The relationship between systemic inflammatory response, screen detection and outcome in colorectal cancer.

AIM: A raised systemic inflammatory response correlates with poorer colorectal cancer (CRC) outcomes. Faecal immunochemical test bowel screening aims to detect early-stage disease. We assessed the relationship between systemic inflammatory response, screen detection and CRC survival. METHOD: A retrospective, observational cohort study compared screen-detected and non-screen-detected CRC patients undergoing resection. Systemic inflammatory response was measured using lymphocyte/monocyte, neutrophil/lymphocyte and platelet/lymphocyte ratios (LMR, NLR, PLR). Covariables were compared using χ2 testing and survival with Cox regression. RESULTS: A total of 761 patients were included (326 screen-detected, 435 non-screen-detected). Screen-detected patients had lower systemic inflammatory response: low (<2.4) LMR (28.8% vs. 44.6%; P < 0.001), moderate (3-5) or high (>5) NLR (26.1% vs. 30.6%, P < 0.001; and 7.7% vs. 19.5%, P < 0.001) and high (>150) PLR (47.2% vs. 64.6%; P < 0.001). Median follow-up was 63 months. On univariate analysis, non-screen detection (hazard ratio [HR] 2.346, 95% CI 1.687-3.261; P < 0.001), advanced TNM (P < 0.001), low LMR (HR 2.038, 95% CI 1.514-2.742; P < 0.001), moderate NLR (HR 1.588, 95% CI 1.128-2.235; P = 0.008), high NLR (HR 2.382, 95% CI 1.626-3.491; P < 0.001) and high PLR (HR 1.827, 95% CI 1.326-2.519; P < 0.001) predicted poorer overall survival (OS). Non-screen detection (HR 2.713, 95% CI 1.742-4.226; P < 0.001), TNM (P < 0.001), low LMR (HR 1.969, 95% CI 1.340-2.893; P < 0.001), high NLR (HR 2.368, 95% CI 1.448-3.875; P < 0.001) and high PLR (HR 2.110, 95% CI 1.374-3.240; P < 0.001) predicted poorer cancer-specific survival (CSS). On multivariate analysis, non-screen detection (HR 1.698, 95% CI 1.152-2.503; P = 0.008) and low LMR (HR 1.610, 95% CI 1.158-2.238; P = 0.005) independently predicted poorer OS. Non-screen detection (HR 1.847, 95% CI 1.144-2.983; P = 0.012) and high PLR (HR 1.578, 95% CI 1.018-2.444; P = 0.041) predicted poorer CSS. CONCLUSION: Screen-detected CRC patients have a lower systemic inflammatory response. Non-screen detection and systemic inflammatory response (measured by LMR and PLR respectively) were independent predictors of poorer OS and CSS.

Adverse Tumour and Host Biology May Explain the Poorer Outcomes Seen in Emergency Presentations of Colon Cancer.

OBJECTIVE: To examine the association between tumor/host factors (including the systemic inflammatory response), mode of presentation, and short/long-term outcomes in patients undergoing curative resectional surgery for TNM I to III colon cancer. BACKGROUND: Emergency presentations of colon cancer are associated with worse long-term outcomes than elective presentations despite adjustment for TNM stage. A number of differences in tumor and host factors have been identified between elective and emergency presentations and it may be these factors that are associated with adverse outcomes. METHODS: Patients undergoing curative surgery for TNM I to III colon cancer in the West of Scotland from 2011 to 2014 were identified. Tumor/host factors independently associated with the emergency presentation were identified and entered into a subsequent survival model to determine those that were independently associated with overall survival/cancer-specific survival (OS/CSS). RESULTS: A total of 2705 patients were identified. The emergency presentation was associated with a worse 3-year OS and CSS compared with elective presentations (70% vs 86% and 91% vs 75%). T stage, age, systemic inflammatory grade, anemia (all P < 0.001), N stage ( P = 0.077), extramural venous invasion ( P = 0.003), body mass index ( P = 0.001), and American Society of Anesthesiologists Classification classification ( P = 0.021) were independently associated with emergency presentation. Of these, body mass index [hazard ratio (HR), 0.82], American Society of Anesthesiologists Classification (HR, 1.45), anemia (HR, 1.29), systemic inflammatory grade (HR. 1.11), T stage (HR, 1.57), N stage (HR, 1.80), and adjuvant chemotherapy (HR, 0.47) were independently associated with OS. Similar results were observed for CSS. CONCLUSIONS: Within patients undergoing curative surgery for colon cancer, the emergency presentation was not independently associated with worse OS/CSS. Rather, a combination of tumor and host factors account for the worse outcomes observed.

