|Year : 2019 | Volume
| Issue : 1 | Page : 54-60
Prognostic effect of red cell distribution width-to-platelet ratio in colorectal cancer according to tumor stage and localization
Burak Bilgin1, Mehmet Ali Nahit Sendur1, Mutlu Hizal1, Didem Sener Dede1, Muhammed Bülent Akinci1, Sümeyye Ulutas Kandil2, Samet Yaman2, Abdussamet Yalçin3, Mehmet Kiliç3, Bülent Yalçin2
1 Department of Medical Oncology, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey
2 Department of Internal Medicine, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey
3 Department of General Surgery, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara, Turkey
|Date of Web Publication||13-Mar-2019|
Dr. Mehmet Ali Nahit Sendur
Department of Medical Oncology, Faculty of Medicine, Ankara Yildirim Beyazit University, Çankaya, Ankara 06800
Source of Support: None, Conflict of Interest: None
Introduction: Colorectal cancer (CRC) is one of the most common cancers worldwide and survival is still approximately 24 months. Recently, importance of the molecular features, tumor localization, and also inflammatory status is increased, and most of these entities can be used as a predictive marker for colon tumor. However, since most of these tests are expensive and unachievable, there is a need for new prognostic and predictive markers that can be used easily and are inexpensive.
Aim: We aimed to investigate the prognostic effect of red cell distribution width (RDW)-to-platelet ratio (RPR) which reflects inflammatory status and can be calculated basically by using center blood count (CBC) parameters on CRC according to tumor stage and localization.
Methods: Newly diagnosed 312 CRC patients between 2010 and 2016 were retrospectively analyzed. Patients' demographics, including survival data and tumor characteristics, were obtained from medical charts. RPR was calculated using CBC parameters at the time of diagnosis. Cutoff value for RPR was set at 0.05 and the patient population was divided into two arms (arm A: RPR ≥0.05 and arm B: RPR <0.05). The patients were stratified according to the tumor stage (early and advanced disease) and tumor localization (right sided and left sided).
Results: Totally, 312 patients were enrolled to the study. Nearly 81.9% of the patients were at early stage and 18.1% were at advanced stage at the time of diagnosis. In patients with early-stage disease, no significant disease-free survival and overall survival (OS) was found in both arms (P = 0.88 and P = 0.085, respectively). In arm A, OS was nonsignificantly better in the entire and left-sided advanced tumor compared to arm B. In patients with right-sided advanced cancer, OS was statistically significantly better for arm A compared to arm B (median OS; RPR ≥0.05: 24.8 months vs. <0.05: 13.9 months; P = 0.035).
Discussion: RPR can be a useful prognostic marker in CRC, especially in right-sided advanced tumors.
Conclusion: RPR can be used as a prognostic marker in CRC but should be validated with further investigation.
Keywords: Colorectal cancer, platelet, red cell distribution width, red cell distribution width-to-platelet ratio, tumor localization
|How to cite this article:|
Bilgin B, Sendur MA, Hizal M, Dede DS, Akinci MB, Kandil SU, Yaman S, Yalçin A, Kiliç M, Yalçin B. Prognostic effect of red cell distribution width-to-platelet ratio in colorectal cancer according to tumor stage and localization. J Can Res Ther 2019;15:54-60
|How to cite this URL:|
Bilgin B, Sendur MA, Hizal M, Dede DS, Akinci MB, Kandil SU, Yaman S, Yalçin A, Kiliç M, Yalçin B. Prognostic effect of red cell distribution width-to-platelet ratio in colorectal cancer according to tumor stage and localization. J Can Res Ther [serial online] 2019 [cited 2020 Aug 14];15:54-60. Available from: http://www.cancerjournal.net/text.asp?2019/15/1/54/244226
| > Introduction|| |
Colorectal cancer (CRC) is the third frequent most commonly diagnosed cancer type worldwide and also the third and second leading of cancer-related deaths in female and male patients, respectively. In 2017, estimated numbers of newly diagnosed with CRC and CRC-related deaths are nearly 130,000 and 50,000 at the USA, respectively. Recently, many prognostic and predictive markers (RAS/RAF mutation status, CDX2 status, microsatellite instability [MSI] status, etc.) are found for patients with early- and advanced-stage CRC.,,,, Primary tumor localization is also another interesting area that had been intensively investigated in the last years. We also know that right-sided and left-sided colon tumors have distinct anatomic, molecular, and embryogenic features.
