The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer

Although there is increasing appreciation of the role of the host inflammatory response in determining outcome in patients in colorectal cancer, there has been little concerted effort to favourably manipulate cancer-associated inflammation, either alone or in combination with current oncological treatment. Epidemiological and cardiovascular disease studies have identified aspirin, other nonsteroidal anti-inflammatory drugs and statins as potential chemotherapeutic agents which may manipulate the host inflammatory response to the benefit of the patient with cancer. Similarly, evidence of a chemotherapeutic effect of histamine-2 receptor antagonists, again mediated by an immunomodulatory effect, has previously led to increased interest in their use in gastrointestinal cancer. Extensive pre-clinical data and a limited number of clinical investigations have proposed a direct effect of these agents on tumour biology, with an anti-tumour effect on several of the hallmarks of cancer, including proliferative capacity, evasion from apoptosis and cell cycle regulation, and invasive capability of tumour cells. Furthermore, clinical evidence has suggested a pertinent role in down-regulating the systemic inflammatory response whilst favourably influencing the local inflammatory response within the tumour microenvironment. Despite such compelling results, the clinical applicability of nonsteroidal anti-inflammatory drugs, statins and histamine-2 receptor antagonists has not been fully realised, particularly in patients identified at high risk on the basis of inflammatory parameters. In the present review, we examine the potential role that these agents may play in improving survival and reducing recurrence in patients with potentially curative colorectal cancer, and in particular focus on their effects on the local and systemic inflammatory response

Effect of preoperative oral antibiotics in combination with mechanical bowel preparation on inflammatory response and short‐term outcomes following left‐sided colonic and rectal resections

Background: Preoperative oral antibiotics in addition to intravenous antibiotics and mechanical bowel preparation (MBP) may influence the gut microbiome and reduce both the postoperative systemic inflammatory response to surgery and postoperative infective complications following colorectal resection. This propensity score‐matched study compared outcomes of patients undergoing left‐sided colonic or rectal resection with or without a combination of oral antibiotics and MBP. Methods: The addition of oral antibiotics and MBP to prophylactic intravenous antibiotics in left‐sided colonic and rectal resections was introduced in 2015–2016 at a single institution. Propensity score matching was undertaken to compare the effects of oral antibiotics plus MBP versus neither oral antibiotics nor MBP on the postoperative systemic inflammatory response and short‐term outcomes in patients undergoing left‐sided colonic or rectal resection between 2013 and 2018. Results: Of 396 patients who had propensity score matching for host, anaesthetic and operative factors, 204 matched patients were identified. The addition of oral antibiotics and MBP was associated with a significantly reduced postoperative inflammatory response (reduced postoperative Glasgow Prognostic Score) on day 3 (odds ratio (OR) 0·66, 95 per cent c.i. 0·44 to 0·99; P  = 0·013) and day 4 (OR 0·46, 0·30 to 0·71; P  = 0·001). Significantly reduced overall complications (OR 0·31, 0·17 to 0·56; P  < 0·001), infective complications (OR 0·41, 0·22 to 0·77; P  = 0·011), surgical‐site infection (OR 0·37, 0·17 to 0·83; P  = 0·024) and postoperative length of hospital stay (median 7 days versus 8 days in patients who had intravenous antibiotics alone; P  = 0·050) were also observed. Conclusion: Preoperative oral antibiotics and MBP in addition to prophylactic intravenous antibiotics were associated with a reduction in the postoperative systemic inflammatory response and postoperative complications in patients undergoing resectional left‐sided colonic or rectal surgery

Authors' reply: Effect of preoperative oral antibiotics in combination with mechanical bowel preparation on inflammatory response and short-term outcomes following left-sided colonic and rectal resections

No abstract available

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

Prospects for asteroseismology

The observational basis for asteroseismology is being dramatically strengthened, through more than two years of data from the CoRoT satellite, the flood of data coming from the Kepler mission and, in the slightly longer term, from dedicated ground-based facilities. Our ability to utilize these data depends on further development of techniques for basic data analysis, as well as on an improved understanding of the relation between the observed frequencies and the underlying properties of the stars. Also, stellar modelling must be further developed, to match the increasing diagnostic potential of the data. Here we discuss some aspects of data interpretation and modelling, focussing on the important case of stars with solar-like oscillations.Comment: Proc. HELAS Workshop on 'Synergies between solar and stellar modelling', eds M. Marconi, D. Cardini & M. P. Di Mauro, Astrophys. Space Sci., in the press Revision: correcting abscissa labels on Figs 1 and

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

Characteristics of Early-Onset vs Late-Onset Colorectal Cancer: A Review.