The neoadjuvant rectal score and a novel magnetic resonance imaging based neoadjuvant rectal score are stage independent predictors of long-term outcome in locally advanced rectal cancer.

AIM: Neoadjuvant rectal (NAR) score is an early surrogate for longer-term outcomes in rectal cancer undergoing radiotherapy and resection. In an era of increasing organ preservation, resection specimens are not always available to calculate the NAR score. Post-treatment magnetic resonance imaging (MRI) re-staging of regression is subjective, limiting reproducibility. We explored the potential for a novel MRI-based NAR score (mrNAR) adapted from the NAR formula. METHODS: Locally advanced rectal cancer patients undergoing neoadjuvant therapy (nCRT) and surgery were retrospectively identified between 2008 and 2020 in a single cancer network. mrNAR was calculated by adapting the NAR formula, replacing pathological (p) stages with post-nCRT MR stages (ymr). Cox regression assessed relationships between clinicopathological characteristics, NAR and mrNAR with overall survival (OS) and recurrence-free survival (RFS). RESULTS: In total, 381 NAR and 177 mrNAR scores were calculated. On univariate analysis NAR related to OS (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.33-3.14, p = 0.001) and RFS (HR 2.52, 95% CI 1.77-3.59, p = 0.001). NAR 3-year OS <8 was 95.3%, 8-16 was 88.6% and >16 was 80%. mrNAR related to OS (HR 2.96, 95% CI 1.38-6.34, p = 0.005) and RFS (HR 2.99, 95% CI 1.49-6.00, p = 0.002). 3-year OS for mrNAR <8 was 96.2%, 8-16 was 92.4% and >16 was 78%. On multivariate analysis, mrNAR was a stage-independent predictor of OS and RFS. mrNAR corresponded to NAR score category in only 15% (positive predictive value 0.23) and 47.5% (positive predictive value 0.48) of cases for categories <8 and >16, respectively. CONCLUSIONS: Neoadjuvant rectal score is validated as a surrogate end-point for long-term outcomes. mrNAR categories do not correlate with NAR but have stage-independent prognostic value. mrNAR may represent a novel surrogate end-point for future neoadjuvant treatments that focus on organ preservation.

The relationship between the modified frailty index score (mFI-5), malnutrition, body composition, systemic inflammation and short-term clinical outcomes in patients undergoing surgery for colorectal cancer.

BACKGROUND: While the current literature suggests an association with frailty and clinical outcomes in patients undergoing surgery for colorectal cancer (CRC), the basis of this relationship is unclear. AIM: Examine the relationship between frailty, malnutrition, body composition, systemic inflammation and short-term clinical outcomes in patients undergoing surgery for colorectal cancer. METHODS: Consecutive patients who underwent potentially curative resection for colorectal cancer, between April 2008 and April 2018, were identified from a prospectively maintained database. Frailty was defined using the modified five-item frailty index (mFI-5). Body composition measures included CT-derived skeletal muscle index (SMI) and density (SMD). Systemic inflammatory status was determined using Systemic Inflammatory Grade (SIG). Outcomes of interest were the incidence of post-operative complications and thirty-day mortality. Associations between categorical variables were examined using χ2 test and binary logistics regression analysis. RESULTS: 1002 patients met the inclusion criteria. 28% (n = 221) scored 2 or more on the mFI-5. 39% (n = 388) of patients had a post-operative complication (Clavien-Dindo I-IV) and 1% (n = 11) died within thirty days of surgery. On univariate analysis, mFI-5 frailty score, was significantly associated with advanced age (p < 0.001), colonic tumours (p < 0.001), reduced use of neo-adjuvant chemotherapy (p < 0.05), higher BMI (p < 0.05), low SMD (p < 0.001), elevated NLR (p < 0.05), elevated mGPS (p < 0.05), elevated SIG (p < 0.05), incidence of post-operative complications (p < 0.001) and thirty-day mortality (p < 0.05). On multivariate analysis, male sex (p < 0.05), elevated SIG (p < 0.05) and mFI-5 score (p < 0.01) remained significantly associated with the incidence of post-operative complications. mFI-5 frailty was found to remain significantly associated with the incidence post-operative complications in patients who were SIG 0 (p < 0.05). CONCLUSION: mFI-5 frailty score was found to be significantly associated with age, systemic inflammation and post-operative outcomes in patients undergoing potentially curative resections for CRC. Incorporation of an assessment of systemic inflammatory status in future frailty screening tools may improve their prognostic value.

Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer.

BACKGROUND: To understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer. METHODS: Immunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression. RESULTS: Two patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete 'punctate' areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high 'punctate' IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus. CONCLUSIONS: These results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.

The role of faecal calprotectin in diagnosis and staging of colorectal neoplasia: a systematic review and meta-analysis.

INTRODUCTION: The presence of inflammation is a key hallmark of cancer and, plays an important role in disease progression and survival in colorectal cancer (CRC). Calprotectin detected in the faeces is a sensitive measure of colonic inflammation. The role of FC as a diagnostic test that may categorise patients by risk of neoplasia is poorly defined. This systematic review and meta-analysis aims to characterise the relationship between elevations of FC and colorectal neoplasia. METHODS: A systematic review was performed using the keywords (MESH terms) and a statistical and meta-analysis was performed. RESULTS: A total of 35 studies are included in this review. CRC patients are more likely than controls to have an elevated FC OR 5.19, 95% CI 3.12-8.62, p < 0.001 with a heterogeneity (I2 = 27%). No tumour characteristics significantly correlated with FC, only stage of CRC shows signs that it may potentially correlate with FC. CONCLUSION: FC levels are significantly higher in CRC, with high sensitivity. Its low specificity prevents it from being used to diagnose or screen for CRC.

The role of faecal calprotectin in the identification of colorectal neoplasia in patients attending for screening colonoscopy.

AIM: Although the relationship between colorectal neoplasia and inflammation is well described, the role of faecal calprotectin (FC) in clinical practice to diagnose or screen patients for colorectal neoplasia is less defined. This prospective study characterizes the relationship between FC and colorectal neoplasia in patients within the faecal occult blood testing (FOBT) positive patients in the Scottish Bowel Screening Programme. METHODS: All FOBT positive patients attending for colonoscopy between February 2016 and July 2017 were invited to participate. Patients provided a stool sample for FC before commencing bowel preparation. All demographics and endoscopic findings were collected prospectively. RESULTS: In all, 352 patients were included. 210 patients had FC > 50 µg. Colorectal cancer (CRC) patients had a higher median FC (138.5 µg/g, P < 0.05), in comparison to those without CRC, and 13/14 had an FC > 50 µg/g (93%). FC had a high sensitivity (92.8%) and negative predictive value (99.3%) for CRC, but with a low specificity (41.7%) and positive predictive value (6.2%). FC sensitivity increased sequentially as neoplasms progressed from non-advanced to malignant neoplasia (48.6% non-advanced adenoma vs. 92.9% CRC). However, no significant relationship was observed between FC and non-cancer neoplasia. CONCLUSION: In an FOBT positive screening population, FC was strongly associated with CRC (sensitivity 92.8%, specificity 41.7% for CRC, at 50 µg/g). However, although sensitive for the detection of CRC, FC failed to show sufficient sensitivity or specificity for the detection of non-cancer neoplasia. Based on these results we cannot recommend routine use of FC in a bowel screening population to detect cancer per se, but it is apparent that, with further optimization, faecal assessments including quantification of haemoglobin and inflammation could form part of a risk assessment tool aimed at refining the selection of patients for colonoscopy in both symptomatic and screening populations.

The prevalence and prognostic value of frailty screening measures in patients undergoing surgery for colorectal cancer: observations from a systematic review.

INTRODUCTION: Frailty is a complex multifactorial syndrome characterised by a significant increase in vulnerability and worsened health outcomes. Despite a range of proposed frailty screening measures, the prevalence and prognostic value of frailty in patients undergoing surgery for colorectal cancer is not clear. AIM: The aim of this present review was to examine the use of commonly employed frailty screening measures in patients undergoing surgery for colorectal cancer. METHODS: A systematic search of PubMed and Medline was carried out to identify studies reporting the use of frailty screening tools or measures in patients undergoing surgery for colorectal cancer. The screening measure used and prevalence of frailty within the population were recorded. Outcomes of interest were the incidence of post-operative complications, 30-day mortality and overall survival. RESULTS: Of the 15 studies included (n = 97, 898 patients), 9 studies were retrospective and included patients aged 70 years or older (n = 96, 120 patients). 5 of 12 studies reported that frailty was independently associated with the incidence of post-operative complications. There was also evidence that frailty was independently associated with 30-day mortality (1 of 4 studies, n = 9, 252 patients) and long-term survival (2 of 3 studies, n = 1, 420 patients). CONCLUSIONS: Frailty was common in patients with colorectal cancer and the assessment of frailty may have prognostic value in patients undergoing surgery. However, the basis of the relationship between frailty and post-operative outcomes is not clear and merits further study.

