Exploring the impacts of the COVID-19 crisis for the employment prospects of refugees and people seeking asylum in Australia.

As recent research indicates, refugees and people seeking asylum are suffering disproportionately from the COVID-19 pandemic and have become more and more "shut out" and marginalised. An important pathway to integration and self-reliance is sustainable employment. To explore the impacts of COVID-19 on the employment prospects of refugees and people seeking asylum, we conducted 35 interviews with managers from Australian organisations that employ or assist refugees and asylum seekers in finding employment and 20 interviews with refugees and people seeking asylum. Our interviews indicate that the labour market has become more difficult for these groups in the COVID-19 era due to (1) declines in job availabilities, (2) loss of jobs, (3) increased competition in the labour market and (4) increased discrimination and an "Australian first" mentality. Our interviews further suggest four strategies to improve employment prospects in the current situation: (1) pathways to permanent residency and citizenship for people seeking asylum; (2) access to healthcare and a financial safety net; (3) online training and education; and (4) social procurement.

Correlation of Fecal Immunochemical Testing Levels With Pathology Results in a National Colorectal Cancer Screening Program.

INTRODUCTION: Fecal immunochemical testing (FIT) positivity is determined by a threshold decided by individual screening programs. Data are limited on correlation between FIT levels and pathology identified at colonoscopy. Our aim was to examine the correlation between FIT levels and pathology identified in a national colorectal cancer screening program. METHODS: FIT levels (n = 9,271) were analyzed and correlated with patient demographics and pathology identified, including adenomas, sessile serrated lesions, number/size of adenomas, and presence of dysplasia. Levels were divided into 2 categories: FIT levels were defined as "high" or "low" based on whether they were above or below the median (479 ngHb/mL). Multivariate analysis was performed. RESULTS: A total of 8,084 patients (87%) underwent colonoscopy. Those younger than 65 years (odds ratio [OR] 1.267, 95% confidence interval [CI] 1.107-1.45, P = 0.001), those with an adenoma >10 mm (OR 1.736, 95% CI 01.512-1.991, P < 0.001), and those with left-sided adenomas (OR 1.484, 95% CI 1.266-1.74, P < 0.001) had higher FIT levels. Cancers (OR 2.8, 95% CI 2.09-3.75, P < 0.001) and high-grade dysplasia (OR 1.356, 95% CI 1.08-1.7, P = 0.008) had higher FIT levels, but varied greatly. The number of adenomas was not significant. DISCUSSION: In this study, FIT levels were high for left-sided and large adenomas, suggesting that FIT has poor sensitivity for detection of diminutive and right-sided neoplasia. FIT levels had no association with gender and declined with age. Adenoma burden did not correlate with FIT levels; this is a novel finding. FIT levels vary greatly even in those with advanced neoplasia; therefore, FIT is unlikely to be useful as a risk stratification tool.

Characteristics and attitudes of first round invitees in the Irish National Colorectal Cancer Screening Programme.

Background/objective: Colorectal cancer (CRC) screening is proven to reduce CRC-related mortality. Faecal immunochemical testing (FIT)-positive clients in the Irish National CRC Screening Programme underwent colonoscopy. Round 1 uptake was 40.2%. We sought to identify barriers to participation by assessing knowledge of CRC screening and examining attitudes towards FIT test and colonoscopy. Methods: Questionnaires based on a modified Champion's Health Belief Model were mailed to 3500 invitees: 1000 FIT-positive, 1000 FIT-negative and 1500 non-participants. 44% responded: 550 (46%) FIT-positive, 577 (48%) FIT-negative and 69 (6%) non-responders (NR). Results: 25% of respondents (n=286) did not perceive a personal risk of cancer, did not perceive CRC to be a serious disease and did not perceive benefits to screening. These opinions were more likely to be expressed by men (p=0.035). One-fifth (n=251) found screening stressful. Fear of cancer diagnosis and test results were associated with stress. FIT-positive clients, women and those with social medical insurance were more likely to experience stress. Conclusions: The CRC screening process causes stress to one-fifth of participants. Greater use of media and involvement of healthcare professionals in disseminating information on the benefits of screening may lead to higher uptake in round 2.

