BACKGROUND: The management of recurrent rectal cancer is challenging. At the present time, pelvic exenteration with en bloc sacrectomy offers the only hope of a lasting cure.
OBJECTIVE: The purpose of this study was to evaluate clinical outcome measures and complication rates following sacrectomy for recurrent rectal cancer.
DATA SOURCES: A search was conducted on Pub Med for English language articles relevant to sacrectomy for recurrent rectal cancer with no time limitations.
STUDY SELECTION: Studies reported sacrectomy with survival data for recurrent rectal adenocarcinoma.
MAIN OUTCOME MEASURE: Disease-free survival following sacrectomy for recurrent rectal cancer was the main outcome measured.
RESULTS: A total of 220 patients with recurrent rectal cancer were included from 7 studies, of which 160 were men and 60 were women. Overall median operative time was 717 (570-992) minutes and blood loss was 3.7 (1.7-6.2) L. An R0 (>1-mm resection margin) resection was achieved in 78% of patients. Disease-free survival associated with R0 resection was 55% at a median follow-up period of 33 (17-60) months; however, none of the patients with R1 (<1-mm resection margin) survived this period. Postoperative complication rates and median length of stay were found to decrease with more distal sacral transection levels. In contrast, R1 resection rates increased with more distal transection.
LIMITATION: The studies assessed by this review were retrospective case series and thus are subject to significant bias.
CONCLUSION: Sacrectomy performed for patients with recurrent rectal cancer is associated with significant postoperative morbidity. Morbidity and postoperative length of stay increase with the level of sacral transection. Nevertheless, approximately half of patients eligible for rectal excision with en bloc sacrectomy may benefit from disease-free survival for up to 33 months, with R0 resection predicting disease-free survival in the medium term.

BACKGROUND: ECCO essential requirements for quality cancer care (ERQCC) are checklists and explanations of organisation and actions that are necessary to give high-quality care to patients who have a specific tumour type. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Colorectal cancer: essential requirements for quality care CONCLUSION: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality CRC service. The ECCO expert group is aware that it is not possible to propose a 'one size fits all' system for all countries, but urges that access to multidisciplinary units or centres must be guaranteed for all those with CRC.

INTRODUCTION: Prevention of colorectal cancer (CRC) via reduction of lifestyle risk factors, and participation in bowel screening are two ways in which public engagement could lower mortality from colorectal cancer. This study examined public awareness of lifestyle risk factors and bowel screening, with determination of the factors affecting this.
METHODS: A representative population sample (n = 1969) was surveyed using a study specific postal questionnaire to determine demographics, experience of bowel problems, awareness of lifestyle risk factors, knowledge about the incidence of CRC and potential benefits of screening, as well as personal experience of screening.
RESULTS: The majority of respondents were aged over 50 (74%). 77% had either personal experience or a relative/friend with experience of a bowel problem. Knowledge of dietary advice was better than risks relating to weight and physical activity. Awareness of lifestyle risk factors was significantly worse in those less than 50 years old (p = 0.0004) and with a lower level of education (p = 0.0021). Awareness of bowel cancer diagnosis was significantly lower in those less than 50 years old (p=<0.0001). The most frequent reason for non-completion of a screening kit was that the process was dirty and unpleasant.
CONCLUSION: Initiatives are required to improve awareness of younger people with regard to lifestyle risk factors for CRC, especially since this group stand to benefit most from risk reduction. Those with a lower educational level also had poor awareness but felt that the NHS should not prescribe exercise and lifestyle change; targeting this group would need to take this into account.

BACKGROUND AND OBJECTIVES: We have reviewed our series of rectal cancer patients with circumferential resection margin involvement (R1) with particular regard to survival and prognostic factors.
METHODS: R1 rectal cancer patients undergoing surgery at the Leicester Royal Infirmary between 1998 and 2008. Age, gender, radiological, and pathological tumor characteristics, neoadjuvant and adjuvant therapies were examined as prognostic factors on the overall survival (OS) and disease-free survival (DFS) at 5-year follow-up.
RESULTS: A total of 885 rectal cancers were reviewed. Six hundred ninety-nine patients underwent a mesorectal excision and 71 of them were R1 resections (12.9%). OS was 43.7% (CI95% 33.5-53.8%; median survival 39 months). DFS was 57.4% (CI95% 43.0-71.8%; median survival 31 months). Pelvic recurrence rate occurred in 16 patients (26.2%, CI95% 16.5-36.0%), systemic recurrence rate in 23 patients (37.7%, CI95% 25.5-49.9%). At Cox-regression LNR and adjuvant chemotherapy were associated with both OS and DFS. No significant association was found between OS or DFS and adjuvant radiotherapy.
CONCLUSIONS: In our series of R1 patients, the rates of local recurrence and OS at 5 years were 26.2% and 43.7%, respectively. Factors influencing systemic recurrences (LNR, adjuvant chemotherapy) are more associated with OS and DFS than those potentially affecting locoregional recurrences (adjuvant radiotherapy). J. Surg. Oncol. 2016;114:642-648. © 2016 Wiley Periodicals, Inc.