Relationship between BMI, CT-derived body composition and colorectal neoplasia in a bowel screening population.

INTRODUCTION: Obesity is associated with an increased risk of colorectal cancer (CRC). Unlike the indirect measures such as BMI, CT-Body composition (CT-BC) allows for the assessment of both volume and distribution of adipose tissue. Therefore, the aim of this study was to examine the relationship between host characteristics, BMI, CT-BC measurements and the incidence of colorectal neoplasia. METHODS: Patients undergoing CT Colonography (CTC) as part of the Scottish Bowel Screening Programme, between July 2009 and February 2016, were eligible for inclusion. Data were collected including demographic data, clinicopathological variables and CT-BC measurements including skeletal muscle index (SMI), subcutaneous fat index (SFI) and visceral fat area (VFA). CTC, colonoscopy, and pathology reports were used to identify CRC incidence. Associations between demographic data, clinicopathological variables, CT-BC measurements, colorectal neoplasia and advanced colorectal neoplasia were analysed using univariate and multivariate binary logistics regression. RESULTS: 286 patients met the inclusion criteria. Neoplasia was detected in 105 (37%) of the patients with advanced neoplasia being detected in 72 (69%) of patients. On multivariate analysis sex (p < 0.05) and high VFA (p < 0.001) remained independently associated with colorectal neoplasia. On multivariate analysis a high SFI (p < 0.01) remained independently associated with advanced colorectal neoplasia. BMI was not associated with either colorectal neoplasia or advanced colorectal neoplasia. CONCLUSION: When directly compared to BMI, CT derived fat measurements were more closely associated with the degree of neoplasia in patients undergoing colorectal cancer screening. In patients investigated with CT colonography, CT adipose measures may stratify the risk and grade of neoplasia.

The prognostic value of combined measures of the systemic inflammatory response in patients with colon cancer: an analysis of 1700 patients.

BACKGROUND: The pre-operative systemic inflammatory response (SIR) measured using an acute-phase-protein-based score (modified Glasgow Prognostic Score (mGPS)) or the differential white cell count (neutrophil-lymphocyte ratio (NLR)) demonstrates prognostic significance following curative resection of colon cancer. We investigate the complementary use of both measures to better stratify outcomes. METHODS: The effect on survival of mGPS and NLR was examined using uni/multivariate analysis (UVA/MVA) in patients undergoing curative surgery for colon cancer. The synergistic effect of these scores in predicting OS/CSS was examined using a Systemic Inflammatory Grade (SIG). RESULTS: One thousand seven hundred and eight patients with TNM-I-III colon cancer were included. On MVA both mGPS and NLR were significant for OS (HR 1.16/1.21, respectively). Three-year survival stratified by mGPS was 83-58%(TNM-I-III), 87-65%(TNM-II) and 75-49%(TNM-III), and by NLR was 84-62%(TNM-I-III), 88-69%(TNM-II) and 77-49%(TNM-III). When mGPS and NLR were combined to form an overall SIG 0/1/2/3/4, this stratified 3-year OS 88%/84%/76%/65%/60% and CSS 93%/90%/82%/73%/70%, respectively (both p < 0.001). SIG stratified OS 93-68%/82-48% and CSS 97-80%/86-58% in TNM Stage II/III disease, respectively (all p < 0.001). CONCLUSIONS: The present study shows that the pre-operative SIR in patients undergoing curative surgery for colon cancer is best measured using a SIG utilising mGPS and NLR.

The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer.

