Scottish Bowel Screening Programme colonoscopy quality - scope for improvement?

AIM: The delivery of the Scottish Bowel Screening Programme (SBoSP) is rooted in the provision of a high quality, effective and participant-centred service. Safe and effective colonoscopy forms an integral part of the process. Additional accreditation as part of a multi-faceted programme for participating colonoscopists, as in England, does not exist in Scotland. This study aimed to describe the quality of colonoscopy in the SBoSP and compare this to the English national screening standards. METHODS: Data were collected from the SBoSP between 2007 and 2014. End-points for analysis were caecal intubation, cancer, polyp and adenoma detection, and complications. Overall results were compared with 2012 published English national standards for screening and outcomes from 2006 to 2009. RESULTS: During the study period 53 332 participants attended for colonoscopy. The colonoscopy completion rate was 95.6% overall. The mean cancer detection rate was 7.1%, the polyp detection rate was 45.7% and the adenoma detection rate was 35.5%. The overall complication rate was 0.47%. CONCLUSION: Colonoscopy quality in the SBoSP has exceeded the standard set for screening colonoscopy in England, despite not adopting a multi-faceted programme for screening colonoscopy. However, the overall adenoma detection rate in Scotland was 9.1% lower than that in England which has implications for colonoscopy quality and may have an impact on cancer prevention rates, a key aim of the SBoSP.

An evidence-based treatment algorithm for colorectal polyp cancers: results from the Scottish Screen-detected Polyp Cancer Study (SSPoCS).

OBJECTIVES: Colorectal polyp cancers present clinicians with a treatment dilemma. Decisions regarding whether to offer segmental resection or endoscopic surveillance are often taken without reference to good quality evidence. The aim of this study was to develop a treatment algorithm for patients with screen-detected polyp cancers. DESIGN: This national cohort study included all patients with a polyp cancer identified through the Scottish Bowel Screening Programme between 2000 and 2012. Multivariate regression analysis was used to assess the impact of clinical, endoscopic and pathological variables on the rate of adverse events (residual tumour in patients undergoing segmental resection or cancer-related death or disease recurrence in any patient). These data were used to develop a clinically relevant treatment algorithm. RESULTS: 485 patients with polyp cancers were included. 186/485 (38%) underwent segmental resection and residual tumour was identified in 41/186 (22%). The only factor associated with an increased risk of residual tumour in the bowel wall was incomplete excision of the original polyp (OR 5.61, p=0.001), while only lymphovascular invasion was associated with an increased risk of lymph node metastases (OR 5.95, p=0.002). When patients undergoing segmental resection or endoscopic surveillance were considered together, the risk of adverse events was significantly higher in patients with incomplete excision (OR 10.23, p<0.001) or lymphovascular invasion (OR 2.65, p=0.023). CONCLUSION: A policy of surveillance is adequate for the majority of patients with screen-detected colorectal polyp cancers. Consideration of segmental resection should be reserved for those with incomplete excision or evidence of lymphovascular invasion.

MicroRNA-224 is associated with colorectal cancer progression and response to 5-fluorouracil-based chemotherapy by KRAS-dependent and -independent mechanisms.

BACKGROUND: Colorectal cancers arise from benign adenomas, although not all adenomas progress to cancer and there are marked interpatient differences in disease progression. We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients. METHODS: We used TaqMan low-density array (TLDA) qRT-PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion. RESULTS: MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 KRAS WT cells phenocopied KRAS mutation, increased KRAS activity and ERK and AKT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells. CONCLUSIONS: We describe a novel mechanism of KRAS regulation, and highlight the clinical utility of colorectal cancer-specific miRNAs as disease progression or clinical response biomarkers.

A survey of reporting of colorectal cancer in Scotland: compliance with guidelines and effect of proforma reporting.

