Abstract
Background/Aim
Gastric cancer is a common cause of cancer death worldwide, especially in East Asia. This study evaluated the impact of preoperative modified Neutrophil-Platelet Score (mNPS) on the survival and recurrence of patients with resectable gastric cancer.
Patients and Methods
The study analyzed 168 patients who underwent curative gastrectomy and subsequently received adjuvant treatment for gastric cancer between 2015 and 2021. Univariate and multivariate analyses were performed to identify the risk factors for overall survival (OS) and recurrence-free survival (RFS).
Results
Patients were divided into two groups: 76 patients with an mNPS of 0 were classified into the low-mNPS group, whereas 92 patients with an mNPS of ≥1 were classified into the high-mNPS group. The 3- and 5-year OS rates in the low-mNPS group were 65.6% and 56.2%, respectively, and those in the high-mNPS group were 45.3% and 36.9%, respectively. The difference in OS between the two groups was statistically significant (p=0.007). The 3- and 5-year RFS rates in the low-mNPS group were 45.6% and 38.7%, respectively, whereas those in the high-mNPS group were 33.4% and 28.1%, respectively. The difference in RFS between the two groups was statistically significant (p=0.043). A multivariate analysis showed that the mNPS was a significant independent prognostic factor for OS and RFS.
Conclusion
mNPS is a potential prognostic marker for patients with gastric cancer who underwent curative gastrectomy. Higher mNPS values were associated with lower 3- and 5-year OS and RFS rates, indicating a potential correlation between elevated mNPS and worse outcomes.
Keywords: Gastric cancer, neutrophil, platelet, modified NPS
Gastric cancer is the fourth leading cause of cancer-related death worldwide (1,2). Currently, standard treatments for resectable gastric cancer include curative gastrectomy and perioperative adjuvant chemotherapy (3,4). Although there have been some improvements in the prognosis with the progress of treatment (e.g., optimization of the surgical strategy and development of adjuvant chemotherapy) in recent decades, the survival rate of gastric cancer patients remains poor (5-7), and further progress is needed to improve the probability of survival.
To date, many surrogate markers for predicting the survival rates of patients with gastric cancer have been proposed (8-13). However, markers that accurately reflect the prognosis of gastric cancer patients are uncertain, and more sensitive prognostic markers are needed. If we could accurately predict the prognosis of gastric cancer patients before surgery, we would be able to follow-up and perform examinations more frequently for the early detection of recurrent disease or suggest more intense chemotherapy regimens for high-risk patients, which may improve their prognosis.
Watt et al. proposed the neutrophil-platelet score (NPS) as a predictor of the prognosis of many types of cancer (14). This score is calculated from the peripheral neutrocyte count and platelet count. However, the cutoff value was set based on Western patient data, which may be associated with different outcomes in Asian patients, who are more vulnerable to gastric cancer than any other ethnic group in the world. Okugawa et al. suggested the modified NPS (mNPS), which alters the cutoff value for East Asian populations (15). It is known that in the early stages of the systemic inflammatory response (SIR), recruited neutrophils cause a rapid increase in platelets (16). From this, it is considered that both an increase in the number of neutrophils and activation of platelets are statuses that reflect the state of SIR. Furthermore, SIR is known to reduce cancer prognosis (17). Although many surrogate markers are used to predict the prognosis of cancer patients, the NPS/mNPS directly reflect the SIR status and may reflect cancer outcomes more accurately (14,15). Moreover, because the score is calculated using complete blood cell count (CBC) data alone, it is simple, easy to use, and cost-effective. Because this marker does not require any biochemical tests, it can be used not only in general hospitals but also in local clinics, which may support the wide use of this marker.
We conducted this retrospective cohort study to determine whether the mNPS can be used as a surrogate marker of the oncological prognosis in patients with gastric cancer who receive curative gastrectomy followed by adjuvant chemotherapy.