Impact of the introduction of a new policy of direct faecal immunochemical home screening test provision in a national bowel screening programme, both during and outside of advertising campaigns.

BACKGROUND: BowelScreen, The National Bowel Screening Programme in Ireland, offers free colorectal screening to persons aged 60-69 through a home Faecal Immunochemical Test (FIT) kit. 40.2% uptake in the first screening round was below the programme standard (≥50.0%). To improve uptake, an intervention saw FIT kits sent directly to previously screened clients rather than by the usual invitation process comprising a letter of invitation followed by a FIT kit if requested. The intervention proved successful and was fully implemented into the programme for subsequent clients. Despite the improved uptake it was noted over time that the unsatisfactory FIT rate was approaching the programme standard (≤3%). The aim of this study is to compare uptake by two invite methods occurring contemporaneously alongside advertising and to compare unsatisfactory rates before and after full FIT-Direct implementation. METHODS: Percentage uptake and 95% confidence intervals (CI) were calculated for each invite method before and after advertising and compared using two-proportion z-tests. Rate ratios and 95% CI compared the unsatisfactory FIT rate before and after full-FIT Direct implementation. RESULTS: Uptake was significantly higher amongst FIT-Direct compared with Usual-Invite clients during (91.0% vs 84.9%, p < 0.0001) and outside advertising (93.8% vs 85.3%, p < 0.0001). The unsatisfactory FIT rate was 2.3 times higher (95% CI: 1.84-2.92, p < 0.0001) after full FIT-Direct implementation compared with before. CONCLUSIONS: The FIT-Direct intervention had an overall positive effect on uptake. After adjusting for advertising, uptake of FIT was higher outside advertising periods. Monitoring of the unsatisfactory rate is ongoing; a communication enhancement strategy may be required should this persist.

Impact of a higher fecal immunochemistry test cut-off on pathology detected in subsequent rounds of a colorectal screening program.

BACKGROUND AND AIMS: Fecal immunochemical test (FIT)-based colorectal cancer (CRC) screening is superior to the traditional binary fecal occult blood test. Its quantitative nature allows the investigator to choose a positivity threshold to match cost and endoscope capacity. The optimal threshold is still debated. BowelScreen, the Irish national colorectal cancer screening program, has a cut-off of 45 µg Hb/g feces, and in this study we investigated the impact of this threshold on pathology detected in round 2 in individuals who had a negative result for round 1 FIT (FIT1). METHODS: All individuals with a negative FIT1 result who completed a round 2 FIT (FIT2) 2 years later were included. Pathology outcomes for individuals who had positive FIT2 results were correlated with FIT1 levels. RESULTS: A total of 37,877 individuals had negative FIT1 results and completed FIT2. One thousand two hundred thirty (3.2%) had positive FIT2 results (702 men [57%], median age 69, age range 60-70 years). Quantitative analysis showed that at an FIT1 level <5 µg Hb/g feces, 2.3% had positive FIT2 results. At a higher cut-off of 40.1 to 45 µg Hb/g feces, 15.6% of individuals had positive FIT2 results. One thousand two (81.5%) underwent colonoscopy, with clinical outcomes in all cases. Three hundred fifty-one (35%) had normal colonoscopy results. The proportion of individuals with normal colonoscopy results decreased as FIT1 levels rose. Conversely, advanced pathology (CRC + high-risk adenomas) rates rose from 7% to 50% when FIT1 was <5 compared with 40.1 to 45 µg Hb/g feces, respectively. There were 51 screen-detected cancers in round 2 among individuals with negative FIT1 results (22 stage I, 12 stage II, 14 stage III, 3 stage IV). All 3 stage IV individuals had FIT1 results <20 µg Hb/g feces. CONCLUSIONS: Varying rates of pathology are observed in round 2 of a screening program based on the quantitative level of a negative round 1 FIT result when the positivity threshold is relatively high. A CRC rate of 5.1% within this group appears acceptable. Although patients with incurable cancer were observed, the positivity threshold to capture these cases within round 1 would have been so sensitive that it would create an unsustainable endoscopy referral burden.