AIMS: The main purpose of the study was to present a baseline audit of reporting of colorectal cancers resection specimens in Scotland, audited against the Royal College of Pathologists (RCPath) standards (2007) and NHS Quality Improvement Scotland (NHS QIS) standards. METHODS: 50 consecutive rectal and 50 consecutive colonic cancer cases from 2011 were audited from 10 Scottish health boards involved in colorectal cancer reporting (n=953). The rates of reporting of serosal involvement, extramural venous invasion (EMVI) and the mean numbers of lymph nodes found were audited against RCPath standards and compared between units that routinely used a reporting proforma versus those that did not. RESULTS: The performance in reporting of rectal cancer was generally worse than for colonic cancer, with only three units meeting the RCPath standards for reporting of rectal cancer. There were significant differences between units that routinely used a proforma, with the non-proforma group failing to meet the minimum standards for both serosal involvement (6%) and EMVI (24%). In the non-proforma group, 56% of rectal cases had a mean lymph node count of 12 or more compared with 81% in the proforma group. CONCLUSIONS: Significant differences exist in the frequencies with which important adverse prognostic features are reported by pathologists across 10 Scottish health boards. This has potential implications for patient care. Health boards that make routine use of reporting proformas are more likely to meet RCPath guidelines for reporting of these important pathological parameters.

Patterns of uptake in a biennial faecal occult blood test screening programme for colorectal cancer.

AIM: The patterns of response in faecal occult blood test (FOBT) screening were studied. METHOD: A total of 251,578 people invited three times for faecal occult blood testing were categorized according to how they responded to the invitations, as follows: YNN, NYN, NNY, NYY, YNY, YYN, YYY or NNN (Y = response; N = no response). RESULTS: Overall, 163,038 (64.8%) responded at least once, and of those the biggest category was YYY (98,494, 60.4%). Of 1927 cancers diagnosed in the age group eligible for screening, there were 405 screen-detected cancers, 529 interval cancers and 993 cancers arising in people who had not been screened for over 2 years (i.e. falling outside the interval cancer category). In the YYY group, 79 screen-detected cancers would have been missed had the members of this group responded YNN and 65 had they responded YYN. In the YYN group, 104 screening cancers would have been missed if they had followed the YNN pattern. In most cases, the screen-detected cancers were diagnosed at the last invitation accepted, indicating that, after a diagnosis of cancer, further screening invitations were rarely accepted. Accordingly, the numbers of screen-detected and interval cancers were adjusted for likely pattern of response according to the proportion of the whole population falling into each pattern. With this adjustment, 40.9% of the cancers in the YYY group were screen detected compared with 29.3% in the YYN group and 20.7% in the YNN group (P < 0.001). Among those who responded once, twice and three times, the stage distribution of screen-detected cancers was similar, indicating that the prognosis of screen-detected cancer is unlikely to be poorer if not detected at the first screen. CONCLUSION: This study is the first to examine patterns of response to screening invitations and confirms the importance to individuals of continuing to accept repeated screening invitations.

Low faecal haemoglobin concentration potentially rules out significant colorectal disease.

AIM: The study aimed to determine whether faecal haemoglobin (Hb) concentration can assist in deciding who with lower abdominal symptoms will benefit from endoscopy. METHOD: Faecal Hb concentrations were measured on single samples from 280 patients referred for lower gastrointestinal tract endoscopy from primary care in NHS Tayside who completed a faecal immunochemical test (FIT) for Hb and underwent subsequent endoscopy. RESULTS: Among 739 invited patients, FIT and endoscopy were completed by 280 (median age 63 (18-84) years; 59.6% women), with a median time between FIT and endoscopy of 9 days. Six (2.1%) participants had cancer, 23 (8.2%) had high-risk adenoma (HRA) (more than three adenomas or any > 1 cm), 31 (11.1%) low-risk adenoma (LRA) and 26 (9.3%) inflammatory bowel disease (IBD) as the most serious diagnosis. Those with cancer had a median faecal Hb of > 1000 ng Hb/ml buffer. Those with cancer + HRA + IBD had a median faecal Hb concentration of 75 ng Hb/ml buffer (95% CI 18-204), which was significantly higher than that of all remaining participants without significant colorectal disease (P < 0.0001). Using a cut-off faecal Hb concentration of 50 ng Hb/ml buffer, negative predictive values of 100.0%, 94.4%, 93.4% and 93.9% were found for cancer, HRA, LRA and IBD. Patients with reasons for referral other than rectal bleeding and family history did not have high faecal Hb concentrations. CONCLUSION: Faecal Hb concentration measurements have considerable potential to contribute to reducing unnecessary endoscopy for the majority of symptomatic patients.

