The Glasgow Microenvironment Score and risk and site of recurrence in TNM I-III colorectal cancer.

BACKGROUND: Glasgow Microenvironment Score (GMS) stratifies long-term survival into three groups based on tumour phenotype: peritumoural inflammation (Klintrup-Mäkinen (KM)) and tumour stroma percentage (TSP). However, it is not known if the location of disease recurrence is influenced by the GMS category. METHODS: Seven hundred and eighty-three TNM I-III colorectal cancers (CRC) were included. GMS (GMS0-high KM; GMS1-low KM, low TSP; GMS2-low KM, high TSP) and cancer-specific survival (CSS), overall survival (OS) and disease recurrence were assessed using Cox regression analysis. RESULTS: Of the 783 patients, 221 developed CRC recurrence; 65 developed local recurrence + systemic disease. GMS was independent for CSS (HR 1.50, 95% CI 1.17-1.92, p < 0.001) and OS (HR 1.23, 1.05-1.44, p = 0.01). Higher GMS category was associated with T-stage, N-stage, emergency presentation and venous invasion. GMS was independent for local+systemic recurrence (HR 11.53, 95% CI 1.45-91.85, p = 0.04) and distant-only recurrence (HR 3.01, 95% CI 1.59-5.71, p = 0.002). GMS 2 disease did not appear to have statistically better outcomes with adjuvant chemotherapy in high-risk disease. CONCLUSION: Although confounded by a higher rate of T4 and node-positive disease, GMS 1 and 2 are associated with an increased risk of local and distant recurrence. GMS is an independent poor prognostic indicator for recurrent colorectal cancer. Higher GMS patients may benefit from enhanced postoperative surveillance.

The relationship between pre-operative psoas and skeletal muscle parameters and survival following endovascular aneurysm repair: a systematic review and meta-analysis.

Sarcopenia is characterised by chronically reduced skeletal muscle volume and function, and is determined radiologically by psoas and skeletal muscle measurement. The present systematic review and meta-analysis aims to examine the relationship between pre-operative CT-derived psoas and skeletal muscle parameters and outcomes in patients undergoing EVAR and F/B-EVAR for aortic aneurysm. The MEDLINE database was interrogated for studies investigating the effect of pre-operative CT-diagnosed sarcopenia on outcomes following EVAR and F/B-EVAR. The systematic review was carried out in accordance with PRISMA guidelines. The primary outcome was overall mortality. RevMan 5.4.1 was used to perform meta-analysis. PROSPERO Database Registration Number: CRD42021273085. Ten relevant studies were identified, one reporting skeletal muscle parameters, and the remaining nine reporting psoas muscle parameters, which were used for meta-analysis. There were a total of 2563 patients included (2062 EVAR, 501 F/B-EVAR), with mean follow-up ranging from 25 to 101 months. 836 patients (33%) were defined as radiologically sarcopenic. In all studies, the combined HR for all-cause mortality in sarcopenic versus non-sarcopenic patients was 2.61 (1.67-4.08), p < .001. Two studies reported outcomes on patients undergoing F/B-EVAR; the combined HR for all-cause mortality in sarcopenic versus non-sarcopenic patients was 3.08 (1.66-5.71), p = .004. Radiological sarcopenia defined by psoas or skeletal muscle parameters was associated with inferior survival in patients undergoing both EVAR and F/B-EVAR. Current evidence is limited by heterogeneity in assessment of body composition and lack of a consensus definition of radiological sarcopenia.

The relationship between aortic calcification and anastomotic leak following gastrointestinal resection: A systematic review.

