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BACKGROUND: Selection of patients for preoperative treatment in rectal cancer is controversial. The new 2020 National Institute for Health and Care Excellence (NICE) guidelines, consistent with the National Comprehensive Cancer Network guidelines, recommend preoperative radiotherapy for all patients except for those with radiologically staged T1-T2, N0 tumours. We aimed to assess outcomes in non-irradiated patients with rectal cancer and to stratify results on the basis of NICE criteria, compared with known MRI prognostic factors now omitted by NICE. METHODS: For this retrospective cohort study, we identified patients undergoing primary resectional surgery for rectal cancer, without preoperative radiotherapy, at Basingstoke Hospital (Basingstoke, UK) between Jan 1, 2011, and Dec 31, 2016, and at St Marks Hospital (London, UK) between Jan 1, 2007, and Dec 31, 2017. Patients with MRI-detected extramural venous invasion, MRI-detected tumour deposits, and MRI-detected circumferential resection margin involvement were categorised as MRI high-risk for recurrence (local or distant), and their outcomes (disease-free survival, overall survival, and recurrence) were compared with patients defined as high-risk according to NICE criteria (MRI-detected T3+ or MRI-detected N+ status). Kaplan-Meier and Cox proportional hazards analyses were used to compare the groups. FINDINGS: 378 patients were evaluated, with a median of 66 months (IQR 44-95) of follow up. 22 (6%) of 378 patients had local recurrence and 68 (18%) of 378 patients had distant recurrence. 248 (66%) of 378 were classified as high-risk according to NICE criteria, compared with 121 (32%) of 378 according to MRI criteria. On Kaplan-Meier analysis, NICE high-risk patients had poorer 5-year disease-free survival compared with NICE low-risk patients (76% [95% CI 70-81] vs 87% [80-92]; hazard ratio [HR] 1·91 [95% CI 1·20-3·03]; p=0·0051) but not 5-year overall survival (80% [74-84] vs 88% [81-92]; 1·55 [0·94-2·53]; p=0·077). MRI criteria separated patients into high-risk versus low-risk groups that predicted 5-year disease-free survival (66% [95% CI 57-74] vs 88% [83-91]; HR 3·01 [95% CI 2·02-4·47]; p

PURPOSE Extramural venous invasion (EMVI) is recognized as a poor prognostic factor in rectal cancer. There are well-documented limitations associated with pathology detection of EMVI, including variable reporting and the inability to use it preoperatively to guide neoadjuvant treatment. Magnetic resonance imaging (MRI)-detected EMVI (mrEMVI) has been proposed as an imaging biomarker. This review assesses the prognostic significance of mrEMVI on survival outcomes and whether regression of mrEMVI after neoadjuvant therapy is associated with improvements in survival. METHODS AND MATERIALS An electronic search was carried out using MEDLINE and EMBASE databases using the search terms "rectum," "cancer,", "MRI," and "outcomes." A systematic review and meta-analysis were carried out in accordance with Preferred Reporting for Systematic Reviews and Meta-Analyses guidelines using Review Manager software. A qualitative review was performed. RESULTS A total of 7399 articles were identified, of which 33 were relevant to the review question. After a qualitative assessment, 20 articles were included in the meta-analysis. Baseline mrEMVI positivity is associated with significantly worsened overall survival (hazard ratio [HR] 1.84; 95% confidence interval [CI], 1.33-2.54; P = .0001) and significantly worsened disease-free survival (HR 2.41; 95% CI, 2.02-2.89; P < .00001). After neoadjuvant treatment, a positive mrEMVI status is associated with a significantly worsened overall and disease-free survival. Only 3 papers specifically looked at mrEMVI regression, but the results show that persistent mrEMVI-positive status after treatment is associated with significantly worsened disease-free survival compared with a change in mrEMVI from positive to negative (HR 1.93; 95% CI, 1.39-2.68; P < .0001). A subgroup analysis of MRI-detected lymph node metastases showed no significant association with survival, with a hazard ratio of 1.33 (95% CI, 0.98-1.80; P = .06). CONCLUSION mrEMVI is significantly associated with worsened survival outcomes, both at baseline and after neoadjuvant treatment. Additionally, there is evidence that regression of mrEMVI after neoadjuvant treatment is associated with improved survival compared with mrEMVI persistence. The findings of this review emphasize the need for accurate and consistent reporting of mrEMVI status before and after neoadjuvant treatment and support the inclusion of mrEMVI into staging systems preferentially over lymph node metastases.