Patients and Methods
Patients. Patients who underwent radical surgery for gastric cancer at the Department of Surgery of Yokohama City University Hospital between 2015 and 2021 were selected for this study. Patients were included in this study if they had histologically proven adenocarcinoma, stage I-III gastric cancer according to the 5th edition of the General Rules for Gastric Cancer published by the Japanese Gastric Cancer Association (18), and underwent D2 (or D1+, for T1N0) lymph node dissection with complete R0 surgery.
Surgical procedure and adjuvant chemotherapy. All patients underwent distal or total gastrectomy with lymphadenectomy. If patients were pathologically diagnosed with stage ≥II, disease, they received S-1 80 mg/m2 orally twice daily for the first four weeks of a six-week cycle until one year postoperatively as adjuvant chemotherapy.
Postoperative surgical complications. Postoperative complications were defined as Clavien-Dindo classification grade ≥II. Postoperative death was defined as death due to any cause occurring within 30 days after the date of surgery or during the same hospital stay. The length of postoperative hospital stay and the reoperation rate were also reported.
Definition of modified Neutrophil-Platelet Score (mNPS). The mNPS was calculated as follows: score 0, a patient with a neutrophil count of ≤4,170/μl and a platelet count of ≤26.6×104/μl; score 1, either a neutrophil count of >4,170/μl or a platelet count of >26.6×104/μl; score 2, neutrophil count >4,170/μl; and platelet count >26.6×104/μl. Blood tests were performed on days 1-7 before surgery, and the mNPS was calculated based on these results.
Follow up and statistical analyses. Patients were followed every three months until two years postoperatively, and then every 6 months until 5 years postoperatively, according to the Japanese Gastric Cancer Treatment Guidelines 2018 (18). The significance of differences in mNPS and clinicopathological parameters was determined using the chi-square test. Overall survival (OS) was defined as the period between surgery and death for any reason. Recurrence-free survival (RFS) was defined as the period between surgery and either recurrence or death, whichever occurred first. The Kaplan-Meier method was used to calculate the OS and RFS curves. Univariate and multivariate survival analyses were performed using the Cox proportional hazard model. Two-sided p-values were calculated for all tests and p-values of <0.05 were considered to indicate statistical significance. The SPSS software program (ver. 27.0 J Win; IBM, Armonk, NY, USA) was used for all the statistical analyses.
Results
Patient background characteristics. The total number of eligible patients was 168. We divided these patients into two groups: 76 patients with an mNPS of 0 were classified into the low mNPS group and 92 patients with an mNPS of ≥1 were classified into the high mNPS group. We set the cutoff value for the mNPS based on the 1-, 3-, and 5-year OS rates (Table I) and with reference to prior studies. There was no significant difference in the background characteristics of the two groups.
Table I. Comparison of survival rates stratified by patient characteristics.
OS: Overall survival.
Survival analyses. The risk factors for OS and RFS were evaluated by univariate and multivariate analyses using clinicopathological factors (Table II and Table III). The univariate analyses of factors associated with OS revealed that T status, lymph node metastasis, vascular invasion, and mNPS were significant prognostic factors. Therefore, the mNPS was included in the final multivariate analysis. The low-mNPS group had significantly higher survival rates at 3 and 5 years after surgery than the high-mNPS group (low-mNPS: 65.6% and 56.2%, respectively; high-mNPS: 45.3% and 36.9%; p=0.016). The Kaplan-Meier OS curves are shown in Figure 1. The univariate analyses of factors associated with RFS also showed that the mNPS was a significant prognostic factor, and we included the mNPS in the final multivariate model. The 3- and 5-year RFS rates following surgery in the low mNPS group were 45.6% and 38.7%, respectively, while those in the high mNPS group were 33.4% and 28.1% (p=0.043). The RFS curves are shown in Figure 2. No significant difference was observed between the groups in the site of first recurrence (Table IV). Anastomotic leakage and pneumonia occurred frequently as surgical complications in both the low-mNPS group (35.5% and 21.1%, respectively) and the high-mNPS group (35.9% and 32.6%, respectively), but the difference between the two groups was not statistically significant.
Table II. Uni and multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival.