The impact of population-based faecal occult blood test screening on colorectal cancer mortality: a matched cohort study.

BACKGROUND: Randomised trials show reduced colorectal cancer (CRC) mortality with faecal occult blood testing (FOBT). This outcome is now examined in a routine, population-based, screening programme. METHODS: Three biennial rounds of the UK CRC screening pilot were completed in Scotland (2000-2007) before the roll out of a national programme. All residents (50-69 years) in the three pilot Health Boards were invited for screening. They received a FOBT test by post to complete at home and return for analysis. Positive tests were followed up with colonoscopy. Controls, selected from non-pilot Health Boards, were matched by age, gender, and deprivation and assigned the invitation date of matched invitee. Follow-up was from invitation date to 31 December 2009 or date of death if earlier. RESULTS: There were 379 655 people in each group (median age 55.6 years, 51.6% male). Participation was 60.6%. There were 961 (0.25%) CRC deaths in invitees, 1056 (0.28%) in controls, rate ratio (RR) 0.90 (95% confidence interval (CI) 0.83-0.99) overall and 0.73 (95% CI 0.65-0.82) for participants. Non-participants had increased CRC mortality compared with controls, RR 1.21 (95% CI 1.06-1.38). CONCLUSION: There was a 10% relative reduction in CRC mortality in a routine screening programme, rising to 27% in participants.

Negative screening colonoscopy after a positive guaiac faecal occult blood test: not a contraindication to continued screening.

AIM: In guaiac faecal occult blood test (gFOBT) screening at least 50% of positive individuals will have a colonoscopy negative for colorectal neoplasia. The question of continuing screening in this group has not been addressed. METHOD: Data on participants aged 50-69 years with a positive gFOBT result and a negative colonoscopy were followed through the biennial screening pilot conducted between 2000 and 2007 in Scotland. RESULTS: In the first screening round, 1527 colonoscopies were negative for neoplasia. 1300 were re-invited in the second round, 905 accepted, and 157 had a positive gFOBT result, giving a positivity rate of 17.4%. Colonoscopy revealed 20 subjects with adenoma and six with invasive cancer. In the third screening round 1031 were invited for a third time and 730 accepted: 55 had a positive gFOBT test, giving a positivity rate of 7.5%. In this group, six colonoscopies revealed adenomas but there were no cancers diagnosed. In the third screening round, 108 individuals had had two positive gFOBT results and two subsequent negative colonoscopies. Eighty-four were invited for a third gFOBT, 66 accepted and 19 (25.6%) had a positive result none of whom had an adenoma or carcinoma. CONCLUSION: These data indicate that a negative colonoscopy following a positive gFOBT is not a contraindication for further screening, although this is likely to have a low yield of neoplastic pathology after two negative colonoscopies.

Interval cancers in a FOBT-based colorectal cancer population screening programme: implications for stage, gender and tumour site.

BACKGROUND: Between 2000 and 2007, a demonstration pilot of biennial guaiac faecal occult blood test (GFOBT) screening was carried out in Scotland. METHODS: Interval cancers were defined as cancers diagnosed within 2 years (ie, a complete screening round) of a negative GFOBT. The stage and outcome of the interval cancers were compared with those arising contemporaneously in the non-screened Scottish population. In addition, the gender and site distributions of the interval cancers were compared with those in the screen-detected group and the non-screened population. RESULTS: Of the cancers diagnosed in the screened population, interval cancers comprised 31.2% in the first round, 47.7% in the second, and 58.9% in the third, although this was due to a decline in the numbers of screen-detected cancers rather than an increase in interval cancers. There were no consistent differences in the stage distribution of interval cancers and cancers from the non-screened population, and, in all three rounds, both overall and cancer-specific survival were significantly better for patients diagnosed with interval cancers (p<0.01). The percentage of cancers arising in women was significantly higher in the interval cancer group (50.2%) than in either the screen-detected group (35.3%, p<0.001) or the non-screened group (40.6%, p<0.001). In addition, the proportion of both right-sided and rectal cancers was significantly higher in the interval cancer group than in either the screen-detected (p<0.001) or non-screened (p<0.004) groups. CONCLUSIONS: Although GFOBT screening is associated with substantial interval cancer rates that increase with screening round, the absolute numbers do not. Interval cancers are associated with a better prognosis than cancers arising in a non-screened population, and GFOBT appears to preferentially detect cancers in men and the left side of the colon at the expense of cancers in women and in the right colon and rectum.

