==== Front Cancer Manag ResCancer Manag ResCancer Management and ResearchCancer Management and Research1179-1322Dove Medical Press 10.2147/CMAR.S160901cmar-10-2499Original ResearchAssociation of low skeletal muscle index with increased systematic inflammatory responses and interferon γ-induced protein 10 levels in patients with colon cancer He Wen-Zhuo 1*Yang Qiu-Xia 2*Xie Jin-Ye 3*Kong Peng-Fei 1Hu Wan-Ming 4Yang Lin 1Yang Yuan-Zhong 4Xie Qian-Kun 1Jiang Chang 1Yin Chen-Xi 1Guo Gui-Fang 1Qiu Hui-Juan 1Zhang Bei 1Xia Liang-Ping 1 1 VIP Region, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People’s Republic of China, xialiangping@163.com 2 Department of Medical Imaging, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People’s Republic of China 3 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510060, People’s Republic of China 4 Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, People’s Republic of ChinaCorrespondence: Liang-Ping Xia, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dong feng East Road, Guangzhou, Guangdong 510060, People’s Republic of China, Tel +86 20 8734 3107, +86 139 2641 0608, Fax +86 20 8734 3392, Email xialiangping@163.com* These authors contributed equally to this work 2018 07 8 2018 10 2499 2507 © 2018 He et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background Skeletal muscle depletion is a prognostic factor in patients with cancer. Here, we evaluated the association between the skeletal muscle index (SMI) and local and systemic responses in patients with colon cancer. Patients and methods We analyzed the relationships of the SMI with neutrophil, lymphocyte, monocyte, and platelet counts; the neutrophil-to-lymphocyte ratio; albumin levels; and C-reactive protein levels in a cohort of 561 patients, and with the circulating levels of 39 cytokines in a cohort of 125 patients. We also studied the association between the SMI and tumor local inflammatory response and the effect of SMI on survival. Results The median SMIs for male and female subjects were 44.1 and 34.2 cm2/m2, respectively. We observed positive correlations of the SMI with neutrophil (p=0.022), lymphocyte (p=0.001), and monocyte counts (p=0.003). A low SMI correlated significantly with an increased platelet count (p=0.017), decreased albumin level (p=0.006), neutrophil-to-lymphocyte ratio >3 (p=0.021), and an increased interferon γ-induced protein 10 level (IP-10, r = −0.276, p=0.002). The SMI did not correlate significantly with local inflammatory reactions or the C-reactive protein level. Finally, the SMI was a significant prognosticator in patients with stage III colon cancer (3-year disease-free survival rates: 35.1% for the low SMI arms versus 46.0% in the high SMI arms; HR =2.036; p=0.034). Conclusion This study highlights the association of a low SMI with a high systematic inflammatory response and IP-10 levels. Furthermore, low SMI is a predictor of poor disease-free survival in patients with stage III colon cancer. Keywords colon cancerskeletal muscleinterferon γ-induced protein 10 ==== Body Introduction Skeletal muscle depletion, an indicator of sarcopenia, is associated with poor physical function and nutritional statuses.1 The skeletal muscle index (SMI), which can be easily evaluated using computed tomography (CT), has increasingly attracted research attention. For example, in a surgical context, a low SMI was associated with an increased incidence of surgical site infection and prolongation of the hospital stay.2,3 Moreover, a low SMI has been shown to impair survival and increase chemotherapy-related toxicity.4 A recent study described cross-talk between systemic inflammation and sarcopenia;5 specifically, systemic inflammation may contribute to muscle breakdown, which in turn leads to an enhanced inflammatory response. Cancer cells can cooperate with other cells in the microenvironment and trigger inflammation, a process with various cytokines released.6 The cytokines may contribute to the loss of muscle mass. Additionally, Feliciano et al5 identified a positive association between an increased neutrophil-to-lymphocyte ratio (NLR) and the incidence of sarcopenia in patients with colorectal cancer (CRC). However, the potential associations of sarcopenia with other systemic inflammatory indexes, such