BACKGROUND: The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, and now requires validation and assessment of interactions with adjuvant therapy. METHODS: Two cohorts were utilised; 862 TNM I-III CRC validation cohort, and 2912 TNM II-III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction. RESULTS: GMS independently associated with DFS (p = 0.001) and RFS (p < 0.001). GMS significantly stratified RFS for both low risk (GMS 0 v GMS 2: HR 3.24 95% CI 1.85-5.68, p < 0.001) and high-risk disease (GMS 0 v GMS 2: HR 2.18 95% CI 1.39-3.41, p = 0.001). In TransSCOT, chemotherapy type (pinteraction = 0.013), but not duration (p = 0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX (HR 2.23 95% CI 1.19-4.16, p = 0.012). CONCLUSIONS: This study validates the GMS as a prognostic tool for patients with stage I-III colorectal cancer, independent of TNM, with the ability to stratify both low- and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.

Aortic calcification is associated with non-infective rather than infective postoperative complications following colorectal cancer resection: an observational cohort study.

OBJECTIVES: Complications following colorectal cancer resection are common. The degree of aortic calcification (AC) on CT has been proposed as a predictor of complications, particularly anastomotic leak. This study assessed the relationship between AC and complications in patients undergoing colorectal cancer resection. METHODS: Patients from 2008 to 2016 were retrospectively identified from a prospectively maintained database. Complications were classified using the Clavien-Dindo (CD) scale. Calcification was quantified on preoperative CT by visual assessment of the number of calcified quadrants in the proximal and distal aorta. Scores were grouped into categories: none, minor (< median AC score) and major (> median AC score). The relationship between clinicopathological characteristics and complications was assessed using logistic regression. RESULTS: Of 657 patients, 52% had proximal AC (> median score (1)) and 75% had distal AC (> median score (4)). AC was more common in older patients and smokers. Higher burden of AC was associated with non-infective complications (proximal AC 28% vs 16%, p = 0.004, distal AC 26% vs 14% p = 0.001) but not infective complications (proximal AC 28% vs 29%, p = 0.821, distal AC 29% vs 23%, p = 0.240) or anastomotic leak (proximal AC 6% vs 4%, p = 0.334, distal AC 7% vs 3%, p = 0.077). Independent predictors of complications included open surgery (OR 1.99, 95%CI 1.43-2.79, p = 0.001), rectal resection (OR 1.51, 95%CI 1.07-2.12, p = 0.018) and smoking (OR 2.56, 95%CI 1.42-4.64, p = 0.002). CONCLUSIONS: These data suggest that high levels of AC are associated with non-infective complications after colorectal cancer surgery and not anastomotic leak. KEY POINTS: • Aortic calcification measured by visual quantification of the number of calcified quadrants at two aortic levels on preoperative CT is associated with clinical outcome following colorectal cancer surgery. • An increased burden of aortic calcification was associated with non-infective complications but not anastomotic leak. • Assessment of the degree of aortic calcification may help identify patients at risk of cardiorespiratory complications, improve preoperative risk stratification and assign preoperative strategies to improve fitness for surgery.

The Relationship Between Co-morbidity, Screen-Detection and Outcome in Patients Undergoing Resection for Colorectal Cancer.

BACKGROUND: Bowel cancer screening increases early stage disease detection and reduces cancer-specific mortality. We assessed the relationship between co-morbidity, screen-detection and survival in colorectal cancer. METHODS: A retrospective, observational cohort study compared screen-detected (SD) and non-screen-detected (NSD) patients undergoing potentially curative resection (April 2009-March 2011). Co-morbidity was quantified using ASA, Lee and Charlson Indices. Systemic inflammatory response was measured using the neutrophil lymphocyte ratio (NLR). Covariables were compared using crosstabulation and the χ2 test for linear trend. Survival was analysed using Cox Regression. RESULTS: Of 770 patients, 331 had SD- and 439 NSD-disease. A lower proportion of SD patients had a high ASA (≥3) compared to NSD (27.2% vs 37.3%; p = 0.007). There was no significant difference in the proportion of patients with a high (≥2) Lee Index (16.3% SD vs 21.9% NSD; p = 0.054) or high (≥3) Charlson Index (22.7% SD vs 26.9% NSD; p = 0.181). On univariate analysis, NSD (HR 2.182 (1.594-2.989;p < 0.001)), emergency presentation (HR 3.390 (2.401-4.788; p < 0.001)), advanced UICC-TNM (III or IV) (p < 0.001), high ASA (≥3) (HR 1.857 (1.362-2.532; p < 0.001)), high Charlson Index (≥3) (HR 1.800 (1.333-2.432; p < 0.001)) and high (≥3) NLR (HR 1.825 (1.363-2.442; p < 0.001)) were associated with poorer overall survival (OS). NSD predicted poorer cancer-specific survival (CSS) (HR 2.763 (1.776-4.298; p < 0.001)). On multivariate analysis, NSD retained significance as an independent predictor of poorer OS (HR 1.796 (1.224-2.635; p = 0.003)) and CSS (HR 1.924 (1.193-3.102; p = 0.007)). CONCLUSIONS: Patients with SD cancers have significantly lower ASA scores. After adjusting for ASA, co-morbidity and a broad range of covariables, SD patients retain significantly better OS and CSS.

