***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: In the treatment of colon cancer today , the decision-making involved in the treatment of stage II disease is probably the most challenging aspect . The major question is whether or not these patients should receive postoperative adjuvant chemotherapy . Approximately 75 % of stage II colon cancer is cured by surgery alone . For the remaining 25 % of cases , there is great debate over whether adjuvant chemotherapy is sufficiently effective in enough patients to warrant the exposure to potentially toxic treatments . In the important QUASAR clinical trial , stage II patients were r and omized to either fluorouracil (5-FU)-based therapy or observation . The results demonstrated an approximate 3 % improvement in outcome for the 5-FU-treated patients . This leads to the assumption that treating all stage II patients with adjuvant chemotherapy is gross overtreatment , when essentially 97 % of these patients will not benefit . Clearly the only way to approach this decision is through risk determination . In this article , I will describe the current state of defining high- and low-risk disease , which is mainly through histopathologic characteristics , as well as discuss emerging approaches such as molecular markers and genomic profiling Background : Inflammation contributes to the pathogenesis of colorectal cancer ( CRC ) , and cytokine levels are altered during colorectal carcinogenesis . Methods : The serum levels of 13 cytokines and their relation to clinical and pathological parameters , and systemic inflammatory response ( mGPS , CRP and neutrophil – lymphocyte ratio ) , were analysed from a prospect i ve series of 148 CRC patients and 86 healthy age- and sex-matched controls . Results : CRC patients had higher serum platelet-derived growth factor , interleukin (IL)-6 , IL-7 , and IL-8 levels and lower monocyte chemotactic protein-1 ( MCP-1 ) levels than the controls . A logistic regression model for discriminating the patients from the controls – including the five most predictive cytokines ( high IL-8 , high IL-6 , low MCP-1 , low IL-1ra , and low IP-10 ) – yielded an area under curve value of 0.890 in receiver operating characteristics analysis . Serum cytokines showed distinct correlation with other markers of systemic inflammatory response , and advanced CRCs were associated with higher levels of IL-8 , IL-1ra , and IL-6 . A metastasised disease was accompanied by an orientation towards Th2 cytokine milieu . Conclusion : CRC is associated with extensive alterations in serum cytokine environment , highlighting the importance of study ing relative cytokine level alterations . Serum cytokine profile shows promise in separating CRC patients from healthy controls but its clinical value is yet to be confirmed Serum interleukin-6 ( IL-6 ) , a proinflammatory cytokine , is considered an indicator of inflammation and may be an indicator of colorectal carcinogenesis given that inflammation can promote carcinogenesis . Flavonols , which can be found in fruits and vegetables , may inhibit colorectal carcinogenesis partly by inhibiting inflammation . We estimated odds ratios and 95 % confidence intervals ( 95 % CI ) to determine whether serum IL-6 was associated with colorectal adenoma recurrence and flavonol intake and thus may serve as a risk indicator and as a response indicator to dietary flavonols .  Serum IL-6 concentrations at baseline , year 1 , and year 3 were measured in 872 participants from the intervention arm of the Polyp Prevention Trial , a 4-year trial that examined the effectiveness of a low-fat , high-fiber , high-fruit and vegetable diet  on adenoma recurrence . Intake of flavonols , especially of isorhamnetin , kaempferol , and quercetin , was inversely associated with serum IL-6 concentrations ( highest versus lowest flavonol intake quartile , 1.80 versus 2.20 pg/mL ) and high-risk ( OR , 0.51 ; 95 % CI , 0.26 - 0.98 ) and advanced adenoma recurrence ( OR , 0.17 ; 95 % CI , 0.06 - 0.50 ) . A decrease in IL-6 concentration during the trial was inversely associated with high-risk ( OR , 0.44 ; 95 % CI , 0.23 - 0.84 ) and advanced adenoma recurrence ( OR , 0.47 ; 95 % CI , 0.19 - 1.18 ) . Individuals with above median flavonol intake and equal or below median IL-6 change after baseline had the lowest risk of recurrence of high-risk and advanced adenoma . Our results suggest that serum IL-6 may serve as a risk indicator and as a response indicator to dietary flavonols for colorectal cancer prevention . Cancer Prev Res ; 3(6 ) ; 764–75 . © 2010 AACR Background Cytokines and chemokines in the tumor microenvironment drive metastatic development and their serum levels might mirror the ongoing inflammatory reaction at the tumor site . Novel highly sensitive tools are needed to identify colorectal cancer patients at high risk of recurrence that should be more closely monitored during post-surgical follow up . Here we study whether circulating inflammatory markers might be used to predict recurrence in CRC patients . Methods Circulating levels of the inflammatory cytokines IL-1 , IL-6 , IL-10 , TNFalpha , CCL2 , CXCL8 , VEGF and the acute phase protein Pentraxin-3 were measured by ELISA in preoperative serum sample  s prospect ively collected from a cohort of sixty-nine patients undergoing surgical resection for stage 0–IV CRC and associated with post-operative disease recurrence . Results Cox multivariate analysis showed that combined high levels ( ≥ROC cut off-value ) of CXCL8 , VEGF and Pentraxin3 were associated with increased risk of disease recurrence [ HR : 14.28 ; 95%CI : ( 3.13–65.1 ) ] independently of TNM staging . Kaplan-Meier analysis showed that CXCL8 , VEGF and Pentraxin3 levels were significantly associated with worse survival ( P<0.001 ) . Conclusions Circulating inflammatory mediators efficiently predicted postoperative recurrence after CRC surgery . Therefore , this study suggest that their validation in large-scale clinical trials may help in tailoring CRC post-surgical management The analytical effect of the number of events per variable ( EPV ) in a proportional hazards regression analysis was evaluated using Monte Carlo simulation techniques for data from a r and omized trial containing 673 patients and 252 deaths , in which seven predictor variables had an original significance level of p < 0.10 . The 252 deaths and 7 variables correspond to 36 events per variable analyzed in the full data set . Five hundred simulated analyses were conducted for these seven variables at EPVs of 2 , 5 , 10 , 15 , 20 , and 25 . For each simulation , a r and om exponential survival time was generated for each of the 673 patients , and the simulated results were compared with their original counterparts . As EPV decreased , the regression coefficients became more biased relative to the true value ; the 90 % confidence limits about the simulated values did not have a coverage of 90 % for the original value ; large sample properties did not hold for variance estimates from the proportional hazards model , and the Z statistics used to test the significance of the regression coefficients lost validity under the null hypothesis . Although a single boundary level for avoiding problems is not easy to choose , the value of EPV = 10 seems most prudent . Below this value for EPV , the results of proportional hazards regression analyses should be interpreted with caution because the statistical model may not be valid Increased inflammatory cell infiltration correlates to improved survival in colorectal cancer ( CRC ) . Development and progression of CRC is associated with alterations in serum cytokine levels but their significance is not well defined . In this study , we investigated the relationships between the serum levels of 13 cytokines and the densities of eight types of tumor infiltrating inflammatory cells and their impact on disease-free survival ( DFS ) , cancer-specific survival ( CSS ) and overall survival ( OS ) in a prospect ively recruited group of 147 CRC patients . There were strong positive correlations between the serum concentrations of different cytokines , as well as between the different types of tumor infiltrating immune cells , whereas the associations between serum cytokines and tumor infiltrating immune cells were generally weak . High serum IL-12 levels associated with increased densities of peritumoral CD8(+ ) T cells , intraepithelial CD3(+ ) T cells and intratumoral neutrophils , while high serum CCL4 levels associated with increased densities of peritumoral CD68(+ ) cells . In multivariate survival models , increased infiltration of intraepithelial CD3(+ ) T cells and increased serum CCL4 associated with improved DFS , whereas higher intratumoral CD83(+ ) dendritic cell density and increased serum interferon gamma levels associated with improved CSS and OS . Also high density of peritumoral CD3(+ ) T cells associated with improved CSS . In conclusion , serum cytokines and tumor infiltrating immune cells in CRC represent entities with high intragroup correlations but relatively weak intergroup correlations . The results suggest that tumor infiltrating CD3(+ ) T cells , CD83(+ ) dendritic cells , serum CCL4 and serum interferon gamma represent relevant markers of disease outcome 
    Output:
    
Four studies combined multiple cytokine levels into a single score and found them to be predictive of prognosis whereas the association between individual cytokines and outcome was not demonstrated consistently .