as platelets, monocytes, and C-reactive protein (CRP) levels, remain to be studied.7,8 To our knowledge, no prior study has evaluated the association between the SMI and local tumor environmental factors, such as infiltrating neutrophils and lymphocytes. Against this background, we aimed to investigate the relationships of the SMI with both systemic and local inflammatory factors in patients with CRC. We additionally studied the correlations of the SMI and with the circulating levels of cytokines in a cohort of patients who previously underwent cytokine analysis.9 Patients and methods Patient selection This study was approved by the ethics review board of Sun Yat-sen University Cancer Center. All included patients met the following criteria: 1) primary tumor resection and pathological diagnosis of colon cancer at Sun Yat-sen University Cancer Center between 2009 and 2014; 2) available pretreatment routine blood analysis records; 3) available pre-surgical CT images; and 4) available follow-up information. Patients with infections, hematological disease, hyperpyrexia, intestinal perforation, or intestinal obstruction at diagnosis were excluded. All patients provided written informed consent to participate in the study. Clinical and pathological data A dataset was constructed prospectively at Sun Yat-sen University Cancer Center. The following data were retrospectively collected from medical records: age, sex, height, weight, primary tumor location, TNM staging, differentiation, mucinous histology, primary tumor size, neural invasion, venous invasion, mismatch repair status, and carcinoembryonic antigen (CEA) status. The following systemic inflammation markers were also analyzed: leukocyte, neutrophil, lymphocyte, monocyte, platelet counts, and albumin and CRP levels. Routine blood analyses were conducted using a Sysmex XE-5000™ Automated Hematology System (Sysmex, Shanghai, People’s Republic of China). CRP levels were tested using a Hitachi Automatic Analyzer 7600-020 (Hitachi, Tokyo, Japan). CEA levels were evaluated using a Roche 2010 Chemistry Analyzer (F. Hoffmann-La Roche Ltd, Basel, Switzerland). The NLR, calculated as the ratio of neutrophil to lymphocyte counts, was used to stratify patients into 2 groups (NLR >3 and ≤3). Two pathologists blinded to the clinical data assessed the carcinoma percentage, neutrophil infiltration (both central region and invasive margin), lymphocyte infiltration (central region and invasive margin), and Crohn’s-like reactions, as previously reported.10,11 Inflammatory cell reactions (neutrophils and lymphocytes) were estimated by screening the central tumor areas and invasive margins in hematoxylin and eosin-stained histological sections. All sections containing the most invasive part of the primary tumor were selected to avoid bias, and 4–6 sections were routinely evaluated per tumor. We used a 4-degree scale to assess the infiltration of neutrophils and lymphocytes. A score of 0 indicated an absence of reaction, 1 was weak, 2 indicated moderate, and 3 was severe increase of each cell type. Absent and weak (0–1) were combined as low grade, while moderate to severe increase (2–3) were high grade. If the 2 pathologists reached different conclusions, an agreement was reached through careful discussion. The following cytokines were analyzed in a cohort of patients with metastatic CRC: IL-1α, IL-1β, IL-1RA, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, IL-17, IL-12 P40, IL-12 P70, EGF, eotaxin, G-CSF, GM-CSF, IFNα-2, IFNγ, interferon γ-induced protein 10 (IP-10), MCP-1, MCP-3, MIP-1α, MIP-1β, TNFα, TNFβ, VEGF, FGF-2, TGF-α, FIT-3L, fractalkine, GRO, MDC, sCD40L, and sIL-2Rα. Measurement of SMI The baseline (ie, 1 month before surgery) enhanced CT images (slice thickness: 5 mm) were used to evaluate the SMI. One radiologist identified a single axial image at the third lumbar vertebral level on which both transverse processes were initially fully visualized.12 The axial CT image was then analyzed using the semiautomated GE Reformat postprocessing tool supplied with the GE picture archiving and communication systems workstation (Centricity® Radiology RA1000; GE Medical Healthcare, Little Chal-font, UK) to determine the cross-sectional skeletal muscle at a Hounsfield unit threshold of −29 to 