Impact of deprivation on short- and long-term outcomes after colorectal cancer surgery.

BACKGROUND: The aim of the study was to determine the association between short- and long-term outcomes and deprivation for patients undergoing operative treatment for colorectal cancer in the Northern Region of England. METHODS: This was a retrospective analytical study based on the Northern Region Colorectal Cancer Audit Group database for the period 1998-2002. The Index of Multiple Deprivation 2004, an area-based measure, was recalibrated and used to quantify deprivation. Patients were ranked based on their postcode of residence and grouped into five categories. RESULTS: Of 8159 patients in total, 7352 (90·1 per cent) had surgery; 6953 (94·6 per cent) of the 7352 patients underwent tumour resection and 4935 (67·7 per cent) of 7294 had a margin-negative (R0) resection. Deprivation was not associated with age, sex, tumour site, stage or other tumour-related factors. Compared with the most affluent group, the most deprived patients had fewer elective operations (72·9 versus 76·4 per cent; P = 0·014), more adverse co-morbidity (P < 0·001) and fewer curative resections (65·5 versus 71·2 per cent; P < 0·001). In multivariable analysis, deprivation was not an independent predictor of postoperative death (odds ratio (OR) 0·72, 95 per cent confidence interval 0·48 to 1·06; P = 0·101) but it was a predictor of curative resection (OR 1·24, 1·01 to 1·52; P = 0·042), overall survival (HR 0·83, 0·73 to 0·95; P = 0·006) and relative survival (HR 0·74, 0·58 to 0·95; P = 0·023). CONCLUSION: Deprivation, both independently and by influencing other surgical predictors, impacts on short- and long-term outcomes of patients with colorectal cancer.

Postinfectious irritable bowel syndrome may occur after non-gastrointestinal and intestinal infection.

Postinfectious functional gastrointestinal disorders (FGIDs) may not be specific to gastroenteritis. This pilot study aimed to ascertain the 3- and 6-month incidence of functional gut disorders in people with non-gastrointestinal (GI) infection, gastroenteritis and healthy controls. This was a prospective study of three cohorts recruited from hospital (non-GI infections) and the community (others). FGIDs were diagnosed using self-completed Rome II modular questionnaires administered at baseline, 3 and 6 months. Thirty-six subjects with non-GI infection, 219 healthy subjects and 108 with bacterial gastroenteritis participated. No difference in incidence of FGID was detected between the GI and non-GI infection cohorts. Any FGID was more frequent in people who had a non-GI infection than in controls at both 3 [odds ratio: 4.34 (95% CI: 3.60-16.45)] and 6 months [4.76 (4.42-27.92)]. Irritable bowel syndrome (IBS) alone was more frequent in people with non-GI infections than in controls at 3 months (6.12 [1.30-29.12]) but did not quite reach statistical significance at 6 months (4.58 [0.79-26.46]). Our findings were unexpected. Postinfectious FGIDs may be related to non-GI and GI infection, although not all potential biases were controlled in study design. Further studies need to explore these preliminary findings and, if confirmed, the underlying mechanisms.

Detailed modelling of caffeine metabolism and examination of the CYP1A2 gene: lack of a polymorphism in CYP1A2 in Caucasians.

The cytochrome P450 CYP1A2 is important in the metabolism of both drugs and procarcinogens such as heterocyclic amines. We aimed to clarify the existence of a phenotypic polymorphism and explore the molecular basis of such a polymorphism. Ninety-two non-smoking individuals underwent caffeine phenotyping. The distribution of the 1,7-dimethylxanthine + 1,7-dimethyluracil/caffeine (17U + 17X/137X) ratio and log-transformed data were determined. Probit plots were constructed and the distribution fitted using maximum likelihood method. The CYP1A2 gene, including upstream regulatory regions, was examined for sequence polymorphisms using the single-strand conformation polymorphism technique in 19 individuals and by complete DNA sequencing in two individuals from the extremes of the distribution. We found a similar range (1.45-18.65) and median (6.7) for the 17U + 17X/137X ratio to that found in previous studies of non-smoking Caucasians and no effect of sex. The 17U + 17X/137X ratio gave a normal distribution when log-transformed. Maximum likelihood analysis showed that the log-normal and bimodal distributions had similar deviances but the log-normal distribution was favoured because it has fewer parameters. There was no evidence for significant DNA sequence differences between fast and slow metabolizers, although some differences from published sequences including a silent polymorhpism in exon 7 which were unlikely to be of functional significance were found. We therefore conclude that CYP1A2 does not show functionally significant polymorphism but that the wide interindividual variation in activity may be due to environmental factors.

