An investigation into the relationships between host and tumour related factors and their influence on survival in patients with colorectal cancer

Colorectal cancer is the second commonest cause of cancer death in the western world. In addition to tumour factors such as depth of invasion, lymph node involvement and venous invasion it is increasingly recognised that host factors, are important determinants of survival. In particular the host local and systemic inflammatory responses are stage independent predictors of survival in operable disease. The present thesis further examines the prognostic importance of host and tumour factors in colorectal cancer, specifically: 1. An examination of the prognostic importance of venous invasion (detected using elastica stains) in colorectal cancer. 2. Detailed analysis of the determinants (including age, comorbidity and deprivation) of the systemic inflammatory response and their relationship with survival. 3. The application and validation of a prognostic score providing a measure of the local inflammatory response in colorectal cancer. 4. Detailed analysis of the determinants (including all white cells, lymphocytes and macrophages) of the local inflammatory response and their relationship with survival. 5. The inter-relationships between the local and systemic inflammatory responses in colorectal cancer specifically: early stage disease (node negative) and in patients receiving adjuvant chemotherapy. 6. Mediators (including immunological parameters and vitamin antioxidants) of the local and systemic inflammatory responses and their relationship with survival

The relationship between cardiopulmonary exercise test variables, the systemic inflammatory response, and complications following surgery for colorectal cancer

Background: Both preoperative cardiopulmonary exercise test (CPET)-derived measures of fitness and postoperative C-reactive protein (CRP) concentrations are associated with complications following surgery for colorectal cancer. The aim of the present pilot study was to examine the relationship between CPET and postoperative CRP concentrations in this patient group. Methods: Patients who had undergone CPET prior to elective surgery for histologically confirmed colorectal cancer in a single centre between September 2008 and April 2017 were included. Preoperative VO2 at the anaerobic threshold (AT) and peak exercise were recorded, along with preoperative modified Glasgow Prognostic Score (mGPS) and CRP on each postoperative day. Results: Thirty-eight patients were included. The majority were male (30, 79%), over 65 years old (30, 79%), with colonic cancer (23, 61%) and node-negative disease (24, 63%). Fourteen patients (37%) had open surgery and 24 (63%) had a laparoscopic resection. A progressive reduction in VO2 at peak exercise was significantly associated with both increasing American Society of Anesthesiology (ASA) grade (median, ml/kg/min: ASA 1 = 22, ASA 2 = 19, ASA 3 = 15, ASA 4 = 12, p = 0.014) and increasing mGPS (median, ml/kg/min: mGPS 0 = 18, mGPS 1 = 16, mGPS 2 = 14, p = 0.039) There was no significant association between either VO2 at the AT or peak exercise and postoperative CRP. Conclusions: The present pilot study reports a possible association between preoperative CPET-derived measures of exercise tolerance, and the preoperative systemic inflammatory response, but not postoperative CRP in patients undergoing surgery for colorectal cancer

The impact of preoperative dexamethasone on the magnitude of the postoperative systemic inflammatory response and complications following surgery for colorectal cancer

Background: The magnitude of the postoperative systemic inflammatory response (SIR), as evidenced by C-reactive protein (CRP), is associated with both short- and long-term outcomes following surgery for colorectal cancer. The present study examined the impact of preoperative dexamethasone on the postoperative SIR and complications following elective surgery for colorectal cancer. Methods: Patients who underwent elective surgery, with curative intent, for colorectal cancer at a single center between 2008 and 2016 were included (n = 556) in this study. Data on the use of preoperative dexamethasone were obtained from anesthetic records, and its impact on CRP on postoperative days (PODs) 3 and 4, as well as postoperative complications, was assessed using propensity score matching (n = 276). Results: In the propensity score-matched cohort, preoperative dexamethasone was associated with fewer patients exceeding the established CRP threshold of 150 mg/L on POD 3 (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.26–0.70, p < 0.001) and fewer postoperative complications (OR 0.53, 95% CI 0.33–0.86, p = 0.009). Similar results for both POD 3 CRP and complications were observed when using propensity score-adjusted regression (OR 0.40, 95% CI 0.28–0.57 and OR 0.57, 95% CI 0.41–0.80, respectively) and propensity score stratification (OR 0.41, 95% CI 0.25–0.57 and OR 0.53, 95% CI 0.33–0.86, respectively). Conclusions: Preoperative dexamethasone was associated with a lower postoperative SIR and fewer complications following elective surgery for colorectal cancer

In reply to "Hynes S.O. et al. Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study"

No abstract available

Comparison of the prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated stroma in patients with primary operable colorectal cancer

