Colin H. Richards

The Relationships between Body Composition and the Systemic Inflammatory Response in Patients with Primary Operable Colorectal Cancer

Background Weight loss is recognised as a marker of poor prognosis in patients with cancer but the aetiology of cancer cachexia remains unclear. The aim of the present study was to examine the relationships between CT measured parameters of body composition and the systemic inflammatory response in patients with primary operable colorectal cancer. Patient and Methods 174 patients with primary operable colorectal cancer who underwent resection with curative intent (2003–2010). Image analysis of CT scans was used to measure total fat index (cm2/m2), subcutaneous fat index (cm2/m2), visceral fat index (cm2/m2) and skeletal muscle index (cm2/m2). Systemic inflammatory response was measured by serum white cell count (WCC), neutrophil:lymphocyte ratio (NLR) and the Glasgow Prognostic Score (mGPS). Results There were no relationships between any parameter of body composition and serum WCC or NLR. There was a significant relationship between low skeletal muscle index and an elevated systemic inflammatory response, as measured by the mGPS (p = 0.001). This was confirmed by linear relationships between skeletal muscle index and both C-reactive protein (r = −0.21, p = 0.005) and albumin (r = 0.31, p<0.001). There was no association between skeletal muscle index and tumour stage. Conclusions The present study highlights a direct relationship between low levels of skeletal muscle and the presence of a systemic inflammatory response in patients with primary operable colorectal cancer.

The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer

BACKGROUND Tumour stroma percentage (TSP) has previously been reported to predict survival in patients with colorectal cancer (CRC); however, whether this is independent of other aspects of the tumour microenvironment is unknown. In the present study, the relationship between TSP, the tumour microenvironment and survival was examined in patients undergoing elective, curative CRC resection. PATIENTS AND METHODS Patients undergoing resection at a single centre (1997-2008) were identified from a prospective database. TSP was measured at the invasive margin and its association with cancer-specific survival (CSS) and clinicopathological characteristics examined. RESULTS Three hundred and thirty-one patients were included in the analysis. TSP was associated with CSS in patients with stage I-III disease [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.17-2.92, P = 0.009], independent of age, systemic inflammation, N stage, venous invasion and Klintrup-Mäkinen score. Furthermore, TSP was associated with reduced CSS in patients with node-negative disease (HR 2.14, 95% CI 1.01-4.54, P = 0.048) and those who received adjuvant chemotherapy (HR 2.83, 95% CI 1.23-6.53, P = 0.015), independent of venous invasion and host inflammatory responses. TSP was associated with several adverse pathological characteristics, including advanced T and N stage. Furthermore, TSP was associated with an infiltrative invasive margin and inversely associated with necrosis. CONCLUSIONS The TSP was a significant predictor of survival in patients undergoing elective, curative CRC resection, independent of adverse pathological characteristics and host inflammatory responses. In addition, TSP was strongly associated with local tumour growth and invasion.BACKGROUND Tumour stroma percentage (TSP) has previously been reported to predict survival in patients with colorectal cancer (CRC); however, whether this is independent of other aspects of the tumour microenvironment is unknown. In the present study, the relationship between TSP, the tumour microenvironment and survival was examined in patients undergoing elective, curative CRC resection. PATIENTS AND METHODS Patients undergoing resection at a single centre (1997-2008) were identified from a prospective database. TSP was measured at the invasive margin and its association with cancer-specific survival (CSS) and clinicopathological characteristics examined. RESULTS Three hundred and thirty-one patients were included in the analysis. TSP was associated with CSS in patients with stage I-III disease [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.17-2.92, P = 0.009], independent of age, systemic inflammation, N stage, venous invasion and Klintrup-Mäkinen score. Furthermore, TSP was associated with reduced CSS in patients with node-negative disease (HR 2.14, 95% CI 1.01-4.54, P = 0.048) and those who received adjuvant chemotherapy (HR 2.83, 95% CI 1.23-6.53, P = 0.015), independent of venous invasion and host inflammatory responses. TSP was associated with several adverse pathological characteristics, including advanced T and N stage. Furthermore, TSP was associated with an infiltrative invasive margin and inversely associated with necrosis. CONCLUSIONS The TSP was a significant predictor of survival in patients undergoing elective, curative CRC resection, independent of adverse pathological characteristics and host inflammatory responses. In addition, TSP was strongly associated with local tumour growth and invasion.

Prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer.

Tumour necrosis is a marker of poor prognosis in some tumours but the mechanism is unclear. This study examined the prognostic value of tumour necrosis and host inflammatory responses in colorectal cancer.