Polymorphisms in GSTP1, GSTM1, and GSTT1 and susceptibility to colorectal cancer.

Polymorphisms in glutathione S-transferase (GSTs) may predispose to colorectal cancer through deficient detoxification of environmental carcinogens, although previous results are conflicting. A study with 178 matched case-control pairs was conducted to determine the effect of the GSTT1 and GSTM1 null genotypes and polymorphisms in GSTP1 on colorectal cancer susceptibility. In a secondary analysis, we examined interactions between genotypes and with the N-acetyltransferase 2 (NAT2) genotype. Heterogeneity by age, sex, site, and stage of cancer was also examined. No effect of any genotype for GSTM1, GSTT1, or GSTP1 on colorectal cancer susceptibility was detected. Secondary end points showed that individuals with both the GSTT1 null and NAT2 slow genotypes combined appeared to be at increased risk of colorectal cancer (odds ratio = 2.33; 95% confidence interval, 1.1-5.0). We conclude that GST polymorphisms alone do not predispose to colorectal cancer in northeast England. We also observed possible effects of the GSTT1 null genotype on the age and stage at presentation, and these, together with the findings of an apparent interaction with NAT2 genotypes, need to be confirmed in further studies.

The Angelchik antireflux device: a 5-year experience.

A total of 44 patients had an Angelchik antireflux prosthesis inserted over a 5-year period. Of these, 41 were available for review and were assessed by interview using a modified Visick grading. Of the 23 patients followed up for a minimum of 3 years 74% had an excellent or satisfactory outcome; 92% of patients with symptoms of reflux obtained relief, but less than 50% of those patients presenting with dysphagia had a satisfactory outcome. The incidence of mild postoperative dysphagia increased the longer the period of follow-up. The main cause of a Visick 3 or 4 result was prosthesis migration. We have modified our technique of insertion to reduce these complications, and in a more recent series have achieved a Visick Grade 1 or 2 in up to 92% of patients. We conclude that dysphagia is a relative contraindication to the insertion of the Angelchik prosthesis. Our recent results encourage the use of the prosthesis provided steps are taken to reduce the incidence of migration and pericapsular fibrous tissue formation.

Co-morbidities as predictors of mortality in Clostridium difficile infection and derivation of the ARC predictive score.

Clostridium difficile associated diarrhoea (CDAD) has increased significantly in the last 15 years, but predictors of outcome are inadequately understood. This was a cohort study of 2761 patients in North East England between 2002 and 2009, with the end-point of mortality at 30 days. The role of age, gender and co-morbidities was examined by binary logistic regression. Rounded odds ratios were used to develop a predictive score. A predictive score based on age, renal disease and cancer (ARC score) differentiated groups with differing risk of 30-day mortality (risk for score of 0-3 was 9-21%, score of 4-7 was 31-48% and score of 8 was 66%). Co-morbidities were shown to be important predictors of outcome in CDAD, and can be combined with age in the ARC score to assess the likelihood of survival. This requires further validation in other populations, but has important implications for clinical and research practice.

Thirty-day mortality of Clostridium difficile infection in a UK National Health Service Foundation Trust between 2002 and 2008.

Few standardised data are available on mortality rates in patients with Clostridium difficile infection (CDI). The literature often reports 'attributable' mortality or cannot be universally applied. We aimed to investigate the pattern and trends in all-cause mortality in a large unselected cohort of patients affected by CDI. This was done by means of a retrospective cohort study between 2002 and 2008 of all patients with positive stool toxin tests indicating CDI in one National Health Service (NHS) Trust, comprising three general hospitals and seven community hospitals. Vital status of the patients was determined from two sources. In total, 2571 patients with a first episode of CDI were identified (1638 females; median age 82.1 years). Cumulative mortality at 7 days, 14 days, 30 days and 1 year was 13.4%, 20.8%, 32.5% and 58.7%, respectively. There was no significant difference in mortality between sex, year of diagnosis or hospital site. Mortality at 30 days increased incrementally from 3.4% in those aged <40 years to 41% in those >90 years. Mortality rates were significantly higher than reported by previous studies but were remarkably consistent over the time period and between different hospitals within the Trust. Prognosis falls with increasing age, and the age of this cohort may explain the high 30-day absolute mortality. CDI infection is associated with high early mortality. To reduce mortality, new interventions need to be introduced soon after diagnosis. There is a need for standardised outcome data for CDI.