150, as previously described.13 The skeletal muscle area was then quantified automatically and recorded. The following skeletal muscles were measured: psoas, erector spinae, quadratus lumborum, transversus abdominis, external and internal obliques, and rectus abdominis. The SMI was calculated by dividing the skeletal muscle area by the height squared (cm2/m2). Most previous studies of sarcopenia in patients with CRC have been conducted in Western countries, and accordingly no consensus has been reached regarding the optimal SMI cut-off point for defining sarcopenia in Asian patients with CRC. In our study, therefore, we classified patients into low and high SMI groups according to the median SMI values for men and women, respectively. Patient treatment and follow-up Patients with colon cancer underwent primary tumor resection at our hospital. All patients were chemotherapy-naïve before surgery, and no adjuvant chemotherapy was provided to patients with stage I colon cancer. The administration of adjuvant chemotherapy to patients with stage II colon cancer was determined based on the patient’s risk factors and physician’s decision. Patients with stage III colon cancer were administered ~6-month course of oxaliplatin-based adjuvant chemotherapy. All patients were followed up through outpatient visits and telephone interviews. The last date of follow-up was August 31, 2017. Statistical analyses All statistical analyses were performed using SPSS version 22 (IBM Corporation, Armonk, NY, USA). Frequencies and descriptive statistics were used to compare patient characteristics, and relationships between 2 continuous variables were tested using nonparametric tests or Pearson correlation coefficients as appropriate. Disease-free survival (DFS) was defined as the time from diagnosis to the time of the first event (locoregional recurrence, metastasis, or death). Survival curves were calculated using the Kaplan–Meier method and compared using the log-rank test. A multivariate analysis based on a Cox proportional hazards model was used to test independent significance via the backward elimination of insignificant explanatory variables. A P-value of <0.05 was considered to indicate statistical significance. Results Patient characteristics The study cohort included 343 men and 218 women with a median age of 59 years (range: 19–87 years). Of them, 210 (37.4%) patients had right-sided colon cancer and 346 (61.7%) had left-sided colon cancer. The median SMIs for men and women were 44.1 and 34.2 cm2/m2, respectively. Notably, 383 (68.3%) patients met the definition of sarcopenia according to the cut-off point used in the study by Feliciano et al.5 The distributions of the patients’ clinicopathological features and their correlations with the SMI are shown in Table 1. Particularly, a low SMI was associated with increasing age (p<0.001), a larger primary tumor (p=0.018), and a lower body mass index (p<0.001). SMI and inflammatory factors SMI was not found to correlate with local inflammatory reactions, as shown in Table 2. Then, we studied the relation between SMI and systemic inflammatory response. Among 280 patients with a low SMI, 96 (34.3%) had an NLR >3, whereas only 71 (25.3%) of 281 patients with a high SMI had an NLR >3 among (p=0.021). Similarly, a low SMI was found to correlate significantly with a decreased albumin level (p=0.006), but not with the CRP level (p=0.129). To further evaluate the relationship between the SMI and systemic inflammatory response, correlations of the absolute SMI values with the leukocyte, neutrophil, lymphocyte, monocyte, and platelet counts and CRP levels were investigated (Figure 1). Notably, we found that the SMI correlated positively with leukocyte (p=0.019), neutrophil (p=0.022), lymphocyte (p=0.001), and monocyte counts (p=0.003) and negatively with the platelet count (p=0.017). No significant correlation was observed between the SMI and CRP level (p=0.402). Survival according to SMI and tumor stage The survival data for all 561 patients included in this study are shown in Figure S1. The 3-year DFS rates were 57.0% in the low SMI population and 56.4% in the high SMI population, indicating a lack of a significant association of the SMI with DFS (HR =1.025; p=0.950) in patients with stage I + II disease. However, the