The relationship between patient physiology, the systemic inflammatory response and survival in patients undergoing curative resection of colorectal cancer

Background:It is increasingly recognised that host-related factors may be important in determining cancer outcome. The aim was to examine the relationship between patient physiology, the systemic inflammatory response and survival after colorectal cancer resection.Methods:Patients undergoing potentially curative resection of colorectal cancer were identified from a prospectively maintained database. Patient physiology was assessed using the physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) criteria. The systemic inflammatory response was assessed using the modified Glasgow Prognostic Score (mGPS). Multivariate 5-year survival analysis was carried out with calculation of hazard ratios (HR).Results:A total of 320 patients were included. During follow-up (median 74 months), there were 136 deaths: 83 colorectal cancer related and 53 non-cancer related. Independent predictors of cancer-specific survival were age (HR: 1.46, P<0.01), Dukes stage (HR: 2.39, P<0.001), mGPS (HR: 1.78, P<0.001) and POSSUM physiology score (HR: 1.38, P=0.02). Predictors of overall survival were age (HR: 1.64, P<0.001), smoking (HR: 1.52, P=0.02), Dukes stage (HR: 1.64, P<0.001), mGPS (HR: 1.60, P<0.001) and POSSUM physiology score (HR: 1.27, P=0.03). A relationship between mGPS and POSSUM physiology score was also established (P<0.006).Conclusion:The POSSUM physiology score and the systemic inflammatory response are strongly associated and both are independent predictors of cancer specific and overall survival in patients undergoing potentially curative resection of colorectal cancer.

A Systematic Review of POSSUM and its Related Models as Predictors of Post-operative Mortality and Morbidity in Patients Undergoing Surgery for Colorectal Cancer

IntroductionThe Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) model and its Portsmouth (P-POSSUM) and colorectal (CR-POSSUM) modifications are used extensively to predict and audit post-operative mortality and morbidity. This aim of this systematic review was to assess the predictive value of the POSSUM models in colorectal cancer surgery.MethodsMajor electronic databases, including Medline, Embase, Cochrane Library and Pubmed were searched for original studies published between 1991 and 2010. Two independent reviewers assessed each study against inclusion and exclusion criteria. All data was specific to colorectal cancer surgery. Predictive value was assessed by calculating observed to expected (O/E) ratios.ResultsNineteen studies were included in final review. The mortality analysis included ten studies (4,799 patients) on POSSUM, 17 studies (6,576 patients) on P-POSSUM and 14 studies (5,230 patients) on CR-POSSUM. Weighted O/E ratios for mortality were 0.31 (CI 0.31–0.32) for POSSUM, 0.90 (CI 0.88–0.92) for P-POSSUM and 0.64 (CI 0.63–0.65) for CR-POSSUM. The morbidity analysis included four studies (768 patients) on POSSUM with a weighted O/E ratio of 0.96 (CI 0.94–0.98).ConclusionsP-POSSUM was the most accurate model for predicting post-operative mortality after colorectal cancer surgery. The original POSSUM model was accurate in predicting post-operative complications.

The impact of perioperative risk, tumor pathology and surgical complications on disease recurrence following potentially curative resection of colorectal cancer.

Objective:The objective of the study was to identify determinants of disease recurrence after potentially curative resection of colorectal cancer. Summary Background Data:The identification of patients at increased risk of disease recurrence is currently based on pathological factors. Recently, there has been considerable interest in the potential impact of perioperative factors on long-term colorectal cancer outcome. Few studies have examined pre-, intra-, and postoperative variables in a single cohort. Methods:Four hundred and twenty-three patients with histologically confirmed colorectal cancer who underwent surgery with curative intent between 1997 and 2007 were included. Pre-, intra-, and postoperative variables were recorded. Logistic and Cox regression analyses were performed to identify predictors of surgical complications and disease recurrence, respectively. Results:The postoperative mortality rate was 4% and the morbidity rate 34%. The most important predictors of complications were smoking (odd ratio [OR] 1.32), ASA grade (OR 1.90) and POSSUM operative score (OR 1.32). During follow up (median 80 months), 35% of patients developed disease recurrence. Predictors of recurrence, independent of tumor stage, were POSSUM physiology score (hazard ratio [HR] 1.31) and systemic inflammatory response (HR 1.31). Conclusions:Preoperative risk factors, but not postoperative complications, are associated with early disease recurrence after potentially curative resection of colorectal cancer.

The prognostic value of histological tumor necrosis in solid organ malignant disease: a systematic review

BACKGROUND Tumor necrosis has been proposed as a marker of poor prognosis in a variety of solid organ malignant tumor types. Despite this, its assessment has yet to be adopted into routine clinical practice and the mechanisms underpinning the relationships with cancer outcome are undetermined. AIMS To examine the prognostic value of tumor necrosis in solid organ malignant disease and to summarize the known clinical, pathological and inflammatory associations. METHODS A systematic review of data published from 1966-2011 was undertaken by two reviewers according to a predefined protocol. A total of 57 independent studies relating to renal (n = 23), breast (n = 13), lung (n = 7), colorectal (n = 5) and other solid tumors (n = 9) were included in the final review. CONCLUSION There is now a substantial body of evidence confirming the prognostic value of tumor necrosis in solid organ malignant disease. There are consistent associations between necrosis and the presence of other high-risk tumor characteristics but the survival impact appears to be independent of pathological stage. We propose that relationships with the host inflammatory response, both local and systemic, may explain the influence of tumor necrosis on cancer outcome.

