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.

Regulator of Calcineurin 1 helps coordinate whole-body metabolism and thermogenesis.

Increasing non-shivering thermogenesis (NST), which expends calories as heat rather than storing them as fat, is championed as an effective way to combat obesity and metabolic disease. Innate mechanisms constraining the capacity for NST present a fundamental limitation to this approach, yet are not well understood. Here, we provide evidence that Regulator of Calcineurin 1 (RCAN1), a feedback inhibitor of the calcium-activated protein phosphatase calcineurin (CN), acts to suppress two distinctly different mechanisms of non-shivering thermogenesis (NST): one involving the activation of UCP1 expression in white adipose tissue, the other mediated by sarcolipin (SLN) in skeletal muscle. UCP1 generates heat at the expense of reducing ATP production, whereas SLN increases ATP consumption to generate heat. Gene expression profiles demonstrate a high correlation between Rcan1 expression and metabolic syndrome. On an evolutionary timescale, in the context of limited food resources, systemic suppression of prolonged NST by RCAN1 might have been beneficial; however, in the face of caloric abundance, RCAN1-mediated suppression of these adaptive avenues of energy expenditure may now contribute to the growing epidemic of obesity.

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.

Fathers' views and experiences of their own mental health during pregnancy and the first postnatal year: a qualitative interview study of men participating in the UK Born and Bred in Yorkshire (BaBY) cohort.

BACKGROUND: The prevalence of fathers' depression and anxiety in the perinatal period (i.e. from conception to 1 year after birth) is approximately 5-10%, and 5-15%, respectively; their children face increased risk of adverse emotional and behavioural outcomes, independent of maternal mental health. Critically, fathers can be protective against the development of maternal perinatal mental health problems and their effects on child outcomes. Preventing and treating paternal mental health problems and promoting paternal psychological wellbeing may therefore benefit the family as a whole. This study examined fathers' views and direct experiences of paternal perinatal mental health. METHODS: Men in the Born and Bred in Yorkshire (BaBY) epidemiological prospective cohort who met eligibility criteria (baby born <12 months; completed Mental Health and Wellbeing [MHWB] questionnaires) were invited to participate. Those expressing interest (n = 42) were purposively sampled to ensure diversity of MHWB scores. In-depth interviews were conducted at 5-10 months postpartum with 19 men aged 25-44 years. The majority were first-time fathers and UK born; all lived with their partner. Data were analysed using thematic analysis. RESULTS: Four themes were identified: 'legitimacy of paternal stress and entitlement to health professionals' support', 'protecting the partnership', 'navigating fatherhood', and, 'diversity of men's support networks'. Men largely described their 'stress' with reference to exhaustion, poor concentration and irritability. Despite feeling excluded by maternity services, fathers questioned their entitlement to support, noting that services are pressured and 'should' be focused on mothers. Men emphasised the need to support their partner and protect their partnership as central to the successfully navigation of fatherhood; they used existing support networks where available but noted the paucity of tailored support for fathers. CONCLUSIONS: Fathers experience psychological distress in the perinatal period but question the legitimacy of their experiences. Men may thus be reluctant to express their support needs or seek help amid concerns that to do so would detract from their partner's needs. Resources are needed that are tailored to men, framed around fatherhood, rather than mental health or mental illness, and align men's self-care with their role as supporter and protector. Further research is needed to inform how best to identify and manage both parents' mental health needs and promote their psychological wellbeing, in the context of achievable models of service delivery.

Serum amylase and C-reactive protein in risk stratification of pancreas-specific complications after pancreaticoduodenectomy.

BACKGROUND: Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage and intra-abdominal collections, are drivers of morbidity and mortality after pancreaticoduodenectomy (PD). A serum amylase concentration of 130 units/l or more on postoperative day (POD) 0 has been shown to be an objective surrogate of pancreatic texture, a determinant of PSCs. This study evaluated serial measurements of C-reactive protein (CRP) to refine PSC risk stratification. METHODS: Consecutive patients undergoing PD between 2008 and 2014, with vascular resection if required and without preoperative chemoradiotherapy, had serum investigations from the day before operation until discharge. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP with clinically relevant PSCs for up to 30 days after discharge as outcome measure. RESULTS: Of 230 patients, 95 (41·3 per cent) experienced a clinically relevant PSC. A serum CRP level of 180 mg/l or higher on POD 2 was associated with PSCs, prolonged critical care stay and relaparotomy (all P < 0·050). Patients with a serum amylase concentration of 130 units/l or more on POD 0 who developed a serum CRP level of at least 180 mg/l on POD 2 had a higher incidence of morbidity. Patients were stratified into high-, intermediate- and low-risk groups using these markers. The low-risk category was associated with a negative predictive value of 86·5 per cent for development of clinically relevant PSCs. There were no deaths among 52 patients in the low-risk group, but seven deaths among 79 (9 per cent) in the high-risk group. CONCLUSION: A serum amylase level below 130 units/l on POD 0 combined with a serum CRP level under 180 mg/l on POD 2 constitutes a low-risk profile following PD, and may help identify patients suitable for early discharge.