SMI was found to have prognostic value in patients with stage III disease, with 3-year DFS rates of 35.1% in the low SMI population and 46.0% in the high SMI population (HR =2.036; p=0.034; Figure 2). Furthermore, a multivariate analysis revealed that the prognostic value of the SMI was independent of age, sex, T stage, N stage, the CEA level, and NLR (Table 3). Associations of SMI with circulating levels of cytokines We previously tested the circulating levels of cytokines in another cohort of 176 patients with CRC,9 including 125 patients with colon cancer and available CT scan data within 1 month after diagnosis. The clinical characteristics of these patients are shown in Table S1. A decreased SMI was found to associate with an increased IP-10 level (r = −0.276, p=0.002; Figure 3). No associations were observed between the SMI and other cytokines. Discussion In this study of patients with colon cancer, we found that a low SMI was associated with an increased NLR and decreased albumin level. Additionally, we observed a negative correlation between the SMI and circulating IP-10 level and confirmed a high SMI as a predictor of a better prognosis in patients with stage III colon cancer. By contrast, we did not observe an association between the SMI and tumor local inflammatory environment in our patient cohort. The exact mechanism underlying the correlation between the SMI and inflammation in patients with colon cancer remains elusive.5 In this study, we found that a low SMI correlated with an increased IP-10 level, which was previously found to indicate a poor prognosis and higher levels of systemic inflammation markers in patients with colon cancer.14,15 The previous findings that IP-10 expression can be downregulated by running and vitamin D16,17 suggest that lifestyle changes can correct a low SMI. Consistent with a previous study by Itoh et al,18 we found that SMI correlated with host factors, but not with tumor factors. Additionally, patients with a low SMI may benefit from exercise, and Shin and Lee16 reported that running could reduce IP-10 levels. Other potential interventions include an increased protein intake and the use of (n-3) fatty acids and anti-inflammatory drugs.19 In brief, the potential reversibility and simple evaluability of the SMI merit further attention. As noted previously, most studies of SMI in patients with colon cancer have been conducted in Western countries,19,20 and we used the cut-off value reported by Feliciano et al5 to classify ~70% of patients in our study as having sarcopenia. Although a recent report proposed a diagnostic algorithm to promote sarcopenia research in Asia,1 the most optimal SMI cut-off value remains controversial. We note that the sex-specific SMI cut-off points used in our study are similar to those used previously in other Asian studies18,20 and recommend additional prospective studies with larger cohorts to identify the optimal value. Unlike Feliciano et al,5 we did not observe a relationship between the SMI and DFS in patients with stage II colon cancer. We might attribute this discrepancy to the diverse prognoses of patients with stage II colon cancer.21 Additionally, the patients included in the study by Feliciano et al5 were followed for longer than those in our study. This study had several limitations. First, we applied a retrospective study design and were unable to evaluate the physical performances or muscle strengths of the involved patients. Second, the circulating levels of cytokines were tested only in a cohort of patients with metastatic CRC. Third, as most patients remain alive, we were unable to evaluate overall survival. Conclusion In conclusion, this study highlights the correlations of a low SMI with a high systematic inflammation response and IP-10 level. Finally, we identified a low SMI as a predictor of poor DFS in patients with stage III colon cancer. Data availability The authenticity of this article has been validated by uploading the key raw data onto the Research Data Deposit public platform. (www.researchdata.org.cn), with the approval RDD number as RDDA2018000654. Supplementary materials Figure S1 The survival data in all 561 patients included in this study. Table S1 Clinical characteristics of patients with available CT scan results