A National Bowel Cancer Screening Programme using FIT: Achievements and Challenges.

Colorectal cancer accounts for 11% of all cancer-related deaths in Ireland. With the aim of diagnosing these cancers at an earlier stage, and detecting premalignant lesions, the National Screening Service (NSS) offered a fecal immunochemical test (FIT) to all individuals aged 60 to 69. All individuals in the age range were contacted by post and invited to participate in the programme. Those with a positive FIT result were offered a colonoscopy in an internationally accredited unit. From an eligible population of 488,628, 196,238 individuals participated giving an uptake of 40.2%. Commencing at a FIT threshold of 20 µg Hg/g feces, the positivity rate was 8.6%, which overwhelmed colonoscopy capacity and, thus, the threshold was increased to 45 µg, resulting in an overall 5% positivity rate. A total of 520 individuals had cancer detected (68.3% stage I or II), of which 104 were removed endoscopically (pT1s). Adenomas were present in 54.2% of all colonoscopies, 17.4% deemed high risk. Despite a lower uptake, males were twice as likely to have colorectal cancers as females and had a 59% increased rate of high-risk adenomas diagnosed. Challenges facing the programme include increasing participation, especially among males, and increasing colonoscopy capacity. The ability to alter the sensitivity of FIT to match colonoscopy capacity is a valuable option for such a programme as it ensures that the maximum public health benefit can be achieved within available resources.

A prospective study of faecal immunochemical testing following polypectomy in a colorectal cancer screening population.

INTRODUCTION: 52% of faecal immunohistochemistry test (FIT)-positive clients in the Irish National Colorectal Cancer Screening Programme (BowelScreen) have adenomatous polyps identified at colonoscopy in round 1. Although it is known that advanced adenomas and cancers cause an elevated FIT, it is not known if small (<5 mm) adenomas cause a positive FIT. AIMS: Determine if removal of small polyps in an FIT-based colorectal cancer (CRC) screening programme is associated with a negative FIT on follow-up. METHODS: A single-centre prospective observational study of consecutive participants attending for first round screening colonoscopy who had a positive FIT (>45 µg Hb/g) as part of the Irish Colorectal Cancer Screening Programme. Subjects were consented at the time of colonoscopy and were sent a repeat FIT 4-6 weeks later. Precolonoscopy and postcolonoscopy FITs were compared and correlated with clinical findings and endoscopic intervention. RESULTS: 112 consecutive first round participants were recruited. Eight (7%) had cancer, 75 (67%) adenomatous polyps, 17 (15%) a normal colonoscopy and 12 (11%) other pathology. There was a clear difference in median FIT levels between the four groups (P=0.006). Advanced pathology (tumour or adenomatous polyp >1 cm) was associated with higher FIT than non-advanced pathology (median FIT 346 vs 89 P=0.0003). 83% (86/104) of subjects completed a follow-up FIT. Follow-up FIT remained positive in 20% (17/86). Polypectomy was associated with a reduction in FIT from a median of 100 to 5 µg Hb/g (P<0.0001). Removal of polyps >5 mm was the only factor independently associated with a negative follow-up FIT on multivariate analysis (OR 3.9 (1.3-11.9, P=0.04)). CONCLUSION: FIT is a sensitive test and levels increase with advanced colonic pathology. Polypectomy of advanced adenomas is associated with a negative follow-up FIT. However, alternative causes for a positive FIT should be considered in patients who have adenomas less than 5 mm detected or a normal colonoscopy.

Tumour vasculature immaturity, oxidative damage and systemic inflammation stratify survival of colorectal cancer patients on bevacizumab treatment.

