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.

Route to diagnosis of colorectal cancer and association with survival within the context of a bowel screening programme.

OBJECTIVES: Bowel cancer screening has been introduced to improve colorectal cancer outcomes; however, a significant proportion of cases continue to present with TNM Stage III-IV disease and/or emergently. This study analyses the prior interaction with screening of patients diagnosed with colorectal cancer and factors associated with non-screening diagnosis. STUDY DESIGN: This was a retrospective observational study. METHODS: All patients diagnosed with colorectal cancer in the West of Scotland from 2011 to 2014 were identified. Through data linkage to the Scottish Bowel Cancer Screening Programme, we analysed patient interaction with screening within 2 years before cancer diagnosis. RESULTS: In total, 6549 patients were diagnosed with colorectal cancer, 1217 (19%) via screening. Screening participation was associated with earlier TNM stage, reduced emergency presentations and improved 3-year survival (all P < 0.001). Failure to diagnose through screening was predominantly due to non-invitation (37%), non-return of screening test (29%) or negative test (13%). Three hundred fifty-one patients were below screening age, 79% of whom were aged 40-49 years and 2035 patients were above screening age. Factors associated with non-return of screening test included age, sex, SIMD (all P < 0.001) and raised Charlson score (P = 0.030). Factors associated with negative screening result included sex, anaemia, differentiation, right-sided tumours and venous invasion (P < 0.001). CONCLUSION: Within Scotland, <20% of colorectal cancer is diagnosed through screening despite the existence of a population screening programme. Measures must be taken to improve screening participation including encouragement of those of routine screening age and those age ≥75 years in good health to participate in screening with consideration given to extending screening to under 50s. A significant false-negative rate of testing was observed in the present study and this requires further investigation within a population undergoing screening through faecal immunochemical testing.

A novel tumor-based epithelial-to-mesenchymal transition score that associates with prognosis and metastasis in patients with Stage II/III colorectal cancer.

It is increasingly appreciated that host factors within the tumor center and microenvironment play a key role in dictating colorectal cancer (CRC) outcomes. As a result, the metastatic process has now been defined as a result of epithelial-mesenchymal transition (EMT). Establishment of the role of EMT within the tumor center and its effect on the tumor microenvironment would be beneficial for prognosis and therapeutic intervention in CRC. The present study assessed five immunohistochemical EMT markers within the tumor center on a 185 Stage II/III CRC patient tissue microarray. In 185 patients with CRC, cytoplasmic snail (HR 1.94 95% confidence interval [CI] 1.15-3.29, p = 0.012) and a novel combined EMT score (HR 3.86 95% CI 2.17-6.86, p < 0.001) were associated with decreased cancer-specific survival. The combined EMT score was also associated with increased tumor budding (p = 0.046), and systemic inflammation (p = 0.007), as well as decreased memory T-cells within the stroma (p = 0.030) and at the invasive margin (p = 0.035). Furthermore, the combined EMT score was associated with cancer-specific survival independent of TNM-stage (HR 4.12 95% CI 2.30-7.39, p < 0.001). In conclusion, a novel combined EMT score stratifies patient's survival in Stage II/III CRC and associates with key factors of tumor metastasis. Therefore, the combined EMT score could be used to identify patients at risk of micrometastases and who may benefit from standard adjuvant therapy, potentially in combination with EMT blockade.

The relationship between 18 F-FDG-PETCT-derived markers of tumour metabolism and systemic inflammation in patients with recurrent disease following surgery for colorectal cancer.