BACKGROUND: Anastomotic leak (AL) is a significant complication of gastrointestinal (GI) surgery. Impaired perfusion of the anastomosis is thought to play an important role. The degree of aortic calcification (AC) visible on preoperative CT imaging may be associated with an increased risk of AL following GI resection. This review assessed the relationship between AC and AL in patients undergoing GI resection. MATERIALS AND METHODS: MEDLINE, EMBASE and the Cochrane library were systematically searched between 1946 and 2019. Relevant keywords were grouped to form a sensitive search strategy: surgical procedure (e.g. digestive system surgical procedure), calcification (e.g. vascular calcification, calcium score) and outcome (e.g. anastomotic leak). Studies assessing the degree of AC on preoperative imaging in relation to AL in adult patients requiring resection and anastomosis were included. The quality of each study was assessed using the Newcastle-Ottawa scale. Bias was assessed using the RevMan risk of bias tool. RESULTS: Nine observational studies were included: four in patients undergoing oesophageal resection (n = 1446) and five in patients undergoing colorectal resection (n = 556). AL occurred in 20% of patients following oesophagectomy and 14% of patients following colorectal resection. Adjustment for relevant confounders was limited in most studies. Two studies reported a relationship between the degree of AC and AL in patients undergoing oesophagectomy, independent of age and comorbidity. One study reported an association between AC and AL following colorectal resection, while three studies reported higher calcium scores in the iliac arteries of patients who developed colorectal AL. Overall study quality was moderate to good using the Newcastle-Ottawa scale. Detection and reporting bias was evident in the studies examining AL following colorectal resection. CONCLUSION: The current evidence suggests that the degree of AC may be associated with the development of AL, in particular in patients undergoing oesophagectomy. Further prospective data with adequate adjustment for confounders are required. PROSPERO REGISTRATION NUMBER: CRD42018081128.

Changes in the multidisciplinary management of rectal cancer from 2009 to 2015 and associated improvements in short-term outcomes.

AIM: Significant recent changes in management of locally advanced rectal cancer (LARC) include preoperative staging, use of extended neoadjuvant therapies and minimally invasive surgery (MIS). This study was aimed at characterizing these changes and associated short-term outcomes. METHOD: We retrospectively analysed treatment and outcome data from patients with T3/4 or N+ LARC ≤ 15 cm from the anal verge who were evaluated at a comprehensive cancer centre in 2009-2015. RESULTS: In total, 798 patients were identified and grouped into five cohorts based on treatment year: 2009-2010, 2011, 2012, 2013 and 2014-2015. Temporal changes included increased reliance on MRI staging, from 57% in 2009-2010 to 98% in 2014-2015 (P < 0.001); increased use of total neoadjuvant therapy, from 17% to 76% (P < 0.001); and increased use of MIS, from 33% to 70% (P < 0.001). Concurrently, median hospital stay decreased (from 7 to 5 days; P < 0.001), as did the rates of Grade III-V complications (from 13% to 7%; P < 0.05), surgical site infections (from 24% to 8%; P < 0.001), anastomotic leak (from 11% to 3%; P < 0.05) and positive circumferential resection margin (from 9% to 4%; P < 0.05). TNM downstaging increased from 62% to 74% (P = 0.002). CONCLUSION: Shifts toward MRI-based staging, total neoadjuvant therapy and MIS occurred between 2009 and 2015. Over the same period, treatment responses improved, and lengths of stay and the incidence of complications decreased.

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer.

BACKGROUND: The present study aimed to examine the relationship between tumour invasiveness (T stage), the local and systemic environment and cancer-specific survival (CSS) of patients with primary operable colorectal cancer. METHODS: The tumour microenvironment was examined using measures of the inflammatory infiltrate (Klintrup-Makinen (KM) grade and Immunoscore), tumour stroma percentage (TSP) and tumour budding. The systemic inflammatory environment was examined using modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR). A 5-year CSS was examined. RESULTS: A total of 331 patients were included. Increasing T stage was associated with colonic primary, N stage, poor differentiation, margin involvement and venous invasion (P<0.05). T stage was significantly associated with KM grade (P=0.001), Immunoscore (P=0.016), TSP (P=0.006), tumour budding (P<0.001), and elevated mGPS and NLR (both P<0.05). In patients with T3 cancer, N stage stratified survival from 88 to 64%, whereas Immunoscore and budding stratified survival from 100 to 70% and from 91 to 56%, respectively. The Glasgow Microenvironment Score, a score based on KM grade and TSP, stratified survival from 93 to 58%. CONCLUSIONS: Although associated with increasing T stage, local and systemic tumour environment characteristics, and in particular Immunoscore, budding, TSP and mGPS, are stage-independent determinants of survival and may be utilised in the staging of patients with primary operable colorectal cancer.