The effect of NAT2 genotype and gender on the metabolism of caffeine in nonsmoking subjects.

AIMS: To establish whether gender or N-acetyltransferase 2 (NAT2) genotype influence the urinary 17 U+17X/137X ratio after dosing with caffeine. METHODS: Ninety-two nonsmoking individuals underwent caffeine phenotyping. NAT2 genotype was determined by the polymerase chain reaction followed by a restriction digest (PCR-RFLP). RESULTS: The median ratio for urinary 17 U+17X/137X was 6.7 (range 1.45-18. 65). 55% of subjects were slow acetylators. Gender did not affect the metabolic ratio or NAT2 genotype. Mean 17 U+17X/137X ratio differed between fast (6.75) and slow (8.69) acetylators (95% CI for the difference, 0.32-3.56). CONCLUSIONS: The findings are further evidence that the 17 U+17X/137X urinary ratio is not a robust measure of CYP1A2 activity. A possible mechanism by which the ratio might be influenced by NAT2 genotype is suggested.

Relationship between acetylator status, smoking, and diet and colorectal cancer risk in the north-east of England.

Some previous studies have suggested that the fast phenotype of the N-acetyltransferase NAT2 may confer susceptibility to colorectal cancer because of greater activation of dietary heterocyclic amines, particularly in individuals who also consume well-done red meat, but other studies have not supported this. We describe a large case-control study examining the interaction between dietary, smoking and drinking habits, and acetylation genotype in relation to susceptibility to colorectal cancer. One-hundred-and-seventy-four incident cases and 174 matched controls were recruited. Genotyping for polymorphisms in NAT2 was performed using a method that detects >95% of slow alleles and data on personal habits were collected using a standardized questionnaire. We found no difference in the frequency of the fast acetylator genotype between cases and controls [odds ratio = 0.95 (95% CI 0.61-1.49)], and analysis by sex, age and site also revealed no difference in acetylator genotype. There was, however, considerable heterogeneity in dietary risk factors between fast and slow acetylators. Analysis by acetylator type shows that recent smoking was more frequent in slow acetylator cases than matched controls [OR = 2.31 (1.16-4.6)] and that heavy alcohol consumption was also more frequent in the slow acetylator cases than controls [OR = 2.5 (1.02-7.29)]. In contrast, frequent fried meat intake was seen more frequently in fast acetylator cases than matched controls [OR = 6.0 (1.34-55)]. The odds ratio for the combination of fast acetylator status and frequent fried meat consumption in cases was 6.04 (1.6-26). Our study suggests that there may be different risk factors for colorectal cancer in slow and fast acetylators, and reveals a new observation that slow acetylators may be at risk of colon cancer from smoking. In our community, the overall effect of acetylator status on colorectal cancer risk is neutral.

A comparison of the discriminatory power of the Inflammatory Bowel Disease Questionnaire and the SF-36 in people with ulcerative colitis.

The aim of this study was to compare the discriminatory power of a generic and a condition-specific quality of life measure (the Medical Outcomes Study Short-Form 36 (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ)) with respect to sub-groups defined by disease-related and other factors, in a sample of patients with ulcerative colitis. Disease activity was generally more highly correlated with IBDQ scores than with SF-36 scores. The only significant differences with respect to disease extent were in the SF-36 energy/vitality and social function domains. Age was negatively and weakly to moderately correlated with the physical domains of the SF-36 but positively though weakly correlated with scores on the IBDQ emotional domain and those domains of the SF-36 related to mental well-being. Co-existing chronic illness, even on controlling for age, was associated with significantly poorer scores on the generic measure, but had little influence on IBDQ scores. In conclusion, generic and disease-specific measures of quality of life appear to be complementary rather than interchangeable. We recommend the use of both types of measure in parallel.

Absence of a genetic association between IL-1RN and IL-1B gene polymorphisms in ulcerative colitis and Crohn disease in multiple populations from northeast England.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract of unknown aetiology, phenotypically categorized into ulcerative colitis (UC) and Crohn disease (CD). Genetic factors are of considerable importance in both. The genetic relationship between IBD and the interleukin-1 receptor antagonist and interleukin-1beta genes (IL-1RN, and IL-1B, respectively) has been extensively studied. However, the quality and outcome of the genetic association studies, in particular the association with IL-1RN*2, have been variable and these associations remain controversial. The aim of the present study was to re-investigate these two candidate genes in a large series of IBD patients from a genetically homogeneous population with low levels of population admixture, and provide a definitive answer to this question. METHODS: A total of 529 northern European Caucasoid patients with IBD (347 UC, 182 CD) and 289 racially and geographically matched healthy controls were studied. The IL-1RN and IL-1B genotypes, allele frequencies and most probable haplotypes were determined by standard PCR protocols. RESULTS: There were no significant differences in the distributions of the IL-1RN and IL-1B genotypes, allele frequencies or haplotypes in either patient series compared to healthy controls or between clinical subsets. Genotype distribution and frequency data for allele 2 (IL-1RN*2) in particular showed no significant differences across all patient groups for all three series. CONCLUSION: The findings of this study lead us to reject the IL-1RN*2 association with IBD.