Pyrosequencing-based methods reveal marked inter-individual differences in oncogene mutation burden in human colorectal tumours.

BACKGROUND: The epidermal growth factor receptor-targeted monoclonal antibody cetuximab (Erbitux) was recently introduced for the treatment of metastatic colorectal cancer. Treatment response is dependent on Kirsten-Ras (K-Ras) mutation status, in which the majority of patients with tumour-specific K-Ras mutations fail to respond to treatment. Mutations in the oncogenes B-Raf and PIK3CA (phosphoinositide-3-kinase) may also influence cetuximab response, highlighting the need for a sensitive, accurate and quantitative assessment of tumour mutation burden. METHODS: Mutations in K-Ras, B-Raf and PIK3CA were identified by both dideoxy and quantitative pyrosequencing-based methods in a cohort of unselected colorectal tumours (n=102), and pyrosequencing-based mutation calls correlated with various clinico-pathological parameters. RESULTS: The use of quantitative pyrosequencing-based methods allowed us to report a 13.7% increase in mutation burden, and to identify low-frequency (<30% mutation burden) mutations not routinely detected by dideoxy sequencing. K-Ras and B-Raf mutations were mutually exclusive and independently associated with a more advanced tumour phenotype. CONCLUSION: Pyrosequencing-based methods facilitate the identification of low-frequency tumour mutations and allow more accurate assessment of tumour mutation burden. Quantitative assessment of mutation burden may permit a more detailed evaluation of the role of specific tumour mutations in the pathogenesis and progression of colorectal cancer and may improve future patient selection for targeted drug therapies.

Effect of repeated invitations on uptake of colorectal cancer screening using faecal occult blood testing: analysis of prevalence and incidence screening.

OBJECTIVE: To analyse the effects of prevalence and incidence screening on uptake and detection of cancer in an ongoing, dynamic programme for colorectal screening using faecal occult blood testing. DESIGN: Analysis of prevalence and incidence screening. SETTING: Three rounds of biennial colorectal screening using the guaiac faecal occult blood test in east and north east Scotland, March 2000 to May 2007. PARTICIPANTS: Adults aged 50-69. MAIN OUTCOME MEASURES: Uptake of screening, test positivity (percentage of those invited who returned a test that was positive and triggered an invitation for colonoscopy), positive predictive value, and stage of cancer. RESULTS: Of 510 990 screening episodes in all three rounds, 248 998 (48.7%) were for prevalence, 163 483 (32.0%) were for first incidence, and 98 509 (19.3%) were for second incidence. Uptake of a first invitation for prevalence screening was 53% and for a second and third invitation was 15% and 12%. In the cohort invited for the first round, uptake of prevalence screening rose from 55% in the first round to 63% in the third. The uptake of first incidence screening on a first invitation was 54% and on a second invitation was 86% and on a first invitation for second incidence screening was 46%. The positivity rate in prevalence screening was 1.9% and the uptake of colonoscopy was 87%. The corresponding values for a first incidence screen were 1.7% and 90% and for a second incidence screen were 1.1% and 94.5%. The positive predictive value of a positive faecal occult blood test result for cancer was 11.0% for prevalence screening, 6.5% for the first incidence screen, and 7.5% for the second incidence screen. The corresponding values for the positive predictive value for adenoma were 35.5%, 29.4%, and 26.7%. The proportion of cancers at stage I dropped from 46.5% for prevalence screening to 41% for first incidence screening and 35% for second incidence screening. CONCLUSIONS: Repeat invitations to those who do not take up the offer of screening increases the number of those who accept, for both prevalence screening and incidence screening. Although the positive predictive value for both cancer and adenomas fell between the prevalence screen and the first incidence screen, they did not fall between the first and second incidence screens. The deterioration in cancer stage from prevalence to incidence screening suggests that some cancers picked up at incidence screening may have been missed on prevalence screening, but the stage distribution is still favourable. These data vindicate the policies of continuing to offer screening to those who fail to participate and continuing to offer biennial screening to those who have accepted previous offers.

Effect of gender, age and deprivation on key performance indicators in a FOBT-based colorectal screening programme.