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.

A randomized clinical study to assess ingestion of dentifrice by children.

This study investigated whether there was a difference in amounts of dentifrice ingested by children based on age using pea-sized instructions. The study had a randomized, single-blinded, 3-period, crossover design modelled after Barnhart et al. (1974) with one regular-flavored and two specially-flavored dentifrices used ad libitum. Subjects were enrolled in three groups: 2-4, 5-7, and 8-12 years. They were instructed to brush at home as they would normally with each dentifrice for 3 weeks (9 weeks total). On weekly study-site visits, subjects brushed with the assigned dentifrice containing a lithium marker to measure the amount of dentifrice ingested and used. Averaging across dentifrices, amounts ingested were: 0.205 g (2-4 yr), 0.125 g (5-7 yr) and 0.135 g (8-12 yr), demonstrating 2-4 year-olds ingested significantly more than older children (p ≤ 0.002). Averaging across dentifrices, amounts used were: 0.524 g (2-4 yr), 0.741 g (5-7 yr) and 0.978 g (8-12 yr) suggesting an age-related effect (p < 0.01). Findings also showed that ingestion amount for specially-flavored dentifrices may increase relative to regular-flavored dentifrice for children 2-7 years-old. This research demonstrated that dentifrice ingestion amount decreased significantly with age while usage amount increased with age. Importantly, ingestion and usage levels in younger children reflect "pea-sized" direction and were numerically lower than historical levels reported prior to this direction.

The relationship between tumour budding, the tumour microenvironment and survival in patients with invasive ductal breast cancer.

BACKGROUND: Tumour budding has previously been reported to predict survival in several solid organ tumours, including breast; however, whether this is independent of other aspects of the tumour microenvironment is unknown. In the present study, the relationship between tumour budding, the tumour microenvironment and survival was examined in patients with invasive ductal breast cancer. METHODS: Patients presenting between 1995 and 1998 were studied (n=474). Using routine pathological sections, tumour budding was measured at the invasive margin and its association with clinicopathological characteristics and cancer-specific survival (CSS) was examined. RESULTS: Tumour budding was associated with several adverse pathological characteristics, including lymph node involvement, lymph vessel invasion (LVI), increased tumour stroma percentage (TSP) and weaker local inflammatory infiltrative. Tumour budding was associated with reduced CSS (hazard ratio (HR) 2.08, 95% confidence interval (CI) 1.14-3.09, P=0.004), independent of nodal status, molecular subtypes, tumour necrosis, CD8+, CD138+, LVI, blood vessel invasion and TSP. Further, tumour budding was independently associated with reduced CSS in node-negative patients (HR 2.63, 95% CI 1.16-5.92, P=0.020) and those who have low TSP (HR 1.98, 95% CI 1.09-3.57, P=0.024) and high-grade local inflammatory infiltrative (HR 2.27, 95% CI 1.35-5.36, P=0.014). CONCLUSIONS: Tumour budding was a significant predictor of survival in patients with invasive ductal breast cancer, independent of adverse pathological characteristics and components of tumour microenvironment. The present study further confirms the clinical utility of both tumour and host-based factors of tumour microenvironment.

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.

Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment.

Regulator of calcineurin 1 (RCAN1) controls the activity of calcium/calmodulin-dependent phosphatase calcineurin (CaN), which has been implicated in human anxiety disorders. Previously, we reported that RCAN1 functioned as an inhibitor of CaN activity in the brain. However, we now find enhanced phosphorylation of a CaN substrate, cAMP response element-binding protein (CREB), in the brains of Rcan1 knock-out (KO) mice. Consistent with enhanced CREB activation, we also observe enhanced expression of a CREB transcriptional target, brain-derived neurotrophic factor (BDNF) in Rcan1 KO mice. We also discovered that RCAN1 deletion or blockade of RCAN1-CaN interaction reduced CaN and protein phosphatase-1 localization to nuclear-enriched protein fractions and promoted CREB activation. Because of the potential links between CREB, BDNF, and anxiety, we examined the role of RCAN1 in the expression of innate anxiety. Rcan1 KO mice displayed reduced anxiety in several tests of unconditioned anxiety. Acute pharmacological inhibition of CaN rescued these deficits while transgenic overexpression of human RCAN1 increased anxiety. Finally, we found that Rcan1 KO mice lacked the early anxiogenic response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and had improved latency for its therapeutic anxiolytic effects. Together, our study suggests that RCAN1 plays an important role in the expression of anxiety-related and SSRI-related behaviors through CaN-dependent signaling pathways. These results identify RCAN1 as a mediator of innate emotional states and possible therapeutic target for anxiety.