Perioperative Blood Transfusion is Associated with Postoperative Systemic Inflammatory Response and Poorer Outcomes Following Surgery for Colorectal Cancer.

BACKGROUND: The present study investigated relationships between perioperative blood transfusion, postoperative systemic inflammatory response, and outcomes following surgery for colorectal cancer. METHODS: Data were recorded for patients (n = 544) undergoing potentially curative, elective surgery for colorectal cancer at a single center between 2012 and 2017. Transfusion history was obtained retrospectively from electronic records. Associations between blood transfusion, postoperative C-reactive protein (CRP), albumin, hemoglobin, complications, cancer-specific survival and overall survival (OS) were assessed using propensity score matching (n =116). RESULTS: Of 544 patients, the majority were male (n =294, 54%), over 65 years of age (n =350, 64%), and with colonic (n =347, 64%) node-negative disease (n =353, 65%). Eighty-six patients (16%) required perioperative blood transfusion. In the unmatched cohort, blood transfusion was associated with higher median postoperative day (POD) 3 CRP {143 [interquartile range (IQR) 96-221 mg/L] vs. 120 (IQR 72-188 mg/L); p = 0.004}, lower median POD 3 albumin [24 (IQR 20-26 g/L) vs. 27 (IQR 24-30 g/L); p < 0.001], more postoperative complications [odds ratio (OR) 3.28, 95% confidence interval (CI) 2.03-5.29] and poorer OS [hazard ratio (HR) 3.18, 95% CI 2.08-4.84]. In the propensity score matched cohort, blood transfusion was similarly associated with higher median POD 3 CRP [130 (IQR 93-196 mg/L) vs. 113 (IQR 66-173 mg/L); p = 0.046], lower median POD 3 albumin [24 (IQR 20-26 g/L) vs. 26 (IQR 24-30 g/L); p < 0.001], more postoperative complications (OR 2.91, 95% CI 1.36-6.20) and poorer OS (HR 2.38, 95% CI 0.99-5.73). CONCLUSIONS: Perioperative blood transfusion was associated with postoperative inflammation, complications, and poorer survival in patients undergoing colorectal cancer surgery, with and without propensity score techniques.

Systemic Inflammation and Outcome in 2295 Patients with Stage I-III Colorectal Cancer from Scotland and Norway: First Results from the ScotScan Colorectal Cancer Group.

BACKGROUND: Systemic inflammatory response (SIR) is an adverse prognostic marker in colorectal cancer (CRC) patients. The ScotScan Colorectal Cancer Group was established to examine how markers of the SIR differ between populations and may be utilised to guide prognosis. PATIENTS AND METHODS: Patients undergoing resection of stage I-III CRC from two prospective datasets in Scotland and Norway were included. The relationship between the modified Glasgow Prognostic Score (mGPS; combination of C-reactive protein and albumin) and overall survival (OS) was examined. The relationship between OS, adjuvant chemotherapy regime and mGPS was examined in patients with stage III colon cancer. RESULTS: A total of 2295 patients were included. Patients from Scotland were more inflamed despite controlling for associated characteristics using multivariate logistic regression or propensity score matching (OR 2.82, 95% CI 1.98-4.01, p < 0.001). mGPS had similar independent prognostic value in both cohorts (Scotland: HR 1.27, 95% CI 1.12-1.45; Norway: HR 1.23, 95% CI 1.01-1.49) and stratified survival independent of TNM group in the whole cohort. In patients with stage III colon cancer receiving adjuvant therapy, there appeared to be a survival benefit in systemically inflamed patients receiving oxaliplatin but not single-agent 5-fluorouracil or capecitabine. CONCLUSIONS: The SIR differs between populations from different countries; however prognostic value remains similar. The present study strongly supports the routine reporting of the mGPS in patients with CRC.

The association between markers of tumour cell metabolism, the tumour microenvironment and outcomes in patients with colorectal cancer.

