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

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

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

Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumour and host

Purpose: In patients with colorectal cancer (CRC), a high-density local inflammatory infiltrate response is associated with improved survival, whereas elevated systemic inflammatory responses are associated with poor survival. One potential unifying mechanism is the IL-6/JAK/STAT3 pathway. The present study examines the relationship between tumour total STAT3 and phosphorylated STAT3Tyr705 (pSTAT3) expression, host inflammatory responses and survival in patients undergoing resection of stage I-III CRC. Experimental Design: Immunohistochemical assessment of STAT3/pSTAT3 expression was performed using a tissue microarray and tumour cell expression divided into tertiles using the weighted histoscore. The relationship between STAT3/pSTAT3 expression and local inflammatory (CD3+, CD8+, CD45R0+, FOXP3+ T-cell density and Klintrup-Mäkinen grade) and systemic inflammatory responses and cancer-specific survival were examined. Results: 196 patients were included in the analysis. Cytoplasmic and nuclear STAT3 expression strongly correlated (r=0.363, P<0.001); nuclear STAT3 and pSTAT3 expression weakly correlated (r=0.130, P=0.068). Cytoplasmic STAT3 was inversely associated with the density of CD3+ (P=0.012), CD8+ (P=0.003) and FOXP3+ T-lymphocytes (P=0.002) within the cancer cell nests and was associated with an elevated systemic inflammatory response as measured by modified Glasgow Prognostic Score (mGPS2: 19% vs. 4%, P=0.004). The combination of nuclear STAT3/pSTAT3 stratified five-year survival from 81% to 62% (P=0.012), however was not associated with survival independent of venous invasion, tumour perforation or tumour budding. Conclusion In patients undergoing CRC resection, STAT3 expression was associated with adverse host inflammatory responses and reduced survival. Up-regulation of tumour STAT3 may be an important mechanism whereby the tumour deregulates local and systemic inflammatory responses

Potential immune priming of the tumor microenvironment with FOLFOX chemotherapy in locally advanced rectal cancer

Strategies to enhance tumor immunogenicity may expand the role of immunotherapy beyond the mismatch repair-deficient subtype. In this pilot study, biopsies were performed at baseline and after four cycles of FOLFOX in eight patients receiving neoadjuvant chemotherapy for stage II/III locally advanced rectal cancer. Immunostaining was performed for T cell subsets (CD3+, CD8+, CD45RO+); macrophages (CD163+); T regulatory cells (FOXP3+); and expression of MHC class I, PD-1 and PD-L1. Changes in cell number or intensity were quantified and correlated with treatment response. Pretreatment patterns of immune infiltrates were mixed and did not correlate with treatment response. Posttreatment increases in T cell infiltrates (CD3+, CD8+ and CD45RO+) and MHC-I expression were observed in five patients. CD163+ cell numbers increased in four patients. FOXP3+ cells numbers increased in two patients, decreased in two other patients and remained unchanged in three patients. PD-1 scores increased in seven patients, and PD-L1 scores increased in four patients. Changes in tumor T cell responses did not correlate with treatment response. Changes in FOXP3+ cells were associated with treatment response in some patients: two patients with increases in FOXP3+ cells had poor responses, whereas the patient with the greatest reduction in FOXP3+ cells had a complete response. The patient with a complete clinical response had a much higher increase in MHC-I expression than other patients. These results suggest that chemotherapy can increase immune activity in the tumor microenvironment and could potentially be utilized to prime immune responses prior to immunomodulatory treatments

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