Introduction The incidence and patterns of local recurrence of colon cancer are not well reported. The aim of this study was to investigate the contemporary rates and patterns of local recurrence after sigmoid cancer resection, comparing pre and post-operative biomarkers in predicting local disease recurrence. Materials and methods A multi-centre, retrospective analysis of 414 patients undergoing resectional surgery for sigmoid colon cancer was conducted. Multivariable Cox Proportional Hazard models were created to identify variables associated with local disease recurrence. Patterns of recurrence and prognostic significance of pre and post-operative variables were identified. Results In 414 patients, the local recurrence rate was 12.6%. The R1/R2 rate was 2.4%. Local recurrence occurred most commonly within the peri-anastomotic region (50%), followed by the peritoneum (33%). On multivariate analysis, local recurrence was predicted by pathological T stage (HR 1.15) and R1 resection (HR 2.95), but also computerised tomography (CT) identified tumour deposits (HR 2.40) and local peritoneal infiltration (2.70). Conclusions Contemporary local recurrence rates for sigmoid cancer are high at 12.6%. Outcomes may be improved if local recurrence is reduced at the most common sites such as the peri-anastomotic area or peritoneum. Extra-nodal CT-imaging biomarkers of local peritoneal infiltration and tumour deposits were prognostically significant on multivariate analysis in addition to pathology staging variables.

Plant height has been a major target for selection of high-yielding varieties in wheat. Two height-reducing loci (Rht-B1 and Rht-D1) have been widely used since the Green Revolution. However, these genes also negatively affect other agronomic traits such as kernel weight. Identifying alternative height-reducing loci could benefit wheat improvement. This study focused on the genetics of plant height in 260 historical and contemporary winter wheat accessions via genome-wide association studies using 38,693 single nucleotide polymorphism (SNP) markers generated through genotyping by sequencing, two Kompetitive Allele Specific Polymorphism markers, and phenotypic data recorded in two seasons (2016 and 2018). The 260 accessions showed wide variation in plant height. Most accessions developed after 1960 were shorter than earlier accessions. The broad-sense heritability for plant height was high (H2 = 0.82), which was also supported by a high correlation (r = 0.82, P

The MYC proto-oncogene is among the most commonly dysregulated genes in human cancers. We report screening data from the iMYC trial, an ongoing phase II study assessing ibrutinib monotherapy in advanced pretreated MYC- and/or HER2-amplified oesophagogastric cancer, representing the first attempt to prospectively identify MYC amplifications in this tumour type for the purposes of therapeutic targeting.Screening utilising a fluorescent in situ hybridisation (FISH) assay for assessment of tumour MYC amplification has been instituted. An experimental digital droplet polymerase chain reaction (ddPCR) assay to assess MYC amplification in both tumour and circulating-tumour (ct)DNA has been developed and investigated.One hundred thirty-five archival tumour specimens have undergone successful FISH analysis with 23% displaying evidence of MYC amplification. Intertumour heterogeneity was observed, with the percentage of cancer cells harbouring MYC amplification ranging widely between samples (median 51%, range 11-94%). Intratumoural clonal diversity of MYC amplification was also observed, with a significant degree of variance in amplification ratios (Bartlett's test for equal variance p 0.001), and an association between greater variance in MYC amplification and improved outcome with prior first-line chemotherapy. ddPCR was most accurate in quantifying MYC amplification in tumour-derived DNA from cases with a high proportion (70%) of amplified cells within the tumour specimen but was not reliable in samples containing a low proportion of amplified cells or in ctDNA.Our results illustrate the utility of FISH to assess MYC amplification prospectively for a biomarker-selected trial by providing reliable and reproducible results in real time, with a high degree of heterogeneity of MYC amplification observed. We show that ddPCR can potentially detect high-level MYC amplifications in tumour tissue.

Background Colon cancer outcomes are now inferior to rectal cancer outcomes. The sigmoid colon is the most common site of colonic cancer. The aim of this review was to investigate the oncological outcomes for sigmoid cancer. Methods A systematic review and meta-analysis was performed. We included any study of the oncological outcomes for sigmoid cancer such as local recurrence, distant recurrence and disease free survival. A systematic search was conducted in Medline from inception to November 2016. Study quality was evaluated with the Newcastle-Ottawa Scale. The study was registered on PROSPERO (CRD42017069326). Results The search terms returned 1323 results. We identified a total of 17 eligible studies including 5953 patients. The pooled local recurrence rate was 10.5% in 15 studies with 5148 patients (95% CI 0.07–0.14) and heterogeneity measured by I2 was 94%. The pooled distant recurrence rate was 19.5% (7 studies, 2040 patients, 95% CI (0.14–0.25), I2 90%). The pooled disease free survival at 5 years was 80.4% (5 studies, 2336 patients, 95% CI 78.6%–82.1%, I2 11.5%.). The median Newcastle-Ottawa score was 4 out of 9. R1 and R2 resections were excluded or not described in 16/17 studies. Two studies described R1 and R2 rates of 15–20%. Conclusion The pooled local recurrence rate of sigmoid cancer of 10.5% is higher than contemporary rates of local recurrence of rectal cancer. A large number of papers fail to describe or include R1 resections of sigmoid cancer, which are frequently described as palliative.