OBJECTIVES: To assess the effect of gender, age and deprivation on key performance indicators in a colorectal cancer screening programme. SETTING: Between March 2000 and May 2006 a demonstration pilot of biennial guaiac faecal occult blood test (gFOBT) colorectal screening was carried out in North-East Scotland for all individuals aged 50-69 years. METHODS: The relevant populations were subdivided, by gender, into four age groups and into five deprivation categories according to the Scottish Index of Multiple Deprivation (SIMD), and key performance indicators analysed within these groups. RESULTS: In all rounds, uptake of the gFOBT increased with age (P < 0.001), decreased with increasing deprivation in both genders (P < 0.001), and was consistently higher in women than in men in all age and all SIMD groups. In addition, increasing deprivation was negatively associated with uptake of colonoscopy in men with a positive gFOBT (P < 0.001) although this effect was not observed in women. Positivity rates increased with age (P < 0.001) and increasing deprivation (P < 0.001) in both genders in all rounds, although they were higher in men than in women for all age and SIMD categories. Cancer detection rates increased with age (P < 0.001), were higher in men than in women in all age and SIMD categories, but were not consistently related to deprivation. In both genders, the positive predictive value (PPV) for cancer increased with age (P < 0.001) and decreased with increasing deprivation (P < 0.001) in all rounds and was consistently higher in men than in women in all age and SIMD categories. CONCLUSIONS: In this population-based colorectal screening programme gender, age, and deprivation had marked effects on key performance indicators, and this has implications both for the evaluation of screening programmes and for strategies designed to reduce inequalities.

Activating K-Ras mutations outwith 'hotspot' codons in sporadic colorectal tumours - implications for personalised cancer medicine.

BACKGROUND: Response to EGFR-targeted therapies in colorectal cancer patients has been convincingly associated with Kirsten-Ras (K-Ras) mutation status. Current mandatory mutation testing for patient selection is limited to the K-Ras 'hotspot' codons 12 and 13. METHODS: Colorectal tumours (n=106) were screened for additional K-Ras mutations, phenotypes compared in transformation and Ras GTPase activating assays and gene and pathway changes induced by individual K-Ras mutants identified by microarray analysis. Taqman-based gene copy number and FISH analyses were used to investigate K-Ras gene amplification. RESULTS: Four additional K-Ras mutations (Leu(19)Phe (1 out of 106 tumours), Lys(117)Asn (1 out of 106), Ala(146)Thr (7 out of 106) and Arg(164)Gln (1 out of 106)) were identified. Lys(117)Asn and Ala(146)Thr had phenotypes similar to the hotspot mutations, whereas Leu(19)Phe had an attenuated phenotype and the Arg(164)Gln mutation was phenotypically equivalent to wt K-Ras. We additionally identified a new K-Ras gene amplification event, present in approximately 2% of tumours. CONCLUSIONS: The identification of mutations outwith previously described hotspot codons increases the K-Ras mutation burden in colorectal tumours by one-third. Future mutation screening to facilitate optimal patient selection for treatment with EGFR-targeted therapies should therefore be extended to codon 146, and in addition should consider the unique molecular signatures associated with individual K-Ras mutations.

Results from the first three rounds of the Scottish demonstration pilot of FOBT screening for colorectal cancer.

OBJECTIVES: To assess the effects of the first three rounds of a pilot colorectal screening programme based on guaiac faecal occult blood testing (gFOBT) and their implications for a national population-based programme. METHODS: A demonstration pilot programme was conducted in three Scottish NHS Boards. Residents aged between 50 and 69 years registered on the Community Health Index were included in the study. RESULTS: In the first round, the uptake was 55.0%, the positivity rate was 2.07% and the cancer detection rate was 2.1/1000 screened. In the second round, these were 53.0%, 1.90% and 1.2/1000, respectively, and in the third round, 55.3%, 1.16% and 0.7/1000, respectively. In the first round, the positive predictive value of the gFOBT was 12.0% for cancer and 36.5% for adenoma; these fell to 7.0% and 30.3% in the second round and were maintained at 7.5% and 29.1% in the third round. The percentage of screen-detected cancers diagnosed at Dukes' stage A was 49.2% in the first round, 40.1% in the second round and 36.3% in the third round. CONCLUSIONS: These results are compatible with those of previous randomised trials done in research settings, demonstrating that population-based colorectal cancer screening is feasible in Scotland and should lead to a comparable reduction in disease-specific mortality.

