Ideally, tumors that might cause morbidity and mortality should be treated, preferably early, with proven, convincing, and effective therapy to prevent tumor progression or recurrence, while maintaining a favorable risk-benefit profile for the individual patient. For patients with colorectal cancer (CRC), this diagnostic, prognostic, and therapeutic precision is currently impossible. Despite significant improvements in diagnostic procedures, a sizable number of patients with CRC have liver metastases either at presentation or will subsequently develop it. And in many parts of the world, most cancer-related deaths are still due to metastases that are resistant to conventional therapy. Metastases to the liver occur in more than 50% of patients with CRC and represent the major determinant of outcome following curative treatment of the primary tumor. Liver resection offers the best chance of cure for metastases confined to the liver. However, due to a paucity of randomized controlled trials, its timing is controversial and a hotly debated topic. This article reviews some of the main controversies surrounding the surgical management of colorectal cancer liver metastases (CRLM).

Aims: The purpose of the research was to investigate the benefits of a hereditary colorectal cancer registry in the management of patients and families with Lynch syndrome. In study one, a systematic review was performed to quantify the impact of registration and screening on colorectal cancer (CRC) incidence and mortality, with comparison between familial adenomatous polyposis (FAP) and Lynch syndrome (LS). In study two, a regional Lynch syndrome registry was utilised to evaluate the uptake of predictive testing and colorectal screening among first-degree relatives (FDRs) and investigate novel methods for engaging at-risk relatives, including an enhanced role for the general practitioner (GP). In study three, the registry was used to investigate proposed associations between Lynch syndrome and prostate and bladder cancer. In study four, mismatch repair-deficient (dMMR) CRCs from Lynch syndrome patients and randomised-controlled trials (RCTs) were used to evaluate a novel prognostic biomarker, beta-2 microglobulin (B2M). Methods: An electronic database search was conducted to identify studies describing CRC incidence and/or mortality in FAP or LS, with comparison of either: 1) screened and unscreened patients or 2) patients ‘before and after’ establishment of the registry. Using the Manchester regional Lynch syndrome registry database, the uptake of predictive testing and colorectal screening among FDRs was assessed with Kaplan-Meier analysis. Novel strategies for improving engagement were explored via a patient advisory group discussion and a regional primary care questionnaire. Cases of prostate and bladder cancer in male mutation carriers and their male FDRs were identified, and cumulative and relative risks were calculated, using expected rates from cancer registry data. DNA from 350 dMMR CRC specimens from Lynch syndrome patients and RCTs were tested for B2M mutations using Sanger sequencing, and correlated with clinical outcome. Results: 43 studies were included in the systematic review (33 FAP; 10 Lynch). Registry-based screening was associated with a significant reduction in CRC incidence and in Lynch syndrome, CRC-related mortality was negligible in those undergoing surveillance. 242 Lynch syndrome families were recorded on the Manchester Lynch syndrome registry. 329 of 591 (55.7%) eligible FDRs had undergone predictive testing. Uptake was significantly lower in males and younger age groups (<25 yrs). Compliance with colorectal screening was excellent following a mutation positive predictive test but poor in untested individuals (97.3% vs 35.0%). Eight prostate cancers were identified in 821 male LS mutation carriers and male FDRs. MSH2 mutation carriers had a ten-fold increased risk of prostate cancer (RR 10.41; 95%CI 2.80, 26.65) but no association with bladder cancer was identified. 69/286 (24.1%) of dMMR CRCs contained significant B2M mutations. B2M mutations were associated with complete absence of recurrence (0/39) during follow-up in the QUASAR trial (stage II), compared with 14/77 (18.2%) in wild-type B2M (p=0.005). Conclusion: Studies consistently report that registration and screening result in a reduction of CRC incidence and mortality in FAP and LS (Level 2a evidence, Grade B recommendation). Funding and managerial support for registries should be made available. Uptake of predictive testing and colorectal screening in Lynch syndrome could be substantially improved, particularly among males and younger age groups, but this requires advances in communication with at-risk relatives. It is unlikely that GPs will actively participate without considerable support from genetics services. A trial of PSA screening in MSH2 mutation carriers from 50 years would be appropriate. B2M mutation status has potential clinical utility as a prognostic biomarker in stage II dMMR CRC.