A series of clinical trials in the last several decades has resulted in the development of multimodality treatment of locally advanced rectal cancer that includes neoadjuvant (preoperative) chemoradiotherapy, total mesorectal excision, and postoperative adjuvant chemoradiotherapy. Owing to this regimen, patients with locally advanced rectal cancer have better survival rates than patients with colon cancer, but at the cost of substantial morbidity and reduced quality of life. The challenge is to identify treatment approaches that maintain or even improve oncologic outcomes while preserving quality of life. We have identified different tumor characteristics that are associated with recurrence and probability of survival for locally advanced rectal cancer. This risk stratification, based on baseline clinical staging and tumor response to chemoradiotherapy, has led us to question whether all patients with locally advanced rectal cancer require every component of the multimodal regimen. In this article, we will review recent evidence that some patients with locally advanced rectal cancer can be spared one or more treatment modalities without compromising long-term oncologic outcomes and while preserving quality of life.

OBJECTIVES: Receptor for advanced glycation end products (RAGE) expressed on adipocytes and immune cells can bind to ligand N(ε)-(carboxymethyl)-lysine (CML) and trigger dysregulation of adipokines and chronic inflammation. Soluble RAGE (sRAGE) mitigates the detrimental effect of RAGE. We examined the associations between circulating levels of CML-AGE and sRAGE and colorectal cancer (CRC).
METHODS: In a case-cohort study of the Women's Health Initiative Study, blood levels of CML-AGE and sRAGE were measured using ELISA. We used multivariable Cox regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident CRC in relation to quartiles (Q) of biomarker levels.
RESULTS: Average follow-up was 7.8 years for 444 cases and 805 subcohort members. In the subcohort, CML-AGE and sRAGE were inversely correlated with BMI (P values<0.0001). Levels of CML-AGE and sRAGE were not associated with CRC. In BMI-specific analysis, the association between sRAGE and CRC was observed. Among women with BMI≥25kg/m(2), those with highest levels of sRAGE had significantly lower risk for CRC as compared to women with lowest levels of sRAGE (HRQ4versusQ1: 0.39; 95% CI: 0.17-0.91). This inverse association was not observed among women with BMI <25kg/m(2) (P value for interaction=0.01).
CONCLUSIONS: Among postmenopausal women, the RAGE pathway may be involved in obesity-related CRC.

BACKGROUND: Prone extralevator abdominoperineal excision of the rectum (ELAPE) has been introduced to improve the circumferential resection margins (CRM) compared with traditional APER.
OBJECTIVE: We present short-term results achieved with prone ELAPE preceded by neoadjuvant chemoradiotherapy during the last 5 years of activity.
DESIGN: A retrospective review was conducted.
SETTINGS AND PATIENTS: Prone ELAPE operations performed between September 2010 and August 2014 at Leicester Royal Infirmary preceded by neoadjuvant chemoradiotherapy.
INTERVENTIONS AND MAIN OUTCOME MEASURES: Data regarding demographics, staging, neoadjuvant therapies, intraoperative perforations, and perineal complications were collected.
RESULTS: Seventy-two patients were included. Pretreatment radiological T4 were 25.0%, histological T4 2.8%. Intraoperative perforations occurred in 2.8%, CRM was involved in 11.1%. Perineal complications consisted of superficial wound infections (20.8%), full thickness dehiscences (16.7%), hematomas (9.7%), pelvic collections (6.9%), and perineal hernias (5.6%).
CONCLUSIONS: In our experience, prone ELAPE preceded by long-course chemoradiotherapy has been successfully used in the last 5 years to resect low rectal tumors. Perineal wound complications rates are similar to those presented in series using direct perineal closures. J. Surg. Oncol. 2016;114:86-90. © 2016 Wiley Periodicals, Inc.