Magnetic resonance imaging (MRI) has gained increasing importance in the management of rectal cancer over the last two decades. The role of MRI in patients with rectal cancer has expanded beyond the tumor-node-metastasis (TNM) system in both staging and restaging scenarios and has contributed to identifying "high" and "low" risk features that can be used to tailor and personalize patient treatment; for instance, selecting the patients for neoadjuvant chemoradiation (NCRT) before the total mesorectal excision (TME) surgery based on risk of recurrence. Among those features, the status of the circumferential resection margin (CRM), extramural vascular invasion (EMVI), and tumor deposits (TD) have stood out. Moreover, MRI also has played a role in surgical planning, especially when the tumor is located in the low rectum, when the relationship between tumor and the anal canal is important to choose the best surgical approach, and in cases of locally advanced or recurrent tumors invading adjacent pelvic organs that may require more complex surgeries such as pelvic exenteration. As approaches using organ preservation emerge, including transanal local excision and "watch-and-wait", MRI may help in the patient selection for those treatments, follow up, and detection of tumor regrowth. Additionally, potential MRI-based prognostic and predictive biomarkers, such as quantitative and semi-quantitative metrics derived from functional sequences like diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE), and radiomics, are under investigation. This review provides an overview of the current role of MRI in rectal cancer in staging and restaging and highlights the main areas under investigation and future perspectives.

The role of imaging has become central in the pre-operative decision-making process for patients with rectal cancer. The detailed information that is available from high-resolution imaging studies not only provides prognostic information but also allows the surgeon to anticipate potential pitfalls during the operation. The greater the amount of detail known about the tumour, the more selective one can be in the use of pre-operative radiotherapy, which can reduce unnecessary morbidity for minimal gain. Magnetic resonance imaging (MRI) is the most useful modality for the local staging of rectal cancer as it provides the most detail on the important prognostic factors that influence treatment. These include height of tumour from the anal verge, tumour depth of penetration, nodal disease, venous invasion, involvement of the circumferential resection margin. However, endoanal ultrasound (EAUS) is particularly good at staging early tumours and aids in identifying those that are suitable for local excision. We review the important considerations in the pre-operative staging of rectal cancer.

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.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 2015.14 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.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.

Aim To compare the preoperative staging accuracy of computed tomography (CT) and 3-T magnetic resonance imaging (MRI) in colon cancer, and to investigate the prognostic significance of identified risk factors. Materials and methods Fifty-eight patients undergoing primary resection of their colon cancer were prospectively recruited, with 53 patients included for final analysis. Accuracy of CT and MRI were compared for two readers, using postoperative histology as the reference standard. Patients were followed-up for a median of 39 months. Risk factors were compared by modality and reader in terms of metachronous metastases and disease-free survival (DFS), stratified for adjuvant chemotherapy. Results Accuracy for the identification of T3c+ disease was non-significantly greater on MRI (75% and 79%) than CT (70% and 77%). Differences in the accuracy of MRI and CT for identification of T3+ disease (MRI 75% and 57%, CT 72% and 66%) and N+ disease (MRI 62% and 63%, CT 62% and 56%) were also non-significant. Identification of extramural venous invasion (EMVI+) disease was significantly greater on MRI (75% and 75%) than CT (79% and 54%) for one reader ( p =0.029). T3c+ disease at histopathology was the only risk factor that demonstrated a significant difference in rate of metachronous metastases (odds ratio [OR] 8.6, p =0.0044) and DFS stratified for adjuvant therapy (OR=4, p =0.048). Conclusion T3c or greater disease is the strongest risk factor for predicting DFS in colon cancer, and is accurately identified on imaging. T3c+ disease may therefore be the best imaging entry criteria for trials of neoadjuvant treatment.

Background: Primary chemotherapy has been tested as a possible approach for patients with high risk features but predicted clear mesorectal margins on preoperative MRI assessment. This study investigates the prognostic relevance of baseline and post-treatment MRI and pathology staging in rectal cancer patients undergoing primary chemotherapy. Patients and methods: Forty-six patients with T3 tumour> = 2mm from the mesorectal fascia were prospectively treated with Neoadjuvant Capecitabine, Oxaliplatin and Bevacizumab prior to surgery between 2009 and 2011. The baseline and posttreatment MRI: T, Nodal and Extra-mural venous invasion (EMVI) status were recorded as well as post-treatment MRI Tumour regression grade (TRG) and modified-RECIST assessment of tumour length. The post-treatment pathology (yp) assessments of T3 substage, N, EMVI and TRG status were also recorded. Three-year disease-free survival (DFS) and cumulative incidence of recurrence were estimated by using the Kaplan-Meier product-limit method, and Cox proportional hazards models were used to determine associations between staging and response on MRI and pathology with survival outcomes. Results: About 46 patients underwent neoadjuvant chemotherapy alone for high risk margin safe primary rectal cancer. The median follow-up was 41 months, 5 patients died and 11 patients experienced relapse (2 local, 8 distant and 1 both). In total 23/ 46 patients were identified with MRI features of EMVI at baseline. mrEMVI positive status carried independent prognostic significance for DFS (P = 0.0097) with a hazard ratio of 31.33 (95% CI: 2.3-425.4). The histopathologic factor that was of independent prognostic importance was a final ypT downstage of ypT3a or less, hazard ratio: 14.0 (95% CI: 1.5-132.5). Conclusions: mrEMVI is an independent prognostic factor at baseline for poor outcomes in rectal cancer treated with neoadjuvant chemotherapy while

