A J van Vuuren

Screening for colorectal cancer: randomised trial comparing guaiac-based and immunochemical faecal occult blood testing and flexible sigmoidoscopy

Background: Screening for colorectal cancer (CRC) is widely accepted, but there is no consensus on the preferred strategy. We conducted a randomised trial comparing participation and detection rates (DR) per screenee of guaiac-based faecal occult blood test (gFOBT), immunochemical FOBT (FIT), and flexible sigmoidoscopy (FS) for CRC screening. Methods: A representative sample of the Dutch population (n = 15 011), aged 50–74 years, was 1:1:1 randomised prior to invitation to one of the three screening strategies. Colonoscopy was indicated for screenees with a positive gFOBT or FIT, and for those in whom FS revealed a polyp with a diameter ⩾10 mm; adenoma with ⩾25% villous component or high grade dysplasia; serrated adenoma; ⩾3 adenomas; ⩾20 hyperplastic polyps; or CRC. Results: The participation rate was 49.5% (95% confidence interval (CI) 48.1 to 50.9%) for gFOBT, 61.5% (CI, 60.1 to 62.9%) for FIT and 32.4% (CI, 31.1 to 33.7%) for FS screening. gFOBT was positive in 2.8%, FIT in 4.8% and FS in 10.2%. The DR of advanced neoplasia was significantly higher in the FIT (2.4%; OR, 2.0; CI, 1.3 to 3.1) and the FS arm (8.0%; OR, 7.0; CI, 4.6 to 10.7) than the gFOBT arm (1.1%). FS demonstrated a higher diagnostic yield of advanced neoplasia per 100 invitees (2.4; CI, 2.0 to 2.8) than gFOBT (0.6; CI, 0.4 to 0.8) or FIT (1.5; CI, 1.2 to 1.9) screening. Conclusion: This randomised population-based CRC-screening trial demonstrated superior participation and detection rates for FIT compared to gFOBT screening. FIT screening should therefore be strongly preferred over gFOBT screening. FS screening demonstrated a higher diagnostic yield per 100 invitees than both FOBTs.

Screening for colorectal cancer: random comparison of guaiac and immunochemical faecal occult blood testing at different cut-off levels

Immunochemical faecal occult blood testing (FIT) provides quantitative test results, which allows optimisation of the cut-off value for follow-up colonoscopy. We conducted a randomised population-based trial to determine test characteristics of FIT (OC-Sensor micro, Eiken, Japan) screening at different cut-off levels and compare these with guaiac-based faecal occult blood test (gFOBT) screening in an average risk population. A representative sample of the Dutch population (n=10 011), aged 50–74 years, was 1 : 1 randomised before invitation to gFOBT and FIT screening. Colonoscopy was offered to screenees with a positive gFOBT or FIT (cut-off 50 ng haemoglobin/ml). When varying the cut-off level between 50 and 200 ng ml−1, the positivity rate of FIT ranged between 8.1% (95% CI: 7.2–9.1%) and 3.5% (95% CI: 2.9–4.2%), the detection rate of advanced neoplasia ranged between 3.2% (95% CI: 2.6–3.9%) and 2.1% (95% CI: 1.6–2.6%), and the specificity ranged between 95.5% (95% CI: 94.5–96.3%) and 98.8% (95% CI: 98.4–99.0%). At a cut-off value of 75 ng ml−1, the detection rate was two times higher than with gFOBT screening (gFOBT: 1.2%; FIT: 2.5%; P<0.001), whereas the number needed to scope (NNscope) to find one screenee with advanced neoplasia was similar (2.2 vs 1.9; P=0.69). Immunochemical faecal occult blood testing is considerably more effective than gFOBT screening within the range of tested cut-off values. From our experience, a cut-off value of 75 ng ml−1 provided an adequate positivity rate and an acceptable trade-off between detection rate and NNscope.

Predictors for neoplastic progression in patients with Barrett's Esophagus: a prospective cohort study

OBJECTIVES:Patients with Barretts esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors.METHODS:We included 713 patients with BE (≥2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance.RESULTS:After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3–7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01–1.2), esophagitis (RR 3.5; 95% CI 1.3–9.5), and LGD (RR 9.7; 95% CI 4.4–21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18–40%).CONCLUSIONS:In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Sensitive detection of hepatocellular injury in chronic hepatitis C patients with circulating hepatocyte-derived microRNA-122