AIM: To determine whether aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs) prevent colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD).
METHODS: We performed a systematic review and meta-analysis. We searched for articles reporting the risk of CRC in patients with IBD related to aspirin or NA-NSAID use. Pooled odds ratios (OR) and 95%CIs were determined using a random-effects model. Publication bias was assessed using Funnel plots and Egger's test. Heterogeneity was assessed using Cochran's Q and the I (2) statistic.
RESULTS: Eight studies involving 14917 patients and 3 studies involving 1282 patients provided data on the risk of CRC in patients with IBD taking NA-NSAIDs and aspirin respectively. The pooled OR of developing CRC after exposure to NA-NSAIDs in patients with IBD was 0.80 (95%CI: 0.39-1.21) and after exposure to aspirin it was 0.66 (95%CI: 0.06-1.39). There was significant heterogeneity (I (2) > 50%) between the studies. There was no change in the effect estimates on subgroup analyses of the population studied or whether adjustment or matching was performed.
CONCLUSION: There is a lack of high quality evidence on this important clinical topic. From the available evidence NA-NSAID or aspirin use does not appear to be chemopreventative for CRC in patients with IBD.

BACKGROUND: Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.
METHODS AND FINDINGS: The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed.
CONCLUSIONS: These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

The novel thiourea-functionalized silicon nanoparticles (SiNPs) have been successfully synthesized using allylamine and sulforaphane, an important anticancer drug, followed by a hydrosilylation reaction on the surface of hydrogen terminated SiNPs. Their physiochemical properties have been investigated by photoluminescence emission, Fourier transform infrared spectroscopy (FTIR) and elemental analysis. The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay has been employed to evaluate in vitro toxicity in human colorectal adenocarcinoma (Caco-2) cells and human normal colon epithelial (CCD) cells. The results show significant toxicity of thiourea SiNPs after 72 h of incubation in the cancer cell line, and the toxicity is concentration dependent and saturated for concentrations above 100 μg/mL. Confocal microscopy images have demonstrated the internalization of thiourea-functionalized SiNPs inside the cells. Flow cytometry data has confirmed receptor-mediated targeting in cancer cells. This nanocomposite takes advantage of the epidermal growth factor receptor (EGFR) active targeting of the ligand in addition to the photoluminescence properties of SiNPs for bioimaging purposes. The results suggest that this novel nanosystem can be extrapolated for active targeting of the receptors that are overexpressed in cancer cells such as EGFR using the targeting characteristics of thiourea-functionalized SiNPs and therefore encourage further investigation and development of anticancer agents specifically exploiting the EGFR inhibitory activity of such nanoparticles.

Post-hepatectomy liver failure (PHLF) is a leading cause of morbidity and mortality following major liver resection. The development of PHLF is dependent on the volume of the remaining liver tissue and hepatocyte function. Without effective pre-operative assessment, patients with undiagnosed liver disease could be at increased risk of PHLF. We report a case of a 60-year-old male patient with PHLF secondary to undiagnosed alpha-1-antitrypsin deficiency (AATD) following major liver resection. He initially presented with acute large bowel obstruction secondary to a colorectal adenocarcinoma, which had metastasized to the liver. There was no significant past medical history apart from mild chronic obstructive pulmonary disease. After colonic surgery and liver directed neo-adjuvant chemotherapy, he underwent a laparoscopic partially extended right hepatectomy and radio-frequency ablation. Post-operatively he developed PHLF. The cause of PHLF remained unknown, prompting re-analysis of the histology, which showed evidence of AATD. He subsequently developed progressive liver dysfunction, portal hypertension, and eventually an extensive parastomal bleed, which led to his death; this was ultimately due to a combination of AATD and chemotherapy. This case highlights that formal testing for AATD in all patients with a known history of chronic obstructive pulmonary disease, heavy smoking, or strong family history could help prevent the development of PHLF in patients undergoing major liver resection.

Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex mechanisms to control and regulate bacterial interactions with the mucosal surface. Apical tight junction proteins are critical in the maintenance of epithelial barrier function and control of paracellular permeability. The characterisation of alterations in tight junction proteins as key players in epithelial barrier function in inflammatory bowel diseases is rapidly enhancing our understanding of critical mechanisms in disease pathogenesis as well as novel therapeutic opportunities. Here we give an overview of recent literature focusing on the role of tight junction proteins, in particular claudins, in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.

A prospective study was conducted to identify biomarkers associated with resistance to panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). Patients with previously treated, codon 12/13 KRAS wt, mCRC were prospectively administered panitumumab 6 mg/kg IV q2weeks. Of 34 panitumumab-treated patients, 11 (32%) had progressive disease at 8 weeks and were classified as non-responders. A Nanostring nCounter-based assay identified a 5-gene expression signature (ERBB2, MLPH, IRX3, MYRF, and KLK6) associated with panitumumab resistance (P = 0.001). Immunohistochemistry and in situ hybridization determined that the HER2 (ERBB2) protein was overexpressed in 4/11 non-responding and 0/21 responding cases (P = 0.035). Two non-responding tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 KRAS mutation occurred in one panitumumab-resistant patient and was mutually exclusive with ERBB2/HER2 abnormalities. This study identifies a 5-gene signature associated with non-response to single agent panitumumab, including a subgroup of non-responders with evidence of aberrant ERBB2/HER2 signaling. KRAS wt tumors resistant to EGFRi may be identified by gene signature analysis, and the HER2 pathway plays an important role in resistance to therapy.

Alcohol is a known carcinogen that may be associated with colorectal cancer. However, most epidemiologic studies assess alcoholic beverage consumption using self-reported data, leading to potential exposure misclassification. Biomarkers of alcohol consumption may provide an alternative, complementary approach that reduces misclassification and incorporates individual differences in alcohol metabolism. Therefore, we evaluated the relationship between previously identified alcohol consumption-related metabolites and colorectal cancer and adenoma using serum metabolomics data from two studies. Data on colorectal cancer were obtained from a nested case-control study of 502 US adults (252 cases, 250 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Data on colorectal adenoma were obtained from a case-control study of 197 US adults (120 cases, 77 controls) from the Navy Colon Adenoma Study. Unconditional multivariable logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for eight alcohol consumption-related metabolites identified in a previous analysis: ethyl glucuronide; 4-androstene-3beta,17beta-diol disulfate 1; 5-alpha-androstan-3beta,17beta-diol disulfate; 16-hydroxypalmitate; bilirubin (E,Z or Z,E); cyclo (-leu-pro); dihomo-linoleate (20:2n6); and palmitoleate (16:1n7). We found no clear association between these alcohol consumption-related metabolites and either endpoint. However, we did observe an inverse association between cyclo (-leu-pro) and colorectal adenoma that was only observed in the highest metabolite quantile (OR 4th vs. 1st Quantile = 0.30, 95% CI: 0.12-0.78; P-trend = 0.047), but no association for colorectal cancer. In conclusion, there were no adverse associations between alcohol consumption-related metabolites and colorectal cancer or adenoma.

BACKGROUND: Transanal mesorectal resection has been developed to facilitate minimally invasive proctectomy for rectal cancer.
OBJECTIVE: The purpose of this study was to evaluate the evidence regarding technical parameters, oncological outcomes, morbidity, and mortality after transanal mesorectal resection.
DATA SOURCES: The Cochrane Library, PubMed, and MEDLINE databases were reviewed.
STUDY SELECTION: Systematic review of the literature from January 2005 to September 2015 was used for study selection.
INTERVENTION: Intervention included transanal mesorectal resection for rectal cancer.
MAIN OUTCOME MEASURES: Technical parameters, histological outcomes, morbidity, and mortality were the outcomes measured.
RESULTS: Fifteen predominately retrospective studies involving 449 patients were included (mean age, 64.3 years; 64.1% men). Different platforms were used. The operative mortality rate was 0.4% and the cumulative morbidity rate 35.5%. Circumferential resection margins were clear in 98%, and the resected mesorectum was grade III in 87% of patients. Median follow-up was 14.7 months. There were 4 local recurrences (1.5%) and 12 patients (5.6%) with metastatic disease. No study followed patients long enough to report on 5-year overall and disease-free survival rates. Functional outcome was only reported in 3 studies.
LIMITATIONS: A low number of procedures were performed by expert early adopters. There are no comparative or randomized data included in this study and inconsistent reporting of outcome variables.
CONCLUSIONS: Transanal mesorectal resection for rectal cancer may enhance negative circumferential margin rates with a reasonable safety profile. Contemporary randomized, controlled studies are required before there can be universal recommendation.