Despite treatment of patients with metastatic colorectal cancer (mCRC) with bevacizumab plus chemotherapy, response rates are modest and there are no biomarkers available that will predict response. The aim of this study was to assess if markers associated with three interconnected cancer-associated biological processes, specifically angiogenesis, inflammation and oxidative damage, could stratify the survival outcome of this cohort. Levels of angiogenesis, inflammation and oxidative damage markers were assessed in pre-bevacizumab resected tumour and serum samples of mCRC patients by dual immunofluorescence, immunohistochemistry and ELISA. This study identified that specific markers of angiogenesis, inflammation and oxidative damage stratify survival of patients on this anti-angiogenic treatment. Biomarkers of immature tumour vasculature (% IMM, p=0.026, n=80), high levels of oxidative damage in the tumour epithelium (intensity of 8-oxo-dG in nuclear and cytoplasmic compartments, p=0.042 and 0.038 respectively, n=75) and lower systemic pro-inflammatory cytokines (IL6 and IL8, p=0.053 and 0.049 respectively, n=61) significantly stratify with median overall survival (OS). In summary, screening for a panel of biomarkers for high levels of immature tumour vasculature, high levels of oxidative DNA damage and low levels of systemic pro-inflammatory cytokines may be beneficial in predicting enhanced survival outcome following bevacizumab treatment for mCRC.

Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers.

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair-deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005-December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9-year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.

Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies (e.g. bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro, ex vivo and in vivo screening models. Quininib (2-[(E)-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro, quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1ß and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a αvß3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC.

Predicting response to vascular endothelial growth factor inhibitor and chemotherapy in metastatic colorectal cancer.

BACKGROUND: Bevacizumab improves progression free survival (PFS) and overall survival (OS) in metastatic colorectal cancer patients however currently there are no biomarkers that predict response to this treatment. The aim of this study was to assess if differential protein expression can differentiate patients who respond to chemotherapy and bevacizumab, and to assess if select proteins correlate with patient survival. METHODS: Pre-treatment serum from patients with metastatic colorectal cancer (mCRC) treated with chemotherapy and bevacizumab were divided into responders and nonresponders based on their progression free survival (PFS). Serum samples underwent immunoaffinity depletion and protein expression was analysed using two-dimensional difference gel electrophoresis (2D-DIGE), followed by LC-MS/MS for protein identification. Validation on selected proteins was performed on serum and tissue samples from a larger cohort of patients using ELISA and immunohistochemistry, respectively (n = 68 and n = 95, respectively). RESULTS: 68 proteins were identified following LC-MS/MS analysis to be differentially expressed between the groups. Three proteins (apolipoprotein E (APOE), angiotensinogen (AGT) and vitamin D binding protein (DBP)) were selected for validation studies. Increasing APOE expression in the stroma was associated with shorter progression free survival (PFS) (p = 0.0001) and overall survival (OS) (p = 0.01), DBP expression (stroma) was associated with shorter OS (p = 0.037). Increasing APOE expression in the epithelium was associated with a longer PFS and OS, and AGT epithelial expression was associated with a longer PFS (all p < .05). Increasing serum AGT concentration was associated with shorter OS (p = 0.009). CONCLUSIONS: APOE, DBP and AGT identified were associated with survival outcomes in mCRC patients treated with chemotherapy and bevacizumab.

Determinants of short- and long-term survival from colorectal cancer in very elderly patients.

PURPOSE: Over 5100 colorectal cancers (CRCs) are diagnosed in the United Kingdom in 85 years and older age group per year but little is known of cancer progression in this group. We assessed clinical, pathological and molecular features of CRC with early and late mortality in such patients. METHODS: Data were analysed in relation to early mortality and long-term survival in 90 consecutive patients with CRC aged 85 years or older in a single hospital. RESULTS: Patients not undergoing operation, those with an ASA score of III or greater and those with advanced tumour stage were more likely to die within 30 days. Regression analysis showed that 30 day mortality was independently related to failure to undergo resection (odds ratio (O.R.), 10.0; 95% confidence interval [C.I.], 1.7-58.2; p=0.01) and an ASA score of III or greater (O.R. 13.0; 95% C.I., 1.4-12.6; p=0.03). All cause three and five year survival were 47% and 23% respectively for patients who are alive 30 days after diagnosis. Three and five year relative survivals were 64% and 54%, respectively. Long-term outcome was independently related to tumour stage (relative risk [R.R.], 2; 95% C.I., 1.3-3.1; p=0.001), presence of co-morbid diseases (R.R., 2.8; 95% C.I., 1.3-6.0; p=0.007) and lipid peroxidation status (R.R., 2.9; 95% C.I., 1.1-7.5; p=0.025). CONCLUSIONS: An active multidisciplinary approach to the care of patients with CRC at the upper extreme of life is reasonable. It also seems sensible to individualise care based upon the extent of disease at diagnosis and the presence of co-morbid conditions. Further studies to examine the role of lipid peroxidation are warranted.