and circulating cytokine levels Characteristics Number of patients Age (years)  ≤50 40  51–65 56  >65 29 Sex  Male 83  Female 42 Chemotherapy (the first line)  Oxaliplatin-based regimen 85  Irinotecan-based regimen 40 Primary tumor response  Right-side colon 56  Left-side colon 69 Metastatic site  Liver 93  Other site 32 Histological grade  Well/moderate differentiated 76  Poorly differentiate 49 CEA (ng/mL)  <5 42  ≥5 83 CA19-9 (U/mL)  <35 70  ≥35 55 Abbreviations: CEA, carcinoembryonic antigen; CT, computed tomography. Acknowledgments This work was supported by grants from the Natural Science Foundation of Guangdong, People’s Republic of China (2015A030313010), the Science and Technology Program of Guangzhou, China (1563000305), and the National Natural Science Foundation of the People’s Republic of China (81272641 and 81572409). Disclosure The authors report no conflicts of interest in this work. Figure 1 Correlations between the SMI and the leukocyte (A), neutrophil (B), lymphocyte (C), monocyte (D), platelet counts (E), and CRP level (F). Abbreviations: CRP, C-reactive protein; SMI, skeletal muscle index. Figure 2 DFS of patients with stage I + II (A) and stage III (B) colon cancer, stratified by SMI. Abbreviations: DFS, disease-free survival; SMI, skeletal muscle index. Figure 3 Correlation between the SMI and IP-10 level. Abbreviations: IP-10, interferon γ-induced protein 10; SMI, skeletal muscle index. Table 1 Correlations between SMI and patients’ characteristics Variables Total SMI p-value* Low (%) High (%) Number of patients 561 280 (49.9) 281 (50.1) Age (years) <0.001  ≤50 147 61 (41.5) 86 (58.5)  51–65 246 108 (43.9) 138 (56.1)  >65 168 111 (66.1) 57 (33.9) Sex 1.000  Male 343 171 (49.9) 172 (50.1)  Female 218 109 (50.0) 109 (50.0) Primary tumor 0.108  Right-side colon 210 95 (45.2) 115 (54.8)  Left-side colon 346 181 (52.3) 165 (47.7)  Multiple 5 4 (80.0) 1 (20.0) T stage 0.658  1 19 8 (42.1) 11 (57.9)  2 75 38 (50.7) 37 (49.3)  3 382 187 (49.0) 195 (51.0)  4 85 47 (55.3) 38 (44.7) N stage 0.742  0 391 191 (48.8) 200 (51.2)  1 121 63 (52.1) 58 (47.9)  2 49 26 (53.1) 23 (46.9) Stage 0.634  I 76 37 (48.7) 39 (51.3)  II 321 156 (48.6) 165 (51.4)  III 164 87 (53.0) 77 (47.0) Differentiation 0.393  Well/moderate 436 212 (48.6) 224 (51.4)  Poor 125 68 (54.4) 57 (45.6) Mucinous histology 0.856  Yes 32 17 (53.1) 15 (46.9)  No 526 262 (49.8) 264 (50.2) Neural invasion 0.309  Absent 467 238 (51.0) 229 (49.0)  Present 94 42 (44.7) 52 (55.3) Venous invasion 0.454  Absent 453 230 (50.8) 223 (49.2)  Present 108 50 (46.3) 58 (53.7) CEA (ng/mL) 0.194  ≤5 344 164 (47.7) 180 (52.3)  >5 217 116 (53.5) 101 (46.5) Tumor size (cm) 0.018  ≤2 41 15 (36.6) 26 (63.4)  2–5 378 181 (47.9) 197 (52.1)  >5 141 83 (58.9) 58 (41.1) MMR status 0.797  dMMR 68 35 (51.5) 33 (48.5)  pMMR 493 245 (49.7) 248 (50.3) BMI <0.001  <25 461 255 (55.3) 206 (44.7)  ≥25 100 25 (25.0) 75 (75.0) Diabetes 0.106  Yes 126 71 (56.3) 55 (43.7)  No 435 209 (48.0) 226 (52.0) Hypertension 0.435  Yes 66 36 (54.5) 30 (45.5)  No 495 244 (49.3) 251 (50.7) Notes: * χ2 test was used to compare patient characteristics, and p-value <0.05 shown in bold was statistically significant. Abbreviations: BMI, body mass index; CEA, carcinoembryonic antigen; MMR, mismatch repair; SMI, skeletal muscle index. Table 2 Correlation between skeletal muscle mass and the local tumor microenvironment Tumor microenvironment Total SMI p-value* Low (%) High (%) Carcinoma percentage 0.129  Low 152 84 (55.3) 68 (44.7)  High 409 196 (47.9) 213 (52.1) Neutrophil – central region 0.665  Low grade 216 105 (48.6) 111 (51.4)  High grade 345 175 (50.7) 170 (49.3) Neutrophil – invasive margin 0.339  Low grade 348 168 (48.3) 180 (51.7)  High grade 213 112 (52.6) 101 (47.4) Lymphocytes – central region 0.263  Low grade 223 118 (52.9) 105 (47.1)  High grade 338 162 (47.9) 176 (52.1) Lymphocytes – invasive margin 0.735  Low grade 265 130 (49.1) 135 (51.0)  High grade 296 150 (50.7) 146 (49.3) Crohn’s-like reaction 0.773  Yes 53 25 (47.2) 28 (52.8)  No 505 254 (50.3) 251 (49.7) NLR 0.021  ≤3 394 184 (46.7) 210 (53.3)  >3 167 96 (57.5) 71 (42.5) CRP 0.129  Normal 410 199 (48.5) 211 (51.5)  Elevated 151 81 (53.6) 70 (46.4) Albumin 0.006  Normal 496 237 (47.8) 259 (52.2)  Decreased 65 43 (66.2) 22 (33.8) Notes: * χ2 test