cancer - related inflammation affects many aspects of malignancy , including proliferation and survival of malignant cells , angiogenesis , and therapeutic response . in a previous study that utilizes a mouse model , we showed that an inflammatory response is elicited in the early stages of the postsurgical wound healing process , leading to an increase in the number of inflammatory cells in the peritoneum . this further increases pro - matrix metalloproteinase-9 ( pro - mmp-9 ) , which plays a key role in the growth and progression of peritoneal metastases . based on these experimental results , we hypothesize that the local metastatic microenvironment will be changed during the early inflammatory phase in the process of wound healing . clinically , there have been efforts to demonstrate a correlation between operative systemic inflammation and cancer . some biomarkers representing the degree of systemic inflammation , such as the glasgow prognostic score , neutrophil lymphocyte ratio ( nlr ) , and platelet lymphocyte ratio ( plr ) , have been shown to have prognostic value in many kinds of cancer patients [ 5 - 8 ] . however , these results only focus on the effects of preoperative cancer or inflammation , regardless of etiology of the inflammation . until now , there is only a few research regarding postoperative systemic inflammation on cancer prognosis . in this study , we examine not only the effect of the preoperative inflammatory state on cancer , but also the effects of early postoperative systemic inflammation on cancer prognosis , based on the previous animal study results . six hundred thirty - nine consecutive patients underwent surgery for colorectal cancer at yeouido st . mary 's hospital , the catholic university of korea from january 2006 to december 2009 . patients were excluded if they had colorectal cancer other than adenocarcinoma and carcinoma in situ . however , patients who had preoperative radiation therapy and those who were not able to undergo curative resection were included . routine laboratory measurements , including white blood cell ( wbc ) count , neutrophil count , lymphocyte count , monocyte count , and platelet count , were performed preoperatively , daily until day four postoperatively , and subsequently every two days . we did not consider preoperative infection and inflammatory condition and postoperative infection and inflammatory condition . patients were divided into three groups based on the days spent on the leukocyte count to drop below 10,000/mm after surgery ( dsnlc ; group i , 0 - 1 days ; group ii , 2 - 3 days ; group iii , 4 days ) . for a comparative analysis with the results of the other study , grouping of the variables , such as the wbc count , neutrophil count , lymphocyte count , monocyte count , and platelet count , " right side colon " was defined as both the right colon and the transverse colon . " left side colon " was defined as both the left colon and the recto - sigmoid colon above the peritoneal reflection . staging evaluation was carried out according to the guidelines of american joint committee on cancer , sixth edition . this study was approved by the institutional review board of the college of medicine ( sc11tisi0080 ) . the relationship between the number of days required for the leukocyte count to drop below 10,000/mm after surgery ( group i , 0 - 1 day ; group ii , 2 - 3 days ; group iii , 4 days ) and clinicopathologic factors was assessed using the chi - squared and fisher 's exact tests . the overall duration of survival was calculated from the date of surgery until the date of death . the duration of cancer - free survival was calculated from the date of surgery until the date of detection of disease recurrence , defined using clinical , radiographic or pathological findings . overall and cancer - free survival rates were calculated using the kaplan - meier method , and differences among curves were tested using the log - rank test . variables that were significantly related to the survival rate in a univariate analysis were subsequently included in a multivariate analysis employing the cox multiple regression model . this method finds the ' best ' variables ( p<0.05 ) for which the effects on prognosis are not only significant , but also independent when correlated with the other factors included in the model . all statistical tests were two - tailed and the significance level was set at 0.05 . six hundred thirty - nine consecutive patients underwent surgery for colorectal cancer at yeouido st . mary 's hospital , the catholic university of korea from january 2006 to december 2009 . patients were excluded if they had colorectal cancer other than adenocarcinoma and carcinoma in situ . however , patients who had preoperative radiation therapy and those who were not able to undergo curative resection were included . routine laboratory measurements , including white blood cell ( wbc ) count , neutrophil count , lymphocyte count , monocyte count , and platelet count , were performed preoperatively , daily until day four postoperatively , and subsequently every two days . we did not consider preoperative infection and inflammatory condition and postoperative infection and