Center blood count (CBC) is routinely used as a basic test at the time of diagnosis for various malignant and nonmalignant conditions. Red cell distribution width (RDW) is a part of CBC and reflects the heterogeneity of the red cell by measuring the size of the erythrocyte. The RDW is used firstly as a marker for differentiating the etiology of anemia. Recently, the prognostic importance of the RDW was shown in many malignant and nonmalignant diseases. Especially increased RDW was found as a prognostic indicator for ovarian, lung, and colon cancers,, and associated with worst outcome in various nonmalignant diseases.,,, Previously, studies showed that higher levels of RDW are related to systemic inflammation and correlated with erythrocyte sedimentation rate and C-reactive protein levels. Higher RDW is also caused by poor nutritional status. RDW-to-platelet ratio (RPR) is another marker for reflection of the systemic inflammation and theoretically can be less affected to noninflammatory conditions than RDW alone.
We hypothesized that RPR might be a prognostic marker for CRC because of reflecting systemic inflammation condition. To our knowledge, there are no studies that investigated the prognostic importance of the RPR in CRC. Therefore, in our study, we aimed to investigate the prognostic effect of RPR on CRC according to tumor stage and localization.
| > Materials and Methods|| |
Patients who were diagnosed with CRC in Ankara Yildirim Beyazit University between 2010 and 2016 were retrospectively analyzed. Patients' demographics, including survival data and tumor characteristics, were obtained from medical charts. Patients over 18 years old, Eastern Cooperative Oncology Group performance status between 0 and 4, and the diagnosis of CRC made pathologically with colonoscopic biopsy and tru-cut needle biopsy from metastatic lesions or surgically resected specimens were enrolled in our study. The patients' age, sex, comorbidities, disease stage, primary tumor localization, RAS mutation status, CBC, and other demographic data were obtained from patients' file and electronic medical records. Patients who had active inflammation or inflammatory diseases were excluded from the study. Cecum, ascending colon, and right side of the middle of transverse colon were accepted as right-sided colon tumor and descending colon, sigmoid colon, rectum, and left side of the middle of transverse colon were also accepted as left-sided tumor. Blood samples were collected from patients using routine methods at the time of diagnosis. RPR was calculated for the patient by using the following formula: RDW (%) × 100/platelet (109/L). Cutoff value of RPR was accepted between 0.045 and 0.08 in the previous study; therefore, cutoff value of RPR was set as 0.05 which was the median value to our population. Higher RPR and lower RPR were described as ≥0.05 and <0.05, respectively, and the population was divided into two arms (arm A: RPR ≥0.05 and arm B: <0.05). Overall survival (OS) and disease-free survival (DFS) differences between RPR ≥0.05 and <0.05 arms were investigated according to tumor stage and localization.
Data were presented as median values, and Kolmogorov–Smirnov and Shapiro–Wilk tests were used to assess the normality. Differences in categorical factors were determined with Fisher's exact test. Differences in continuous values between two groups were assessed with Student's t- test for normally distributed variables and nonparametric Mann–Whitney U tests for nonnormally distributed variables as appropriate. The OS and DFS were estimated by the Kaplan–Meier method and were compared by the log-rank test.