Tumour cell anaerobic metabolism has been reported to be a prognostic factor in colorectal cancer. The present study investigated the association between monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumour microenvironment, and outcome in patients with colorectal cancer. A cohort of 150 patients with stage I-III CRC were utilised to assess tumour cell expression of MCT-1, MCT-2, LDH-1 and LDH-5 by immunohistochemistry. Expression levels were dichotomised and associations with tumour factors, the tumour microenvironment and survival analysed. Nuclear LDH-5 associates with poor prognosis (HR 1.68 95% CI 0.99-2.84, p = 0.050) and trends toward increased tumour stroma percentage (TSP, p = 0.125). Cytoplasmic MCT-2 also trends toward increased TSP (p = 0.081). When combined into a single score; nuclear LDH-5 + TSP significantly associated with decreased survival independent of stage (HR 2.61 95% CI 1.27-5.35, p = 0.009), increased tumour budding (p = 0.002) and decreased stromal T-lymphocytes (p = 0.014). Similarly, cytoplasmic MCT-2 + TSP significantly associated with decreased survival (HR 2.32 95% CI 1.31-4.11, p = 0.003), decreased necrosis (p = 0.039), and increased tumour budding (p = 0.004). The present study reports that the combination of TSP and nuclear LDH-5 was significantly associated with survival, increased tumour budding, and decreased stromal T-lymphocytes. This supports the hypothesis that increased stromal invasion promotes tumour progression via modulation of tumour metabolism. Moreover, MCT-2 and LDH-5 may provide promising therapeutic targets for patients with stromal-rich CRC.

The Relationship Between Tumor Budding, Tumor Microenvironment, and Survival in Patients with Primary Operable Colorectal Cancer.

BACKGROUND: Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC). OBJECTIVE: The aim of the present study was to use the ITBCC budding evaluation method to examine the relationship between tumor budding, tumor factors, tumor microenvironment, and survival in patients with primary operable CRC. METHODS: Hematoxylin and eosin-stained slides of 952 CRC patients diagnosed between 1997 and 2007 were evaluated for tumor budding according to the ITBCC criteria. The tumor microenvironment was evaluated using tumor stroma percentage (TSP) and Klintrup-Makinen (KM) grade to assess the tumor inflammatory cell infiltrate. RESULTS: High budding (n = 268, 28%) was significantly associated with TNM stage (p < 0.001), competent mismatch repair (MMR; p < 0.05), venous invasion (p < 0.001), weak KM grade (p < 0.001), high TSP (p < 0.001), and reduced cancer-specific survival (CSS) (hazard ratio 8.68, 95% confidence interval 6.30-11.97; p < 0.001). Tumor budding effectively stratifies CSS stage T1 through to T4 (all p < 0.05) independent of associated factors. CONCLUSIONS: Tumor budding effectively stratifies patients' survival in primary operable CRC independent of other phenotypic features. In particular, the combination of T stage and budding should form the basis of a new staging system for primary operable CRC.

Normocytic anaemia is associated with systemic inflammation and poorer survival in patients with colorectal cancer treated with curative intent.

BACKGROUND: The present study aimed to characterise the prevalence and prognostic impact of normocytic anaemia in patients undergoing curative treatment for colorectal cancer. METHODS: All individuals invited to the first round of bowel cancer screening, diagnosed with colorectal cancer and treated with curative intent from April 2009 to March 2011 in a single health board were included. The modified Glasgow prognostic score (mGPS) was used to quantify preoperative systemic inflammation. Patients were grouped as having microcytic anaemia (Hb < 130 mg/L males, < 120 mg/L females and MCV < 80 fL), normocytic anaemia (Hb < 130 mg/L males, < 120 mg/L females and MCV 80-100 fL), or neither. RESULTS: Of 395,097 patients invited to screening during the study period, 872 were diagnosed with colorectal cancer. Seven hundred seventy-seven patients had FBC measured at diagnosis, of which 78 (10%) had microcytic anaemia, and 180 (23%) normocytic anaemia. On multivariate binary logistic regression, microcytic anaemia was associated with T stage (OR 1.92, 95% CI 1.26-2.91, p = 0.002) and mGPS (OR 1.57, 95% CI 1.10-2.24, p = 0.013), while normocytic anaemia was associated with colonic tumours (OR = 2.51, 95% CI 1.10-4.01, p = 0.025), T stage (OR 1.38, 95% CI 1.05-1.81, p = 0.022), and mGPS (OR 1.52, 95% CI 1.12-2.05, p = 0.007). On univariate Cox regression, there was no significant association between microcytic anaemia and cancer specific survival (CSS) (p = 0.969). Normocytic anaemia was significantly associated with poorer CSS (HR 1.55, 95% CI 1.13-2.12, p = 0.007). CONCLUSIONS: Normocytic anaemia was associated with systemic inflammation and poorer CSS. Inflammation may drive both anaemia and disease recurrence in these patients, and targeting this process may improve both.

