Screen-detected colorectal cancers show improved cancer-specific survival when compared with cancers diagnosed via the 2-week suspected colorectal cancer referral guidelines.

AIM: Biennial screening for colorectal cancer using faecal occult blood testing has been shown to reduce the relative risk of mortality from colorectal cancer. The Norwich screening centre commenced screening in July 2006 and so far has diagnosed over 350 patients with colorectal cancer. We compared the stage at diagnosis and cancer-specific mortality and survival in patients diagnosed through screening with a cohort of symptomatic patients with colorectal cancer within the same age range. METHOD: A comparative analysis was undertaken of all screen-detected colorectal cancer patients diagnosed between July 2006 and December 2010, with an age-matched group of patients diagnosed in the Norfolk and Norwich Hospital through the 2-week suspected colorectal cancer guidelines. RESULTS: Three hundred and fifty-six cases of colorectal cancer were diagnosed through the screening programme, in patients with an age range of 60-79 years. In the same time period, 292 patients in the same age range were diagnosed with colorectal cancer through the 2-week suspected colorectal cancer pathway. Sixteen patients in the screening group had evidence of metastatic disease at presentation compared with 62 in the symptomatic group (χ(2) , P<0.001). The proportion of T1/T2 and Dukes A cancers was significantly greater in the screening group (χ(2) , P < 0.001). There were 21 colorectal cancer-related deaths in the screening group compared with 66 in the symptomatic group. Survival analysis curves showed significantly better survival in the screening group (log-rank analysis P<0.001). CONCLUSION: Screening for colorectal cancer identifies cancers at a significantly earlier stage than in symptomatic patients, with subsequent improvement in cancer-specific survival.

Incidence of perforated diverticulitis and risk factors for death in a UK population.

BACKGROUND: Perforated diverticulitis (PD) remains a serious acute abdominal condition. The aims of this study were to measure its incidence in a large UK population and to identify factors affecting outcomes. METHODS: Computerized searches of hospital coding databases for PD were performed in five hospitals in East Anglia, UK. Data were collected from hospital records over 5 years (1995-2000). Incidence was calculated using population data, and factors associated with mortality and morbidity were identified using univariable and multivariable testing. RESULTS: Some 202 patients with PD were identified, of whom 93.1 per cent underwent surgery and 24.3 per cent died. The age-adjusted adult incidence of perforation was 3.5 per 100 000 per annum, with a standardized female to male ratio of 1.3 (95 per cent confidence interval (c.i.) 1.1 to 1.5) to 1. Risk factors for death were increased age (odds ratio (OR) 3.5 (95 per cent c.i. 1.9 to 6.1)), pre-existing renal disease (OR 18.7 (1.6 to 211.4)) and pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) (OR 3.1 (1.3 to 7.3)). CONCLUSION: PD is uncommon, with the highest incidence in women over 65 years old. Mortality rates are high, particularly in those taking NSAIDs or with pre-existing renal impairment.

Do calcium channel blockers and antimuscarinics protect against perforated colonic diverticular disease? A case control study.

BACKGROUND: The aetiology of perforated colonic diverticular disease (PCDD) remains largely unknown. Perforation may result from a combination of high intracolonic pressures, secondary to excessive colonic segmentation, and impairment of the mucosal barrier. Calcium channel blockers and antimuscarinic drugs, which reduce colonic contractility and tone, could potentially protect against perforation. The aim of this study was to test this hypothesis using a case control design. METHODS: All cases of acute PCDD were identified over a five year period in two hospitals in Norfolk, UK. Each case was matched for age, sex, and date of admission to two controls groups: (1) patients undergoing cataract surgery and (2) patients with basal cell carcinoma. Data on drug use prior to hospital admission were obtained from medical and nursing records and compared between cases and controls. RESULTS: A total of 120 cases of PCDD were identified and matched to 240 controls in each group. A statistically significant protective association was seen between calcium channel blocker use and PCDD using both control groups. The odds ratios were 0.41 (95% confidence interval (CI) 0.18-0.93) using the ophthalmology control group and 0.36 (95% CI 0.16-0.82) using the dermatology control group. CONCLUSIONS: This study has shown for the first time that a protective association exists between calcium channel blockers and PCDD. The validity of this association is supported by the consistent finding in both control groups and the plausible biological mechanisms. Further studies are required to confirm this association but calcium channel blockers may represent a potential preventive therapy in PCDD.

Anti-inflammatory drugs, analgesics and the risk of perforated colonic diverticular disease.