The short inflammatory bowel disease questionnaire is reliable and responsive to clinically important change in ulcerative colitis.

OBJECTIVE: The Short Inflammatory Bowel Disease Questionnaire (SIBDQ) is a health-related quality of life (HRQoL) tool measuring physical, social, and emotional status (score 10-70, poor to good HRQoL). The SIBDQ has been predominantly used in trials for Crohn's disease, and further validation of the SIBDQ is desirable in ulcerative colitis (UC) patients. The primary objective was to further validate the SIBDQ by examining discriminant ability against measures of disease activity. The secondary objectives were to examine reliability and responsiveness to change. METHODS: UC patients attending hospital completed the SIBDQ and two activity indices. Patients' disease status (remission, mild, moderate, or severe relapse) was determined subjectively by the patients and their physician. RESULTS: Scores were obtained for 69 events in 61 patients. mean age 47.8 yr (range 16-79). All classes of disease extent were represented. The mean SIBDQ score was 48.4 (13-70). The difference between mean score in patients in remission and relapse was -20.1 (95% CI = -25.1 to -15.1). The difference for remission and mild relapse was -14.6 (95% CI = -8.9 to -20.2). The correlation between SIBDQ and the activity indices were good, r = -0.83 and r = -0.61. Eight patients presented twice. Those with unchanged disease status showed no significant difference in the mean SIBDQ score. Patients whose disease status had deteriorated from remission to mild relapse, or from mild to moderate relapse demonstrated a mean reduction of 11.8 points (95% CI = 20.1-3.4). CONCLUSIONS: This study contributes to the validation of the SIBDQ as a HRQoL tool in UC. It is reproducible and responsive to changes in disease activity.

The inflammatory bowel disease questionnaire: a valid and reliable measure in ulcerative colitis patients in the North East of England.

BACKGROUND: The validity and reliability of the Inflammatory Bowel Disease Questionnaire (IBDQ) needed to be confirmed before its use in the UK. METHODS: The IBDQ was administered to 28 subjects with ulcerative colitis (UC) on 3 separate occasions over a period of 4 weeks, twice by an interviewer and once by self-completion. Convergent and concurrent validity was assessed by using the Colitis Activity Index (CAI) and the Short Form 36 Health Survey (SF-36). Test-retest reliability and internal consistency were also tested. RESULTS: There were moderately high Pearson correlations between related IBDQ domains and SF-36 dimensions and also between the CAI score and the IBDQ Bowel domain and the SF-36 Pain dimension. Cronbach's alpha, corrected item-total correlations, and intra-class correlation coefficients were high. CONCLUSIONS: The IBDQ is a valid and reliable health-related quality of life scale for use in patients with UC and is suitable for use in the UK.

The CC chemokine receptor 5 delta32 mutation is not associated with inflammatory bowel disease (IBD) in NE England.

Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases of the gastrointestinal tract of unknown aetiology. Evidence of abnormalities in immune regulation and cytokine production in patients with IBD has led to investigations of various immuno-regulatory genes as potential candidate susceptibility loci. Studies using whole genome scanning have highlighted chromosomes 3, 7, 12 and 16. A 32 base-pair deletion in the CC-chemokine receptor-5 gene (CCR5-A32, chromosome 3p21.3) has been associated with susceptibility to IBD. We have investigated CCR5 as a candidate susceptibility gene in 350 patients (251 with ulcerative colitis and 99 with Crohn's disease) and 103 controls using polymerase chain reaction. There were no significant differences in the distribution of CCR5 genotypes or frequencies comparing patients and controls, or associations with extent of colitis. In contrast to preliminary data, these findings suggest no evidence for involvement of this mutation in susceptibility/resistance or disease progression in IBD.

The MRCP (UK) examination from the patient's point of view.