All statistical procedures were performed with SPSS 17.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered statistically significant. A 5% type-1 error level was used to infer statistical significance.
| > Results|| |
Three hundred and sixteen patients with CRC were enrolled to this study. Median ages of patients were 62 years (range: 20–85 years). At diagnosis, stage 1, 2, 3, and 4 disease rates were 11.3%, 30.6%, 40.0%, and 18.1%, respectively. Fifty-six patients (18.1%) had metastasis at the time of diagnosis, whereas 44 patients (13.7%) developed metastasis subsequently. Detailed data about the characteristics of patients at diagnosis are summarized in [Table 1]. The number of patients with RPR ≥0.05 and <0.05 was 168 (53.6%) and 147 (46.4%), respectively. There was no difference in the baseline characteristics of patients between arms A and B except sex in early-stage disease and neutrophil count in advanced-stage disease. Detailed data are summarized in [Table 2].
|Table 2: Comparison of tumor characteristics between red cell distribution width-to-platelet ratio <0.05 (arm A) and red cell distribution width-to-platelet ratio <0.05 (arm B) according to stage|
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In early-stage CRC, median OS and DFS were not reached with a median 37.8-month follow-up, and 5-year OS and DFS rates tend to be nonsignificantly better in arm B compared to that of arm A [Figure 1]. According to the tumor localization, no OS and DFS differences were found between arm A and arm B in both right-sided and left-sided tumors [Figure 2] and [Figure 3].
|Figure 1: Five-year overall survival and disease-free survival of the population. Five-year disease-free survival was 77.4% for red cell distribution width-to-platelet ratio ≥0.05 arm and 78.1% for <0.05 arm. Five-year overall survival for red cell distribution width-to-platelet ratio ≥0.05 and <0.05 arms was 85.5% and 91.7%, respectively. There was no statistically significant difference for overall survival and disease-free survival between the two arms|
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|Figure 2: Five-year disease-free survival of early-stage colorectal cancer according to tumor localization|
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|Figure 3: Five-year overall survival of early-stage colorectal cancer according to tumor localization|
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In advanced-stage CRC, 56 patients diagnosed with metastatic CRC at the time of diagnoses and 44 patients who developed metastasis subsequently were analyzed together; 28 of 100 patients had right-sided and 62 of 100 patients had also left-sided tumors. Median OS for the entire metastatic population was 21.97 months for advanced-stage CRC with a median 19.1-month follow-up and 24-month OS rate was 44.4%. Median OS in right-sided and left-sided tumors was 19.4 and 22.8 months, respectively (P = 0.52) [Figure 4].
|Figure 4: Overall survival according to tumor localization. Median overall survival for right-sided and left-sided tumors was 19.4 and 22.8 months, respectively (P = 0.52)|
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According to the RPR level in advanced CRC, median OS tends to be nonsignificantly better in arm A compared with arm B (median [mOS]; RPR ≥0.05: 22.8 months vs. RPR <0.05: 16.4 months; P = 0.202) [Figure 5]. There was no significant difference for median RPR level between right-sided and left-sided advanced colon tumors. Median RPR in right-sided and left-sided tumors was 0.54 and 0.57, respectively (P = 0.47). Median OS was not statistically significant between two RPR arms in left-sided tumors (22.0 vs. 17.1 months, P = 0.98). On the other hand, mOS was statistically better in arm A compared to arm B in right-sided tumors; mOS for arms A and B was 28.8 and 13.9 months, respectively (P = 0.035, hazard ratio: 0.27, 95% confidence interval: 0.101–0.72) [Figure 6].