inflammatory condition . patients were divided into three groups based on the days spent on the leukocyte count to drop below 10,000/mm after surgery ( dsnlc ; group i , 0 - 1 days ; group ii , 2 - 3 days ; group iii , 4 days ) . for a comparative analysis with the results of the other study , grouping of the variables , such as the wbc count , neutrophil count , lymphocyte count , monocyte count , and platelet count , " right side colon " was defined as both the right colon and the transverse colon . " left side colon " was defined as both the left colon and the recto - sigmoid colon above the peritoneal reflection . staging evaluation was carried out according to the guidelines of american joint committee on cancer , sixth edition . this study was approved by the institutional review board of the college of medicine ( sc11tisi0080 ) . the relationship between the number of days required for the leukocyte count to drop below 10,000/mm after surgery ( group i , 0 - 1 day ; group ii , 2 - 3 days ; group iii , 4 days ) and clinicopathologic factors was assessed using the chi - squared and fisher 's exact tests . the overall duration of survival was calculated from the date of surgery until the date of death . the duration of cancer - free survival was calculated from the date of surgery until the date of detection of disease recurrence , defined using clinical , radiographic or pathological findings . overall and cancer - free survival rates were calculated using the kaplan - meier method , and differences among curves were tested using the log - rank test . variables that were significantly related to the survival rate in a univariate analysis were subsequently included in a multivariate analysis employing the cox multiple regression model . this method finds the ' best ' variables ( p<0.05 ) for which the effects on prognosis are not only significant , but also independent when correlated with the other factors included in the model . all statistical tests were two - tailed and the significance level was set at 0.05 . the male - to - female ratio of patients was 1.48:1 , and the mean age was 62.311.5 years . three hundred fifty patients ( 58.2% ) were under 65 years old , and 250 patients ( 41.7% ) were over 65 years old . the follow - up period ranged from 1 to 72 months ( mean , 27.418.2 months ) . tumors were localized to the right side colon in 156 patients ( 26.0% ) , the left side colon in 250 patients ( 41.7% ) , the rectum in 184 patients ( 30.7% ) and multiple areas in 10 patients ( 1.7% ) . there were no differences between the groups with regards to complication of cancer , which was defined by perforating or obstructing colorectal lesions . among the rectal cancer patients laparoscopic treatment was performed in 69 patients ( 11.5% ) , and conventional treatment was performed in 531 patients ( 88.5% ) . five hundred thirty - one patients ( 88.5% ) underwent r0 resection and 69 patients ( 11.5% ) underwent r1 resection . we observed stage i disease in 140 patients ( 23.3% ) , stage ii disease in 178 patients ( 29.7% ) , stage iii0 disease in 208 patients ( 34.7% ) , and stage iv disease in 52 patients ( 8.7% ) . there were no differences in the characteristics of patients between the three groups , other than neoadjuvant rt and surgical approach methods ( p=0.003 and p=0.005 , respectively ) ( table 1 ) . in total , 548 patients ( 91.3% ) had preoperative wbc counts under 10,000/mm and 52 patients ( 8.7% ) had increased preoperative wbc counts ( over 10,000/mm ) . postoperative wbc counts exceeded 10,000/mm in 417 patients ( 69.5% ) , including 74 cases ( 45.8% ) in group i , 198 cases ( 33.0% ) in group ii , and 127 cases ( 21.2% ) in group iii . preoperative wbc counts correlated significantly with disease stage ( p=0.047 ) . in particular , increased preoperative wbc counts were noted in patients at stages ii and iii ( data not shown ) . however , neither postoperative wbc counts nor the number of days required for the leukocyte count to fall below 10,000/mm correlated with disease stage ( p=0.394 and p=0.402 , respectively ) . patients who received preoperative radiotherapy and patients who had laparoscopic surgery had statistically significant shorter wbc normalization periods compared to patients without preoperative radiotherapy and with conventional surgery . the results did not show a significant difference in the postoperative wbc normalization period for the combined resection of other organs ( p=0.329 ) . the duration of postoperative hospital stay , according to the wbc normalization period , was as follows : group i , 127.1 days ( median , 11.0 days ) ; group ii , 12.37.3 days ( median , 10.0 days ) ; group iii , 14.87.9 days ( median , 12.0 days ) . however , there were no significant differences , between groups i and ii . there are significant correlations between the groups with regards to preoperative neutrophil count ( p<0.001 ) , lymphocyte count ( p=0.001 ) , monocyte count ( p<0.001 ) , and platelet count ( p=0.001 ) , but no correlation between preoperative nlr ( p=0.47 ) ( table 1 ) . in univariate survival analyses , tumor , node , metastasis ( tnm ) stage and monocyte count were significantly associated with cancer - free survival ( p<0.01 for both parameters ) . in addition , cancer - free survival outcomes were significantly worse in patients who required more than four days for the normalization of wbc count ( hazard ratio [ hr ] , 1.652 ; 95% confidence interval [ ci ] , 1.105 to 2.468 ; p=0.014 ) . a tnm stage greater than ii and nlr is significantly associated with the duration of overall survival ( p<0.050 and p=0.045 , respectively ) , but no correlation was observed between dsnlc and duration of overall survival ( table 2 ) . cancer - free and overall survival curves are shown according to the stage , time for leukocyte count to decline below 10,000/mm and monocyte count in figs . 