BACKGROUND: Restorative anterior resection is considered the optimal procedure for most patients with rectal cancer and is frequently preceded by radiotherapy. Both surgery and preoperative radiotherapy impair bowel function, which adversely affects quality of life.
OBJECTIVE: This study aimed to report symptoms associated with and key predictors for bowel-related quality-of-life impairment.
DESIGN: The study included a cross-sectional cohort.
SETTINGS: This was a multicenter study from 12 United Kingdom centers.
PATIENTS: A total of 578 patients with rectal cancer underwent curative restorative anterior resection between 2001 and 2012 (median, 5.25 years postsurgery).
MAIN OUTCOME MEASURES: Patients completed outcome measures that assessed bowel dysfunction (low anterior resection syndrome score), incontinence (Wexner score), and quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30), plus an anchor question: "Overall how does bowel function affect your quality of life?"
RESULTS: The response rate was 80% (462/578). Overall, 85% (391/462) of patients reported bowel-related quality-of-life impairment, with 40% (187/462) reporting major impairment. A large difference in global quality of life (22 points; p < 0.001) was reported for "none" versus "major" impairment, with greatest symptom severity being diarrhea (25 points; p < 0.001), insomnia (24 points; p < 0.001), and fatigue (20 points; p < 0.001). Regression analysis identified major impairment in 60% and 45% of patients with low rectal cancer treated with and without preoperative radiotherapy compared with 47% and 33% of middle/upper rectal cancers with and without preoperative radiotherapy.
LIMITATIONS: Advances in radiotherapy delivery and improvements in posttreatment symptom control, although currently of limited efficacy, imply that the content of this consent aid should be re-evaluated in 5 to 10 years.
CONCLUSIONS: Before a restorative anterior resection, patients with rectal cancer should be informed that bowel-related quality-of-life impairment is common. The key risk factors are neoadjuvant therapy and a low tumor height. This study presents quality-of-life and functional outcome data, along with a consent aid, that will enhance this preoperative patient discussion.

INTRODUCTION: Neoadjuvant chemoradiotherapy (CRT) is indicated in locally advanced rectal adenocarcinoma where there is a high risk of local recurrence based on preoperative imaging. Optimal radiological assessment of CRT response is unknown, and metabolic assessment of the tumor has been suggested to gauge response before surgical resection.
PATIENTS AND METHODS: A systematic search of the MEDLINE database was performed using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement to identify papers comparing pre- and post-CRT PET/CT in patients with locally advanced rectal adenocarcinoma with histopathological assessment of tumor regression. Papers were assessed with the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) tool. Meta-analysis was performed for response index (RI) and SUVmax post-CRT.
RESULTS: Ten of 69 studies met inclusion criteria containing a total of 538 patients. Methodological quality was high with low heterogeneity. In all studies, post-CRT PET/CT showed a reduction in SUVmax and the RI irrespective of histological findings. Tumors confirmed to have regressed after CRT had a mean difference of 12.21% higher RI (95% confidence interval, 6.51-17.91; P < 0.00001) compared with nonresponders. Mean difference between pre- and post-CRT SUVmax groups was -2.48 (95% confidence interval, -3.06 to -1.89; P < 0.00001) with histopathological responders having a lower post-CRT SUVmax.
CONCLUSIONS: The available evidence suggests that PET/CT may be a useful addition to the current imaging modalities in the assessment of treatment response.

PURPOSE: This paper proposes to characterize the continuum of colorectal cancer (CRC) using multiple texture features extracted from multispectral optical microscopy images. Three types of pathological tissues (PT) are considered: benign hyperplasia, intraepithelial neoplasia and carcinoma.
MATERIALS AND METHODS: In the proposed approach, the region of interest containing PT is first extracted from multispectral images using active contour segmentation. This region is then encoded using texture features based on the Laplacian-of-Gaussian (LoG) filter, discrete wavelets (DW) and gray level co-occurrence matrices (GLCM). To assess the significance of textural differences between PT types, a statistical analysis based on the Kruskal-Wallis test is performed. The usefulness of texture features is then evaluated quantitatively in terms of their ability to predict PT types using various classifier models.
RESULTS: Preliminary results show significant texture differences between PT types, for all texture features (p-value < 0.01). Individually, GLCM texture features outperform LoG and DW features in terms of PT type prediction. However, a higher performance can be achieved by combining all texture features, resulting in a mean classification accuracy of 98.92%, sensitivity of 98.12%, and specificity of 99.67%.
CONCLUSIONS: These results demonstrate the efficiency and effectiveness of combining multiple texture features for characterizing the continuum of CRC and discriminating between pathological tissues in multispectral images.