|Figure 5: Overall survival for red cell distribution width-to-platelet ratio ≥0.05 and <0.05 in advanced colorectal cancer (median overall survival; red cell distribution width-to-platelet ratio ≥0.05: 22.8 months vs. red cell distribution width-to-platelet ratio <0.05: 16.4 months; P = 0.202)|
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|Figure 6: Overall survival for red cell distribution width-to-platelet ratio ≥0.05 and <0.05 in left-sided tumor (median overall survival; red cell distribution width-to-platelet ratio ≥0.05: 22.8 months vs. <0.05: 17.1 months; P = 0.98) and overall survival for red cell distribution width-to-platelet ratio ≥0.05 and <0.05 in right-sided tumor (median overall survival; red cell distribution width-to-platelet ratio ≥0.05: 28.8 months vs. <0.05: 13.9 months; P = 0.035; hazard ratio: 0.27, 95% confidence interval: 0.101–0.72)|
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| > Discussion|| |
In our study, we found that RPR may be used as a prognostic factor especially for patients with right-sided advanced CRCs. In early-stage disease, we did not find any association between RPR and OS and DFS. On the other hand, the association between RPR and OS was not significant in the entire population and left-sided tumors, whereas there was the statistically significant association in right-sided tumors. To our knowledge, this is the first study which evaluated the effect of RPR to survival in CRC.
RDW is a simple and inexpensive parameter which is measured in the complete blood count. RDW level can reflect various conditions such as iron deficiency, Vitamin B12 deficiency, myelodysplastic syndrome, hemolytic anemia, poor nutritional status, and also systemic inflammation. The exact mechanisms of inflammation on RDW are unclear, but potential mechanisms are impairing iron metabolism, inhibiting the response to erythropoietin, and decreasing red blood cell survival due to increased inflammatory cytokines., There are many trials that investigate the association between RDW level and disease outcomes in various malignancies. In these trials, higher RDW which reflects increased systemic inflammation and poor nutritional status was found as the poor prognostic factor, especially in lung, ovarian, breast, and also colon cancers.,,,, These findings are attributed to the negative effect of systemic inflammation on malignant disease, but the exact mechanisms are not clear yet. Spell et al. showed that RDW level was significantly higher in colon cancer than control group. However, interestingly, RDW level was significantly higher in right-sided colon tumors than left-sided colon tumors. The authors of this trial interpreted that RDW level was higher in the right-sided tumors as a consequence of iron deficiency anemia. Another trial also showed that RDW level was higher in colon tumor compared with colon polyps. However, to our knowledge, there is no trial that investigated the prognostic effect of RDW on CRC in the literature.
Platelet count is another parameter which is measured in the CBC and may be affected by systemic inflammatory status. Many soluble mediators secreted as a consequence of the systemic inflammation can activate platelet function and also increase the number of platelets. Bambace and Holmes showed that increased platelet count can be seen commonly in many cancer types and also found that platelet count inversely correlated with survival. The role of the platelet count in CRC is not clear yet. Many trials suggested that higher platelet count is associated with poor outcomes, whereas some trials could not demonstrate a significant correlation between platelet count and survival.,,
RPR is a marker which is easily calculated by using CBC parameters and it can reflect systemic inflammatory status. Since RDW and platelet count can be affected by noninflammatory conditions such as poor nutritional status, bone marrow disease, and anemia, RPR is the more reliable marker which can be less affected by noninflammatory condition for reflection of the inflammatory status. In the light of the literature, there are limited trials that investigated the association between RPR and nonmalignant diseases. In these trials, higher RPR level was found to be associated with poor prognosis in pancreatitis and acute myocardial infarction and was also found predictive for the development of hepatic fibrosis in patients with chronic hepatitis.,,, To our knowledge, this is the first trial that investigates the association between RPR and malignant disease. In our trial, OS and DFS were found better but not statistically significant in patients with RPR level <0.05 than ≥0.05 in early-stage CRC, regardless of the stage. On the other hand, OS and DFS were tend to better in RPR ≥0.05 arm compared with <0.05 arm in right-sided early-stage colon tumor, but these results were not statistically significant. In left-sided tumor, results were similar with the overall population. In advanced-stage CRC, OS was found to be statistically significantly better in the right-sided patients with RPR ≥0.05. However, OS was also found to be better for patients with RPR ≥0.05 in left-sided tumors and entire colon but not statistically significant.