Prognostic and therapeutic implications of Apc mutations in colorectal cancer.

The adenomatous polyposis coli gene (Apc) is mutated in most colorectal cancers. The multifunctional character of the Apc protein in the regulation of beta-catenin-mediated gene transcription and cytoskeletal proteins has been well described. An important question is how this protein affects the behaviour of cells within a tumour and how its mutational status influences the prognosis for these tumours. Here we provide an overview of the functions of Apc and examine how this information can be used in the prognosis and development of directed therapy in colorectal cancer.

Automated immunochemical quantitation of haemoglobin in faeces collected on cards for screening for colorectal cancer.

BACKGROUND: Simple card collection systems are becoming available for faecal immunochemical tests (FITs) as well as guaiac faecal occult blood tests (gFOBTs). FITs are now obtainable that allow quantitation of haemoglobin, so that the analytical detection limit can be set to give a positivity rate that is manageable in terms of the available colonoscopy. A combination of a card collection device and an automated FIT analytical system could be advantageous. METHODS: The quantitation of haemoglobin in samples collected on cards with a new analytical system and the relationship between faecal haemoglobin concentration and pathology were investigated in a cohort of gFOBT-positive individuals. RESULTS: All groups had large ranges of haemoglobin concentration and there was overlap between the groups. Median haemoglobin concentrations in participants with normal findings on colonoscopy (167), diverticular disease (43), hyperplastic polyps (41), low risk adenoma (63), higher risk adenoma (35) and cancer (27) were 13.5, 15.6, 16.8, 15.2, 65.6 and 168.9 ng/ml haemoglobin, respectively. Those with diverticular disease, hyperplastic polyps and low risk adenoma were not significantly different from the normal group (p>0.2), but those with higher risk adenoma had significantly higher concentrations (p<0.001), as did those with cancer (p<0.001). Receiver operating characteristic analysis demonstrates that the cut-off concentration can be set to give appropriate clinical characteristics; optimum sensitivity and specificity are achieved at 26.7 ng/ml. CONCLUSIONS: The haemoglobin in faeces on simple FIT card collection devices can be immunoturbidimetrically analysed quantitatively, and the concentration relates to the presence or absence of significant neoplastic disease.

Relationship between point gene mutation, chromosomal abnormality, and tumour suppressor gene methylation status in colorectal adenomas.

Epigenetic mechanisms in carcinogenesis may have a significant role in the development of colorectal cancer. To investigate this phenomenon in early-stage disease, promoter methylation status in the tumour suppressor genes APC, MGMT, hMLH1, P14/P14ARF, and CDKN2A/P16 was investigated in 78 colorectal adenomas. These had previously been characterized for mutations of APC, KRAS, and TP53 genes and for chromosomal abnormality by comparative genomic hybridization (CGH). APC hypermethylation was seen in 52 tumours (66.7%). APC showed either methylation or mutation in 66 lesions (84.6%), but these events were not statistically associated. MGMT methylation was detected in 39 cases (50%). Adenomas with this abnormality showed a significantly lower number of chromosomal changes by CGH (p < 0.02), confirming that DNA repair defect of this type is associated with a lower level of chromosomal instability. An hMLH1 methylation defect was seen in only one adenoma (1.3%), from a patient who had a synchronous cancer showing the same defect. Methylation of P14 (P14ARF) was seen in 31 adenomas (39.7%) and CDKN2A (P16) abnormality in 25 (32.1%). DNA methylation at two or more loci was seen in 46 tumours (59%), while 11 lesions (14.1%) showed no evidence of hypermethylation at any of the loci studied. Methylation at any or all of MGMT, P14 or P16 was significantly associated with APC methylation (p = 0.01). Those neoplasms with more than two methylated genes showed significantly fewer chromosomal abnormalities than adenomas with one or no methylated loci (p < 0.001). There was no association between specific individual chromosomal abnormalities, APC, KRAS or TP53 mutations and any pattern of methylation abnormality. We conclude that methylation abnormality is very common in pre-invasive colorectal neoplasia, and that high level methylation is associated with low level chromosomal instability.