Background: Colon cancer outcomes are now inferior to rectal cancer outcomes. The sigmoid colon is the most common site of colonic cancer. The aim of this review was to investigate the oncological outcomes for sigmoid cancer. Methods: A systematic review and meta-analysis was performed. We included any study of the oncological outcomes for sigmoid cancer such as local recurrence, distant recurrence and disease free survival. A systematic search was conducted in Medline from inception to November 2016. Study quality was evaluated with the Newcastle-Ottawa Scale. The study was registered on PROSPERO (CRD42017069326). Findings: The search terms returned 1323 results. We identified a total of 17 eligible studies including 5953 patients. The pooled local recurrence rate was 10.5% (15 studies, 5148 patients, 95% CI 0.07 - 0.14) and heterogeneity measured by I2 was 94%. The pooled distant recurrence rate in 7 studies with 2040 patients was 19.5% (7 studies, 2040 patients, 95% CI 0.14 - 0.25, I2 90%). The pooled disease free survival at 5 years was 80.4% (5 studies, 2336 patients, 95% CI 78.6%-82.1%, I2 11.5%.). The median Newcastle-Ottawa score was 4 out of 9. R1 and R2 resections were excluded or not described in 16/17 studies. Two studies described R1 and R2 rates of 15-20%. Interpretation: The pooled local recurrence rate of sigmoid cancer of 10.5% is higher than contemporary rates of local recurrence of rectal cancer. A large number of papers fail to describe or include R1 resections of sigmoid cancer, which are frequently described as palliative. High quality studies that include their R1 resections are required to establish the actual recurrence rate of sigmoid cancer. Funding Statement: The authors declare: "There was no funding source for this study." Declaration of Interests: The authors declare "no competing interests." Ethics Approval Statement: A systematic review and meta-analysis was planned and conducted according to PRISMA guidelines. The review was prospectively registered on the PROSPERO database (CRD42017069326).

Objective Intensified preoperative treatments have been increasingly investigated in locally advanced rectal cancer (LARC), but limited data are available for the impact of these regimens on quality of life (QoL) and bowel function (BF). We assessed these outcome measures in EXPERT-C, a randomized phase 2 trial of neoadjuvant capecitabine combined with oxaliplatin (CAPOX), followed by chemoradiation therapy (CRT), total mesorectal excision, and adjuvant CAPOX with or without cetuximab in magnetic resonance imaging-defined, high-risk LARC. Methods and Materials QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR29 questionnaires. Bowel incontinence was assessed using the modified Fecal Incontinence Severity Index questionnaire. Results Compared to baseline, QoL scores during preoperative treatment were better for symptoms associated with the primary tumor in the rectum (blood and mucus in stool, constipation, diarrhea, stool frequency, buttock pain) but worse for global health status, role functioning, and symptoms related to the specific safety profile of each treatment modality. During follow-up, improved emotional functioning and lessened anxiety and insomnia were observed, but deterioration of body image, increased urinary incontinence, less sexual interest (men), and increased impotence and dyspareunia were observed. Cetuximab was associated with a deterioration of global health status during neoadjuvant chemotherapy but did not have any long-term detrimental effect. An improvement in bowel continence was observed after preoperative treatment and 3 years after sphincter-sparing surgery. Conclusions Intensifying neoadjuvant treatment by administering induction systemic chemotherapy before chemoradiation therapy improves tumor-related symptoms and does not appear to have a significantly detrimental effect on QoL and BF, in both the short and the long term.

KRAS mutation has been reported as a marker of radio-resistance in rectal cancer and unfavourable outcome in both colon and rectal cancer. This study suggests that a single-nucleotide polymorphism of the KRAS gene (LCS-6 variant) may predict response to neoadjuvant treatment and mitigate the poor prognosis associated with KRAS mutation in locally advanced rectal cancer., Background Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. Patients and methods We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan–Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995). Conclusion This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.

Background: RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial. Methods: Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed. Results: Eleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n = 40; CAPOX-C, n = 38). In this population, after a median follow-up of 63.8 months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p = 0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p = 0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p = 0.20). Conclusions: RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted. (C) 2014 Elsevier Ltd. All rights reserved.

The role of imaging has become central in the pre-operative decision-making process for patients with rectal cancer. The detailed information that is available from high-resolution imaging studies not only provides prognostic information but also allows the surgeon to anticipate potential pitfalls during the operation. The greater the amount of detail known about the tumour, the more selective one can be in the use of pre-operative radiotherapy, which can reduce unnecessary morbidity for minimal gain. Magnetic resonance imaging (MRI) is the most useful modality for the local staging of rectal cancer as it provides the most detail on the important prognostic factors that influence treatment. These include height of tumour from the anal verge, tumour depth of penetration, nodal disease, venous invasion, involvement of the circumferential resection margin. However, endoanal ultrasound (EAUS) is particularly good at staging early tumours and aids in identifying those that are suitable for local excision. We review the important considerations in the pre-operative staging of rectal cancer.