The role of dietary polyphenols in the moderation of the inflammatory response in early stage colorectal cancer.

Current focus in colorectal cancer (CRC) management is on reducing overall mortality by increasing the number of early-stage cancers diagnosed and treated with curative intent. Despite the success of screening programs in down-staging CRC, interval cancer rates are substantial and other strategies are desirable. Sporadic CRC is largely associated with lifestyle factors including diet. Polyphenols are phytochemicals ingested as part of a normal diet, which are abundant in plant foods including fruits/berries and vegetables. These may exert their anti-carcinogenic effects via the modulation of inflammatory pathways. Key signal transduction pathways are fundamental to the association of inflammation and disease progression including those mediated by NF-κB and STAT, PI3K and COX. Our aim was to examine the evidence for the effect of dietary polyphenols intake on tumor and host inflammatory responses to determine if polyphenols may be effective as part of a dietary intervention. There is good epidemiological evidence of a reduction in CRC risk from case-control and cohort studies assessing polyphenol intake. It would be premature to suggest a major public health intervention to promote their consumption; however, dietary change is safe and feasible, emphasizing the need for further investigation of polyphenols and CRC risk.

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 generalized 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). Two hundred and forty-six 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.

Surgical outcome in patients undergoing reversal of Hartmann's procedures: a multicentre study.

AIM: Recent evidence has suggested that a laparoscopic rather than an open approach to reversal of Hartmann's procedure (ROH) may be associated with fewer complications. Much of the data for comparison are historical or based on small case series. The aims of this study were to determine the morbidity and mortality of ROH in 10 hospitals in the modern era and to identify risk factors for complications. METHOD: A multicentre study of patients undergoing ROH (2007-2013) was performed. Data were collected retrospectively from perioperative health databases and casenotes where appropriate on patient demographics, laboratory investigations and operative details. Complications were classified as minor (I-II) or major (III-IV) based on the Clavien-Dindo criteria. Risk factors for complications were assessed by multivariate analysis with calculation of OR with 95% CI. RESULTS: Ten hospitals in Scotland provided data on 252 patients undergoing ROH. Most operations were open (85%) with 15% started laparoscopically (conversion rate 64%). In the postoperative period, 35 (14%) patients had a major complication, including anastomotic leakage in 10 (4%) and postoperative death in one (0.4%). Patients with a complication stayed significantly longer in hospital (12 days vs 7 days, P < 0.001). On multivariate analysis, a wound complication after the original Hartmann's procedure (OR = 3.85, 95% CI: 1.08-13.75, P = 0.038) was associated with any complication after ROH, but only American Society of Anesthesiologists (ASA) grade (OR = 3.35, 95% CI: 1.38-8.09, P = 0.007) was independently associated with the development of a major complication. CONCLUSION: ROH has a low postoperative mortality but significant morbidity. Most operations are still performed by open surgery, and in those attempted laparoscopically, the conversion rate is high.

Cancer and systemic inflammation: treat the tumour and treat the host.

Determinants of cancer progression and survival are multifactorial and host responses are increasingly appreciated to have a major role. Indeed, the development and maintenance of a systemic inflammatory response has been consistently observed to confer poorer outcome, in both early and advanced stage disease. For patients, cancer-associated symptoms are of particular importance resulting in a marked impact on day-to-day quality of life and are also associated with poorer outcome. These symptoms are now recognised to cluster with one another with anorexia, weight loss and physical function forming a recognised cluster whereas fatigue, pain and depression forming another. Importantly, it has become apparent that these symptom clusters are associated with presence of a systemic inflammatory response in the patient with cancer. Given the understanding of the above, there is now a need to intervene to moderate systemic inflammatory responses, where present. In this context the rationale for therapeutic intervention using nonselective anti-inflammatory agents is clear and compelling and likely to become a part of routine clinical practice in the near future. The published literature on therapeutic intervention using anti-inflammatory agents for cancer-associated symptoms was reviewed. There are important parallels with the development of useful treatments for the systemic inflammatory response in patients with rheumatological disease and cardiovascular disease.

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.

Comparison of visual and automated assessment of tumour inflammatory infiltrates in patients with colorectal cancer.

