A meta-analysis assessing the survival implications of subclassifying T3 rectal tumours.

AIM: Although T3 tumour subclassifications have been linked to prognosis, its mandatory adoption in histopathological reports has not been incorporated. This article focusses on the survival outcomes in patients with T3 rectal cancer according to extramural spread beyond the muscularis propria. METHODS: A systematic review of all studies up to January 2016, without language restriction, was identified from MEDLINE, Cochrane Controlled Trials Register (1960-2016) and Embase (1991-2016). All studies reporting on survival and T3 tumours with a defined cut-off of 5 mm ± 1 mm tumour invasion beyond the muscularis propria for rectal cancers were included. Hazard ratios were extracted directly from the studies or from survival curves using the technique described by Parmar. Quality assessment was performed using the Newcastle-Ottawa scale. RESULTS: Tumours with invasion more than 5 ± 1 mm from the muscularis propria had statistically significantly worse overall survival (natural log of the hazard ratio [lnHR]: 1.40 [1.06, 2.04], p < 0.001) and there was no statistically significant heterogeneity (χ2 = 1.541, df = 3, p = 0.673, I2 = 0). There was statistically significantly worse disease-free survival in more invasive tumours (lnHR: 1.49 [1.19, 2.00], p < 0.001) and cancer specific survival (lnHR: 1.22 [0.917, 1.838], p < 0.001). Overall survival in patients who had preoperative therapy was higher in patients with less invasion beyond the muscularis propria [p < 0.01]. CONCLUSIONS: Subclassifying all T3 rectal tumours according to the depth of spread with a cut-off of 5±1 mm beyond the muscularis propria is prognostically relevant for overall survival, disease-free survival and cancer-specific survival irrespective of the nodal status; therefore, subclassifying T3 tumours should be a reporting requirement in histopathology reports.

An audit comparing the reporting of staging MRI scans for rectal cancer with the London Cancer Alliance (LCA) guidelines.

BACKGROUND: This article focuses on the audit and assessment of clinical practice before and after introduction of MRI reporting guidelines. Standardised proforma based reporting may improve quality of MRI reports. Uptake of the use may be facilitated by endorsement from regional and national cancer organisations. METHODS: This audit was divided into 2 phases. MRI reports issued between April 2014 and June 2014 were included in the first part of our audit. Phase II included MRI reports issued between April 2015 and June 2015. RESULTS: 14 out of 15 hospitals that report MRI scans in the LCA responded to our audit proposal. The completion rate of key MRI metrics/metrics was better in proforma compared to prose reports both before (98% vs 73%; p < 0.05) and after introduction of the guidelines (98% vs 71%; p < 0.05). There was an approximate doubling of proforma reporting after the introduction of guidelines and workshop interventions (39% vs 65%; p < 0.05). Evaluation of locally advanced cancers (tumours extending to or beyond the circumferential resection margin) for beyond TME surgery was reported in 3% of prose reports vs. 42% in proformas. CONCLUSIONS: Incorporation of standardised reporting in official guidelines improved the uptake of proforma based reporting. Proforma based reporting captured more MRI reportable items compared to prose summaries, before and after the implementation of guidelines. MRI reporting of advanced cancers for beyond TME surgery falls short of acceptable standards but is more detailed in proforma based reports. Further work to improve completion especially in beyond TME reporting is required.

Significance of extranodal tumour deposits in colorectal cancer: A systematic review and meta-analysis.

AIMS: The presence and significance of extranodal tumour deposits (ENTDs) in colorectal cancer (CRC) continue to cause controversy in terms of origin, classification and prognostic significance. This review aims to assess current evidence on the origin of ENTDs in CRC and their effect on overall and disease-free survival. METHODS: A systematic review and meta-analysis were carried out in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. End-points included prevalence of ENTDs, relationship with extramural venous invasion (EMVI), overall survival (OS) and disease-free survival (DFS). Pooled hazard ratios (HRs) and odds ratios (ORs) were calculated using Stata software. RESULTS: Twenty-six studies comprising 19,980 patients were included. The prevalence of ENTDs ranged from 10.2% to 44.2% (median 21.3%). There was a significantly increased odds of having ENTD if EMVI was present with a pooled OR of 2.51 (95% CI 2.27-2.77) p ≤ 0.001. The pooled HR for adverse OS in patients with ENTD was 1.63 (95% CI 1.44-1.61), p ≤ 0.001. For adverse DFS the pooled HR was 1.77 (95% CI 1.37-2.11), p ≤ 0.001. CONCLUSION: This meta-analysis confirms the negative impact of ENTDs on OS and DFS despite variations in classification and prevalence. ENTDs are significantly associated with EMVI. The prognostic implications of ENTDs are not sufficiently recognised in current staging systems. TNM 8 has failed to address this and has not made use of the available evidence to determine the correct position of ENTDs according to their prognostic effect. The prognostic hierarchy should be N0, N1, N2 with N1c being the most severe. Additionally the exclusion of lesions of vascular, lymphatic and perineural origin by TNM 8 has no evidence base.