We know that right-sided and left-sided colon tumors have distinct molecular features. MSI, CpG island methylator phenotype, BRAF mutation, and the other gene expression such as ERCC1, PODXL, and ANXA10 were found more common in right-sided tumor than left-sided tumor. All of these abnormalities are associated with poor prognosis and decreased response of the chemotherapy and targeted therapy. Right-sided colon tumors have also more T-cell lymphocyte infiltration, especially high MSI profile. As a consequence of these mutation and lymphocyte infiltration, right-sided tumor was accepted as more immunogenic than left-sided tumor.
Although median RPR levels of the right-sided and left-sided colon tumors were not significantly different in our study, RPR which is a marker that reflects inflammatory status can be a useful marker in right-sided tumor rather than left-sided tumor. The results of our study also support this expectation. However, we did not analyze mutation status (such as MSI and BRAF) of our population. This issue is the major limitation of our study since mutation status and mutation load can influence the outcomes and also inflammatory response.
Two other limitations also existed in our study. First, this study was performed retrospectively with a limited number of patients at a single institution. Second, serum levels of factors that can influence RDW and platelet count (e.g., iron, Vitamin B12, and folic acid) were not determined.
| > Conclusion|| |
RPR can be a cost-effective, simple, and useful marker for reflection of inflammatory status. This study showed that RPR can be used as a prognostic marker in CRC, but there are still some confusing data. Therefore, the results of this study should be validated with further investigation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al.
Colorectal cancer statistics, 2017. CA Cancer J Clin 2017;67:177-93.
Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, et al.
CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med 2016;374:211-22.
Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al.
Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247-57.
Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS, et al.
Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: A meta-analysis of randomized, controlled trials. Ann Oncol 2015;26:13-21.
Markovic S, Dimitrijevic I, Zogovic B, Markovic V, Barisic G, Krivokapic Z, et al.
Current trends in clinical genetics of colorectal cancer. J BUON 2016;21:1042-9.
Ioannou M, Papamichali R, Samara M, Paraskeva E, Papacharalambous C, Baxevanidou K, et al.
Diagnostic value of immunohistochemistry for the detection of the BRAF V600E mutation in colorectal carcinoma. J BUON 2016;21:618-25.
Mik M, Berut M, Dziki L, Trzcinski R, Dziki A. Right- and left-sided colon cancer – Clinical and pathological differences of the disease entity in one organ. Arch Med Sci 2017;13:157-62.
Ichinose J, Murakawa T, Kawashima M, Nagayama K, Nitadori JI, Anraku M, et al.
Prognostic significance of red cell distribution width in elderly patients undergoing resection for non-small cell lung cancer. J Thorac Dis 2016;8:3658-66.
Qin Y, Wang P, Huang Z, Huang G, Tang J, Guo Y, et al.
The value of red cell distribution width in patients with ovarian cancer. Medicine (Baltimore) 2017;96:e6752.
Spell DW, Jones DV Jr., Harper WF, David Bessman J. The value of a complete blood count in predicting cancer of the colon. Cancer Detect Prev 2004;28:37-42.
Balta S, Demirkol S, Hatipoglu M, Ardic S, Arslan Z, Celik T, et al.
Red cell distribution width is a predictor of mortality in patients with severe sepsis and septic shock. Am J Emerg Med 2013;31:989-90.
Weuve J, Mendes de Leon CF, Bennett DA, Dong X, Evans DA. The red cell distribution width and anemia in association with prevalent dementia. Alzheimer Dis Assoc Disord 2014;28:99-105.
Sánchez-Chaparro MA, Calvo-Bonacho E, González-Quintela A, Cabrera M, Sáinz JC, Fernández-Labandera C, et al.
Higher red blood cell distribution width is associated with the metabolic syndrome: Results of the ibermutuamur CArdiovascular RIsk assessment study. Diabetes Care 2010;33:e40.
Ozsu S, Ozcelik N, Oztuna F, Ozlu T. Prognostic value of red cell distribution width in patients with sarcoidosis. Clin Respir J 2015;9:34-8.
Lippi G, Targher G, Montagnana M, Salvagno GL, Zoppini G, Guidi GC, et al.
Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients. Arch Pathol Lab Med 2009;133:628-32.
Baicus C, Caraiola S, Rimbas M, Patrascu R, Baicus A; for Grupul de Studiu al Scaderii Ponderale Involuntare, et al.
Utility of routine hematological and inflammation parameters for the diagnosis of cancer in involuntary weight loss. J Investig Med 2011;59:951-5.
Koma Y, Onishi A, Matsuoka H, Oda N, Yokota N, Matsumoto Y, et al.
Increased red blood cell distribution width associates with cancer stage and prognosis in patients with lung cancer. PLoS One 2013;8:e80240.
de Gonzalo-Calvo D, de Luxán-Delgado B, Rodríguez-González S, García-Macia M, Suárez FM, Solano JJ, et al.
Interleukin 6, soluble tumor necrosis factor receptor I and red blood cell distribution width as biological markers of functional dependence in an elderly population: A translational approach. Cytokine 2012;58:193-8.
Xie D, Marks R, Zhang M, Jiang G, Jatoi A, Garces YI, et al.
Nomograms predict overall survival for patients with small-cell lung cancer incorporating pretreatment peripheral blood markers. J Thorac Oncol 2015;10:1213-20.
Huang DP, Ma RM, Xiang YQ. Utility of red cell distribution width as a prognostic factor in young breast cancer patients. Medicine (Baltimore) 2016;95:e3430.
Montagnana M, Danese E. Red cell distribution width and cancer. Ann Transl Med 2016;4:399.
Ay S, Eryilmaz MA, Aksoy N, Okus A, Unlu Y, Sevinc B, et al.
Is early detection of colon cancer possible with red blood cell distribution width? Asian Pac J Cancer Prev 2015;16:753-6.
Stokes KY, Granger DN. Platelets: A critical link between inflammation and microvascular dysfunction. J Physiol 2012;590:1023-34.
Bambace NM, Holmes CE. The platelet contribution to cancer progression. J Thromb Haemost 2011;9:237-49.
Lin MS, Huang JX, Zhu J, Shen HZ. Elevation of platelet count in patients with colorectal cancer predicts tendency to metastases and poor prognosis. Hepatogastroenterology 2012;59:1687-90.
Sasaki K, Kawai K, Tsuno NH, Sunami E, Kitayama J. Impact of preoperative thrombocytosis on the survival of patients with primary colorectal cancer. World J Surg 2012;36:192-200.
Nyasavajjala SM, Runau F, Datta S, Annette H, Shaw AG, Lund JN, et al.
Is there a role for pre-operative thrombocytosis in the management of colorectal cancer? Int J Surg 2010;8:436-8.
Taefi A, Huang CC, Kolli K, Ebrahimi S, Patel M. Red cell distribution width to platelet ratio, a useful indicator of liver fibrosis in chronic hepatitis patients. Hepatol Int 2015;9:454-60.
Cetinkaya E, Senol K, Saylam B, Tez M. Red cell distribution width to platelet ratio: New and promising prognostic marker in acute pancreatitis. World J Gastroenterol 2014;20:14450-4.
Wang H, Xu H, Wang X, Wu R, Gao X, Jin Q, et al.
Red blood cell distribution width to platelet ratio is related to histologic severity of primary biliary cirrhosis. Medicine (Baltimore) 2016;95:e3114.
Pusuroglu H, Cakmak HA, Akgul O, Erturk M, Surgit O, Akkaya E, et al.
The prognostic value of admission red cell distribution width-to-platelet ratio in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Rev Port Cardiol 2015;34:597-606.
Shen H, Yang J, Huang Q, Jiang MJ, Tan YN, Fu JF, et al.
Different treatment strategies and molecular features between right-sided and left-sided colon cancers. World J Gastroenterol 2015;21:6470-8.
Buckowitz A, Knaebel HP, Benner A, Bläker H, Gebert J, Kienle P, et al.
Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer 2005;92:1746-53.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]