BACKGROUND: Cancer-associated inflammation is increasingly recognised to be an important determinant of oncological outcome. In colorectal cancer, the presence of peri-tumoural inflammatory/lymphocytic infiltrates predicts improved survival. To date, these infiltrates, assessed visually on haematoxylin and eosin (H&E) stained sections, have failed to enter routine clinical practice, partly due to their subjective assessment and considerable inter-observer variation. The present study aims to develop an automated scoring method to enable consistent and reproducible assessment of tumour inflammatory infiltrates in colorectal cancer. METHODS: 154 colorectal cancer patients who underwent curative resection were included in the study. The local inflammatory infiltrate was assessed using the method described by Klintrup-Makinen. H&E tumour sections were uploaded to an image analysis programme (Slidepath, Leica Biosystems). An image analysis algorithm was developed to count the inflammatory cells at the invasive margin. The manual and automated assessments of the tumour inflammatory infiltrates were then compared. RESULTS: The automated inflammatory cell counts assessed using the freehand annotation method (p<0.001) and the rectangular box method (p<0.001) were significantly associated with both K-M score (p<0.001) and K-M grade (p<0.001). The inflammatory cell counts were divided using quartiles to group tumours with similar inflammatory cell densities. There was good agreement between the manual and automated scoring methods (intraclass correlation coefficient (ICC)=0.82). Similar to the visual K-M scoring system, the automated K-M classification of the inflammatory cell counts, using quartiles, was significantly associated with venous invasion (p<0.05) and modified Glasgow Prognostic Score (mGPS) (p⩽0.05). On univariate survival analysis, both automated K-M category (p<0.05) and automated K-M grade (p<0.005) were associated with cancer-specific survival. CONCLUSION: The results of the present study demonstrate that automated assessment effectively recapitulates the clinical value of visual assessment of the local inflammatory cell infiltrate at the invasive margin of colorectal tumours. In addition, it is possible to obtain an objective assessment of tumour inflammatory infiltrates using routinely stained H&E sections. An automated, computer-based scoring method is therefore a workable and cost-effective approach to clinical assessment of local immune cell infiltrates in colorectal cancer.

Flexible sigmoidoscopy following a positive faecal occult blood test within a bowel screening programme may reduce the detection of neoplasia.

AIM: Colorectal cancer screening using the faecal occult blood test (FOBt) detects a disproportionate number of left-sided tumours. This study aims to examine the theoretical impact on neoplasia detection rates of a sigmoidoscopy-first protocol in FOBt-positive patients undergoing colonoscopy. METHOD: From retrieved endoscopy/pathology reports, pathology up to and including the splenic flexure was assumed detectable by sigmoidoscopy. High-risk polyps prompting subsequent colonoscopy were classed as three or more polyps, one polyp of ≥ 1 cm, villous or tubulovillous components or the presence of high-grade dysplasia. RESULTS: Between April 2009 and April 2011, 4631 patients underwent colonoscopy as a result of a positive FOBt in Greater Glasgow and Clyde. Cancer was detected in 398 (9%) and adenomas were detected in 1985 (47%) of which 1323 (67%) were deemed significant according to British Society of Gastroenterology guidelines. Applying the flexible sigmoidoscopy-first model, cancer would have been detected in 329 (8%) patients and adenomas in 1640 (39%), of which 1140 (70%) would have been significant. In total, 1546 (37%) patients would have required subsequent colonoscopy, following which 21 patients would have a new diagnosis of cancer. The positive predictive values (PPVs) for neoplasia (47 vs 57%, P < 0.001), significant neoplasia (35 vs 41%, P < 0.001) and cancer (8 vs 9%, P = 0.007) were all lower in the sigmoidoscopy-first model. CONCLUSION: A significant reduction in the detection of both adenomas and cancers would be seen if the sigmoidoscopy-first protocol were to be used following a positive FOBt. Furthermore, a significant proportion of patients would be subjected to two procedures, with considerable implications for both the patient and cost.

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.

Comparison of the prognostic value of longitudinal measurements of systemic inflammation in patients undergoing curative resection of colorectal cancer.