BACKGROUND: Acute perforated colonic diverticular disease has a mortality rate of up to 30 per cent, but little is known about its aetiology. The aim of this study was to test the hypothesis that three classes of drugs, namely non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics and corticosteroids, are risk factors for perforated diverticular disease. METHODS: All patients with confirmed perforated colonic diverticular disease were identified over a 5-year period in two hospitals in Norfolk, UK. Two control groups were selected and matched for age, sex and hospital of admission. Data on medication use were obtained from hospital records. Odds ratios for each drug were calculated using conditional logistic regression. RESULTS: Opioid analgesics, NSAIDs and corticosteroids were all positively associated with perforated colonic diverticular disease. The odds ratio for opioid analgesics was 1.8 (95 per cent confidence interval (c.i.) 1.1 to 3.0) in the analysis with ophthalmology controls and 3.1 (95 per cent c.i. 1.8 to 5.5) in that with dermatology controls. Respective odds ratios for NSAIDs were 4.0 (95 per cent c.i. 2.1 to 7.6) and 3.7 (95 per cent c.i. 2.0 to 6.8), and those for corticosteroids were 5.7 (95 per cent c.i. 2.2 to 14.4) and 7.8 (95 per cent c.i. 2.6 to 23.3). CONCLUSION: Opioid analgesics, NSAIDs and corticosteroids are all positively associated with perforated colonic diverticular disease. The consistency of these associations, together with plausible biological mechanisms, suggests that these drugs may have a causative role in this condition.

Postoperative stay following colorectal surgery: a study of factors associated with prolonged hospital stay.

AIM: To study the factors that contribute to postoperative stay following colorectal surgery. DESIGN: A prospective observational study. SETTING: Three colorectal surgical units - a teaching hospital, a large district general hospital and a district general hospital. PARTICIPANTS: 350 patients undergoing colorectal surgery. MAIN OUTCOME MEASURES: 28 pre-, peri- and postoperative patient- and treatment-related factors. RESULTS: Stepwise regression analysis suggests that the factors that significantly lengthen postoperative stay include a low albumin on admission, stoma formation, operative blood loss, urinary and respiratory complications, wound infections, postoperative ventilation and social delay at the time of discharge. The postoperative stay was not affected by patient age or by the seniority of the surgical team. CONCLUSIONS: Factors have been identified that determine the postoperative length of stay. These data may allow better planning and treatment of patients undergoing colorectal surgery.

Epidemiology of perforated colonic diverticular disease.

Perforated colonic diverticular disease results in considerable mortality and morbidity. This review appraises existing evidence on the epidemiology and mechanisms of perforation, highlights areas of further study, and suggests an epidemiological approach towards preventing the condition. Computerised searches were used to identify published articles relating to the epidemiology, pathophysiology, and clinical features of perforated colonic diverticular disease. Several drug and dietary exposures have potential biological mechanisms for causing perforation. Of these only non-steroidal anti-inflammatory drugs have been consistently identified as risk factors in aetiological studies. The causes of perforated colonic diverticular disease remain largely unknown. Further aetiological studies, looking specifically at perforation, are required to investigate whether cause-effect relationships exist for both drug and dietary exposures. The identification of risk factors for perforation would allow primary public health prevention, secondary risk factor modification, and early prophylactic surgery to be aimed at people at high risk.

Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor.

The distribution of polymorphisms in the glutathione S-transferase (GST) family genes has been studied in 355 healthy controls and 206 cancer (59 proximal and 147 distal) patients. All controls were subjected to flexible sigmoidoscopy. Odds ratios (OR) after stratification by age, gender and smoking were slightly higher in the cancer group as a whole for GSTM1-null (*0/*0), GSTT1-null (*0/*0) and GSTM3 *A/*B or *B/*B when compared with the control group, but the differences did not reach statistical significance. GSTP1 variants had no effect. Separate analysis of patients with proximal and distal tumours has shown stronger associations for the distal cancers, the GSTM3*B allele presence being significantly more frequent in these patients [OR = 1.77; 95% confidence interval (CI) = 1.15-2.74]. Taking into account strong linkage between the GSTM1*A and GSTM3*B alleles, a separate analysis of the GSTM1-nulled individuals was undertaken. The combination of GSTM1-null genotype with GSTM3*B allele presence (*A/*B or *B/*B) was significantly overrepresented among patients with proximal and distal tumours taken together (OR = 2.12; 95% CI = 1.24-3.63), and especially in distal cancer patients (OR = 2.75; 95% CI = 1.56-4.84). Male individuals displayed a stronger association between the presence of the GSTM1-null in combination with GSTM3 *A/*B or *B/*B and distal tumours with a higher odds ratio (OR = 3.57; 95% CI = 1.73-7.36). In contrast, the frequency of GSTM1 *B/*0 or *B/*B combined with GSTM3 *A/*A was significantly lower in patients with distal colorectal cancer, especially in males (OR = 0.37; 95% CI = 0.15-0.92). Neither of these combinations was associated with proximal tumours. Our findings suggest that interactions of polymorphic genotypes within the GSTM gene cluster affect individual susceptibility to colorectal carcinogenesis, the GSTM3*B variant presence being a risk factor especially in combination with the GSTM1-null genotype.