Interobserver agreement of radiologists assessing the response of rectal cancers to preoperative chemoradiation using the MRI tumour regression grading (mrTRG).

AIM: To investigate whether the magnetic resonance imaging (MRI) tumour regression grading (mrTRG) scale can be taught effectively resulting in a clinically reasonable interobserver agreement (>0.4; moderate to near perfect agreement). MATERIALS AND METHODS: This study examines the interobserver agreement of mrTRG, between 35 radiologists and a central reviewer. Two workshops were organised for radiologists to assess regression of rectal cancers on MRI staging scans. A range of mrTRGs on 12 patient scans were used for assessment. RESULTS: Kappa agreement ranged from 0.14-0.82 with a median value of 0.57 (95% CI: 0.37-0.77) indicating good overall agreement. Eight (26%) radiologists had very good/near perfect agreement (κ>0.8). Six (19%) radiologists had good agreement (0.8≥κ>0.6) and a further 12 (39%) had moderate agreement (0.6≥κ>0.4). Five (16%) radiologists had a fair agreement (0.4≥κ>0.2) and two had poor agreement (0.2>κ). There was a tendency towards good agreement (skewness: 0.92). In 65.9% and 90% of cases the radiologists were able to correctly highlight good and poor responders, respectively. CONCLUSIONS: The assessment of the response of rectal cancers to chemoradiation therapy may be performed effectively using mrTRG. Radiologists can be taught the mrTRG scale. Even with minimal training, good agreement with the central reviewer along with effective differentiation between good and intermediate/poor responders can be achieved. Focus should be on facilitating the identification of good responders. It is predicted that with more intensive interactive case-based learning a κ>0.8 is likely to be achieved. Testing and retesting is recommended.

Loss of expression and promoter methylation of SLIT2 are associated with sessile serrated adenoma formation.

Serrated adenomas form a distinct subtype of colorectal pre-malignant lesions that may progress to malignancy along a different molecular pathway than the conventional adenoma-carcinoma pathway. Previous studies have hypothesised that BRAF mutation and promoter hypermethylation plays a role, but the evidence for this is not robust. We aimed to carry out a whole-genome loss of heterozygosity analysis, followed by targeted promoter methylation and expression analysis to identify potential pathways in serrated adenomas. An initial panel of 9 sessile serrated adenomas (SSA) and one TSA were analysed using Illumina Goldengate HumanLinkage panel arrays to ascertain regions of loss of heterozygosity. This was verified via molecular inversion probe analysis and microsatellite analysis of a further 32 samples. Methylation analysis of genes of interest was carried out using methylation specific PCR (verified by pyrosequencing) and immunohistochemistry used to correlate loss of expression of genes of interest. All experiments used adenoma samples and normal tissue samples as control. SSA samples were found on whole-genome analysis to have consistent loss of heterozygosity at 4p15.1-4p15.31, which was not found in the sole TSA, adenomas, or normal tissues. Genes of interest in this region were PDCH7 and SLIT2, and combined MSP/IHC analysis of these genes revealed significant loss of SLIT2 expression associated with promoter methylation of SLIT2. Loss of expression of SLIT2 by promoter hypermethylation and loss of heterozygosity events is significantly associated with serrated adenoma development, and SLIT2 may represent a epimutated tumour suppressor gene according to the Knudson "two hit" hypothesis.

The impact of the two-week wait referral pathway on rectal cancer survival.