Each year approximately 3,200 volunteer patients attend the examinations of the Royal College of Physicians in England and Wales. A confidential postal questionnaire concerning patients' experiences and satisfaction was administered to those attending North Tees General Hospital in June 1992 with a 90% response rate. The majority of patients derive some enjoyment from the experience and do not mind being repeatedly examined, some even up to eight times per session; but they do feel neglected if examined only once per session. Twenty-two per cent of first time attenders would have liked to have had more information about the proceedings beforehand.

Experiences of volunteer patients during undergraduate examinations: printed information can lead to greater satisfaction.

BACKGROUND: Whilst most patients are happy to participate in medical examinations, previous studies have shown that some are dissatisfied with the information that they receive beforehand. OBJECTIVES: To demonstrate that patient satisfaction can be improved by the provision of written information. METHODS: Thirty-seven patients attending the final MBBS examination were sent written information about what to expect. The patients' experiences were assessed by means of an anonymous postal questionnaire 1 week after the examination. Their satisfaction with the level of information received beforehand was compared with that of an historical cohort who had received no written information. RESULTS: The patients had few complaints about their experience of participating in examinations and many enjoyed it. Only 5% of patients registered dissatisfaction with the level of information that was provided, compared with 18% in the previous study (P = 0.077). CONCLUSIONS: Written information led to a (near significant) improvement in patients satisfaction when compared to a previous cohort. We recommend that all patients attending for medical examinations should be provided with written information.

Defining relapse of ulcerative colitis using a symptom-based activity index.

BACKGROUND: Several tools exist to assess disease activity in patients with ulcerative colitis (UC), but a definition of relapse does not exist. The aim of the study was to determine the score in the Simple Clinical Colitis Activity Index (SCCAI) that defined relapse. The reliability and validity of the SCCAI when self-administered was also examined. METHODS: Patients with UC routinely attending hospital completed the SCCAI questionnaire, which was later administered by their clinician blinded to the scoring process. In the absence of a gold standard definition of relapse, a subjective global assessment of disease status was made by the clinician. The SCCAI was evaluated in a separate cohort of patients. RESULTS: Seventy-one presentations were analysed; mean age 48 years, 49% male, 37% relapse rate. The mean patient score was 4.2 (range 0-14) and mean physician score 3.8 (0-14). A score of 5 or more defined relapse with 92% sensitivity, 93% specificity, 88% positive predictive value and 95% negative predictive value. The difference between the scores obtained by the patient and clinician (0.35, 95% CI 0.09-0.62) was small. Correlation with a more complex symptom and laboratory-based activity index was very high (r = 0.79, P < 0.01). The index was quick to use and comparative results for sensitivity and specificity were recorded in the second cohort of patients. CONCLUSIONS: The SCCAI is a simple tool that can be accurately and quickly self-administered, correlates well with a more complex disease activity index, and can be used to define relapse of UC with high specificity and sensitivity.

Esophageal mucin: an adherent mucus gel barrier is absent in the normal esophagus but present in columnar-lined Barrett's esophagus.

OBJECTIVES: The presence of a protective adherent mucus gel barrier against gastric reflux in the healthy esophagus is uncertain. The aim was to characterize the surface mucin composition and determine the extent of any adherent mucus gel layer on the normal esophagus, and compare this with that in Barrett's esophagus. METHODS: Isolated surface mucins were characterized by density centrifugation, gel filtration chromatography, and chemical composition. Adherent surface mucus was visualized in situ on unfixed and cryostat sections of mucosa and biopsies using a method that preserves mucus layer thickness. RESULTS: There was a complete absence of adherent mucus gel layers on normal human, pig, and rat esophagi. This was in contrast to the thick adherent mucous layer (median thickness = 100-200 microm) seen on the corresponding gastric mucosa. Small quantities of glycoprotein with a composition characteristic of a secretory mucin were isolated from the pig esophagus surface. The mucin, density range between 1.44 and 1.48 g x ml(-1), contained 80% carbohydrate and was rich in serine, threonine, and proline. The mucin fragmented into smaller glycoprotein units on proteolysis and partially on reduction. Cryostat sections from columnar-lined esophageal biopsies had a substantial adherent surface mucous layer (median thickness = 90 microm, interquartile range = 84-94 microm) staining for neutral mucins (gastric-type epithelium) and acidic mucins (intestinal metaplasia). CONCLUSIONS: A secretory mucin, with an analysis distinct from that of gastric or salivary mucin, is present in very small quantities on the esophageal mucosa and in amounts insufficient to form an adherent gel layer. It is unlikely that mucus has a role in protecting the normal esophagus against reflux. However, an adherent mucous layer was observed over columnar-lined esophagus, and this may protect against reflux.