How frequently do large bowel diverticula perforate? An incidence and cross-sectional study.

The aetiology of perforation of large bowel diverticula is poorly understood and a case-control study is required to identify the causes. Before such a study can be attempted, the incidence must be determined and groups at particular risk identified. Cases of perforated large bowel diverticula living in the Norwich postal code region treated between 1995 and 1997 were identified. Fifty-eight cases presented in a population of 531 241. The incidence was 4.0 cases per 100,000 per year, increased with age and was higher in men than women (5.8 vs 3.1). The most frequently used drugs were non-steroidal anti-inflammatory drugs (NSAIDs) (29%) and opiate analgesics (26% of cases). This is the first report of the incidence of perforated diverticular disease and allows a calculation of the population size needed to recruit sufficient cases for an aetiological investigation. The differences in incidence between genders should prompt a search for factors which differ between the sexes such as diet. NSAIDs are a known risk factor, although the data show that opiate analgesics should be investigated.

K-ras mutations, rectal crypt cells proliferation, and meat consumption in patients with left-sided colorectal carcinoma.

It has been suggested that N-nitroso compounds derived from meat may increase the risk of K-ras mutations in the human colon. We sought evidence of associations between red meat consumption, frequency and type of K-ras mutations in resected tumours, and the rate of crypt cell proliferation (CCP) in the normal mucosa of patients with left-sided colorectal carcinoma. Meat consumption was assessed by food frequency questionnaire, and CCP was determined in rectal biopsies obtained prior to surgery. K-ras mutations in the resected tumours were determined using a PCR-based oligonucleotide hybridization assay. Fifteen K-ras mutations were detected in tumours from 43 patients; 13/15 in codon 12, 3/15 in codon 13, and 1/15 in both codons 12 and 13. All mutations were G-->A or G-->T transitions. There was no statistically significant difference between intakes of red meat in patients with a K-ras mutation (92.4 +/- 9.7 g/day) and those without (82.3 +/- 7.7 g/day). Rectal CCP was significantly higher in patients than in healthy controls, but there was no correlation with meat consumption or K-ras mutation. These data do not support the hypothesis that meat consumption is a risk factor for acquisition of K-ras mutations during colorectal carcinogenesis.

Consumption of fish oil leads to prompt incorporation of eicosapentaenoic acid into colonic mucosa of patients prior to surgery for colorectal cancer, but has no detectable effect on epithelial cytokinetics.

Fish oil (FO) was previously reported to partially normalize colorectal crypt cell cytokinetics in patients with colorectal neoplasms. We determined the effect of FO on the fatty acid composition of colonic mucosa and mesenteric adipose tissue and on rectal crypt cell proliferation in patients undergoing surgery for colonic carcinoma. Patients (49-28 males; 21 females) were randomly assigned to consume FO capsules (2 g b.d.; FO group) containing 1.4 g eicosapentaenoic acid (EPA) and 1.0 g docosahexaenoic acid per day, or safflower oil capsules (2 g b.d.; placebo group) for an average of 12.3 +/- 0.5 d prior to surgery. Rectal biopsies were obtained at entry, at surgery, and 8-12 wk postsurgery. Colonic biopsies and samples of mesenteric adipose tissue were analyzed for fatty acids by gas-liquid chromatography. Mitosis was determined in whole crypt mounts. The proportion of EPA (g/100 g total fatty acids) in mucosal lipids was significantly greater in FO patients compared to the placebo group, but there was no effect on mesenteric adipose tissue. However self-reported use of FO supplements prior to surgery was associated with higher levels of EPA in adipose tissue. There was no significant effect of FO on the frequency or spatial distribution of crypt cell mitosis. EPA from marine oil supplements is rapidly incorporated into the colonic mucosal lipids of humans, but the levels achieved in the present study did not modify colorectal cytokinetics.

Comparison of duplex ultrasonography and venography in the diagnosis of deep venous thrombosis.