A 75-year-old man previously underwent pneumonectomy for lung cancer. He subsequently had colorectal adenocarcinoma, and resection of metastases from his remaining lung was performed. Venovenous extracorporeal membrane oxygenation was used for perioperative respiratory support to facilitate intraoperative deflation of the remaining lung and optimization of the surgical field. Venovenous extracorporeal membrane oxygenation was continued postoperatively, allowing immediate extubation, thus avoiding strain on suture lines. Advantages, and potential risks, of venovenous extracorporeal membrane oxygenation for thoracic surgery are discussed.

Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. The identification of colonic polyps can reduce CRC mortality through earlier diagnosis of cancers and the removal of polyps: the precursor lesion of CRC. Following the finding and removal of colonic polyps at an initial colonoscopy, some patients are at an increased risk of developing CRC in the future. This is the rationale for post-polypectomy surveillance colonoscopy. However, not all individuals found to have colonic adenomas have a risk of CRC higher than that of the general population. This review examines the literature on post-polypectomy surveillance including current international clinical guidelines. The potential benefits of surveillance procedures must be weighed against the burden of colonoscopy: resource use, the potential for patient discomfort, and the risk of complications. Therefore surveillance colonoscopy is best utilised in a selected group of individuals at a high risk of developing cancer. Further study is needed into the specific factors conferring higher risk as well as the efficacy of surveillance in mitigating this risk. Such evidence will better inform clinicians and patients of the relative benefits of colonoscopic surveillance for the individual. In addition, the decision to continue with surveillance must be informed by the changing profile of risks and benefits of further procedures with the patient's advancing age.

PURPOSE: Nelfinavir, a PI3K pathway inhibitor, is a radiosensitizer that increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach.
EXPERIMENTAL DESIGN: Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1,250 mg b.i.d.) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pretreatment, after 7 days of nelfinavir and prior to the last fraction of RT. Biopsies taken pretreatment and 7 days after the last fraction of RT were analyzed for tumor cell density (TCD).
RESULTS: There were 3 drug-related grade 3 adverse events: diarrhea, rash, and lymphopenia. On DCE-MRI, there was a mean 42% increase in medianKtrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P= 0.01). Overall, 5 of 9 evaluable patients exhibited good tumor regression on MRI assessed by tumor regression grade (mrTRG).
CONCLUSIONS: This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow.

PURPOSE: Factors associated with early mortality after surgery and treatment with adjuvant chemotherapy in colon cancer are poorly understood. We aimed to characterize the determinants of early mortality in a large cohort of colon cancer trial participants.
METHODS: A pooled analysis of 37,568 patients in 25 randomized trials of adjuvant systemic therapy was conducted. Multivariable logistic regression models with several definitions of early mortality (30, 60, and 90 days, and 6 months) were constructed, adjusting for clinically and statistically significant variables. A nomogram for 6-month mortality was developed and validated.
RESULTS: Median age among patients was 61 years, patient demographics included 54% men and 90% White, 29% and 71% had stage II and III disease, respectively, and 79%, 20%, and 1% had an Eastern Cooperative Oncology Group performance status (PS) of 0, 1, and ≥ 2, respectively. Early mortality was low: 0.3% at 30 days, 0.6% at 60 days, 0.8% at 90 days, and 1.4% at 6 months. Of those patients who died by 6 months post-random assignment, 40% had documented disease recurrence prior to death. Early disease recurrence was associated with a markedly increased risk of death during the first 6 months post-treatment (hazard ratio, 82.6; 95%CI, 66.9 to 102.1). In prognostic analyses, advanced age, male sex, poorer PS, increasing ratio of positive to examined lymph nodes, earlier decade of enrollment, and higher tumor stage and grade predicted a greater likelihood of early mortality, whereas treatment received was not strongly predictive. A multivariable model for 6-month mortality showed strong optimism-adjusted discrimination (concordance index, 0.73) and calibration.
CONCLUSION: Early mortality was infrequent but more prevalent in patients with advanced age and a PS of ≥ 2, underscoring the need to carefully consider the risk-to-benefit ratio when making treatment decisions in these subgroups.