Table III. Uni and multivariate Cox proportional hazards analysis of clinicopathological factors for recurrence free survival.
Figure 1. Overall survival of patients with gastric cancer of the highmodified neutrophil-platelet score (mNPS) and low-mNPS groups.
Figure 2. Recurrence-free survival of patients with gastric cancer of the high- modified neutrophil-platelet score (mNPS) and low-mNPS groups.
Table IV. Patterns of recurrence according to platelet-lymphocyte ratio.
Discussion
The present study investigated whether the mNPS reflects the prognosis of patients with gastric cancer who undergo curative gastrectomy. The major finding of this study was that the low-mNPS group had significantly better OS and RFS than the high-mNPS group. This means that the mNPS might be a good predictor of the prognosis in patients who receive curative gastrectomy followed by adjuvant chemotherapy. Thus, we suggest that calculating the mNPS will help to accurately predict the prognosis of patients with gastric cancer and to facilitate the provision of better therapy for these patients, which may result in a good prognosis.
Watt et al. revealed that the NPS is an independent prognostic factor for resectable colorectal cancers and many types of solid cancers, including gastric cancer, and is a superior to other surrogate markers for predicting the prognosis of patients with cancer (14). There are many kinds of prognostic markers for cancer; the neutrophil-lymphocyte ratio (NLR) is one of them (11,19). Recently, Ishizuka et al. suggested the combination of the platelet count and NLR (COP-NLR) as a cumulative predictor of outcomes in patients with cancer by adding platelet count to the evaluation items (12). Since 1865, when Trousseau et al. reported that platelet counts and the levels of coagulation factors were increased in patients with cancer, the correlation between the platelet count and the prognosis of cancer patients has received considerable attention (20). Prior studies have shown that platelets are abnormally activated and tend to coagulate, and that increased platelet counts are related to a poor prognosis in patients with advanced cancer (20,21). Moreover, platelets interact with neutrophils in the early phase of inflammation (22-26), which induces poor outcomes in patients with cancer. Thus, the COP-NLR may reflect the inflammatory status and predict the prognosis of patients with cancer. However, Watt et al. asserted in their study that the NPS is a more accurate marker of the cancer prognosis than the COP-NLR because the NPS was identified as an independent prognostic factor for resectable colorectal cancers in a multivariate analysis, while the COP-NLR was not (14). They also reported that among the variables in the differential white cell count, the neutrophil count is the most important factor for predicting the prognosis, while the lymphocyte count has less influence (14,27). This may be because the NPS is a better predictor than the NLR and COP-NLR. As another marker, while the modified Glasgow Prognostic Score (mGPS) reflects the systemic inflammatory response similarly to the NPS (28-30), it requires the measurement of the serum albumin value and the C-reactive protein value. In contrast, the NPS is simpler to calculate.
The cutoff value of the NPS was determined in some previous Western studies and fits to large populations in Western countries (14,27,31). However, Okugawa et al. questioned whether the cutoff value was appropriate for other ethnicities (32), especially East Asians, who show the highest incidence of gastric cancer in the world (1). They analyzed the NPS values of 621 Japanese patients with gastric cancer (only three patients were classified as NPS 2) and revealed that the original cutoff value of the NPS did not fit the Japanese population. They investigated other cutoff values for East Asian populations and suggested the modified NPS (mNPS) as a surrogate marker for patients with gastric cancer in East Asia. They analyzed the mNPS values of 621 patients with gastric cancer who underwent gastrectomy, including patients with distant metastasis. They showed that a high mNPS was significantly correlated with disease development and poor oncological outcomes in patients with gastric cancer (15). The present study used the mNPS classification.
The present study shows that the mNPS affects both OS and RFS, which means that the mNPS may reflect the ability of tumor growth. A previous study using a mouse model of loss of platelet function revealed that platelets promote cancer metastasis, and other studies mentioned that the continuous use of antiplatelet drugs (e.g., aspirin) in low doses results in better cancer outcomes and reduces the risk of cancer metastasis (33-36). Considering these findings, the platelet value in cancer patients can reflect the cancer prognosis and the risk of metastasis, and this may have also been associated with the poor outcomes of the high-mNPS group in our study.