AIM: The aim of this study was to compare the outcome of patients with rectal cancer referred through the two-week wait (TWW) system with those identified by routine referral pathways (non-TWW). METHOD: A prospective study was carried out of 125 consecutive patients diagnosed with rectal cancer between January 2000 and December 2005 (6 years) in one district general hospital. Data were recorded prospectively in a local clinicopathological registry. The patients were divided into two groups: group 1 (TWW) and group 2 (routine referral pathway). RESULTS: Fifty-two (41%) of the 125 patients were diagnosed through the TWW (group 1). There was no significant difference in patient demographics, including baseline tumour characteristics, between the two groups. There was no difference in preoperative or postoperative T stage between the two groups (P = 0.63). There was no significant difference in circumferential margin positivity (five of 52 in group 1 vs four of 73 in group 2; P = 0.52) or local recurrence rates (P = 0.37). The 5-year all-cause mortality was 49% for group 1 and 52% for group 2 (P = 0.3). The overall disease-free survival was similar in the two groups (1521 days for group 1 vs 1591 days for group 1, P = 0.29). CONCLUSION: Referral under the TWW strategy does not translate into improved survival in rectal cancer.

Straight to colonoscopy: the ideal patient pathway for the 2-week suspected cancer referrals?

INTRODUCTION: The UK has a higher mortality for colon cancer than the European average. The UK Government introduced a 2-week referral target for patients with colorectal symptoms meeting certain criteria and 62-day target for the delivery of treatment from the date of referral for those patients diagnosed with cancer. Hospitals are expected to meet 100% and 95% of these targets, respectively; therefore, an efficient and effective patient pathway is required to deliver diagnosis and treatment within this period. It is suggested that 'straight-to-test' will help this process and we have examined our implementation of 'straight-to-colonoscopy' as a method of achieving this aim. PATIENTS AND METHODS: We carried out a retrospective audit of 317 patients referred under the 2-week rule over a 1-year period between October 2004 and September 2005 and were eligible for 'straight-to-colonoscopy'. Demographic data, appropriateness of referral and colonoscopy findings were obtained. The cost effectiveness and impact on waiting period were also analysed. RESULTS: A total of 317 patients were seen within 2 weeks. Cancer was found in 23 patients and all were treated within 62 days. Forty-four patients were determined by the specialist to have been referred inappropriately because they did not meet NICE referral guidelines. No cancer was found in any of the inappropriate referrals. The use of straight-to-test colonoscopy lead to cost savings of £26,176 (£82.57/patient) in this group compared to standard practice. There was no increase in waiting times. CONCLUSIONS: Straight-to-colonoscopy for urgent suspected cancer referrals is a safe, feasible and cost-effective method for delivery of the 62-day target and did not lead to increase in the endoscopy waiting list.

A pilot study of ultrasound guided Durasphere injection in the treatment of faecal incontinence.

AIM: To assess injection of Durasphere under direct endoanal ultrasound guidance as a treatment for faecal incontinence. METHOD: A total of 23 patients with varying degrees of persistent faecal leakage and/or soiling were recruited. Durasphere was injected in the intersphincteric plane under direct ultrasound guidance. All patients were given a general anaesthetic. Patients had ano-rectal physiology, endoanal ultrasound, continence scoring and quality of life measures assessed at 0, 1, 3, 6 and 12 months. RESULTS: A total of 21 patients were followed up for at least 12 months, with two being excluded at the follow-up stage. Friedman two-way analysis of variance of the Cleveland Clinic Score, Faecal Incontinence Quality of Life Score and Diary Response Score demonstrated a significant sustained improvement. There was no significant improvement in number of bowel movements. There was a significant difference in anal squeeze pressure after therapy, but no significant difference in anal resting pressure. Six patients reported no improvement after Durasphere therapy. CONCLUSIONS: Durasphere gave sustained improvements in quality of life and continence scores in this study group. Strict criteria are needed to ascertain suitability for Durasphere therapy.

Do guidelines improve clinical practice? - a national survey on surveillance colonoscopies.