1 , 2 , and 3 , respectively . no correlation was revealed between the elevated preoperative and postoperative wbc counts ( 1010 ) and cancer - free or overall survival . in a multivariate analysis of these significant variables ( except curative resection ) , tnm stage ( stage ii : hr , 3.545 ; 95% ci , 1.571 to 7.997 ; p=0.002 ; stage iii : hr , 6.115 ; 95% ci , 2.818 to 13.447 ; p<0.001 ; stage iv : hr , 15.928 ; 95% ci , 6.974 to 36.378 ; p<0.001 ) , an interval longer than four days for normalization of wbc counts ( hr , 1.509 ; 95% ci , 0.999 to 2.278 ; p=0.050 ) , and monocyte count ( hr , 2.133 ; 95% ci , 1.262 to 3.605 ; p=0.005 ) were independently associated with cancer - free survival ( table 3 ) . the male - to - female ratio of patients was 1.48:1 , and the mean age was 62.311.5 years . three hundred fifty patients ( 58.2% ) were under 65 years old , and 250 patients ( 41.7% ) were over 65 years old . the follow - up period ranged from 1 to 72 months ( mean , 27.418.2 months ) . tumors were localized to the right side colon in 156 patients ( 26.0% ) , the left side colon in 250 patients ( 41.7% ) , the rectum in 184 patients ( 30.7% ) and multiple areas in 10 patients ( 1.7% ) . there were no differences between the groups with regards to complication of cancer , which was defined by perforating or obstructing colorectal lesions . among the rectal cancer patients laparoscopic treatment was performed in 69 patients ( 11.5% ) , and conventional treatment was performed in 531 patients ( 88.5% ) . five hundred thirty - one patients ( 88.5% ) underwent r0 resection and 69 patients ( 11.5% ) underwent r1 resection . we observed stage i disease in 140 patients ( 23.3% ) , stage ii disease in 178 patients ( 29.7% ) , stage iii0 disease in 208 patients ( 34.7% ) , and stage iv disease in 52 patients ( 8.7% ) . there were no differences in the characteristics of patients between the three groups , other than neoadjuvant rt and surgical approach methods ( p=0.003 and p=0.005 , respectively ) ( table 1 ) . in total , 548 patients ( 91.3% ) had preoperative wbc counts under 10,000/mm and 52 patients ( 8.7% ) had increased preoperative wbc counts ( over 10,000/mm ) . postoperative wbc counts exceeded 10,000/mm in 417 patients ( 69.5% ) , including 74 cases ( 45.8% ) in group i , 198 cases ( 33.0% ) in group ii , and 127 cases ( 21.2% ) in group iii . preoperative wbc counts correlated significantly with disease stage ( p=0.047 ) . in particular , increased preoperative wbc counts were noted in patients at stages ii and iii ( data not shown ) . however , neither postoperative wbc counts nor the number of days required for the leukocyte count to fall below 10,000/mm correlated with disease stage ( p=0.394 and p=0.402 , respectively ) . patients who received preoperative radiotherapy and patients who had laparoscopic surgery had statistically significant shorter wbc normalization periods compared to patients without preoperative radiotherapy and with conventional surgery . the results did not show a significant difference in the postoperative wbc normalization period for the combined resection of other organs ( p=0.329 ) . the duration of postoperative hospital stay , according to the wbc normalization period , was as follows : group i , 127.1 days ( median , 11.0 days ) ; group ii , 12.37.3 days ( median , 10.0 days ) ; group iii , 14.87.9 days ( median , 12.0 days ) . however , there were no significant differences , between groups i and ii . there are significant correlations between the groups with regards to preoperative neutrophil count ( p<0.001 ) , lymphocyte count ( p=0.001 ) , monocyte count ( p<0.001 ) , and platelet count ( p=0.001 ) , but no correlation between preoperative nlr ( p=0.47 ) ( table 1 ) . in univariate survival analyses , tumor , node , metastasis ( tnm ) stage and monocyte count in addition , cancer - free survival outcomes were significantly worse in patients who required more than four days for the normalization of wbc count ( hazard ratio [ hr ] , 1.652 ; 95% confidence interval [ ci ] , 1.105 to 2.468 ; p=0.014 ) . a tnm stage greater than ii and nlr is significantly associated with the duration of overall survival ( p<0.050 and p=0.045 , respectively ) , but no correlation was observed between dsnlc and duration of overall survival ( table 2 ) . cancer - free and overall survival curves are shown according to the stage , time for leukocyte count to decline below 10,000/mm and monocyte count in figs . 