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 the tumour stroma percentage, clinicopathological characteristics and outcome in patients with operable ductal breast cancer.

BACKGROUND: The percentage of tumour stroma (TSP) has recently been reported to be a novel independent predictor of outcome in patients with a variety of common solid organ tumours. The aim of this study was to examine the relationship between TSP, clinicopathological characteristics and outcome in patients with invasive ductal breast cancer, in particular node negative and triple negative disease. METHODS: A total of 361 patients with primary operable invasive ductal breast cancer were included in this study. The TSP was assessed visually on the haematoxylin and eosin-stained tissue sections. With a cutoff value of 50% TSP, patients with ≤ 50% stroma were classified as the low-TSP group and those with >50% stroma were classified as the high-TSP group. RESULTS: A total of 109 (30%) patients had high TSP. Patients with high TSP were old age (P=0.035), had more Her-2-positive tumours (P=0.029), low-grade tumour inflammatory infiltrate (P=0.034), low CD68+macrophage infiltrate (P<0.001), low CD4+ (P=0.023) and low CD8+ T-lymphocytes infiltrate (P=0.017), tumour recurrence (P=0.015) and shorter cancer-specific survival (P<0.001). In node-negative patients (n=207), high TSP was associated with low CD68+macrophage infiltrate (P=0.001), low CD4+ (P=0.040) and low CD8+ T-lymphocytes infiltrate (P=0.016) and shorter cancer-specific survival (P=0.005). In triple negative patients (n=151), high TSP was associated with high tumour grade (P=<0.001), lymph node positivity (P=0.027), low CD68+macrophage infiltrate (P=0.011) and shorter cancer-specific survival (P=0.035). The 15-year cancer-specific survival rate was 79% vs 21% in the low-TSP group vs high-TSP group. In multivariate survival analysis, a high TSP was associated with reduced cancer-specific survival in the whole cohort (P=0.001), node-negative patients (P=0.007) and those who received systemic adjuvant therapy (P=0.021), independent of other pathological characteristics including host inflammatory response. However, TSP was not an independent prognostic factor for triple negative patients (P=0.151). CONCLUSIONS: A high TSP in primary operable invasive ductal breast cancer was associated with recurrence and poorer long-term survival. The inverse relation with the tumour inflammatory infiltrate highlights the importance of the amount of tumour stroma on immunological response in patients with primary operable ductal breast cancer. Implementing this simple and reproducible parameter in routine pathological examination may help optimise risk stratification in patients with invasive ductal breast 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.

Educational barriers of nurses caring for sick and at-risk infants in India.

AIM: To gain ideas and information from healthcare providers to optimize the education and clinical practices of nurses caring for sick or at-risk newborns in India. BACKGROUND: Improving infant survival has been identified as a Millennium Development Goals; however, India still faces many challenges with 3.1 million neonatal deaths and 2.6 million stillbirths annually. Skilled nursing care has been associated with decreased morbidity and mortality in newborns. However, core competencies in newborn care education and training are lacking for nurses. METHODS: Qualitative data were collected from 12 focus groups with 101 newborn care providers from three areas of India as well as from a 2-day stakeholders' meeting. Data analysis was undertaken using descriptive and thematic content analysis. RESULTS: Perceived challenges included limited manpower and high nurse turnover, lack of access to evidence-based orientation to newborn care and problems with access to appropriate learner-based, neonatal training. Relevant, ongoing education opportunities, led by nursing leaders were identified to be important solutions. CONCLUSION: Findings provide insight into the current healthcare system in India with specific reference to the nursing care of at-risk newborns. There is a lack of existing resources to provide standardized and specific orientation curricula for nurses. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Policy makers in health and education need to: support and enact learner-based orientation and continuing educational opportunities as well as ongoing competency-based education programmes; encourage nurse leader involvement and support; and provide sustainable system-related supports. Nurses and other health providers need to work together to influence government policy.

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 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.