Circulating IL-6 concentrations link tumour necrosis and systemic and local inflammatory responses in patients undergoing resection for colorectal cancer

Background:Cancer-associated inflammation, in the form of local and systemic inflammatory responses, appear to be linked to tumour necrosis and have prognostic value in patients with colorectal cancer. However, their relationship with circulating biochemical mediators is unclear. The aim of the present study was to examine the interrelationships between circulating mediators, in particular interleukin-6 (IL-6) and tumour necrosis, and local and systemic inflammatory responses in patients undergoing resection for colorectal cancer.Methods:Data were collected from preoperative blood tests for 118 patients who underwent resection for colorectal cancer. Analysis of circulating IL-6, IL-10, vascular endothelial growth factor (VEGF), differential white cell count, C-reactive protein, and albumin were carried out. Routine pathology specimens were examined for tumour characteristics including necrosis and the extent of the inflammatory cell infiltrate. Body composition was examined using body mass index (BMI), total body fat, subcutaneous body fat, visceral fat, and skeletal muscle mass.Results:Circulating IL-6 concentrations were significantly associated with increased T stage (P<0.05), tumour necrosis (P<0.001), IL-10 (P<0.001), VEGF (P<0.001), modified Glasgow Prognostic Score (mGPS; P<0.001), white cell (P<0.01) and platelet (P<0.01) counts, and low skeletal muscle index (P<0.01). When normalised for T stage, tumour necrosis was associated with IL-6 (P<0.001), IL-10 (P<0.01), VEGF (P<0.001), mGPS (P<0.001), neutrophil–lymphocyte ratio (NLR; P<0.05), white cell (P<0.001), neutrophil (P<0.05), and platelet counts (P<0.005), and skeletal muscle index (P<0.001).Conclusion:The present study provides, for the first time, supportive evidence for the hypothesis that tumour necrosis, independent of T stage, is associated with elevated circulating IL-6 concentrations, thereby modulating both local and systemic inflammatory responses including angiogenesis that, in turn, may promote tumour progression and metastases.

The clinical utility of the local inflammatory response in colorectal cancer.

BACKGROUND The host immune response is important in the prevention of tumour progression in solid organ cancers. The aim was to evaluate the clinical utility of the local inflammatory response in patients with colorectal cancer. METHODS Three hundred and sixty-five patients with primary operable colorectal cancer were included. The local inflammatory response was assessed using three different methods; (1) individual T-cell subtypes (CD3, CD8, CD45R0, FOXP3), (2) an immunohistochemistry-based immune score (Galon Immune Score) and (3) a histopathological assessment (Klintrup-Makinen grade). Relationships with tumour and host characteristics were established and the prognostic value of each method compared. RESULTS A strong infiltration of tumour infiltrating lymphoctyes (TILs) was associated with improved cancer-specific survival. When individual T-cell subtypes were considered, CD3-positive cells were the strongest predictor of survival at the invasive margin (CD3(+) IM) while CD8-positive cells were the strongest predictor in the cancer cell nests (CD8(+) CCN). Infiltration of T-cells was related to early tumour stage, expanding growth pattern and lower levels of venous invasion but was not influenced by host characteristics or degree of systemic inflammation. In summary, CD3(+) IM, CD8(+) CCN, The Galon Immune Score and the Klintrup-Makinen grade all exhibited similar survival relationships in both node-positive and node-negative colorectal cancer. CONCLUSION A coordinated adaptive immune response is an important factor in predicting outcome in patients with primary operable colorectal cancer. By comparing different methodologies we have provided a foundation on which to develop a standardised approach for assessing the local inflammatory response in these patients.

The relationships between cellular components of the peritumoural inflammatory response, clinicopathological characteristics and survival in patients with primary operable colorectal cancer

Background:The host inflammatory response is an important determinant of cancer outcome. We examined different methods of assessing the local inflammatory response in colorectal tumours and explored relationships with both clinicopathological characteristics and survival.Methods:Cohort study of patients (n=130) with primary operable colorectal cancer and mature follow-up. Local inflammatory response at the invasive margin was assessed with: (1) a semi-quantitative assessment of peritumoural inflammation using Klintrup–Makinen (K–M) grading and (2) an assessment of individual immune cell infiltration (lymphocytes, plasma cells, neutrophils, macrophages and eosinophils).Results:The peritumoural inflammatory response was K–M low grade in 48% and high grade in 52%. Inflammatory cells were primarily macrophages, lymphocytes and neutrophils with relatively few plasma cells or eosinophils. On univariate analysis, K–M grade, lymphocyte infiltration and plasma cell infiltration were associated with cancer-specific survival. On multivariate analysis, only systemic inflammatory response, TNM (tumour, node and metastases) stage, venous invasion, tumour necrosis and K–M grade were independently associated with cancer-specific survival. There was no relationship between local infiltration of inflammatory cells and a systemic inflammatory response. However, high K–M grade, lymphocyte infiltration and plasma cell infiltration were associated with a number of favourable pathological characteristics, including an absence of venous invasion.Conclusion:Infiltration of inflammatory cells in the invasive margin of colorectal tumours is beneficial to survival. The adaptive immune response appears to have a prominent role in the prevention of tumour progression in patients with colorectal cancer.