1 , 2 , and 3 , respectively . no correlation was revealed between the elevated preoperative and postoperative wbc counts ( 1010 ) and cancer - free or overall survival . in a multivariate analysis of these significant variables ( except curative resection ) , tnm stage ( stage ii : hr , 3.545 ; 95% ci , 1.571 to 7.997 ; p=0.002 ; stage iii : hr , 6.115 ; 95% ci , 2.818 to 13.447 ; p<0.001 ; stage iv : hr , 15.928 ; 95% ci , 6.974 to 36.378 ; p<0.001 ) , an interval longer than four days for normalization of wbc counts ( hr , 1.509 ; 95% ci , 0.999 to 2.278 ; p=0.050 ) , and monocyte count ( hr , 2.133 ; 95% ci , 1.262 to 3.605 ; p=0.005 ) were independently associated with cancer - free survival ( table 3 ) . in univariate survival analyses , tumor , node , metastasis ( tnm ) stage and monocyte count were significantly associated with cancer - free survival ( p<0.01 for both parameters ) . in addition , cancer - free survival outcomes were significantly worse in patients who required more than four days for the normalization of wbc count ( hazard ratio [ hr ] , 1.652 ; 95% confidence interval [ ci ] , 1.105 to 2.468 ; p=0.014 ) . a tnm stage greater than ii and nlr is significantly associated with the duration of overall survival ( p<0.050 and p=0.045 , respectively ) , but no correlation was observed between dsnlc and duration of overall survival ( table 2 ) . cancer - free and overall survival curves are shown according to the stage , time for leukocyte count to decline below 10,000/mm and monocyte count in figs . 1 , 2 , and 3 , respectively . no correlation was revealed between the elevated preoperative and postoperative wbc counts ( 1010 ) and cancer - free or overall survival . in a multivariate analysis of these significant variables ( except curative resection ) , tnm stage ( stage ii : hr , 3.545 ; 95% ci , 1.571 to 7.997 ; p=0.002 ; stage iii : hr , 6.115 ; 95% ci , 2.818 to 13.447 ; p<0.001 ; stage iv : hr , 15.928 ; 95% ci , 6.974 to 36.378 ; p<0.001 ) , an interval longer than four days for normalization of wbc counts ( hr , 1.509 ; 95% ci , 0.999 to 2.278 ; p=0.050 ) , and monocyte count ( hr , 2.133 ; 95% ci , 1.262 to 3.605 ; p=0.005 ) were independently associated with cancer - free survival ( table 3 ) . first , inflammatory diseases increase the risk of developing many types of cancer and inflammatory cells . second , chemokines and cytokines are present in the microenvironment of all tumors in experimental animal models and in humans from the earliest stages of development . as mentioned above , our experimental mouse model creates an inflammatory reaction in the peritoneum and confers an increased metastatic burden at the wound site compared with the undamaged normal peritoneal tissues . furthermore , this model demonstrates an abundance of pro - inflammatory cells at the wound site , which likely induces mesothelial cells in the peritoneum . consequently , an increase in the mesothelial cells and other inflammatory cells constitute a pro - metastatic microenvironment in the normal peritoneum . in addition , in the early stages of wound healing , wound metastasis occurs . for wounds with continued inflammation , we confirmed that wound metastasis occurs even after seven days of wound healing . the glasgow prognostic score ( gps ) , which includes only serum c - reactive protein and serum albumin , has a prognostic value independent of stage in patients with advanced or primary operable cancer . in addition , the nlr and plr have been shown to have an independent prognostic value in a variety of cancers [ 5 - 8 ] . these studies demonstrate that the prognostic values of nlr or plr are independent of tumor stage , conventional scoring systems and treatment modalities . furthermore , studies conducted by leitch et al .   show that monocyte count and gps are independently associated with cancer - specific survival . in this study , monocyte count was significantly associated with cancer - free survival in a univariate survival analysis . postoperative wbc count ( 1010 ) did not reveal any correlation with cancer - free survival or overall survival . most studies mentioned above examined the effects of the preoperative inflammatory condition . however , the research presented in this report does not focus on one point of time , but rather on a certain period of an inflammatory condition that will have a great effect on the metastatic microenvironment . this idea was brought on by the fact that mmp-9 increases in the first three days postoperatively during wound healing and that the early postoperative changes affect peritoneal metastasis , as observed in the author 's prior animal model experiment study [ 4 - 12 ] . thus , in the current study , regardless of the preoperative and postoperative inflammatory status , the groups were classified by the normalization of wbc count . the period in which the metastatic microenvironment is exposed to inflammation was defined as the period until the wbc count is normalized . the results did not show significant differences between the groups , the cancer location , the extent of curative resection , or stage . these results demonstrate that the differences in surgical methods according to stage did not affect the postoperative