Medications with anticoagulant properties increase the likelihood of a negative colonoscopy in faecal occult blood test population screening.

OBJECTIVE: The aim of this study was to evaluate the effect of medication with anticoagulant properties on the false positive rate in a population-based faecal occult blood test (FOBt) colorectal screening programme. METHODS: Eight hundred and forty-six consecutive individuals found to be FOBt-positive in the Scottish arm of the national colorectal cancer screening pilot were studied. All were aged between 50 and 69 years and underwent colonoscopy. Before the procedure the participants' current medication was recorded, and correlated with the colonoscopic findings. RESULTS: Of 846 participants, 301 (35.6%) were taking regular anticoagulant medication at the time of FOB testing. Of these, 143 (47.5%) had colorectal neoplasia found on colonoscopy, whereas of those not taking anticoagulant medication, 308 (56.5%) were found to have neoplasia. This 9% difference was statistically significant (P = 0.012). CONCLUSION: These results indicate that in a population screened for colorectal neoplasia by FOB testing, anticoagulant medication being taken at the time of testing is associated with an increased likelihood of a negative colonoscopy.

The prognostic significance of K-ras, p53, and APC mutations in colorectal carcinoma.

BACKGROUND: Accumulation of molecular alterations, including mutations in Kirsten-ras (K-ras), p53, and adenomatous polyposis coli (APC), contribute to colorectal carcinogenesis. Our group has previously characterised a panel of sporadic colorectal adenocarcinomas for mutations in these three genes and has shown that p53 and K-ras mutations rarely occur in the same colorectal tumour. This suggests that mutations in these genes are on separate pathways to colorectal cancer development and may influence patient prognosis independently. AIMS: To correlate the presence or absence of mutations in K-ras, p53, and APC with survival in a cohort of colorectal cancer patients. PATIENTS: A series of 107 inpatients treated surgically for colorectal cancer in Tayside, Scotland between November 1997 and December 1999. METHODS: Colorectal tumours were characterised for mutations in K-ras, p53, and APC. Kaplan-Meier survival curves were constructed using overall survival and disease specific survival as the primary end points. Patient survival was analysed using the log rank test and Cox proportional hazards model. RESULTS: Patients with K-ras mutations had significantly poorer overall survival than patients without K-ras mutations (p = 0.0098). Multivariate analysis correcting for Dukes' stage, age, and sex confirmed this (hazard ratio 2.9 (95% confidence interval 1.4-6.2); p = 0.0040). K-ras mutations were also significantly associated with poorer disease specific survival. The presence of APC and p53 mutations did not affect survival in this cohort of patients (p = 0.9034 and p = 0.8290, respectively). CONCLUSIONS: Our data indicate that the presence of K-ras mutations predicts poor patient prognosis in colorectal cancer, independently of tumour stage.

Lower gastrointestinal symptoms are not predictive of colorectal neoplasia in a faecal occult blood screen-positive population.

BACKGROUND: The aim of this study was to evaluate the incidence of lower gastrointestinal symptoms in faecal occult blood (FOB) test-positive participants in a colorectal screening programme, and to compare the colonoscopic findings in symptomatic and asymptomatic individuals. METHODS: Five hundred and sixty-three consecutive individuals with a positive FOB test in the Scottish arm of the national colorectal cancer screening pilot were studied. All were aged between 50 and 69 years and underwent colonoscopy. Before the procedure the participants were given a standard questionnaire to elicit gastrointestinal symptoms; these were correlated with the colonoscopic findings. RESULTS: Of the 563 participants, 439 (78.0 per cent) had one or more lower gastrointestinal symptoms and 124 (22.0 per cent) were symptom free. Taking adenoma and carcinoma together, 322 (57.2 per cent) of the subjects were found to have colorectal neoplasia, and 128 (22.7 per cent) had a completely normal colon. Rectal bleeding was the most common symptom, followed by change in bowel habit, abdominal pain, tenesmus, unexplained weight loss, rectal pain and unexplained anaemia. No significant associations were found between any of these symptoms and the findings at colonoscopy. CONCLUSION: In a FOB test-positive screened population, lower gastrointestinal symptoms are common, but are not predictive of colorectal neoplasia.