The aim of the present study was to compare the clinical utility of two measures of the inflammatory cell infiltrate - a H&E-based assessment of the generalised inflammatory cell infiltrate (the Klintrup-Mäkinen (KM) grade), and an immunohistochemistry-based assessment of combined CD3+ and CD8+ T-cell density (the “Immunoscore”), in conjunction with assessment of the tumor stroma percentage (TSP) in patients undergoing resection of stage I-III colorectal cancer (CRC). 246 patients were identified from a prospectively maintained database of CRC resections in a single surgical unit. Assessment of KM grade and TSP was performed using full H&E sections. CD3+ and CD8+ T-cell density was assessed on full sections and the Immunoscore calculated. KM grade and Immunoscore were strongly associated (P<0.001). KM grade stratified cancer-specific survival (CSS) from 88% to 66% (P=0.002) and Immunoscore from 93% to 61% (P<0.001). Immunoscore further stratified survival of patients independent of KM grade from 94% (high KM, Im4) to 60% (low KM, Im0/1). Furthermore, TSP stratified survival of patients with a weak inflammatory cell infiltrate (low KM: from 75% to 47%; Im0/1: from 71% to 38%, both P<0.001) but not those with a strong inflammatory infiltrate. On multivariate analysis, only Immunoscore (HR 0.44, P<0.001) and TSP (HR 2.04, P<0.001) were independently associated with CSS. These results suggest that the prognostic value of an immunohistochemistry-based assessment of the inflammatory cell infiltrate is superior to H&E-based assessment in patients undergoing resection of stage I-III CRC. Furthermore, assessment of the tumor-associated stroma, using TSP, further improves prediction of outcome

How and why systemic inflammation worsens quality of life in patients with advanced cancer

Introduction: The presence of an innate host systemic inflammatory response has been reported to be a negative prognostic factor in a wide group of solid tumour types in both the operable and advanced setting, both local and distant. In addition, this host systemic inflammatory response is associated with both clinician reported patient performance status and self-reported measures of quality of life in patients with cancer. Areas covered: A variety of mechanisms are thought to underlie this, including the influence of the host immune response on physical symptoms such as pain and fatigue, its effect on organ systems associated with physical ability and well being such as skeletal muscle, and bone marrow. Furthermore, this innate inflammatory response is thought to have a direct negative impact on mood through its action on the central nervous system. Expert commentary: It is clear that the host systemic inflammatory response represents a target for intervention in terms of both improving quality of life and prognosis in patients with advanced cancer. Based on this paradigm, future research should focus both on pathways which might be targeted by novel agents, but also on whether existing anti-inflammatory drugs might be of benefit

Evaluation of a tumor microenvironment-based prognostic score in primary operable colorectal cancer

Purpose: The tumor microenvironment is recognized as an important determinant of progression and outcome in colorectal cancer. The aim of the present study was to evaluate a novel tumor microenvironment–based prognostic score, based on histopathologic assessment of the tumor inflammatory cell infiltrate and tumor stroma, in patients with primary operable colorectal cancer. Experimental Design: Using routine pathologic sections, the tumor inflammatory cell infiltrate and stroma were assessed using Klintrup–Mäkinen (KM) grade and tumor stroma percentage (TSP), respectively, in 307 patients who had undergone elective resection for stage I–III colorectal cancer. The clinical utility of a cumulative score based on these characteristics was examined. Results: On univariate analysis, both weak KM grade and high TSP were associated with reduced survival (HR, 2.42; P = 0.001 and HR, 2.05; P = 0.001, respectively). A cumulative score based on these characteristics, the Glasgow Microenvironment Score (GMS), was associated with survival (HR, 1.93; 95% confidence interval, 1.36–2.73; P < 0.001), independent of TNM stage and venous invasion (both P < 0.05). GMS stratified patients in to three prognostic groups: strong KM (GMS = 0), weak KM/low TSP (GMS = 1), and weak KM/high TSP (GMS = 2), with 5-year survival of 89%, 75%, and 51%, respectively (P < 0.001). Furthermore, GMS in combination with node involvement, venous invasion, and mismatch repair status further stratified 5-year survival (92% to 37%, 93% to 27%, and 100% to 37%, respectively). Conclusions: The present study further confirms the clinical utility of assessment of the tumor microenvironment in colorectal cancer and introduces a simple, routinely available prognostic score for the risk stratification of patients with primary operable colorectal cancer

The relationship between anaesthetic technique, clinicopathological characteristics and the magnitude of the postoperative systemic inflammatory response in patients undergoing elective surgery for colon cancer