Colorectal cancer is a serious malignant disease with an incidence of over 1.8 million new cases per year worldwide. There are about 8 000 patients diagnosed with CRC in the Czech Republic each year, and about half of them present with an advanced disease. Screening program identifies patients in the early stages of CRC resulting in overall better prognosis and survival. There is also a lack of biomarkers of early CRC detection and of response to treatment. The first aim of our project was to conduct a national multicentre prospective observational study to evaluate the impact of CRC screening within the framework of a Czech population screening programme. Between March 2013 and September 2015, a total of 265 patients were enrolled in 12 centres across the Czech Republic. Patients were divided into screening and control groups and compared for pathology status and clinical characteristics. Screening was defined as a primary screening colonoscopy or a colonoscopy after a positive FOBT in an average-risk population. The distribution of CRC stages was significantly favourable in the screening group compared with the control group (stages 0, I and II, 63% versus 43.3%; p <0.001). The presence of distant (M1) and local metastases (N1 and N2) was significantly less prevalent in the screening group (0%,...

African American (AA) men in the state of Alabama are affected by colorectal cancer (CRC) more than all other races. The purpose of this phenomenological study was to gain understanding of colorectal cancer screening health benefits in AA men in Mobile, Alabama. The health beliefs model (HBM) developed by Hochum, Rosemstock, and Kegels was used to to explore the barriers and facilitators to CRC screening in AA men with health insurance in Mobile, Alabama. The research questions explored knowledge, perceptions, and facilitators to CRC screening among AA men age 40 to 75. Participants were selected using purposive sampling and data were collected through face-to-face individual interviews with 13 participants living in Mobile, Al. Data were inductively coded and subjected to a thematic analysis procedure. The study findings revealed that participants had a general knowledge of cancer but a low awareness of CRC screening. Findings also revealed a perceived gap in CRC screening education from participants' doctors. Few reported understanding or remembering a conversation about the need for CRC screening during their last doctor's visit. There was no indication that age or level of education played a meaningful role in participants' knowledge or perception of CRC screening requirements. Positive social change implications stemming from this study include recommendations to Alabama public health officials and policy makers to invest in the development of intervention and education efforts to increase CRC screening among AA men, which in turn, may reduce CRC related morbidity and mortality.

Ideally, tumors that might cause morbidity and mortality should be treated, preferably early, with proven, convincing, and effective therapy to prevent tumor progression or recurrence, while maintaining a favorable risk-benefit profile for the individual patient. For patients with colorectal cancer (CRC), this diagnostic, prognostic, and therapeutic precision is currently impossible. Despite significant improvements in diagnostic procedures, a sizable number of patients with CRC have liver metastases either at presentation or will subsequently develop it. And in many parts of the world, most cancer-related deaths are still due to metastases that are resistant to conventional therapy. Metastases to the liver occur in more than 50% of patients with CRC and represent the major determinant of outcome following curative treatment of the primary tumor. Liver resection offers the best chance of cure for metastases confined to the liver. However, due to a paucity of randomized controlled trials, its timing is controversial and a hotly debated topic. This article reviews some of the main controversies surrounding the surgical management of colorectal cancer liver metastases (CRLM).

Travelling wave ion mobility spectrometry (TWIMS) in combination with ultra-high performance liquid chromatography (UHPLC) and mass spectrometry (MS) has been applied successfully for the untargeted, global metabolic profiling of biofluids such as mouse plasma and saliva. Methods based on UHPLC-MS alone and in combination with ion mobility spectrometry (UHPLC-IM-MS) have been developed and validated for the untargeted metabolite profiling of saliva, obtained non-invasively by passive drool. Three separate metabolic profiling studies have been carried out in conjunction with bioinformatics strategies to identify potential metabolomic biomarker ions that are associated with efficacy of rice bran in colorectal cancer, physiological stress and that have the potential for the diagnosis of asthma. The advantages offered by the utility of ion mobility in UHPLC-MS based metabolic profiling studies, including the increased analytical space, mass spectral clean-up of contaminants such as PEG post-UHPLC-IM-MS analysis, enhancement of the selectivity of targeted metabolites as well as the potential for the identification of metabolites by comparison of ion mobility drift times have been highlighted. Ten potential metabolic biomarker ions of asthma have been identified from the moderate asthmatics from untargeted metabolite profiling of saliva by UHPLC-MS. A predictive model based on partial least squares discriminant analysis (PLS-DA) has been constructed using these ten discriminant ions, which demonstrates good predictive capability for moderate asthmatics and controls. Potential metabolic biomarker ions of physiological stress have been identified through untargeted metabolite profiling analysis of saliva samples collected before and after exercise by UHPLC-IM-MS. Valerolactam has been identified as a potential biomarker of physiological stress from saliva by comparison of retention time, ion mobility drift time and MS/MS spectra with a standard of δ-valerolactam.