Mortality in inflammatory bowel disease patients under 65 years of age.

OBJECTIVE: To assess mortality in inflammatory bowel disease (IBD) patients under 65 years of age and to identify the factors related to death in this age group. METHODS. We studied 2570 IBD patients who were diagnosed as having disease before 65 years of age and attended a single tertiary referral center area between 1983 and 2012. Follow-up was censored at 65 years. The causes of death were determined from death certificates obtained from the Irish registry office of births, marriages and deaths. Observed all-cause survival was compared with expected survival of persons of the same age and sex in the general population. Expected survival was obtained from national life tables produced by the central statistics office. Survival estimates were calculated for disease type, disease site, gender, the presence of primary sclerosing cholangitis (PSC), immunomodulator use, biologic therapy use, presence of fistulating disease and prior surgery. RESULTS: Fifty-two deaths were reported in the population younger than 65 years, of which 41 were IBD related. We found little difference in survival in the first 25 years of follow-up, but relative survival decreased in both the Crohn's disease (CD) and ulcerative colitis (UC) cohort thereafter, so that 30-year mortality was excessive in both groups. An adjusted multivariate regression analysis of patients with CD identified PSC as the only predictor of premature mortality (p = 0.003). PSC was also identified as the only independent predictor of mortality in UC patients (p = 0.03). CONCLUSIONS: The presence of PSC poses the greatest risk for mortality in both UC and CD.

Microscopic colitis: clinical characteristics, treatment and outcomes in an Irish population.

BACKGROUND AND AIMS: Many aspects of microscopic colitis remain poorly understood. Our aim was to report a single centre experience with this condition. METHODS: Two hundred and twenty-two patients (52 male, 170 female; median age 64 years; range 32-90) diagnosed between 1993 and 2010 were studied. Medical notes were reviewed, and data on age, gender, clinical features, history of autoimmune diseases, medication use, cigarette smoking, histology and outcome were collected. RESULTS: There were 99 cases of lymphocytic and 123 of collagenous colitis. Diarrhoea was almost invariably present (98 %) while abdominal pain (24 %), weight loss (10 %), faecal incontinence (8 %) and blood PR (5 %) were also described. Twenty-eight percent had concomitant autoimmune diseases, most commonly coeliac disease. Patients were taking a variety of medications at diagnosis thought to be associated with microscopic colitis including NSAIDs (22 %), aspirin (19 %), statins (15 %), proton pump inhibitors (19 %) and SSRIs (10 %) at diagnosis. Prior to the widespread use of budesonide in our institution, 33 % of patients required two or more medications during therapy compared to 15 % following the introduction of budesonide (p = 0.001). Thirty-eight percent of patients achieved spontaneous remission with either no treatment or simple anti-diarrhoeals. Using a multivariate model, the only factor associated with spontaneous remission was male gender (RR 1.9; 95 % CI 1.0-3.6; p = 0.04). Two patients had refractory microscopic colitis; one required a colectomy while a more recent case has responded to anti-TNFα therapy. CONCLUSION: Microscopic colitis is predominantly a benign and self-limiting disorder. The introduction of budesonide has revolutionised treatment of this lesser studied inflammatory bowel disease.

Depth-dependent differences in community structure of the human colonic microbiota in health.