Background/aim: The magnitude of the postoperative systemic inflammatory response (SIR) is now recognised to be associated with both short and long-term outcomes in patients undergoing surgery for colon cancer. During such surgery, it is unclear whether the anaesthetic regimens influence the magnitude of the postoperative SIR, independent of other factors. The aim of the present study was to examine the association between anaesthetic agents, clinicopathological characteristics and the magnitude of the postoperative SIR in patients undergoing elective surgery for colon cancer. Methods: Patients with colon cancer who underwent elective open or laparoscopic surgery between 2008 and 2016 (n = 409) were studied at a single center. The relationship between type of anaesthesia, surgical technique; open (n = 241) versus laparoscopic (n = 168) and clinicopathological characteristics was examined by using chi-square testing. The chi-square test was used to determine which anaesthetic group influences the POD 2 CRP for only patients undergoing elective open colon surgery. Results: The majority of patients were <75 years old, male, normal weight or obese, underwent open surgery and had regional anaesthesia, in particular an epidural approach. There was a significant association between type of anaesthesia and post-operative CRP on day 2 (p <0.001) in patients undergoing open surgery but not laparoscopic surgery. Other factors associated with type of anaesthesia included; year of operation (p <0.01), surgical technique (p <0.001), and preoperative dexamethasone (p <0.01). Conclusion: In patients undergoing surgery for elective colon cancer, the type of anaesthesia varied over time. The type of anaesthesia appears to influence the magnitude of the postoperative SIR on post-operative day 2 in open surgery but not laparoscopic surgery. Future work using prospective study design is required to better define this relationship

Staging the tumor and staging the host: A two centre, two country comparison of systemic inflammatory responses of patients undergoing resection of primary operable colorectal cancer

Background: How systemic inflammation-based prognostic scores such as the modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR) differ across populations of patients with colorectal cancer (CRC) remains unknown. The present study examined the mGPS and NLR in patients from United Kingdom (UK) and Japan. Methods: Patients undergoing resection of TNM I-III CRC in two centres in the UK and Japan were included. Differences in clinicopathological characteristics and mGPS (0-CRP≤10 mg/L, 1-CRP>10 mg/L, 2-CRP>10 mg/L, albumin<35 g/L) and NLR (≤5/>5) were examined. Results: Patients from UK (n = 581) were more likely to be female, high ASA and BMI, present as an emergency (all P < 0.01) and have higher T stage compared to those from Japan (n = 559). After controlling for differences in tumor and host characteristics, patients from Japan were less likely to be systemically inflamed (OR: mGPS: 0.37, 95%CI 0.27–0.50, P < 0.001; NLR: 0.53, 95%CI 0.35–0.79, P = 0.002). Conclusion: Systemic inflammatory responses differ between populations with colorectal cancer. Given their prognostic value, reporting of systemic inflammation-based scores should be incorporated into future studies reporting patient outcomes. Summary: Although the systemic inflammatory response is recognised as a prognostic factor in patients with colorectal cancer, it is not clear how these may differ between distinct geographical populations. The present study examines differences in the prevalence of elevated systemic inflammatory responses (modified Glasgow Prognostic Score and neutrophil:lymphocyte ratio) between two populations undergoing resection of colorectal cancer in the United Kingdom and Japan

A systematic review of the role of systemic inflammation-based prognostic scores in patients with abdominal aortic aneurysm

Background and aims: Activation of the systemic inflammatory response (SIR) is associated with inferior outcomes across a spectrum of disease. Routinely available measures of the SIR (neutrophil:lymphocyte ratio (NLR), platelet:lymphocyte ratio (PLR), systemic immune-inflammatory index (SII), systemic inflammatory grade (SIG)) have been shown to provide prognostic value in patients undergoing surgical intervention. The present study aimed to review the literature describing the prognostic association of NLR, PLR, SII and SIG in patients undergoing intervention for abdominal aortic aneurysm (AAA). Methods: This PRISMA guidelines were followed. The MEDLINE database was interrogated for relevant studies investigating the effect of peri-operative systemic inflammation-based prognostic systems on all-cause mortality in patients undergoing OSR and EVAR for AAA. Inter-study heterogeneity precluded meaningful meta-analysis; qualitative analysis was instead performed. Results: There were 9 studies included in the final review reporting outcomes on a total of 4571 patients; 1256 (27 %) patients underwent OSR, and 3315 (73 %) patients underwent EVAR. 4356 (95 %) patients underwent a procedure for unruptured AAA, 215 (5 %) patients underwent an emergency procedure for ruptured AAA0.5 studies reported early (inpatient or 30-day) mortality; 2 of these found that elevated NLR predicted inferior survival, however PLR did not provide prognostic value. 6 studies reported long-term mortality; elevated NLR (5 studies), PLR (1 study), and SIG (1 study) predicted inferior survival. Conclusions: It appears that activation of the SIR is associated with inferior prognosis in patients undergoing intervention for AAA, however the evidence is limited by heterogenous methodology and lack of consensus regarding optimal cutoff. Prospero database registration number: CRD42022363765