Knowledge of HMW-GS composition and rye translocations of U.S. eastern soft winter (ESW) wheat, and their associations with protein characteristics will be helpful for the identification and selection of genotypes possessing the appropriate gluten strength for wheat-based products. HMW-GS composition and rye translocations of 149 ESW wheat varieties and their relationships with lactic acid solvent retention capacity and SDSS volume were determined. Subunits 2*, 7 + 8 and 2 + 12 are the predominant HMW-GSs in ESW wheat with frequencies of 72.7%, 47.7% and 36.7%, respectively. Two rare subunits, 2.. at Glu-A1 locus and 2+121 at Glu-D1 locus, were detected for the first time in ESW wheat, with frequencies of 1.6% and 21.9%, respectively. 1BL/1RS and 1AL/1RS translocations were observed in 18.8% and 10.9% of ESW wheat, respectively. Subunits 13 + 16, 5 + 10, and the absence of 1BL/1RS translocation showed associations with strong protein strength, whereas subunits 2+121 were associated with weak protein strength. Four HMW-GS profiles (2*, 7 + 8, 2+121), (2*, 7 + 8, 5 + 10), (2*, 7 + 9, 2 + 12), and (2*, 7 + 8, 2 + 12) were predominantly observed in 50.1% of ESW wheat. ESW wheat genotypes carrying subunits 13 + 16 or 7* + 8 at Glu-B1 locus and 5 + 10 at Glu-D1 locus without 1BL/1RS translocation are expected to produce wheat grain containing strong-gluten proteins.

Introduction The aim of this study was to determine the outcomes associated with simultaneous resections compared to patients undergoing sequential resections for synchronous colorectal liver metastases. Method Consecutive patients undergoing hepatic resections between 2000 and 2012 for synchronous colorectal liver metastases were identified from a prospectively maintained database. Results Of the 112 hepatic resections that were performed, 36 were simultaneous resections and 76 were sequential resections. There was no difference in disease severity: number of metastases ( P 0.228), metastatic size ( P 0.58), the primary tumour nodal status ( P 0.283), CEA ( P 0.387) or the presence of extra-hepatic metastases ( P 1.0). Major hepatic resections were performed in 23 (64%) and 60 (79%) of patients in the simultaneous and sequential groups respectively ( P 0.089). Intra-operatively no differences were found in blood loss ( P 1.0), duration of surgery ( P 0.284) or number of adverse events ( P 1.0). There were no differences in post-operative complications ( P 0.161) or post-operative mortality ( P 0.241). The length of hospital stay was 14 (95% CI 12.0–18.0) and 18.5 (95% CI 16.0–23.0) days in the simultaneous and sequential groups respectively ( P 0.03). The 3-year overall survival was 75% and 64% in the simultaneous and sequential groups respectively ( P 0.379). The 3-year hepatic recurrence free survival was 61% and 46% in the simultaneous and sequential groups respectively ( P 0.254). Conclusion Simultaneous resections result in similar short-term and long-term outcomes as patients receiving sequential resections with comparable metastatic disease and are associated with a significant reduction in the length of stay.

Optimal management of rectal cancer depends on obtaining accurate and detailed staging information at the time of diagnosis. The majority of this comes from radiological staging investigations such as computed tomography (CT), magnetic resonance imaging (MRI) and endoanal ultrasound (EAUS). Whilst there is little debate on the use of CT to assess distant spread of disease, there is still variation in the use of MRI or EAUS in the local staging of rectal cancer. Both techniques have their roles but MRI is better able to visualise the entire rectum and mesorectum as well as accurately identify the circumferential resection (CRM) margin in relation to the tumour edge. Breach of the CRM is one of the most important predictors of local recurrence and knowledge of its relationship to the tumour determines initial management. MRI has additional advantages in being able to identify other poor prognostic factors such as extramural venous invasion (EMVI) and mucin deposition, which further influence oncological treatment. It also provides the surgeon with accurate information on the relationship of the tumour to surrounding structures and the sphincter complex which is important for surgical planning. This review highlights the important determinants of local staging in rectal cancer and presents the evidence to answer the question as to which is a better imaging modality—MRI or EAUS?

Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and efficacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with >= 5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m(2), l-folinic acid 175 mg, fluorouracil 400 mg/m(2) bolus, then 2400 mg/m(2) by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the first 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratification variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3-4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no significant differences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0.81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0.10). Preoperative therapy resulted in significant downstaging of TNM5 compared with the postoperative group (p=0.04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p

Comparison between magnetic resonance imaging (MRI) and pathology in the assessment of tumour regression grade (TRG) in rectal cancer (RC)