OBJECTIVE: The aims of this study were to develop techniques for spatial microbial assessment in humans and to establish colonic luminal and mucosal spatial ecology, encompassing longitudinal and cross-sectional axes. DESIGN: A microbiological protected specimen brush was used in conjunction with a biopsy forceps to sample the colon in nine healthy volunteers undergoing colonoscopy. Terminal Restriction Fragment Length Polymorphism analysis was used to determine the major variables in the spatial organization of the colonic microbiota. RESULTS: Protected Specimen Brush sampling retrieved region-specific, uncontaminated samples that were enriched for bacterial DNA and depleted in human DNA when compared to biopsy samples. Terminal Restriction Fragment Length Polymorphism analysis revealed a segmentation of bacterial communities between the luminal brush and biopsy-associated ecological niches with little variability across the longitudinal axis of the colon and reduced diversity in brush samples. CONCLUSION: These results support the concept of a microbiota with little longitudinal variability but with some degree of segregation between luminal and mucosal communities.

The influence of CTGF single-nucleotide polymorphisms on outcomes in Crohn's disease.

OBJECTIVE: To examine the association between single-nucleotide polymorphisms (SNPs) in CTGF (connective tissue growth factor) and patient outcomes after terminal ileal resection for Crohn's disease. BACKGROUND: The primary indication for intestinal resection in Crohn's disease is fibrostenotic terminal ileal disease. CTGF is a cytokine overexpressed in the intestine of patients with Crohn's disease that influences outcomes in other disease processes. METHODS: DNA was extracted from formalin-fixed, paraffin-embedded tissue from 147 patients with Crohn's disease who had undergone terminal ileal resection between 1981 and 2009. Genotyping was performed for 4 CTGF SNPs (rs9402373, rs12526196, rs6918698, and rs9399005), which modulate nuclear factor binding and CTGF production, and a smad3 SNP (rs17293632) involved in the CTGF pathway. Patients were phenotyped using the Montreal Disease Classification. RESULTS: Sixty-seven of 147 patients (45.6%) were male; the mean age at diagnosis was 30.3 ± 12.6 years and the mean follow-up duration was 8.3 ± 7.1 years. Genotype-phenotype analysis demonstrated that the rs6918698GG genotype was associated with an older age of disease onset [>40 years; 30.6% vs 13.2%; odds ratio (OR): 2.891; 95% confidence interval (CI): 1.170-7.147). The rs9402373CC genotype was positively associated with type B1 disease (50.7% vs 26.3%; OR: 2.876; 95% CI: 1.226-6.743) and negatively associated with B2 disease (37.0% vs 65.0%; OR: 0.317; 95% CI: 0.144-0.699). None of the 5 SNPs assessed influenced clinical or surgical recurrence of Crohn's disease after intestinal resection. On multivariate analysis, male sex odds ratio (OR): 0.235; 95% CI: 0.073-0.755; P = 0.015] and never having smoked tobacco (OR: 0.249; 95% CI: 0.070-0.894; P = 0.033) reduced the risk, whereas having a prior appendectomy increased the risk (OR: 5.048; 95% CI: 1.632-15.617; P = 0.005) of surgical recurrence. CONCLUSIONS: These data implicate the rs6918698GG genotype with an age of disease onset of greater than 40 years in Crohn's disease whereas the rs9402373CC genotype is associated with a nonstricturing, nonpenetrating disease phenotype. CTGF SNPs do not influence the rate of recurrence after terminal ileal resection for Crohn's disease.

Efficacy of Adalimumab as a long term maintenance therapy in ulcerative colitis.

INTRODUCTION: Adalimumab is a recombinant human IgG1 monoclonal antibody to TNF-alpha. There are limited data with regard to its efficacy in ulcerative colitis. We report experience of adalimumab in ulcerative colitis in a single centre with a focus on the ability of this agent to maintain response and avoid colectomy in the medium to long-term. METHODS: Twenty-three ulcerative colitis patients (mean age 32 years; 7 female) who received adalimumab were identified from a prospectively maintained database of over 2700 IBD patients. The primary study endpoint was treatment failure defined as discontinuation of adalimumab due to lack of efficacy, as defined by requiring an alternative maintenance therapy or colectomy, or intolerance. Colectomy rate was recorded as a secondary endpoint. RESULTS: Most patients (96%) had received immunosuppressants prior to adalimumab therapy (infliximab 20/23 87%). Sixteen of 23 patients (70%) discontinued adalimumab. Six primary failures, 8 secondary loss of response, one had unacceptable side effects and one discontinued treatment after 6 months but remains in remission. Overall estimated cumulative treatment failure rates at 6, 12 and 24 months were 50%, 65% and 72% respectively. Median follow-up in patients continuing adalimumab is 23 months (IQR 17-31 months). Treatment failure was unrelated to patient age, gender, disease extent, smoking status or CRP. Colectomy free survival was 59% at 2 years. No patient experienced a major adverse event. CONCLUSION: Adalimumab shows some efficacy as a maintenance strategy in Ulcerative Colitis, but only a limited proportion of patients remain well on continued treatment at 2 years.