BACKGROUND: The systemic inflammation-based prognostic scores, modified Glasgow Prognostic Score (mGPS) and the neutrophil-lymphocyte ratio (NLR) are now recognised to be useful in predicting survival in a variety of solid organ malignancies, including colorectal cancer (CRC) before treatment. However, there would appear to have been no direct comparison of these longitudinal measurements of systemic inflammation. Therefore, the aim of the present study was to compare the prognostic value of longitudinal measures of systemic inflammation, the mGPS and NLR in patients undergoing potentially curative resection for CRC. METHODS: Three hundred and twenty-six patients underwent potentially curative resection for CRC between 2006 and 2010. Full biochemical and haematological data both pre- and post-operatively (3-6 months) were available for 206 patients. RESULTS: In 206 patients, there was no significant overall change in either the mGPS or the NLR, from pre- to post-operatively. On univariate survival analysis, T-stage (P<0.001), tumour, node, metastasis stage (P<0.005), pre-operative mGPS (P<0.05), pre-operative NLR (<0.05), post-operative mGPS (P<0.001) and post-operative NLR (P<0.005) were associated with cancer-specific survival. On multivariate survival analysis, comparing pre-operative mGPS and NLR, both pre-operative mGPS and NLR were independently associated with reduced cancer-specific survival (mGPS hazard ratio (HR) 1.97, CI 1.16-3.34, P<0.05, and NLR HR 3.07, CI 1.23-7.63, P<0.05). When the same multivariate comparison was carried out on post-operative data, only the post-operative mGPS was independently associated with cancer-specific survival (HR 4.81, CI 2.13-10.83, P<0.001). CONCLUSION: The results of the present study support the longitudinal assessment of the systemic inflammatory response, in particular the mGPS, in patients undergoing potentially curative resection for CRC.

The impact of aspirin, statins and ACE-inhibitors on the presentation of colorectal neoplasia in a colorectal cancer screening programme.

BACKGROUND: There is increasing evidence that aspirin, statins and ACE-inhibitors can reduce the incidence of colorectal cancer. The aim of the present study was to assess the impact of these medications on an individual's risk of advanced neoplasia in a colorectal cancer screening programme. METHODS: A prospectively maintained database of the first round of screening in our geographical area was analysed. The outcome measure was advanced neoplasia (cancer or intermediate or high risk adenomata). RESULTS: Of the 4188 individuals who underwent colonoscopy following a positive occult blood stool test, colorectal pathology was present in 3043(73%). Of the 3043 patients with colorectal pathology, 1704(56%) had advanced neoplasia. Patients with advanced neoplasia were more likely to be older (OR 1.38; 95% CI 1.19-1.59) and male (OR 1.66; 95% CI 1.43-1.94) (both P<0.001). In contrast, those on aspirin (OR 0.68; 95% CI 0.56-0.83), statins (OR 0.65; 95% CI 0.55-0.78) or ACE inhibitors (OR 0.71; 95% CI 0.57-0.89) were less likely to have advanced neoplasia at colonoscopy (all P<0.05). CONCLUSION: In patients undergoing colonoscopy following a positive occult blood stool test with documented evidence of aspirin, statin or ACE-inhibitor usage, advanced neoplasia is less likely, suggesting that the usage of these medications may have a chemopreventative effect.

Impact of the bowel-screening programme on the diagnosis of colorectal cancer in Ayrshire and Arran.