Study limitations. First, this was a retrospective, mono-institutional, cohort study. A subsequent prospective, multi-institutional study or a large-scale propensity analysis is needed. Second, there is ample room for improvement in the cutoff values. The cutoff values for the NPS were set based on European data, and they were modified for East Asian populations in the mNPS. However, whether there is a true cut-off value that can be applied universally remains unclear. If we could draw ROC curves from worldwide data, it could be possible to set true cutoff values that are widely applicable throughout the world. Third, the appropriate timing for evaluating the mNPS was not fixed. We conducted routine blood tests within one week before the operation, almost at the time of admission, as was reported in previous studies, but there is no mention of accurate examination dates, while only “preoperative” values were reported in the original NPS study.
In conclusion, we suggest that the mNPS is a good predictor of oncological outcomes in patients with gastric cancer who underwent curative gastrectomy and received adjuvant chemotherapy. The mNPS can accurately predict the prognosis of patients with gastric cancer, and could facilitate the provision of better therapy, which could lead to better outcomes.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
Authors’ Contributions
KO and TA contributed substantially to concept and design. KO, TA, YM, and IH made substantial contributions to the data acquisition, analysis, and interpretation. KO, TA, YM, IH, HT, NK, AK, KK, SS, NY, AS, and YR were involved in drafting the manuscript or revising it critically for important intellectual content. KO and TA approved the final version to be published.
Acknowledgements
This study was supported in part by the nonprofit organization Yokoyama Surgical Research Group (YSRG).
References
- 1.Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA CanceJ Clin. 2018;68(6):394–424. doi: 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
- 2.Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020;396(10251):635–648. doi: 10.1016/S0140-6736(20)31288-5. [DOI] [PubMed] [Google Scholar]
- 3.Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357(18):1810–1820. doi: 10.1056/NEJMoa072252. [DOI] [PubMed] [Google Scholar]
- 4.Kakeji Y, Yoshida K, Kodera Y, Kochi M, Sano T, Ichikawa W, Lee S, Shibahara K, Shikano T, Kataoka M, Ishiguro A, Ojima H, Sakai Y, Musha N, Takase T, Kimura T, Takeuchi M, Fujii M. Three-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 plus docetaxel versus S-1 alone in stage III gastric cancer: JACCRO GC-07. Gastric Cancer. 2022;25(1):188–196. doi: 10.1007/s10120-021-01224-2. [DOI] [PubMed] [Google Scholar]
- 5.Lordick F, Carneiro F, Cascinu S, Fleitas T, Haustermans K, Piessen G, Vogel A, Smyth EC, ESMO Guidelines Committee Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(10):1005–1020. doi: 10.1016/j.annonc.2022.07.004. [DOI] [PubMed] [Google Scholar]
- 6.Japanese Gastric Cancer Association Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14(2):101–112. doi: 10.1007/s10120-011-0041-5. [DOI] [PubMed] [Google Scholar]
- 7.Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, Das P, Enzinger PC, Enzler T, Fanta P, Farjah F, Gerdes H, Gibson MK, Hochwald S, Hofstetter WL, Ilson DH, Keswani RN, Kim S, Kleinberg LR, Klempner SJ, Lacy J, Ly QP, Matkowskyj KA, McNamara M, Mulcahy MF, Outlaw D, Park H, Perry KA, Pimiento J, Poultsides GA, Reznik S, Roses RE, Strong VE, Su S, Wang HL, Wiesner G, Willett CG, Yakoub D, Yoon H, McMillian N, Pluchino LA. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20(2):167–192. doi: 10.6004/jnccn.2022.0008. [DOI] [PubMed] [Google Scholar]