AIM: 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (18 F-FDG-PETCT)-derived markers of tumour metabolism have been reported to have prognostic significance in a variety of tumours. Host inflammation is also recognized to have prognostic significance. The aim of the present study was to investigate the relationship between these markers and host systemic inflammation in patients undergoing elective surgery for colorectal cancer. METHOD: Patients with histologically confirmed colorectal cancer who underwent elective surgery between 2008 and 2015 and also underwent 18 F-FDG-PETCT at a single centre were included (n = 103). The neutrophil-lymphocyte ratio (NLR) and modified Glasgow Prognostic Score (mGPS) were derived from routine blood tests. The maximum standardized uptake (SUVmax), peak standardized uptake (SUVpeak), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were measured. RESULTS: There was no association between 18 F-FDG-PETCT measures of tumour metabolism and systemic inflammation in the 33 patients who underwent preoperative imaging. Of the 70 patients with recurrent disease who underwent 18 F-FDG-PETCT during follow-up, patients with NLR ≥ 5 had a significantly higher SUVmax (20 vs 7, P = 0.002), SUVpeak (14 vs 5, P < 0.001), MTV (29 g vs 2 g, P = 0.001) and TLG (338 g vs 9 g, P < 0.001). Similarly, patients with a mGPS of 1-2 at the time of 18 F-FDG-PETCT had a significantly higher median SUVmax (11 vs 6, P = 0.048), SUVpeak (8 vs 4, P = 0.046), MTV (13 ml vs 2 ml, P = 0.005) and TLG (146 g vs 10 g, P = 0.004). CONCLUSION: The present study reports a direct association between 18 F-FDG-PETCT-derived measures of tumour metabolism and systemic inflammation in patients with recurrent colorectal cancer.

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.

A comparison of tumour and host prognostic factors in screen-detected vs nonscreen-detected colorectal cancer: a contemporaneous study.

AIM: In addition to TNM stage there are adverse tumour and host factors, such as venous invasion and the presence of an elevated systemic inflammatory response (SIR), that influence the outcome in colorectal cancer. The present study aimed to examine how these factors varied in screen-detected (SD) and nonscreen-detected (NSD) tumours. METHOD: Prospectively maintained databases of the prevalence round of a biennial population faecal occult blood test screening programme and a regional cancer audit database were analysed. Interval cancers (INT) were defined as cancers identified within 2 years of a negative screening test. RESULTS: Of the 395 097 people invited, 204 535 (52%) responded, 6159 (3%) tested positive and 421 (9%) had cancer detected. A further 708 NSD patients were identified [468 (65%) nonresponders, 182 (25%) INT cancers and 58 (10%) who did not attend or did not have cancer diagnosed at colonoscopy]. Comparing SD and NSD patients, SD patients were more likely to be male, and have a tumour with a lower TNM stage (both P < 0.05). On stage-by-stage analysis, SD patients had less evidence of an elevated SIR (P < 0.05). Both the presence of venous invasion (P = 0.761) and an elevated SIR (P = 0.059) were similar in those with INT cancers and in those that arose in nonresponders. CONCLUSION: Independent of TNM stage, SD tumours have more favourable host prognostic factors than NSD tumours. There is no evidence that INT cancers are biologically more aggressive than those that develop in the rest of the population and are hence likely to be due to limitations of screening in its current format.

Temporal trends in mode, site and stage of presentation with the introduction of colorectal cancer screening: a decade of experience from the West of Scotland.

BACKGROUND: Population colorectal cancer screening programmes have been introduced to reduce cancer-specific mortality through the detection of early-stage disease. The present study aimed to examine the impact of screening introduction in the West of Scotland. METHODS: Data on all patients with a diagnosis of colorectal cancer between January 2003 and December 2012 were extracted from a prospectively maintained regional audit database. Changes in mode, site and stage of presentation before, during and after screening introduction were examined. RESULTS: In a population of 2.4 million, over a 10-year period, 14 487 incident cases of colorectal cancer were noted. Of these, 7827 (54%) were males and 7727 (53%) were socioeconomically deprived. In the postscreening era, 18% were diagnosed via the screening programme. There was a reduction in both emergency presentation (20% prescreening vs 13% postscreening, P⩽0.001) and the proportion of rectal cancers (34% prescreening vs 31% pos-screening, P⩽0.001) over the timeframe. Within non-metastatic disease, an increase in the proportion of stage I tumours at diagnosis was noted (17% prescreening vs 28% postscreening, P⩽0.001). CONCLUSIONS: Within non-metastatic disease, a shift towards earlier stage at diagnosis has accompanied the introduction of a national screening programme. Such a change should lead to improved outcomes in patients with 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.

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.

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.

Androgen receptor phosphorylation at serine 515 by Cdk1 predicts biochemical relapse in prostate cancer patients.