was used to compare patient characteristics, and p-value <0.05 shown in bold was statistically significant. Abbreviations: CRP, C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; SMI, skeletal muscle index. Table 3 Multivariate analysis of prognostic factors in patients with stage III colon cancer Variables B p-value Exp (B) 95% CI for exp (B) Age 0.289 0.199 1.334 0.859–2.073 Sex 0.177 0.608 1.193 0.608–2.341 T stage 0.097 0.746 1.102 0.612–1.987 N stage 0.531  N1 1.187 0.285 3.278 0.371–28.918  N2 −0.035 0.928 0.966 0.457–2.040 NLR −0.266 0.553 0.766 0.318–1.847 CEA 0.260 0.455 1.297 0.656–2.564 SMI 0.734 0.039 2.083 1.037–4.186 Abbreviations: CEA, carcinoembryonic antigen; Exp (B), exponent of B; NLR, neutrophil-to-lymphocyte ratio; SMI, skeletal muscle index. ==== Refs References 1 Chen LK Liu LK Woo J Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia J Am Med Dir Assoc 2014 15 2 95 101 24461239 2 Reisinger KW van Vugt JL Tegels JJ Functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery Ann Surg 2015 261 2 345 352 24651133 3 van Vugt JLA Buettner S Levolger S Low skeletal muscle mass is associated with increased hospital expenditure in patients undergoing cancer surgery of the alimentary tract PLoS One 2017 12 10 e0186547 29088245 4 Chemama S Bayar MA Lanoy E Sarcopenia is associated with chemotherapy toxicity in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal cancer Ann Surg Oncol 2016 23 12 3891 3898 27352205 5 Feliciano EMC Kroenke CH Meyerhardt JA Association of systemic inflammation and sarcopenia with survival in nonmetastatic colorectal cancer: results from the C SCANS study JAMA Oncol 2017 3 12 e172319 28796857 6 Curtale G MiRNAs at the crossroads between innate immunity and cancer: focus on macrophages Cells 2018 7 2 pii:E12 7 Richards CH Roxburgh CS MacMillan MT The relationships between body composition and the systemic inflammatory response in patients with primary operable colorectal cancer PLoS One 2012 7 8 e41883 22870258 8 Reisinger KW Derikx JP van Vugt JL Sarcopenia is associated with an increased inflammatory response to surgery in colorectal cancer Clin Nutr 2016 35 4 924 927 26205321 9 Chen ZY He WZ Peng LX A prognostic classifier consisting of 17 circulating cytokines is a novel predictor of overall survival for metastatic colorectal cancer patients Int J Cancer 2015 136 3 584 592 24916890 10 Klintrup K Makinen JM Kauppila S Inflammation and prognosis in colorectal cancer Eur J Cancer 2005 41 17 2645 2654 16239109 11 Ogino S Nosho K Irahara N Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype Clin Cancer Res 2009 15 20 6412 6420 19825961 12 Shen W Punyanitya M Wang Z Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image J Appl Physiol (1985) 2004 97 6 2333 2338 15310748 13 Heymsfield SB Smith R Aulet M Appendicular skeletal muscle mass: measurement by dual-photon absorptiometry Am J Clin Nutr 1990 52 2 214 218 2375286 14 Blank S Nienhuser H Dreikhausen L Inflammatory cytokines are associated with response and prognosis in patients with esophageal cancer Oncotarget 2017 8 29 47518 47532 28537901 15 Kibe S Yutani S Motoyama S Phase II study of personalized peptide vaccination for previously treated advanced colorectal cancer Cancer Immunol Res 2014 2 12 1154 1162 25351849 16 Shin YO Lee JB Leukocyte chemotactic cytokine and leukocyte subset responses during ultra-marathon running Cytokine 2013 61 2 364 369 23273667 17 Scolletta S Colletti M Di Luigi L Crescioli C Vitamin D receptor agonists target CXCL10: new therapeutic tools for resolution of inflammation Mediators Inflamm 2013 2013 876319 23690671 18 Itoh S Shirabe K Matsumoto Y Effect of body composition on outcomes after hepatic resection for hepatocellular carcinoma Ann Surg Oncol 2014 21 9 3063 3068 24719020 19 Shachar SS Williams GR Muss HB Nishijima TF Prognostic value of sarcopenia in adults with solid tumours: a meta-analysis and systematic review Eur J Cancer 2016 57 58 67 26882087 20 Huang DD Chen XX Chen XY Sarcopenia predicts 1-year mortality in elderly patients undergoing curative gastrectomy for gastric cancer: a prospective study J Cancer Res Clin Oncol 2016 142 11 2347 2356 27573385 21 Labianca R Nordlinger B Beretta GD Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2013 24 Suppl 6 vi64 vi72 24078664