BACKGROUND: Colonoscopic services are increasingly being utilized in surveillance of conditions predisposing to colorectal cancers (CRC). The ACPGBI/BSG guidelines are the most commonly followed recommendations. Numerous retrospective studies have shown poor compliance with them. We conducted a national survey of colonoscopic practitioners investigating attitudes, awareness and implementation of surveillance guidelines. METHOD: A postal questionnaire was sent to a random population of 250 ACPGBI and 200 BSG members. Questions assessed practice as regards colorectal polyp surveillance, family screening and surveillance for past history of CRC. RESULTS: The ACPGBI/BSG guidelines were the most commonly followed recommendations. Only 17.2% of practitioners used the criteria that would ensure accurate implementation of guidelines for colorectal adenoma surveillance. With regards to familial surveillance for CRC, 53.5% respondents assessed familial risk accurately, while 69.3% recommended surveillance incorrectly. A total of 48.8% of ACPGBI members recommended five yearly colonoscopies following curative treatment for CRC. CONCLUSION: This study has revealed the widespread ignorance of guidelines, which will potentially translate into the gross over utilization of colonoscopic resources. Strategies to improve and audit guideline implementation must be integral to guideline formation. Methods to improve accurate guideline implementation need to be explored.

Surveillance colonoscopies for colorectal polyps--too often, too many! An Audit at a Large District General Hospital.

INTRODUCTION: The British society of Gastroenterologists (BSG) have laid down guidelines for surveillance colonoscopies in patients with large bowel adenomatous polyps. However, numerous studies have shown the gross over-utilization of colonoscopic services in their management. We audited our practice of polyp management and looked at guideline compliance amongst patients on our colonoscopic surveillance list. METHOD: All patients undergoing adenoma surveillance and those with newly detected adenomas over a 2-month period were included in the first loop of the audit. Data on the colonoscopic findings, histology and management were retrieved from paper and on-line records. The BSG guidelines were printed, laminated and displayed in the colorectal clinics. Following this, we re-audited (second loop) our practice. In the second part of the study, we randomly retrieved 533/1800 case notes from our colonoscopic waiting list. Amongst those on surveillance for polyps, compliance was ascertained as regards need for procedure and appropriateness of surveillance interval. FINDINGS: Fifty-four patients were included in the first loop and 59 during the second loop of the audit. Guidelines were followed in 16% (4/25, 95% CI: 0.054-0.33) of patients in the first loop and 46.5% (13/28, 95% CI: 0.293-0.642) in the second loop (P = 0.017). Of the patients on our colonoscopic waiting list for adenomatous polyps, 17.7% satisfied guidelines, 23.4% did not require any further surveillance and 58.9% were booked for a procedure earlier than recommended. CONCLUSION: The mere framing of guidelines is insufficient to improve clinical practice. Strategies to improve implementation need to be explored. Audit of individual practice is recommended.

Accuracy of CT prediction of poor prognostic features in colonic cancer.

Whilst imaging of poor prognostic features in rectal cancers has assisted pre-operative treatment stratification, such features have yet to be evaluated in colonic cancers. This study aims to develop criteria for identifying poor prognostic features in colonic tumours and assess the accuracy of CT prediction against histopathology. Criteria were developed for predicting T-stage and N-stage, the presence of extramural vascular invasion and involvement of the retroperitoneal surgical margin (RSM). These criteria were tested on 33 patients with colonic cancer who underwent pre-operative high-resolution CT of their tumour. Two radiologists (Obs 1 and Obs 2) identified independently these poor prognostic features and the results were compared with the final histopathological results. Histological agreement and interobserver variation were calculated using the kappa test. Accuracy of CT prediction of tumour extension beyond muscularis propria was 82% (Obs 1) and 70% (Obs 2). Correct prediction of RSM involvement was 76% (95% confidence interval (CI): 57.8-88.9%) and 79% (95%CI: 61.1-91%) for Obs1 and Obs 2, respectively, with significant agreement between observers (kappa = 0.455, p = 0.050). Prognosis was correctly predicted using CT in 82% (95%CI: 61.5-81.2%) (Obs1) and 85% (95%CI: 68.1-94.9%) (Obs2) with moderate agreement (kappa = 0.459, kappa = 0.527, respectively) with histology. In conclusion, CT has potential as the imaging modality of choice in the pre-operative prediction of poor prognostic features in colonic cancers and could play a role in future treatment stratification.

Prognostic significance of magnetic resonance imaging-detected extramural vascular invasion in rectal cancer.