- 8.Kushiyama S, Sakurai K, Kubo N, Tamamori Y, Nishii T, Tachimori A, Inoue T, Maeda K. The preoperative Geriatric Nutritional Risk Index predicts postoperative complications in elderly patients with gastric cancer undergoing gastrectomy. In Vivo. 2018;32(6):1667–1672. doi: 10.21873/invivo.11430. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Mohri Y, Tanaka K, Toiyama Y, Ohi M, Yasuda H, Inoue Y, Kusunoki M. Impact of preoperative neutrophil to lymphocyte ratio and postoperative infectious complications on survival after curative gastrectomy for gastric cancer: a single institutional cohort study. Medicine (Baltimore) 2016;95(11):e3125. doi: 10.1097/MD.0000000000003125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Toiyama Y, Shimura T, Yasuda H, Fujikawa H, Okita Y, Kobayashi M, Ohi M, Yoshiyama S, Hiro J, Araki T, Inoue Y, Mohri Y, Kusunoki M. Clinical burden of C-reactive protein/albumin ratio before curative surgery for patients with gastric cancer. Anticancer Res. 2016;36(12):6491–6498. doi: 10.21873/anticanres.11248. [DOI] [PubMed] [Google Scholar]
- 11.Miyamoto R, Inagawa S, Sano N, Tadano S, Adachi S, Yamamoto M. The neutrophil-to-lymphocyte ratio (NLR) predicts short-term and long-term outcomes in gastric cancer patients. Eur J Surg Oncol. 2018;44(5):607–612. doi: 10.1016/j.ejso.2018.02.003. [DOI] [PubMed] [Google Scholar]
- 12.Ishizuka M, Oyama Y, Abe A, Kubota K. Combination of platelet count and neutrophil to lymphocyte ratio is a useful predictor of postoperative survival in patients undergoing surgery for gastric cancer. J Surg Oncol. 2014;110(8):935–941. doi: 10.1002/jso.23753. [DOI] [PubMed] [Google Scholar]
- 13.Zhang S, Li JZ, Du T, Li HQ, Hu RH, Ma CY, Cui XM, Song C, Jiang XH. The modified Glasgow Prognostic Score predicts survival in gastric cancer patients with normal CEA and CA19-9. Can J Gastroenterol Hepatol. 2022;2022:3953004. doi: 10.1155/2022/3953004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Watt DG, Proctor MJ, Park JH, Horgan PG, McMillan DC. The Neutrophil-Platelet Score (NPS) predicts survival in primary operable colorectal cancer and a variety of common cancers. PLoS One. 2015;10(11):e0142159. doi: 10.1371/journal.pone.0142159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Okugawa Y, Toiyama Y, Yamamoto A, Omura Y, Kusunoki K, Yin C, Ide S, Kitajima T, Koike Y, Fujikawa H, Yasuda H, Okita Y, Hiro J, Yoshiyama S, Ohi M, Araki T, Kusunoki M. Modified neutrophil-platelet score as a promising marker for stratified surgical and oncological outcomes of patients with gastric cancer. Surg Today. 2020;50(3):223–231. doi: 10.1007/s00595-019-01873-y. [DOI] [PubMed] [Google Scholar]
- 16.Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, Nácher M, Pitaval C, Radovanovic I, Fukui Y, McEver RP, Filippi MD, Lizasoain I, Ruiz-Cabello J, Zarbock A, Moro MA, Hidalgo A. Neutrophils scan for activated platelets to initiate inflammation. Science. 2014;346(6214):1234–1238. doi: 10.1126/science.1256478. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15(11):e493–e503. doi: 10.1016/S1470-2045(14)70263-3. [DOI] [PubMed] [Google Scholar]
- 18.Japanese Gastric Cancer Association Japanese gastric cancer treatment guidelines 2018 (5th edition) Gastric Cancer. 2021;24(1):1–21. doi: 10.1007/s10120-020-01042-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Zahorec R. Ratio of neutrophil to lymphocyte counts—rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy. 2001;102(1):5–14. [PubMed] [Google Scholar]
- 20.Schlesinger M. Role of platelets and platelet receptors in cancer metastasis. J Hematol Oncol. 2018;11(1):125. doi: 10.1186/s13045-018-0669-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer. 2005;104(12):2822–2829. doi: 10.1002/cncr.21496. [DOI] [PubMed] [Google Scholar]