wbc count or dsnlc . in a univariate analysis , the presence of increased wbcs in the preoperative stages did not affect the duration of disease - free survival or overall survival . on the other hand , sustained inflammation over four days did affect disease - free survival and overall survival . we can analyze that this sustained inflammation can also have a systematic effect , like the result of three day inflammatory cell increase of wound healing process having an effect on peritoneal metastasis . moreover , dsnlc was independently associated with cancer - free survival in a multivariate survival analysis . other studies have shown that an elevated gps may reflect an altered innate immune response , as gps was also associated with increased numbers of neutrophils and monocytes . this may suggest that activation of innate immunity , rather than down - regulation of acquired immunity , is the most important factor in determining a poor outcome in patients with colorectal cancer . one study also revealed that an early increase in wbcs during surgery correlates with an increased innate immune response . in addition , an increase in wbcs is a better prognostic parameter than an increase in monocytes or nlr . in this study , an early operative increase in wbc correlates with increased innate immunity , and this increase is predictive of a poorer outcome for colorectal cancer more so than monocyte or nlr increase , which only shows an increase in innate immunity at one point of time . preoperative wbc count shows a correlation with an increase of cancer stage , with the exception of stage iv . iv , since neoadjuvant chemotherapy can be performed , an increase in wbcs may be lower than in stages ii and iii . in addition , patients receiving preoperative radiation show statistically significant shorter periods for normalization of wbc counts compared to patients not receiving radiation therapy . generally , in radiation therapy , numerous inflammatory cells are recruited into the irradiation field . gross inflammatory scores and microscopic inflammatory scores are significantly higher at the colonic anastomotic line after preoperative irradiation . however , in colorectal cancer , the systemic effect of radiotherapy may not be substantial , and instead , the accompanying chemotherapy may be the reason for a shorter period of normalization of wbc count . in addition , there is a shorter wbc count normalization period following laparoscopic surgery ; this is an advantage of minimally invasive surgery . en bloc resection with radical lymphadenectomy is performed by laparoscopic surgery in our center in the same manner of open surgery . since there is no difference in operative extent between surgical methods , the shorter wbc count normalization period and decreased persistence of inflammation is attributable to laparoscopic surgery . however , there is no difference in the duration of disease - free survival between laparoscopic and open surgery . postoperative increase in wbc count has many contributory factors , such as cancer cell itself , surgical complications , radiation therapy , chemotherapy and surgical methods . whatever the causative factor , the increase in postoperative wbcs affects the metastatic microenvironment and eventually contributes to cancer recurrences . wbc count decrease was observed in cases that had preoperative radiation or chemotherapy . for laparoscopic surgery , more research is necessary as there are relatively few cases ; thus other factors , such as selection bias , can influence the results . complicated cancer was defined by perforating or obstructing colorectal lesions shows a correlation with an increase of preoperative wbc count ( p=0.004 ) , but there were no differences between the groups ( p=0.694 , data not shown ) . this fact shows that complicated colorectal cancer was not correlative with the normalization of wbc count unless the lesion persists . in addition , the wbc count normalization period after surgery did not correlate with the presence of combined resection , but rather correlated with the duration of postoperative hospital stay . in this study , three factors ( surgical approach method , preoperative radiation therapy and postoperative hospital stay ) were found to be associated with the difference in time of the period of normalization of wbc count . postoperative complications , factors in the preoperative period or factors that can affect the cancer itself may also be considered . among these additional factors , unfortunately , postoperative complications were not recorded prospectively . postoperative complications were omitted as a factor , leading to inaccuracy in the retrospective study , and this represents a shortcoming of this study . taking into account the postoperative hospital stay , it can be inferred that postoperative complications are likely to have a correlation . in summary , postoperative early inflammatory phase and preoperative monocyte count correlate with the poor prognosis of colon cancer even after the calibration of stage . thus , we can conclude that preoperativeand postoperative inflammatory response and period unfavorably affect the metastatic microenvironment .