Purpose It is a widely held view that anterior resection (AR) for rectal cancer is an oncologically superior operation to abdominoperineal excision (APE). However, some centres have demonstrated better outcomes with APE. We conducted a systematic review of high-quality studies within the total mesorectal excision (TME) era comparing outcomes of AR and APE. Methods A literature search was performed to identify studies within the TME era comparing AR and APE with regard to the following: circumferential resection margin (CRM) status, tumour perforation rates, specimen quality, local recurrence, overall survival (OS; 3 or 5 year), cancer-specific survival (CSS) and disease-free survival (DFS). Additional data regarding patient demographics and tumour characteristics was collected. Results Twenty four studies fulfilled the eligibility criteria with Newcastle–Ottawa scores of six or greater. Where a significant difference was found, all studies reported lower and more advanced tumours for APE and 4/5 studies observed more frequent use of neoadjuvant and adjuvant therapies in APE patients. Tumour perforation rates and CRM involvement where reported, were significantly greater for APE. 8 out of 10 studies showing significant differences in local recurrence reported higher rates for APE but no differences were observed with distant recurrence. Where differences were noted, AR was reported to have increased DFS, CSS and OS compared to APE. Conclusions Patients treated with AR have lower rates of tumour perforation and CRM involvement and tend to have better outcomes with regard to disease recurrence and survival. However, tumours treated by APE are lower and more locally advanced.

Current management of early-stage rectal cancer comprises combinations of surgery, radiotherapy, and chemotherapy, with the presence or absence of several validated high-risk features determining which treatment modalities will be used and the order of administration. In high-risk individuals, most centers have adopted neoadjuvant combined chemotherapy and radiotherapy followed by surgery as the initial approach. However, long-term toxicity, limited survival gains, and high rates of distant failure have called this approach into question, with early data suggesting that neoadjuvant chemotherapy alone may be feasible in selected patient groups. This review discusses the current data and feasibility of managing early stage rectal cancer with neoadjuvant chemotherapy before surgical resection.

Aim To determine the accuracy of computed tomography (CT) in detecting disease with invasion beyond the muscularis propria (MP) and malignant lymph nodes. Materials and methods A literature search of Ovid, Embase, the Cochrane database, and Medline using Pubmed, Google™ Scholar and Vivisimo™ search engines was performed to identify studies reporting on the accuracy of CT to predict the staging of colonic tumours. Publication bias was demonstrated by Funnel plots. The sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated using a bivariate random effects model and hierarchical summary operating curves (HSROC) were generated. Results Nineteen studies fulfilled all the necessary inclusion criteria. The pooled sensitivity, specificity, DOR for detection of tumour invasion were 86% (95% CI: 78–92%); 78% (95% CI: 71–84%); 22.4 (95% CI: 11.9–42.4). Similarly, the values for nodal detection were 70% (95% CI: 63–73%); 78% (95% CI: 73–82%); 8.1(95% CI: 4.7–14.1). In the subgroup analysis, the best results were obtained in studies utilizing multidetector CT (MDCT). Conclusion Preoperative staging CT accurately distinguishes between tumours confined to the bowel wall and those invading beyond the MP; however, it is significantly poorer at identifying nodal status. MDCT provides the best results.

Lateral pelvic lymph-node metastases occur in 10-25% of patients with rectal cancer, and are associated with higher local recurrence and reduced survival rates. A meta-analysis was undertaken to assess the value of extended lateral pelvic lymphadenectomy in the operative management of rectal cancer.We searched Medline, Embase, Ovid, Cochrane Library, and Google Scholar for studies published between 1965 and 2009 that compared extended lymphadenectomy (EL) with standard rectal resection. 20 studies, which included 5502 patients from one randomised, three prospective non-randomised, and 14 retrospective case-control studies published between 1984 and 2009, met our search criteria and were assessed. 2577 patients underwent EL and 2925 underwent non-EL for rectal cancer. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. End-points evaluated included peri-operative outcomes, 5-year survival and recurrence rates.Operating time was significantly longer in the EL group by 76.7 min (95% CI 18.77-134.68; p=0.0096). Intra-operative blood loss was greater in the EL group by 536.5 mL (95% CI 353.7-719.2; p0.0001). Peri-operative mortality (OR 0.81, 95% CI 0.34-1.93; p=0.63) and morbidity (OR 1.45, 95% CI 0.89-2.35; p=0.13) were similar between the two groups. Data from individual studies showed that male sexual dysfunction and urinary dysfunction (three studies: OR 3.70, 95% CI 1.66-8.23; p=0.0012) were more prevalent in the EL group. There were no significant differences in 5-year survival (hazard ratio [HR] 1.09, 95% CI 0.78-1.50; p=0.62), 5-year disease-free survival (HR 1.23, 95% CI 0.75-2.03, p=0.41), and local (OR 0.83, 95% CI 0.61-1.13; p=0.23) or distant recurrence (OR 0.93, 95% CI 0.72-1.21; p=0.60).Extended lymphadenectomy does not seem to confer a significant overall cancer-specific advantage, but does seem to be associated with increased urinary and sexual dysfunction.

Computer tomography (CT) has been the principal investigation in the staging of colon cancers. The information obtained with routine CT has been limited to identifying the site of the tumour, size of the tumour, infiltration into surrounding structures and metastatic spread. The Foxtrot trial National Cancer Research Institute (NCRI) has been specifically designed to evaluate the efficacy of neoadjuvant treatment in colon cancers by using preoperative chemotherapy with or without an anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody to improve outcome in high-risk operable colon cancer. Patients are selected based on their staging CT examination. The criteria for poor prognosis are T4 and T3 tumours with more than 5mm extramural depth. Thus the success of the trial would depend upon the confidence of the radiologist to identify the patients that would receive the neoadjuvant treatment. The aim of this review is to explain the process of identifying high-risk features seen on the staging CT images. This will help to identify a cohort of patients that could truly benefit from neoadjuvant strategies.

