology (EJSO) . 2008 ; 34 ( 7 ): 727 ±9. https://doi.org/10.1016/j.ejso. 2008 . 01 .016 PMID: 18356004
34. Libby P , Ridker PM , Maseri A. Inflammation and Atherosclerosis. Circulation. 2002 ; 105 ( 9 ): 1135 ± 43 . https://doi.org/10.1161/hc0902.104353 PMID: 11877368
35. Rost NS , Wolf PA , Kase CS , Kelly-Hayes M , Silbershatz H , Massaro JM , et al. Plasma Concentration of C-Reactive Protein and Risk of Ischemic Stroke and Transient Ischemic Attack . The Framingham Study . 2001 ; 32 ( 11 ): 2575 ±9. https://doi.org/10.1161/hs1101.098151
36. Muir KW , Weir CJ , Alwan W , Squire IB , Lees KR . C-Reactive Protein and Outcome After Ischemic Stroke . Stroke . 1999 ; 30 ( 5 ): 981 ±5. https://doi.org/10.1161/01.str. 30.5.981 PMID: 10229731
37. Zhou F , Zhou L , Guo T , Wang N , Hao H , Zhou Y , et al. Plasma proteomics reveals coagulation, inflammation, and metabolic shifts in H-type hypertension patients with and without acute ischemic stroke . Oncotarget . 2017 ; 8 ( 59 ): 100384 ± 95 . Epub 2017/12/17. https://doi.org/10.18632/oncotarget.22233 PMID: 29245986 .
38. Ridker PM , Glynn RJ , Hennekens CH . C-Reactive Protein Adds to the Predictive Value of Total and HDL Cholesterol in Determining Risk of First Myocardial Infarction . Circulation . 1998 ; 97 ( 20 ): 2007 ±11. https://doi.org/10.1161/01.cir. 97 .20. 2007 PMID: 9610529
39. Hashimoto K , Ikeda Y , Korenaga D , Tanoue K , Hamatake M , Kawasaki K , et al. The impact of preoperative serum C-reactive protein on the prognosis of patients with hepatocellular carcinoma . Cancer . 2005 ; 103 ( 9 ): 1856 ± 64 . Epub 2005/03/22. https://doi.org/10.1002/cncr.20976 PMID: 15779015 .
40. Nozoe T , Saeki H , Sugimachi K. Significance of preoperative elevation of serum C-reactive protein as an indicator of prognosis in esophageal carcinoma . American journal of surgery . 2001 ; 182 ( 2 ): 197 ± 201 . Epub 2001/09/28. PMID: 11574097 .
41. Gockel I , Dirksen K , Messow CM , Junginger T. Significance of preoperative C-reactive protein as a parameter of the perioperative course and long-term prognosis in squamous cell carcinoma and adenocarcinoma of the oesophagus . World journal of gastroenterology . 2006 ; 12 ( 23 ): 3746 ± 50 . Epub 2006/ 06/15. https://doi.org/10.3748/wjg.v12. i23 .3746 PMID: 16773693 .
42. Lamb GW , McMillan DC , Ramsey S , Aitchison M. The relationship between the preoperative systemic inflammatory response and cancer-specific survival in patients undergoing potentially curative resection for renal clear cell cancer . British journal of cancer . 2006 ; 94 ( 6 ): 781 ± 4 . Epub 2006/03/09. https://doi. org/10.1038/sj.bjc.6603034 PMID: 16523196 .
43. Johnson T , Harris W , Watkins A , Michigan A , Ogan K , Pattaras J , et al. CRP- based classification of localized renal cell carcinoma into low, intermediate and high riskof mortality 2011 . e667 p.
44. Gakis G , Todenhofer T , Renninger M , Schilling D , Sievert KD , Schwentner C , et al. Development of a new outcome prediction model in carcinoma invading the bladder based on preoperative serum C-reactive protein and standard pathological risk factors: the TNR-C score . BJU international. 2011 ; 108 ( 11 ): 1800 ± 5 . Epub 2011/04/22. https://doi.org/10.1111/j. 1464 - 410X . 2011 . 10234 . x PMID : 21507193 .
45. Prins RC , Rademacher BL , Mongoue-Tchokote S , Alumkal JJ , Graff JN , Eilers KM , et al., editors. Creactive protein as an adverse prognostic marker for men with castration-resistant prostate cancer (CRPC): confirmatory results . Urologic Oncology: Seminars and Original Investigations; 2012: Elsevier.
46. Thomsen M , Kersten C , Sorbye H , Skovlund E , Glimelius B , Pfeiffer P , et al. Interleukin-6 and C-reactive protein as prognostic biomarkers in metastatic colorectal cancer . Oncotarget . 2016 ; 7 ( 46 ): 75013 ± 22 . Epub 2016/10/16. https://doi.org/10.18632/oncotarget.12601 PMID: 27738330 .
47. Hefler LA , Concin N , Hofstetter G , Marth C , Mustea A , Sehouli J , et al. Serum C-reactive protein as independent prognostic variable in patients with ovarian cancer. Clinical cancer research: an official journal of the American Association for Cancer Research . 2008 ; 14 ( 3 ): 710 ± 4 . Epub 2008/02/05. https:// doi.org/10.1158/ 1078 - 0432 .ccr- 07 -1044 PMID: 18245530 .
48. Szkandera J , Stotz M , Absenger G , Stojakovic T , Samonigg H , Kornprat P , et al. Validation of C-reactive protein levels as a prognostic indicator for survival in a large cohort of pancreatic cancer patients . British journal of cancer . 2014 ; 110 ( 1 ): 183 . https://doi.org/10.1038/bjc. 2013 .701 PMID: 24201751
49. Gagnon B , Abrahamowicz M , Xiao Y , Beauchamp ME , MacDonald N , Kasymjanova G , et al. Flexible modeling improves assessment of prognostic value of C-reactive protein in advanced non-small cell lung cancer . British journal of cancer . 2010 ; 102 ( 7 ): 1113 ± 22 . Epub 2010/03/18. https://doi.org/10.1038/ sj.bjc.6605603 PMID: 20234363 .
50. Heikkila K , Ebrahim S , Lawlor DA . A systematic review of the association between circulating concentrations of C reactive protein and cancer . Journal of epidemiology and community health . 2007 ; 61 ( 9 ): 824 ± 33 . Epub 2007/08/19. https://doi.org/10.1136/jech. 2006 .051292 PMID: 17699539 .
51. Yi JH , Wang D , Li ZY , Hu J , Niu XF , Liu XL . C-reactive protein as a prognostic factor for human osteosarcoma: a meta-analysis and literature review . PLoS One . 2014 ; 9 ( 5 ): e94632 . Epub 2014 /05/08. https://doi.org/10.1371/journal.pone.0094632 PMID: 24800842 .