BACKGROUND: Prostate cancer cell growth is dependent upon androgen receptor (AR) activation, which is regulated by specific kinases. The aim of the current study is to establish if AR phosphorylation by Cdk1 or ERK1/2 is of prognostic significance. METHODS: Scansite 2.0 was utilised to predict which AR sites are phosphorylated by Cdk1 and ERK1/2. Immunohistochemistry for these sites was then performed on 90 hormone-naive prostate cancer specimens. The interaction between Cdk1/ERK1/2 and AR phosphorylation was investigated in vitro using LNCaP cells. RESULTS: Phosphorylation of AR at serine 515 (pAR(S515)) and PSA at diagnosis were independently associated with decreased time to biochemical relapse. Cdk1 and pCdk1(161), but not ERK1/2, correlated with pAR(S515). High expression of pAR(S515) in patients with a PSA at diagnosis of ≤20 ng ml(-1) was associated with shorter time to biochemical relapse (P=0.019). This translated into a reduction in disease-specific survival (10-year survival, 38.1% vs 100%, P<0.001). In vitro studies demonstrated that treatment with Roscovitine (a Cdk inhibitor) caused a reduction in pCdk1(161) expression, pAR(S515)expression and cellular proliferation. CONCLUSION: In prostate cancer patients with PSA at diagnosis of ≤20 ng ml(-1), phosphorylation of AR at serine 515 by Cdk1 may be an independent prognostic marker.

The in situ local immune response, tumour senescence and proliferation in colorectal cancer.

BACKGROUND: Immune cell infiltrates are important determinants of colorectal cancer (CRC) outcome. Their presence may be driven by tumour or host-specific factors. From previous studies in mice, senescence, a state of cell cycle arrest, may moderate tumour progression through upregulation of antitumour immune responses. The relationships between senescence and immune infiltrates have not previously been studied in humans. We explore whether a marker of senescence (p16(ink4a)) in combination with low level expression of a proliferation marker (ki-67) relate to T cell infiltrates in CRC, and whether p16(ink4a), Ki-67 and immune infiltrates have similar prognostic value. METHODS: Immunostaining of p16(inka) and Ki-67 was performed within a CRC tissue microarray. Nuclear p16(inka) and Ki-67 were categorised as high/low. T-cell markers, CD3, CD45RO, CD8 and FOXP3 were scored separately as high/low grade in three areas of the tumour: the invasive margin (IM), tumour stroma and cancer cell nests (CCNs). results: Two hundred and thirty stage I-III cancers were studied. High nuclear p16(ink4a) was expressed in 63% and high proliferation (Ki-67 >15%) in 61%. p16(ink4a) expression was associated with reduced CD45RO+ cells at the IM (P<0.05) and within the stroma (P<0.05) and reduced CD8+ cells at the IM (P<0.01). A low Ki-67 proliferative index was associated with reduced density of CD3+ cells in CCNs (P<0.01), reduced CD45RO+ cells at the IM (P<0.05) and within the CCNs (P<0.001), reduced FOXP3+ cells at the IM (P<0.001), within the stroma (P=0.001) and within CCNs (P<0.001) and reduced CD8+ cells at the IM (P<0.05) and within the CCNs (P<0.05). Tumours with both a low proliferative index and expression of p16(ink4a) demonstrated similar consistent relationships with reduced densities of T-cell infiltrates. On multivariate analysis, TNM stage (P<0.001), low CD3 cells at the IM (P=0.014), low CD8 cells at the IM (P=0.037), low proliferation (Ki-67; P=0.013) and low senescence (p16(ink4a); P=0.002) were independently associated with poorer cancer survival. CONCLUSION: Senescence, proliferation and immune cell infiltrates are independent prognostic factors in CRC. Although related to survival, p16(ink4a)-associated senescence is not associated with an upregulation of antitumour T-cell responses.

Contribution of surgical specialization to improved colorectal cancer survival.