Purpose: To test whether a psycho-educational program affects mental wellbeing in persons treated for colorectal cancer and their next-of-kin. Design: A prospective, longitudinal, randomized controlled trial. Setting: Surgical clinic at a university hospital in Sweden. Sample: 105 colorectal cancer patients and 71 next-of-kin were allocated to a psycho­educational program or to standard care. Methods: Mental wellbeing was evaluated with the Mood Adjective Check List and The Hospital Anxiety and Depression Scale at baseline and at 1, 6, and 12 months. The program consisted of seven meetings, including lecture and time for reflection with other patients/next­of-kin. Main Research Variable: Overall mood, activity, calmness, pleasantness, anxiety, and depression. Findings: The psycho-educational program increased overall mood, calmness, and pleasantness among patients after one month but had no effect on activity, anxiety, or depression. The program had no effect on the overall mood, activity, calmness, pleasantness, anxiety, or depression among next-of-kin. Conclusion: The psycho-educational program had a short-term effect on overall patient mood, calmness, and pleasantness but not on next-of-kin. Implications for Nursing: A psycho-educational program including lecture and time for reflection can be used with a colorectal cancer patient population to improve some aspects of their mental wellbeing.

Introduction: Early growth response 1 (EGR1) is a zinc-finger transcription factor involved in the regulation of cell growth. It can act as either a tumour suppressor or a tumour promoter with a role in the induction of apoptosis in cancer cells by various pathways and is likely to play a role in colorectal cancer (CRC). EGR1 also appears to play a significant role in inflammatory pathways, therefore a possible role in Inflammatory Bowel Disease (IBD) is hypothesised. Patients with IBD have a greater risk of developing CRC, which is increased with duration of symptoms and severity of inflammation and dysplasia. The aim of this study is to determine whether EGR1 is differentially expressed in diseased colon tissue and to investigate novel EGR1-protein interactions in CRC cell lines. Methods: The relative EGR1 expression in CRC cell lines and in normal mucosa and tumours of colorectal cancer patients was determined by qRT-PCR. IBD patient samples were also examined for differential EGR1 expression levels by qRT-PCR, before and after stimulation with inflammatory mediators. Statistical analysis of the data was performed using ‘R’ statistical package, with the mixed-model ANOVA. Statistical significance was set at < 0.05. The genotype of three EGR1 variants was determined in the samples using PCR and sequencing, and the methylation status of regions of the EGR1 promoter was determined using bisulfite sequencing. A yeasttwo hybrid screen was conducted with EGR1 as bait, and screened against a SW480 CRC cell line library. Interesting novel interactions were investigated using immunocytochemistry and immunoprecipitation, as was the novel interaction between EGR1 and NOD2 and between EGR1 and components of the cytoskeleton. Results: Investigation into the relative EGR1 mRNA expression in CRC has shown that there is differential expression of EGR1 between matched normal mucosa and tumour. EGR1 expression is decreased in IBD patients compared with healthy controls. Induction of EGR1 by inflammatory stimuli also appears to be aberrant in these patients. The differential expression of EGR1 was not associated with aberrant methylation of a large region of the EGR1 promoter in either the CRC or IBD patients or with the genotype of EGR1 variants. EGR1 localises to both the cytoplasm and the nucleus in CRC cell lines and this study demonstrate interactions with the IBD susceptibility protein NOD2 and with components of the cyotskeleton. A yeast-two hybrid screen conducted with EGR1 as bait using a CRC cell line library has identified several other novel protein interactions of EGR1 in CRC cell lines. Conclusion: EGR1 is differentially expressed in both CRC and IBD, and in the case of IBD shows aberrant activity, suggesting that EGR1 may play a role in both colorectal diseases. EGR1 interacts with the IBD protein NOD2, and components of the cytoskeleton in CRC cells. Several novel protein interactions with EGR1 have been identified and warrant further study.