- 22.Blair P, Rex S, Vitseva O, Beaulieu L, Tanriverdi K, Chakrabarti S, Hayashi C, Genco CA, Iafrati M, Freedman JE. Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ Res. 2009;104(3):346–354. doi: 10.1161/CIRCRESAHA.108.185785. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Demers M, Wagner DD. NETosis: a new factor in tumor progression and cancer-associated thrombosis. Semin Thromb Hemost. 2014;40(3):277–283. doi: 10.1055/s-0034-1370765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13(4):463–469. doi: 10.1038/nm1565. [DOI] [PubMed] [Google Scholar]
- 25.Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, Scadden DT, Wagner DD. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U.S.A. 2012;109(32):13076–13081. doi: 10.1073/pnas.1200419109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Bystricky B, Reuben JM, Mego M. Circulating tumor cells and coagulation—Minireview. Crit Rev Oncol Hematol. 2017;114:33–42. doi: 10.1016/j.critrevonc.2017.04.003. [DOI] [PubMed] [Google Scholar]
- 27.Watt DG, Martin JC, Park JH, Horgan PG, McMillan DC. Neutrophil count is the most important prognostic component of the differential white cell count in patients undergoing elective surgery for colorectal cancer. Am J Surg. 2015;210(1):24–30. doi: 10.1016/j.amjsurg.2014.12.031. [DOI] [PubMed] [Google Scholar]
- 28.Forrest LM, McMillan DC, McArdle CS, Angerson WJ, Dunlop DJ. Evaluation of cumulative prognostic scores based on the systemic inflammatory response in patients with inoperable non-small-cell lung cancer. Br J Cancer. 2003;89(6):1028–1030. doi: 10.1038/sj.bjc.6601242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Toiyama Y, Miki C, Inoue Y, Tanaka K, Mohri Y, Kusunoki M. Evaluation of an inflammation-based prognostic score for the identification of patients requiring postoperative adjuvant chemotherapy for stage II colorectal cancer. Exp Ther Med. 2011;2(1):95–101. doi: 10.3892/etm.2010.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Inoue Y, Iwata T, Okugawa Y, Kawamoto A, Hiro J, Toiyama Y, Tanaka K, Uchida K, Mohri Y, Miki C, Kusunoki M. Prognostic significance of a systemic inflammatory response in patients undergoing multimodality therapy for advanced colorectal cancer. Oncology. 2013;84(2):100–107. doi: 10.1159/000343822. [DOI] [PubMed] [Google Scholar]
- 31.Leitch EF, Chakrabarti M, Crozier JE, McKee RF, Anderson JH, Horgan PG, McMillan DC. Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer. Br J Cancer. 2007;97(9):1266–1270. doi: 10.1038/sj.bjc.6604027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Khera A, McGuire DK, Murphy SA, Stanek HG, Das SR, Vongpatanasin W, Wians FH, Grundy SM, De Lemos JA. Race and gender differences in C-reactive protein levels. J Am Coll Cardiol. 2005;46(3):464–469. doi: 10.1016/j.jacc.2005.04.051. [DOI] [PubMed] [Google Scholar]
- 33.Kunita A, Kashima TG, Morishita Y, Fukayama M, Kato Y, Tsuruo T, Fujita N. The platelet aggregation-inducing factor aggrus/podoplanin promotes pulmonary metastasis. Am J Pathol. 2007;170(4):1337–1347. doi: 10.2353/ajpath.2007.060790. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci U.S.A. 1968;61(1):46–52. doi: 10.1073/pnas.61.1.46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Enache R. Effect of daily aspirin on long-term risk of death due to cancer. Maedica (Bucur) 2010;5(4):313. [PMC free article] [PubMed] [Google Scholar]
- 36.Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade TW. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754):1741–1750. doi: 10.1016/S0140-6736(10)61543-7. [DOI] [PubMed] [Google Scholar]