Next-generation sequencing of spatially and temporally separated biopsies and circulating tumor DNA directs therapy in response to tumor evolution and acquired resistance in colorectal cancer.

BACKGROUND AND STUDY AIMS: Understanding patients' experience of screening programs is crucial for service improvement. The English Bowel Cancer Screening Programme (BCSP) aims to achieve this by sending out questionnaires to all patients who undergo a colonoscopy following an abnormal fecal occult blood test result. This study used the questionnaire data to report the experiences of these patients.
PATIENTS AND METHODS: Data on patients who underwent colonoscopy between 2011 and 2012 were extracted from the BCSP database. Descriptive statistics were used to summarize key questionnaire items relating to informed choice, psychological wellbeing, physical experience, and after-effects. Multilevel logistic regression was used to test for associations with variables of interest: sex, age, socioeconomic status, colonoscopy results, and screening center performance (adenoma detection rate, cecal intubation rate, proportion of colonoscopies involving sedation).
RESULTS: Data from 50,858 patients (79.3 % of those eligible) were analyzed. A majority reported a positive experience on items relating to informed choice (e. g. 95.7 % felt they understood the risks) and psychological wellbeing (e. g. 98.3 % felt they were treated with respect). However, an appreciable proportion experienced unexpected test discomfort (21.0 %) or pain at home (14.8 %). There were few notable demographic differences, although women were more likely than men to experience unexpected discomfort (25.1 % vs. 18.0 %; P < 0.01) and pain at home (18.2 % vs. 12.3 %; P < 0.01). No associations with center-level variables were apparent.
CONCLUSIONS: Colonoscopy experience was generally positive, suggesting high satisfaction with the BCSP. Reported pain and unexpected discomfort were more negative than most other outcomes (particularly for women); measures to improve this should be considered.

BACKGROUND: New screening tests for colorectal cancer continue to emerge, but the evidence needed to justify their adoption in screening programs remains uncertain.
METHODS: A review of the literature and a consensus approach by experts was undertaken to provide practical guidance on how to compare new screening tests with proven screening tests.
RESULTS: Findings and recommendations from the review included the following: Adoption of a new screening test requires evidence of effectiveness relative to a proven comparator test. Clinical accuracy supported by programmatic population evaluation in the screening context on an intention-to-screen basis, including acceptability, is essential. Cancer-specific mortality is not essential as an endpoint provided that the mortality benefit of the comparator has been demonstrated and that the biologic basis of detection is similar. Effectiveness of the guaiac-based fecal occult blood test provides the minimum standard to be achieved by a new test. A 4-phase evaluation is recommended. An initial retrospective evaluation in cancer cases and controls (Phase 1) is followed by a prospective evaluation of performance across the continuum of neoplastic lesions (Phase 2). Phase 3 follows the demonstration of adequate accuracy in these 2 prescreening phases and addresses programmatic outcomes at 1 screening round on an intention-to-screen basis. Phase 4 involves more comprehensive evaluation of ongoing screening over multiple rounds. Key information is provided from the following parameters: the test positivity rate in a screening population, the true-positive and false-positive rates, and the number needed to colonoscope to detect a target lesion.
CONCLUSIONS: New screening tests can be evaluated efficiently by this stepwise comparative approach.