The early detection of metastatic disease in colorectal cancer either at initial presentation or during follow up has been shown to benefit patients. This is because surgical resection for small volume isolated metastases can be curative and early detection of such disease improves the chances of cure. Even after metastatectomy, continued surveillance is worthwhile since repeat resection for recurrent disease is associated with favourable long-term survival [1−3]. The percentage of patients in whom long term cure is achievable following resection of metastatic disease in lungs or liver has increased in recent years and there is a continuing trend of improving survival and cure rates. Technological advances in imaging have played an important part in contributing to this improvement. This has been achieved through more accurate preoperative imaging leading to rigorous patient selection [4−6]. The relative merits of intensive image based follow up versus a less intensive method have been subject to debate. The evidence base however appears to favour more intensive follow-up. For example, a meta-analysis suggested that more intensive follow up combining CEA monitoring, outpatient clinical assessment and yearly CT scanning improves survival compared with less intensive follow up that does not utilise CT imaging [7]. The meta-analysis showed that intensive follow up was associated with a reduced time to first relapse and significant absolute reduction in mortality rate of 9−13%. Since these trials pre-dated the current wider trend of more aggressive hepatic resections and the use of combined therapies which, in their own right, have improved survival it is likely that the potential survival benefit from intensive follow up may be even greater than identified in the metaanalysis. The American Society of Clinical Oncology has made the following recommendations: – Annual computed tomography (CT) of the chest and abdomen for 3 years after primary therapy for patients who are at higher risk of recurrence and who could be candidates for curative-intent surgery – Pelvic CT scan for rectal cancer surveillance, especially for patients with several poor prognostic factors, including those who have not been treated with radiation – Colonoscopy at 3 years after operative treatment, and, if results are normal, every 5 years thereafter; flexible proctosigmoidoscopy every 6 months for 5 years for rectal cancer patients who have not been treated with pelvic radiation – History and physical examination every 3 to 6 months for the first 3 years, every 6 months during years 4 and 5, and subsequently at the discretion of the physician – Carcinoembryonic antigen every 3 months postoperatively for at least 3 years after diagnosis, if the patient is a candidate for surgery or systemic therapy – Chest x-rays, CBCs, and liver function tests are not recommended, and molecular or cellular markers should not influence the surveillance strategy based on available evidence. The liver is not only the most frequent site of metastatic disease but the sole site of metastasis in up to 30−40% of colorectal patients. Metastatic disease to the lungs occurs in (15%), followed by ovarian metastases (6−8%) [8], bones (5%) and brain. The spleen, kidneys, pancreas, adrenals, breast, thyroid and skin are rarely involved. In selecting patients for curative hepatic resection thin collimation CT or MR imaging of the liver with liver specific contrast agents are of critical importance in delineating the distribution of metastases and assessing overall resectability. MR imaging has a further important role to play in characterising coexisting benign lesions. In preoperative assessment of liver metastases, the following should be taken into account: – Accurate delineation of anatomical distribution of metastases and segmental sparing in patients undergoing hepatic resection – Confirmation of absence of widespread multi segmental micro metastatic disease within the liver – Confirmation of absence of extra hepatic disease – Discrimination between coexisting benign lesions and metastases

The past decade has seen pronounced changes in the treatment of locally advanced rectal cancer. Historically, the standard of care involved surgery followed by adjuvant radiotherapy or chemoradiotherapy. More recently, the emergence of neo-adjuvant chemoradiotherapy has fundamentally changed the management of patients with locally advanced disease. In clinical trials, pathological complete responses of up to 25% have raised the question as to whether surgery can be avoided in a select cohort of patients. A trial of omission of surgery for selected patients with complete response after preoperative chemoradiotherapy has shown favourable long-term results. In this article, we outline emerging factors for achieving pathological complete response, non-operative strategies to date, methods for prediction of response to chemoradiotherapy, and future directions with the addition of MRI as a radiological guide to complete response.

Large variations in recurrence rates have been reported with the best results following total mesorectal excision (TME) surgery for low and middle rectal cancers. However, the low rectal cancers still have higher rates of local recurrence (up to 30%) whether operated by low anterior resection or abdominoperineal excision (APE) due to high rates of circumferential margin involvement. The treatment of choice for low rectal cancers that encroach upon the potential circumferential resection margin is surgery combined with preoperative neoadjuvant treatment. Preoperative chemotherapy combined with long-term radiotherapy reduces recurrence rates and preoperative loco-regional staging can help to select the patients more likely to benefit from neo-adjuvant therapy. Surface coil MRI is the most promising modality for patient selection, which can provide good views of the circumferential resection margin especially the presence or absence of tumour encroaching the intersphincteric plane.