Die Entwicklung von Fernmetastasen ist die Haupttodesursache bei Tumorerkrankten und der entscheidende klinisch relevante Schritt während der Tumorprogression. Die Seed and Soil Theorie von Stephen Paget besagt, dass verschiedene Tumorzellen spezifische Zielorgane während der Metatasierung bevorzugen. Während das häufigste Target der kolorektalen Karzinome die Leber ist, hat der triple-negative molekulare Subtyp von Brustkrebs die Neigung, in das Gehirn zu metastasieren. Interessanterweise spielen sowohl deregulierte EGFR (Epithelial growth factor receptor) als auch WNT Signalwege in diesen beiden Entitäten eine entscheidende Rolle. Das Ziel der Arbeit ist, die Rolle der beiden Signalwege in soliden Tumorzelllinien in Bezug auf die Tumorprogression und Kolonisation zu untersuchen. Im Rahmen der molekularen Charakterisierung der Zelllinien zeigten sich die Mammakarzinomzelllinie 410.4 und die kolorektale Tumorzelllinie CMT-93 als passende Modellsysteme für unsere Fragestellung. Anschließend wurden der EGFR und der WNT Signalweg in diesen Zellen im Sinne von gain of function und loss of function moduliert und die Auswirkungen auf Aspekte der Tumorprogression analysiert. In CMT-93 Zellen wurde ein EGFR Knockdown etabliert. Während der Knockdown keinen Einfluss auf die Proliferation hat, vermindert er die Invasion der Zellen. Somit konnte dem effizienten Knockdown eine funktionelle Wirksamkeit zugeschrieben werden. Eine EGFR Überexpression konnte sowohl in 410.4 als auch in CMT-93 Zellen etabliert werden. Die Analyse der jeweiligen Signalkaskadenweiterleitung ergab zwar Änderungen und somit eine funktionelle Relevanz, dies blieb jedoch ohne Auswirkungen auf das Invasionspotential der Zelllinien. Ein Knockdown von β-Catenin konnte in 410.4 zwar etabliert werden, blieb jedoch ohne funktionelle Auswirkungen. Eine stabile Überexpression von β-Catenin war nicht erfolgreich, da dies offenbar mit der Viabilität der Zellen interferierte. Die Relevanz des β-Catenin-abhängigen WNT Signalwegs in den beiden gewählten Zelllinien konnte somit nicht abschließend geklärt werden. Des Weiteren wurde die Bedeutung des nicht-kanonischen WNT Signalwegs via ROR2 und WNT11 untersucht. Dabei ergab sich, dass die Überexpression von WNT11 und ROR2 in 410.4 Zellen deren Invasion durch einen RHOA-abhängigen Mechnismus steigert und einen Einfluss auf den PI3K Signalweg hat. Es ist anzunehmen, dass WNT11 als downstream Target über ROR2 induziert wird und über einen positiven Feedback-Loop via ROR2 eine autokrine Stimulation ausübt.

The base excision repair protein, MBD4 (also known as MED1) is known to be transcriptionally coupled to a mismatch repair protein MLH1. To date the significance of this coupling has not been elucidated and the significance of MBD4 within the mismatch repair system and apoptotic pathway is still being understood. Recently a novel alternatively spliced form of MBD4 has been identified and termed sMBD4. To date the significance of sMBD4 is unknown. MBD4 and sMBD4 share a common glycosylase domain and this is the domain through which MBD4 is reported to interact with MLH1. It was the aim of this study to determine if sMBD4 was also a binding partner of MLH1 to help elucidate a potential role of sMBD4 and to further characterise the binding domain between MLH1 and MBD4. Recombinant proteins were utilised in binding assays however, a specific protein – protein interaction could not be determined. Regular aspirin intake is associated with a reduction in the incidence of colorectal cancer. Aspirin has been shown to be cytotoxic to colorectal cancer cells in vitro. The molecular basis for this cytotoxicity is controversial, with a number of competing hypotheses in circulation. One suggestion is that the protective effect is related to the induction of DNA mismatch repair (MMR) proteins in DNA MMR proficient cells. As MBD4 has previously been suggested to be coupled to MLH1 expression by a post‐translational mechanism the cytotoxicy of aspirin in relation to MBD4 expression was examined. This study reports that aspirin does not up‐regulate MBD4 gene transcription in vitro in the DNA mismatch repair proficient/p53 mutant colorectal cancer cell line SW480. However, MBD4 gene transcription was up‐regulated upon treatment with the aspirin precursor, salicylic acid. The suggested involvement of the DNA repair proteins in the mechanism of action of aspirin promoted the investigation into the expression of DNA damage signalling pathways genes upon aspirin exposure. This study utilised a commercially available PCR array to analyse the expression of 84 DNA damage signalling genes in the SW480 colorectal cancer cell line upon aspirin treatment. It is reported that treatment of the SW480 cell line with aspirin caused changes in mRNA expression of several key genes involved in DNA damage signalling including a significant down‐regulation in expression of the genes encoding ATR, BRCA1 and MAPK12 and increases in the expression of XRCC3 and GADD45α genes. Regulation of these genes could potentially have profound effects on colorectal cancer cells and may play a role in the observed chemo‐protective effect of aspirin in vivo.Further to this, protein expression was analysed to determine if correlation could be established with the changes in mRNA expression observed. Although a correlation was not seen between transcript and protein levels of ATR, BRCA1 and GADD45α, an increase in XRCC3 protein expression upon aspirin treatment in SW480 cells was observed by immunoblotting, immunofluorescence and immunohistochemical analysis. This study indicates that alterations in gene expression seen in microarray studies need to be verified at the protein level. Furthermore, this study reports the novel discovery of XRCC3 gene and protein expression being susceptible to exposure to the non‐steroidal anti‐inflammatory drug, aspirin.