BACKGROUND: Extramural vascular invasion (EMVI) is a poor prognostic feature in colorectal cancer. The accuracy of magnetic resonance imaging (MRI) in detecting EMVI and predicting relapse-free survival (RFS) was compared retrospectively with the histological reference standard. METHODS: Preoperative magnetic resonance images from patients diagnosed with rectal and sigmoid cancer were reviewed and an MRI-EMVI score (range 0 to 4) was assigned. Comparison was made with histology and clinical outcome. RESULTS: Some 142 patients with a median follow-up of 3.3 (range 0.9-5.7) years were reviewed. Histological EMVI was reported in a quarter of patients. The sensitivity and specificity of MRI detection of EMVI in 94 patients undergoing primary surgery were 62 and 88 per cent respectively. On univariable analysis, RFS at 3 years was 35 per cent for patients with an MRI-EMVI score of 3-4, compared with 74 per cent for those with a score of 0-2 (P < 0.001), similar to values in patients with positive and negative histological EMVI status respectively (34 versus 73.7 per cent; P < 0.001). CONCLUSION: High MRI-EMVI scores may help in predicting disease relapse.

Predictive poor prognostic factors in colonic carcinoma.

INTRODUCTION: Five-year survival in rectal cancer has been steadily improving since the introduction of neoadjuvant chemoradiation and total mesorectal excision surgery. In contrast, 5-year survival rates and management of colonic carcinoma remain relatively unchanged. This study aims to identify poor prognostic factors in colonic cancer patients that could potentially be predicted pre-operatively to identify a subset of patients amenable to neoadjuvant treatment strategies. METHODS: Database compilation of all operable rectal and colonic cancer patients presenting to a single district general hospital over 5 years. Data were documented on presentation and site of tumour, TNM staging, differentiation and extramural venous invasion. RESULTS: There was no significant difference in 4-year survival between rectal (57.5%) and right (57%) or left sided (52.5%) colonic cancers (p=0.4689). On multivariate analysis, N2-stage, T4-stage and emergency presentation were identified as independent prognostic factors. On univariate analysis, in addition to the above factors, presence of venous invasion (p=0.001) and poor differentiation (p=0.0003) of tumour also predicted for poor 5-year survival. CONCLUSION: T4-stage and N2-stage and extramural venous invasion are poor prognostic factors that could be identified pre-operatively with suitably accurate imaging. Such patients could then be considered for a pre-operative treatment strategy.

Systematic review: adipose tissue, obesity and gastrointestinal diseases.

BACKGROUND: Obesity is increasingly being recognized as a risk factor for a number of benign and malignant gastrointestinal conditions. However, literature on the underlying pathophysiological mechanisms is sparse and ambiguous. Insulin resistance is the most widely accepted link between obesity and disease, particularly colorectal cancer. The recognition that intra-abdominal fat is immunologically active sheds new light not only on the pathogenesis of obesity-related gastrointestinal conditions, but also on inflammatory conditions such as Crohn's disease. AIM: To describe the biology of adipose tissue, its impact on the immune system and explores the possible underlying mechanisms linking obesity to gastrointestinal diseases. It also looks at the role of mesenteric fat in determining severity and course of Crohn's disease. METHODS: Relevant English-language literature and abstracts cited on MEDLINE database were reviewed. RESULTS: Our recent finding of an association between obesity and subclinical bowel inflammation suggests that, apart from promoting generalized immune activation, fat also evokes local immune responses. We propose that the proinflammatory milieu promoted by obesity could underlie many of these associations and that the mechanism implicating insulin resistance may merely represent an epiphenomenon. In Crohn's disease, on the other hand, intra-abdominal fat may provide a protective mechanism. CONCLUSION: The potential of adipose tissue as a therapeutic target is vast and needs exploration.

Use of plasma MMP-2 and MMP-9 levels as a surrogate for tumour expression in colorectal cancer patients.