AIM: Bowel screening aims to reduce colorectal-cancer mortality by the detection and treatment of early-stage asymptomatic disease and the removal of precancerous adenomas. Bowel screening started in Ayrshire and Arran in September 2007. We report the impact of this screening on the diagnosis and stage of colorectal cancer and characterize screen-detected cancers in comparison with those diagnosed through other pathways. METHOD: Diagnoses were identified from an audit database. Referrals were grouped into screen detected, routine, urgent and emergency presentations. RESULTS: Between January 2001 and December 2010, 2289 diagnoses of colorectal cancer were made. From 2001 to 2006, the mean (range) number of new colorectal-cancer diagnoses per year was 210 (198-220). Between 2007 and 2010, the mean (range) number of diagnoses per year was 256 (239-274), a significant (P = 0.008) increase. Since September 2007, 877 colorectal cancers have been diagnosed: 17% were screen detected; 11% were detected as a result of routine GP referral; 51% were detected after urgent GP referral; and 21% were emergency presentations. TNM stage increased with urgency of referral. Approximately two-thirds (66%) of screen-detected colorectal cancers were node negative vs 25% of emergency presentations (P < 0.001). Most screen-detected cancers were distal to the splenic flexure (75%). Screened cancers had favourable pathology; lower T and N stages (both P < 0.001), less venous invasion (P < 0.001) and better differentiation (P < 0.05). Similar results were seen after stratification for TNM stage. Screening has not yet resulted in a significant shift towards early-stage disease since 2007. CONCLUSION: Screening has been associated with an increase in the numbers of both new and early-stage colorectal cancers. Screen-detected cancers are predominantly early-stage disease with favourable pathology. At present, it remains to be seen whether screening will ultimately translate into an overall reduction in advanced-stage disease.

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.

The role of the in situ local inflammatory response in predicting recurrence and survival in patients with primary operable colorectal cancer.

Colorectal cancer progression and survival is dependent on complex interactions between the tumour and the host. The pronounced local inflammatory response in and around the tumour is thought to represent the in situ host anti-tumour immune response. Since early reports, 40 years ago, there has been a continuing interest in establishing the cellular composition of immune cell infiltrates and their relationship with survival in colorectal cancer. In this review, we comprehensively examine the evidence for the local inflammatory cell reaction/in situ immune response in predicting outcome in primary operable colorectal cancer and make recommendations as to how such information may be incorporated into routine clinical assessment. Generally, an increasing number/density of immune cells in and around the tumour is associated with improved outcome in over 100 studies. Whilst the prognostic value of a generalized lymphocytic infiltrate or non-specific peritumoural inflammatory response is strongly related to survival based on 40 different studies, it is also apparent that most individual immune cell types relate to recurrence and cancer specific survival. The evidence is particularly robust for tumour infiltrating T lymphocytes and their subsets (CD3+, CD8+, CD45RO+, FOXP3+) in addition to tumour associated macrophages, dendritic cells and neutrophils. Taken together, the evidence suggests both adaptive and innate anti-tumour immune responses play key roles in determining cancer progression. In order to establish routine clinical utility there is a need to rationalise this prognostic information, published over a 40 years period, into a standardized assessment of tumour inflammatory cell infiltrate. Such standardization may also guide development of novel therapeutic interventions.

Determinants of short- and long-term outcome in patients undergoing simultaneous resection of colorectal cancer and synchronous colorectal liver metastases.

PURPOSE: The optimal surgical strategy for patients presenting with colorectal liver metastases has yet to be determined. Short- and long-term outcomes must be considered if simultaneous resection of primary and liver metastases is to gain acceptance. We examine the prognostic value of patient and tumour characteristics in predicting short- and long-term outcomes following simultaneous resection for synchronous disease. METHODS: Forty-six patients undergoing simultaneous resection between April 2002 and June 2010 in a single institution were included. Patient characteristics included preoperative ASA grade and POSSUM. Tumour characteristics included TNM stage, Petersen Index and the Clinical Risk Score. RESULTS: There were no postoperative deaths. The most common complications were atrial fibrillation (seven patients) and pneumonia (seven patients). Mean hospital stay with an uncomplicated postoperative recovery was 11 days versus 17 days with complicated recovery. Age (p = 0.015), ASA grade (p = 0.010) and POSSUM score (p = 0.032) were associated with postoperative complications. No pathological characteristics of the primary or secondary tumours related to surgical morbidity. Median follow-up was 37 months (5-87) during which 24 patients died, 23 from cancer. Twenty-seven had disease recurrence. N stage of the primary (p = 0.035), high-risk Petersen Index of the primary (p = 0.010) and Clinical Risk Score ≥ 3 (p = 0.005) were associated with poorer recurrence-free and cancer-specific survival. CONCLUSIONS: Post operative morbidity was determined by patient factors rather than operative or tumour characteristics. In addition to the Clinical Risk Score, pathological characteristics of the primary are important determinants of long-term outcome following simultaneous resection for synchronous disease.