BACKGROUND: Reorganization of colorectal cancer services has led to surgery being increasingly, but not exclusively, delivered by specialist surgeons. Outcomes from colorectal cancer surgery have improved, but the exact determinants remain unclear. This study explored the determinants of outcome after colorectal cancer surgery over time. METHODS: Postoperative mortality (within 30 days of surgery) and 5-year relative survival rates for patients in the West of Scotland undergoing surgery for colorectal cancer between 1991 and 1994 were compared with rates for those having surgery between 2001 and 2004. RESULTS: The 1823 patients who had surgery in 2001-2004 were more likely to have had stage I or III tumours, and to have undergone surgery with curative intent than the 1715 patients operated on in 1991-1994. The proportion of patients presenting electively who received surgery by a specialist surgeon increased over time (from 14·9 to 72·8 per cent; P < 0·001). Postoperative mortality increased among patients treated by non-specialists over time (from 7·4 to 10·3 per cent; P = 0·026). Non-specialist surgery was associated with an increased risk of postoperative death (adjusted odds ratio 1·72, 95 per cent confidence interval (c.i.) 1·17 to 2·55; P = 0·006) compared with specialist surgery. The 5-year relative survival rate increased over time and was higher among those treated by specialist compared with non-specialist surgeons (62·1 versus 53·0 per cent; P < 0·001). Compared with the earlier period, the adjusted relative excess risk ratio for the later period was 0·69 (95 per cent c.i. 0·61 to 0·79; P < 0·001). Increased surgical specialization accounted for 18·9 per cent of the observed survival improvement. CONCLUSION: Increased surgical specialization contributed significantly to the observed improvement in longer-term survival following colorectal cancer surgery.

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.

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.

A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer.

BACKGROUND: The neutrophil lymphocyte ratio (NLR) has prognostic value in patients with a variety of cancers. Many chemotherapeutic trial databases hold information on white cell and neutrophil counts only. The aim of the present study was to compare the prognostic value of the NLR with a derived score (dNLR), composed of white cell and neutrophil counts. METHODS: Patients (n=27,031) who were sampled incidentally between 2000 and 2007 for neutrophil, lymphocyte and white cell counts, and also had a diagnosis of cancer (Scottish Cancer Registry), were identified. Of this group, 12,118 patients who had been sampled within 2 years of their cancer diagnosis were studied. RESULTS: On follow-up, there were 7366 deaths, of which 6198 (84%) were cancer deaths. The median time from blood sampling to diagnosis was 2.1 months. The area under the receiver-operating characteristic (ROC) curve for cancer-specific survival was 0.650 for the NLR and 0.640 for the dNLR. The NLR and dNLR were independently associated with survival in all cancers studied (all P<0.001). The optimal thresholds, on the basis of hazard ratios and area under the curve, were 4 : 1 for the NLR and 2 : 1 for the dNLR. CONCLUSION: The results of the present study show that the dNLR has similar prognostic value to the NLR. Therefore, the universally available dNLR is to be commended for use in the risk stratification of patients undergoing chemotherapy.

The relationship between tumour necrosis, tumour proliferation, local and systemic inflammation, microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma.

BACKGROUND: There is increasing evidence that the local and systemic inflammatory responses are associated with survival in oesophageal cancer. The aim of this study was to examine the relationship between tumour necrosis, tumour proliferation, local and systemic inflammation and microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma. METHODS: The interrelationship between tumour necrosis, tumour proliferation, local inflammatory response (Klintrup-Makinen criteria, intra-tumoural CD8+ lymphocyte and macrophage infiltration), systemic inflammatory response (modified Glasgow Prognostic score (mGPS)), and microvessel density was examined in 121 patients undergoing potentially curative resection for oesophageal adenocarcinoma (including type I and II tumours of the gastro-oesophageal junction). RESULTS: Tumour necrosis was not significantly associated with any tumour measure other than the degree of differentiation. On multivariate analysis, only age (HR 1.93, 95% CI 1.23-3.04, P=0.004), mGPS (HR 2.91, 95% CI 1.51-5.62, P=0.001), positive to total lymph node ratio (HR 2.38, 95% CI 1.60-3.52, P<0.001) and macrophage infiltration (HR 1.49, 95% CI 1.02-2.18, P=0.041) were independently associated with cancer-specific survival in oesophageal adenocarcinoma. Intra-tumoural macrophages were associated with tumour proliferation (P<0.001) and CD8+ lymphocytes infiltration (P<0.01). CONCLUSION: The results of this study suggest that tumour necrosis does not link local and systemic inflammatory responses and is not significantly associated with survival. In contrast, tumour macrophage infiltration appears to have a central role in the proliferative activity and the coordination of the inflammatory cell infiltrate and is independently associated with poorer survival in patients with oesophageal adenocarcinoma.