The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes

The influence of systemic inflammation on treatment response and survival in anal squamous cell cancer

AIMS:The incidence of anal squamous cell cancer (SCCA) is rising. Although chemoradiotherapy (CRT) provides a chance of cure, a proportion of patients have an incomplete response or develop recurrence. This study assessed the value of inflammation-based prognostic indicators, including the modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR), in patients with SCCA treated by CRT with curative intent. MATERIAL AND METHODS:Patients with histologically confirmed SCCA were identified from pathology records. Medical records were retrospectively reviewed and clinical, pathological and treatment characteristics were abstracted. The mGPS (0 = normal C-reactive protein [CRP] and albumin, 1 = CRP &gt;10 mg/l and 2 = CRP &gt;10 mg/l and albumin &lt;35 mg/l) and NLR were calculated from routine blood tests obtained prior to CRT. RESULTS:In total, 118 patients underwent CRT for SCCA between December 2007 and February 2018. Of these, 99 patients had appropriate pretreatment blood results available. Systemic inflammation as indicated by NLR &gt;3 and mGPS &gt;0 was present in 41% and 39% of patients, respectively. Most patients had T2 or larger tumours (n = 85, 86%) without nodal involvement (n = 64, 65%). An elevated mGPS was associated with more advanced T-stage (56% versus 35%, P = 0.036). NLR &gt;5 was associated with nodal positivity (56% versus 31%, P = 0.047). On multivariate analysis, more advanced T-stage (odds ratio 7.49, 95% confidence interval 1.51-37.20, P = 0.014) and a raised mGPS (odds ratio 5.13, 95% confidence interval 1.25-21.14, P = 0.024) were independently related to incomplete CRT response. An elevated mGPS was prognostic of inferior survival (hazard ratio 3.09, 95% confidence interval 1.47-6.50, P = 0.003) and cancer-specific survival (hazard ratio 4.32, 95% confidence interval 1.54-12.15, P = 0.006), independent of TNM stage. CONCLUSION:Systemic inflammation, as measured by the mGPS, is associated with an incomplete CRT response and is independently prognostic of inferior survival in patients with SCCA. The mGPS may offer a simple marker of inferior outcome that could be used to identify high-risk patients

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 (p16ink4a) in combination with low level expression of a proliferation marker (ki-67) relate to T cell infiltrates in CRC, and whether p16ink4a, Ki-67 and immune infiltrates have similar prognostic value.&lt;p&gt;&lt;/p&gt; Methods: Immunostaining of p16inka and Ki-67 was performed within a CRC tissue microarray. Nuclear p16inka 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).&lt;p&gt;&lt;/p&gt; Results: Two hundred and thirty stage I–III cancers were studied. High nuclear p16ink4a was expressed in 63% and high proliferation (Ki-67 &gt;15%) in 61%. p16ink4a expression was associated with reduced CD45RO+ cells at the IM (P&#60;0.05) and within the stroma (P&#60;0.05) and reduced CD8+ cells at the IM (P&#60;0.01). A low Ki-67 proliferative index was associated with reduced density of CD3+ cells in CCNs (P&#60;0.01), reduced CD45RO+ cells at the IM (P&#60;0.05) and within the CCNs (P&#60;0.001), reduced FOXP3+ cells at the IM (P&#60;0.001), within the stroma (P=0.001) and within CCNs (P&#60;0.001) and reduced CD8+ cells at the IM (P&#60;0.05) and within the CCNs (P&#60;0.05). Tumours with both a low proliferative index and expression of p16ink4a demonstrated similar consistent relationships with reduced densities of T-cell infiltrates. On multivariate analysis, TNM stage (P&#60;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 (p16ink4a; P=0.002) were independently associated with poorer cancer survival.&lt;p&gt;&lt;/p&gt; Conclusion: Senescence, proliferation and immune cell infiltrates are independent prognostic factors in CRC. Although related to survival, p16ink4a-associated senescence is not associated with an upregulation of antitumour T-cell responses.&lt;p&gt;&lt;/p&gt