The relationship between right-sided tumour location, tumour microenvironment, systemic inflammation, adjuvant therapy and survival in patients undergoing surgery for colon and rectal cancer.

BACKGROUND: There has been an increasing interest in the role of tumour location in the treatment and prognosis of patients with colorectal cancer (CRC), specifically in the adjuvant setting. Together with genomic data, this has led to the proposal that right-sided and left-sided tumours should be considered as distinct biological and clinical entities. The aim of the present study was to examine the relationship between tumour location, tumour microenvironment, systemic inflammatory response (SIR), adjuvant chemotherapy and survival in patients undergoing potentially curative surgery for stage I-III colon and rectal cancer. METHODS: Clinicopathological characteristics were extracted from a prospective database. MMR and BRAF status was determined using immunohistochemistry. The tumour microenvironment was assessed using routine H&E pathological sections. SIR was assessed using modified Glasgow Prognostic Score (mGPS), neutrophil:lymphocyte ratio (NLR), neutrophil:platelet score (NPS) and lymphocyte:monocyte ratio (LMR). RESULTS: Overall, 972 patients were included. The majority were over 65 years (68%), male (55%), TNM stage II/III (82%). In all, 40% of patients had right-sided tumours and 31% had rectal cancers. Right-sided tumour location was associated with older age (P=0.001), deficient MMR (P=0.005), higher T stage (P<0.001), poor tumour differentiation (P<0.001), venous invasion (P=0.021), and high CD3+ within cancer cell nests (P=0.048). Right-sided location was consistently associated with a high SIR, mGPS (P<0.001) and NPS (P<0.001). There was no relationship between tumour location, adjuvant chemotherapy (P=0.632) or cancer-specific survival (CSS; P=0.377). In those 275 patients who received adjuvant chemotherapy, right-sided location was not associated with the MMR status (P=0.509) but was associated with higher T stage (P=0.001), venous invasion (P=0.036), CD3+ at the invasive margin (P=0.033) and CD3+ within cancer nests (P=0.012). There was no relationship between tumour location, SIR or CSS in the adjuvant group. CONCLUSIONS: Right-sided tumour location was associated with an elevated tumour lymphocytic infiltrate and an elevated SIR. There was no association between tumour location and survival in the non-adjuvant or adjuvant setting in patients undergoing potentially curative surgery for stage I-III colon and rectal cancer.

ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer.

BACKGROUND: In colorectal cancer (CRC), BRAF mutations influence tumour progression. In mismatch repair-deficient (dMMR) tumours, BRAF mutations are associated with a good prognosis, whereas in MMR-competent tumours, they are detrimental. The differential expression of the downstream MAPK pathway members, which are constitutively activated in BRAF mutant patients, may account for these differences. METHODS: Phosphorylation of ERK, p38MAPK and JNK was assessed by immunohistochemistry, utilising CRC tissue microarrays. A discovery cohort (n = 187) and a validation cohort (n = 801) were analysed for associations with BRAF mutations, clinicopathological characteristics and cancer-specific survival (CSS). RESULTS: In 801 CRC patients, nuclear ERK phosphorylation (HR 0.65 95% CI 0.48-0.88, p = 0.004) and the combined nuclear pERK/p-p38 score (HR 0.61 95% CI 0.45-0.82, p = 0.001) were independently associated with CSS, and were further associated with increased BRAF mutations (p = 0.003 and p = 0.002). When stratified for BRAF status, only MMR-competent patients harbouring the mutation and a strong combined nuclear pERK/p-p38 score (HR 0.49 95% CI 0.27-0.89, p = 0.016) demonstrated improved CSS. This improvement in CSS was specific to stage III CRC (HR 0.25 95% CI 0.10-0.64, p = 0.002). CONCLUSIONS: MMR-competent stage III tumours harbouring BRAF mutations have an improved prognosis when strong nuclear phosphorylation of both ERK and p38MAPK is present.