Sixty-five patients with suspected deep venous thrombosis (DVT) in 68 limbs were entered consecutively into a study to compare venography with duplex ultrasonography scanning. Both tests were performed on 64 limbs, venography being contraindicated in four. Overall, duplex scanning correctly identified 86 per cent of DVTs diagnosed on venography and correctly excluded 80 per cent with negative venograms. Nearly all errors arose in the diagnosis of calf DVT. In the femoral vein duplex scanning had a specificity of 100 per cent and a sensitivity of 95 per cent. In addition, duplex scanning provided data on the limb not undergoing venography. Of 55 limbs that underwent bilateral duplex scanning, five had thrombus in the femoropopliteal segment and a negative contralateral venogram. In addition, three Baker's cysts were diagnosed. Duplex scanning can be used in patients in whom venography is contraindicated and may also provide information about the contralateral limb. We regard femoropopliteal duplex scanning as sufficiently accurate that treatment can be initiated on the basis of the scan. Duplex scanning should replace venography as the standard method of diagnosing femoropopliteal DVT; radiographic studies should now be required only when the scan result is in doubt.

Variations in steroid receptor status with disease stage in breast cancer.

Oestrogen and progesterone receptor (ER and PgR) distribution in three clinical subgroups of 421 breast carcinomas was analysed. The groups comprised (1) early breast cancer (T1-2a, N0M0; n = 64); (2) untreated advanced fungating cancer (n = 27) and (3) advanced cancer relapsing after endocrine therapy (n = 29). Receptor distribution in each of the subgroups was compared to that of the total population. The advanced fungating group contained no ER--ve/PgR--ve tumours and the distribution was also significantly different from the total population (P less than 0.001 by Chi-squared test). The proportion of tumours in the total population that contained greater than 40 fmol/mg ER was 187/421 (44.4%). There was no significant difference between the early breast cancer group and the total population (P greater than 0.9). However, the proportion of tumours containing ER greater than 40 fmol/mg in the advanced fungating cancer group (16/27, 59.3%) was significantly higher than in the total population (P less than 0.01). This difference may be partially explained by the older age at presentation in this group. In the relapsed after endocrine therapy group only four of 29 (13.8%) contained ER greater than 40 fmol/mg which was significantly different from the total (P less than 0.001). There was a higher proportion of early breast cancers containing PgR greater than 40 fmol/mg than in the total population (P less than 0.001). There was no significant difference between PgR distribution in the advanced fungating and relapsed groups compared to the total population. The data suggest that patients presenting with advanced fungating cancer are more likely to respond to endocrine therapy than the population as a whole, and that in breast cancer that has relapsed following endocrine therapy receptor levels decrease with progression of the disease.

Effect of steroid hormones on human colorectal adenocarcinoma xenografts, of known steroid-receptor status, in nude mice.

The effect of hormone therapy on the growth of human colonic adenocarcinoma xenografts in nude mice was evaluated. Primary xeno-transplantation for ten different human colorectal adenocarcinomas into nude mice yielded a tumour take of 50%. One of these host tumours was found to contain androgen receptors (8 fmol/mg cytosol protein; Kd 0.73 x 10(-9) M), which were maintained in the xenograft at the third and ninth passages, but not expressed at the tenth and twelfth passages. The host tumour and its xenograft did not express either oestrogen or progesterone receptors. Administration of dihydrotestosterone led to inhibition of xenograft growth at the ninth passage compared with untreated controls (P less than 0.05), but had no effect on xenograft growth at the tenth and twelfth passages when androgen receptors were absent. Stilboestrol and progesterone failed to influence xenograft growth. In conclusion, dihydrotestosterone administration led to inhibition of xenograft growth only in the presence of androgen receptor, suggesting that some colorectal cancers might be considered steroid-hormone-sensitive tumours.

A hybrid ligand method for androgen receptor measurement.

Existing techniques for androgen receptor (AR) assay are complicated by cross-reactivity of ligand binding affinities that can lead to incorrect estimation of receptor concentration. Two most frequently used ligands are [3H]dihydrotestosterone [( 3H]DHT) and [3H]methyltrienolone [( 3H]R1881), which in addition to binding to AR also bind to sex hormone binding globulin (SHBG; Kd = 1.5 nM) and progesterone receptors (PgR; Human Kd = 1 nM, rat Kd = 6 nM) respectively. Triamcinolone acetonide (TMA) is commonly used to block binding of [3H]R1881 to PgR, however at high concentrations TMA itself will bind AR (Kd = 7 microM). We have developed a hybrid ligand method for the measurement of AR in the presence of SHBG and PgR. This method used [3H]R1881 as the high specific activity labelled tracer and DHT as the unlabelled competitor of specific AR binding. Using this assay, 20% of human colorectal carcinomas were found to contain AR.