BACKGROUND: Epidemiological studies have shown a potential association between sex hormones and colorectal cancer. The risk of colorectal cancer in breast cancer patients who may have been exposed to increased levels of endogenous sex hormones and/or exogenous sex hormones (e.g. anti-hormonal therapy) has not been thoroughly evaluated.
METHODS: Using the National Swedish Cancer Register we established a population-based prospective cohort of breast cancer patients in women diagnosed in Sweden between 1961 and 2010. Subsequent colorectal cancers were identified from the same register. Standardized incidence ratios (SIRs) and 95% confidence intervals (95%CIs) were used to estimate the risk of colorectal cancer after a diagnosis of breast cancer. The association between breast cancer therapy and risk of colorectal cancer was evaluated in a subcohort of breast cancer patients treated in Stockholm between 1977 and 2007. Hazard ratios (HRs) and 95%CIs were estimated using Cox regression models.
RESULTS: In a cohort of 179,733 breast cancer patients in Sweden, 2571 incident cases of colorectal cancer (1008 adenocarcinomas in the proximal colon, 590 in the distal colon and 808 in the rectum) were identified during an average follow-up of 9.68 years. An increased risk of colorectal adenocarcinoma was observed in the breast cancer cohort compared with that in the general population (SIR=1.59, 95%CI: 1.53, 1.65). Adenocarcinoma in the proximal colon showed a non-significantly higher SIR (1.72, 95%CI: 1.61, 1.82) compared with the distal colon (1.46, 95%CI: 1.34, 1.58). In the subcohort of 20,171 breast cancers with available treatment data, 299 cases with colorectal cancers were identified. No treatment-dependent risk of colorectal cancer was observed among the breast cancer patients.
CONCLUSION: An increased risk of colorectal adenocarcinoma - especially in the proximal colon - was observed in the breast cancer cohort. Breast cancer treatment did not alter this risk.

BACKGROUND: Chronic inflammation and oxidative stress are thought to be involved in colorectal cancer development. These processes may contribute to leakage of bacterial products, such as lipopolysaccharide (LPS) and flagellin, across the gut barrier. The objective of this study, nested within a prospective cohort, was to examine associations between circulating LPS and flagellin serum antibody levels and colorectal cancer risk.
METHODS: A total of 1,065 incident colorectal cancer cases (colon, n = 667; rectal, n = 398) were matched (1:1) to control subjects. Serum flagellin- and LPS-specific IgA and IgG levels were quantitated by ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI), adjusting for multiple relevant confouding factors.
RESULTS: Overall, elevated anti-LPS and anti-flagellin biomarker levels were not associated with colorectal cancer risk. After testing potential interactions by various factors relevant for colorectal cancer risk and anti-LPS and anti-flagellin, sex was identified as a statistically significant interaction factor (Pinteraction < 0.05 for all the biomarkers). Analyses stratified by sex showed a statistically significant positive colorectal cancer risk association for men (fully-adjusted OR for highest vs. lowest quartile for total anti-LPS + flagellin, 1.66; 95% CI, 1.10-2.51; Ptrend, 0.049), whereas a borderline statistically significant inverse association was observed for women (fully-adjusted OR, 0.70; 95% CI, 0.47-1.02; Ptrend, 0.18).
CONCLUSION: In this prospective study on European populations, we found bacterial exposure levels to be positively associated to colorectal cancer risk among men, whereas in women, a possible inverse association may exist.
IMPACT: Further studies are warranted to better clarify these preliminary observations.

AIM: To systematically review the survival outcomes relating to extramural venous invasion in rectal cancer.
METHODS: A systematic review was conducted using PRISMA guidelines. An electronic search was carried out using MEDLINE, EMBASE, CINAHL, Cochrane library databases, Google scholar and PubMed until October 2014. Search terms were used in combination to yield articles on extramural venous invasion in rectal cancer. Outcome measures included prevalence and 5-year survival rates. These were graphically displayed using Forest plots. Statistical analysis of the data was carried out.
RESULTS: Fourteen studies reported the prevalence of extramural venous invasion (EMVI) positive patients. Prevalence ranged from 9%-61%. The pooled prevalence of EMVI positivity was 26% [Random effects: Event rate 0.26 (0.18, 0.36)]. Most studies showed that EMVI related to worse oncological outcomes. The pooled overall survival was 39.5% [Random effects: Event rate 0.395 (0.29, 0.51)].
CONCLUSION: Historically, there has been huge variation in the prevalence of EMVI through inconsistent reporting. However the presence of EMVI clearly leads to worse survival outcomes. As detection rates become more consistent, EMVI may be considered as part of risk-stratification in rectal cancer. Standardised histopathological definitions and the use of magnetic resonance imaging to identify EMVI will improve detection rates in the future.

Complete response to chemoradiotherapy for rectal cancer is becoming a common clinical entity. Techniques to diagnose complete response and how to survey these patients without operative intervention are still unclear. We review the most recent evidence. Barriers to firm conclusions regarding this are heterogeneity of diagnostic definitions, differing surveillance protocols, and a lack of randomised studies.