Matrix metalloproteinases, and notably the gelatinases MMP-2 and MMP-9, have important roles in tumour invasion, metastasis and angiogenesis. Our study investigates the distribution of MMP-2 and MMP-9 in colorectal cancer, the correlation with plasma levels, changes following surgical resection and whether plasma levels reflect clinical staging and disease course. MMP-2 and MMP-9 expression in 48 colorectal tumours and 13 adenomatous polyps was analysed by RT-PCR, immunohistochemistry, and quantified by ELISA of tumour lysates. Concentrations of MMP-2 and MMP-9 in plasma samples from these patients and 36 other patients who underwent curative resections were measured by ELISA prior to and 6-12 months after surgery. MMP-2 expression was significantly increased in colorectal cancer tissues compared to matched normal colon as measured by ELISA. Active MMP-2 was localised by immunohistochemistry to regions where tumour cells invaded the muscularis with little staining in more superficial areas. Plasma MMP-2 levels were also significantly elevated in patients with colorectal cancer, with significant reductions following curative resections at all stages. Similarly, MMP-9 expression was significantly increased in colorectal cancer tissues, predominantly in the tumour stroma. Plasma levels of MMP-9 were significantly elevated at all stages in colorectal cancer patients and a significant reduction was seen following curative resections. With both MMP-2 and MMP-9, the strongest correlation with clinical staging in colorectal cancer was represented by the total plasma concentration of the enzymes, both falling to within the normal range following curative surgery. Plasma levels of these enzymes may therefore have potential as a noninvasive indicator of invasion or metastasis in colorectal cancer or as a marker of disease status during follow-up.

Plasma basic fibroblast growth factor levels in colorectal cancer: a clinically useful assay?

Angiogenic cytokines in the plasma and serum of cancer patients may serve as 'surrogate' markers of tumour neoangiogenesis. Serum VEGF correlates with disease stage in colorectal cancer (CRC), but the role of bFGF in CRC is uncertain. This study aimed to assess plasma bFGF levels in CRC patients before treatment, during chemoradiotherapy and at one-year follow-up. Plasma samples were taken from 124 CRC patients, 26 polyp patients and 55 controls, and bFGF levels were measured by ELISA. 19 patients underwent pre-operative chemoradiotherapy. One-year follow-up samples were available from 48 disease-free patients and 18 patients with progressive disease. There were no detectable differences between plasma bFGF levels in polyp, Dukes' A or B patients (4.55, 5.77, 4.25 pg/ml, respectively), but there was a significant increase in metastatic CRC patients [Dukes' C and D (7.42 and 6.6 pg/ml; P = 0.004 and 0.048, respectively)], relative to median control levels of 4.14 pg/ml. At follow-up, there was a significant fall in plasma bFGF levels in disease-free patients (pre-op 6.09 and follow-up 3.45 pg/ml, P = 0.0004), but a non-significant rise in 18 patients with progressive disease (pre-treatment 5.90 and follow-up 9.99 pg/ml, P = 0.33). Pre-treatment plasma bFGF in patients receiving chemo-radiotherapy was similar in those with responsive and non-responsive tumours. There were no detectable changes in plasma bFGF through the adenoma-carcinoma sequence or patient groups with non-metastatic cancers. Elevated plasma bFGF was, however, associated with metastatic spread. The significant fall in bFGF in disease-free patients following therapy suggests that bFGF may be useful in clinical practice.

VEGF-A, VEGF-C, and VEGF-D in colorectal cancer progression.

We aimed to assess the relationship of the angiogenic cytokines VEGF-A, VEGF-C, and VEGF-D and their receptors VEGFR-2 and VEGFR-3 in the adenoma-carcinoma sequence and in metastatic spread of colorectal cancer (CRC). mRNA expression levels were measured using semi-quantitative reverse transcription polymerase chain reaction in 70 CRC (35 with paired mucosae) and 20 adenomatous polyps. Immunohistochemistry and ELISA assessed protein expression. VEGF-D mRNA expression was significantly lower in both polyps and CRCs compared with normal mucosa (P=.0002 and.002, respectively), whereas VEGF-A and VEGF-C were significantly raised in CRCs (P=.006 and.004, respectively), but not polyps (P=.22 and P=.5, respectively). Receptor expression was similar in tumor tissue and normal mucosae. Tumors with lymph node metastases had significantly higher levels of VEGF-A compared with non-metastatic tumors (P=.043). There was no association between VEGF-C or VEGF-D and lymphatic spread. The decrease in VEGF-D occurring in polyps and carcinomas may allow the higher levels of VEGF-A and VEGF-C to bind more readily to the VEGF receptors, and produce the angiogenic switch required for tumor growth. Increased expression of VEGF-A within CRCs was associated with lymphatic metastases, and therefore, this member of the VEGF family may be the most important in determining metastatic spread.