Effects of radiation on levels of DNA damage in normal non-adjacent mucosa from colorectal cancer cases.

PURPOSE: Defects in DNA repair pathways have been linked with colorectal cancer (CRC). Adjuvant radiotherapy has become commonplace in the treatment of rectal cancer however it is associated with a higher rate of second cancer formation. It is known that radiation results in DNA damage directly or indirectly by radiation-induced bystander effect (RIBE) by causing double-strand breaks (DSBs). The majority of work in RIBE has been performed in cell lines and limited studies have been in or ex vivo. METHODS: The first study aim was to examine by immunohistochemistry, levels of DSB (expression of the protein MRE11) in normal colonic tissue outside the irradiated field post neo-adjuvant radiotherapy (group 1). These levels were compared to (a) irradiated tumour tissue post neo-adjuvant radiation within the same group, (b) a CRC patient group (group 2) who had not undergone neo-adjuvant radiotherapy and (c) a non-cancer patient group (group 3). The second aim was to determine if MRE11 expression levels were related to survival or radio-sensitivity post neo-adjuvant radiotherapy. RESULTS: There was a highly significant increase in MRE 11 expression in group 1 versus groups 2 and 3 (p < 0.001). There was no association between MRE11 levels and survival or radio-sensitivity. CONCLUSION: Our findings show radiotherapy causes DSBs at significantly higher levels in normal colonic mucosa of patients post neo-adjuvant treatment which may represent RIBE. If this damage remains unrepaired, increased levels of genomic instability may contribute to the higher occurrence of second cancers in patients treated post neo-adjuvant radiotherapy.

Prolonged avoidance of repeat surgery with endoscopic balloon dilatation of anastomotic strictures in Crohn's disease.

BACKGROUND AND AIMS: There is a high rate of stricturing post-operative recurrence in Crohn's disease (CD) particularly at sites of surgical anastomosis, and over 50% of these patients will require a repeat resection. Endoscopic dilatation of anastomotic strictures is an alternative to surgical resection in selected patients. We aimed to evaluate the safety and long term efficacy of endoscopic balloon dilatation of symptomatic anastomotic strictures in CD. METHODS: Retrospective analysis of a prospectively maintained inflammatory bowel disease database of patients attending a single academic centre (n=1244 patients with CD) who underwent dilatation. RESULTS: Fifty-five dilatations were performed in 31 patients (mean age 43 ± SD 12, 47% female). Median follow-up period was 46 months (IQR 14-62). Ninety percent of patients had successful initial dilatation and no complications occurred. Six (21%) avoided further dilatations or surgery in the follow-up period. Stricture recurrence was detected in 22 patients; 15 (54%) patients had repeat dilatations and seven (25%) went straight to surgery. Eight (28%) patients were managed with repeat dilatations of the stricture (median dilatations=2 range 2-6) and seven (25%) required surgery despite repeat dilatations. Median time from first dilatation to repeat surgery was 14.5 months (IQR 3-28) and to repeat dilatation was 13.8 months (IQR 4-28). There was no difference in immunomodulator use, biologic use and smoking status between the groups requiring surgery versus dilatation only. CONCLUSION: Endoscopic balloon dilatation of anastomotic strictures is safe and effective in providing symptomatic relief in CD patients. Forty-five percent of patients had a sustained response to single/serial balloon dilatation with avoidance of further surgical resection for a median interval of 46 months. Post-operative medical therapy and smoking status did not predict requirement for recurrent dilatation or surgery.