Phase II study of irinotecan and 5-fluorouracil/leucovorin in patients with primary refractory or relapsed advanced oesophageal and gastric carcinoma Background: The purpose of this study was to assess the efficacy and toxicity of irinotecan and 5-fluorouracil (5-FU) in primary refractory or relapsed locally advanced or metastatic oesophagogastric (O-G) carcinoma. Patients and methods: Patients with documented progression on or within 3 months of chemotherapy were recruited between July 2000 and May 2002. Irinotecan (180 mg/m(2)) was given with 5-FU (400 mg/m(2) bolus) and leucovorin (folinic acid) (125 mg/m(2)) followed by 5-FU (1200 mg/m(2) infusion over 48 h) every 2 weeks. Response confirmed by computed tomography was assessed at 12 and 24 weeks. Results: Thirty-eight of 40 registered patients (95%) were assessable. Median follow-up was 9.3 months and median age was 59.0 years. Thirty-three patients (86.8%) had metastatic disease and 37 patients (97.4%) had previously received platinum-based chemotherapy. Overall response rate was 29% (95% confidence interval 15.4% to 45.9%) while an additional 34% had stable disease. Improvement in tumour-related symptoms included dysphagia 78.6%, reflux 60.0%, pain 54.5%, anorexia 64.3% and weight loss 72.7%. Grade 3/4 toxicities were anaemia 13.2%, neutropenia 26.4%, febrile neutropenia 5.2%, stomatitis 2.6%, nausea and vomiting 13.2% and diarrhoea 7.9%. Median failure- free survival was 3.7 months and median overall survival was 6.4 months. Conclusion: 5-FU/irinotecan is a valuable regimen for second-line treatment in 5-FU/platinum-resistant O-G carcinoma.

The majority of rectal cancers have local disease only at presentation, but despite meticulous surgery, a number of factors will influence outcome. Preoperative identification of adverse prognostic factors provides a rational basis for selecting preoperative therapy. Thin section MRI can influence preoperative therapeutic algorithms by T and N staging, demonstrating operability, and the potential risk of circumferential margin involvement. Endosonography may contribute to this, but has a greater role in determining intramural invasion for early tumors. The assessment of residual tumor after chemoradiotherapy remains difficult; PET scanning has been used in this situation [32], but has not been compared with MRI and is unlikely to show only residual cells with extensive fibrosis.

KRAS mutations in circulating tumour DNA (ctDNA) in MRI-defined, high-risk, locally-advanced rectal cancer (LARC) patients (pts) from the EXPERT-C trial

Prognostic role of the LCS-6 KRAS variant in locally advanced rectal cancer : Results of the EXPERT-C trial

Aim: Intensified preoperative treatment regimens have been increasingly investigated in locally advanced rectal cancer. However, there are very limited data on the impact of these regimens on patient quality of life (QoL) and bowel function. We assessed patient QoL and bowel function in EXPERT-C, a randomised, phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy (CRT), total mesorectal excision and adjuvant CAPOX ± cetuximab in MRI-defined, high-risk, locally advanced rectal cancer. Methods: Patient reported QoL was assessed using the EORTC QLQ-C30 and the colorectal cancer EORTC QLQ-CR29 questionnaire. Scores which differed by ≥10 percent points were considered clinically significant. Bowel incontinence was assessed using a modified Cleveland Clinic Incontinence Score (mCCIS) questionnaire. Results: Of 164 study patients, 157 (95.1%) completed a QLQ-C30 and a QLQ-CR29 questionnaire and 147 (89.6%) a mCCIS questionnaire, at baseline. Compared to baseline, QoL scores were worse for role functioning, fatigue, appetite loss, taste, hair loss, throughout neoadjuvant treatment, for nausea/vomiting and dry mouth during and/or after neoadjuvant chemotherapy (NACT), and for sore skin and impotence after CRT. QoL scores were better for blood and mucus in stool throughout neoadjuvant treatment, and for diarrhoea, stool frequency, faecal incontinence and buttock pain during NACT. A significant difference was observed between QoL scores after NACT and those after CRT for sexual interest in women, diarrhoea, sore skin and buttock pain (all worse after CRT). When the two treatment groups were analysed separately, patients who received cetuximab had worse QoL scores for body image, dry mouth and taste throughout neoadjuvant treatment and sexual interest in women after CRT compared to patients treated without cetuximab. Long-term QoL data and data on bowel function will be presented at the meeting. Conclusions: This is the first study reporting on QoL and bowel function in locally advanced rectal cancer patients treated with NACT followed by CRT. QoL and functional outcome should be important endpoints to use in clinical trials investigating intensified neoadjuvant treatment strategies. Disclosure: D. Cunningham: has received research funding from Amgen, Roche, Sanofi-Aventis, and Merck- Serono; A. Cervantes Ruiperez: has had advisory roles with Merck-Serono and Roche. He has received research funding from Roche and honoraria from Roche and Merck-Serono; I. Chau: has had advisory roles with Merck Serono, Roche, and Sanofi-Aventis. He has received research funding from Merck and Roche, and honoraria from Roche and Sanofi-Aventis. All other authors have declared no conflicts of interest.