As chronic hepatitis C patients with progressive disease can present themselves with normal ALT levels, more sensitive biomarkers are needed. MicroRNAs are newly discovered small noncoding RNAs that are stable and detectable in the circulation. We aimed to investigate the association between hepatocyte‐derived microRNAs in serum and liver injury in patients with chronic hepatitis C. The hepatocyte‐derived miR‐122 and miR‐192 were analysed in sera of 102 chronic HCV‐infected patients and 24 healthy controls. Serum levels of miR‐122 and miR‐192 correlated strongly with ALT (R = 0.67 and R = 0.65, respectively, P < 0.001 for both). Median levels of miR‐122 and miR‐192 in HCV‐infected patients were 23 times and 8 times higher as in healthy controls (P < 0.001 for both). Even within the HCV‐infected patients with a normal ALT (n = 38), the levels of miR‐122 and miR‐192 were 12 times and 4 times higher compared with healthy controls (P < 0.001 for both). Multivariate logistic regression analyses showed that only miR‐122 was a significant predictor of the presence of chronic HCV infection (P = 0.026). Importantly, miR‐122 was also superior in discriminating chronic HCV‐infected patients with a normal ALT from healthy controls compared with the ALT level (AUC = 0.97 vs AUC = 0.78, P = 0.007). In conclusion, our study confirmed that liver injury is associated with high levels of hepatocyte‐derived microRNAs in circulation and demonstrated that in particular miR‐122 is a sensitive marker to distinguish chronic hepatitis C patients from healthy controls. More sensitive blood markers would benefit especially those patients with minor levels of hepatocellular injury, who are not identified by current screening with ALT testing.

Pharmacogenetics of thiopurine therapy in paediatric IBD patients

Background  Azathioprine is widely used in the treatment of children with inflammatory bowel disease. The occurrence and type of adverse events to azathioprine may be related to thiopurine S‐methyltransferase (TPMT) enzyme activity and to inosine triphophate pyrophosphatase (ITPase) deficiency.

Screening for colorectal cancer: Comparison of perceived test burden of guaiac-based faecal occult blood test, faecal immunochemical test and flexible sigmoidoscopy

BACKGROUND Perceived burden of colorectal cancer (CRC) screening is an important determinant of participation in subsequent screening rounds and therefore crucial for the effectiveness of a screening programme. This study determined differences in perceived burden and willingness to return for a second screening round among participants of a randomised population-based trial comparing a guaiac-based faecal occult blood test (gFOBT), a faecal immunochemical test (FIT) and flexible sigmoidoscopy (FS) screening. METHODS A representative sample of the Dutch population (aged 50-74years) was randomised to be invited for gFOBT, FIT and FS screening. A random sample of participants of each group was asked to complete a questionnaire about test burden and willingness to return for CRC screening. RESULTS In total 402/481 (84%) gFOBT, 530/659 (80%) FIT and 852/1124 (76%) FS screenees returned the questionnaire. The test was reported as burdensome by 2.5% of gFOBT, 1.4% of FIT and 12.9% of FS screenees (comparing gFOBT versus FIT p=0.05; versus FS p<0.001). In total 94.1% of gFOBT, 94.0% of FIT and 83.8% of FS screenees were willing to attend successive screening rounds (comparing gFOBT versus FIT p=0.84; versus FS p<0.001). Women reported more burden during FS screening than men (18.2% versus 7.7%; p<0.001). CONCLUSIONS FIT slightly outperforms gFOBT with a lower level of reported discomfort and overall burden. Both FOBTs are better accepted than FS screening. All three tests have a high level of acceptance, which may affect uptake of subsequent screening rounds and should be taken into consideration before implementing a CRC screening programme.

Advance notification letters increase adherence in colorectal cancer screening: A population-based randomized trial

OBJECTIVE The population benefit of screening depends not only on the effectiveness of the test, but also on adherence, which, for colorectal cancer (CRC) screening remains low. An advance notification letter may increase adherence, however, no population-based randomized trials have been conducted to provide evidence of this. METHOD In 2008, a representative sample of the Dutch population (aged 50-74 years) was randomized. All 2493 invitees in group A were sent an advance notification letter, followed two weeks later by a standard invitation. The 2507 invitees in group B only received the standard invitation. Non-respondents in both groups were sent a reminder 6 weeks after the invitation. RESULTS The advance notification letters resulted in a significantly higher adherence (64.4% versus 61.1%, p-value 0.019). Multivariate logistic regression analysis showed no significant interactions between group and age, sex, or socio-economic status. Cost analysis showed that the incremental cost per additional detected advanced neoplasia due to sending an advance notification letter was € 957. CONCLUSION This population-based randomized trial demonstrates that sending an advance notification letter significantly increases adherence by 3.3%. The incremental cost per additional detected advanced neoplasia is acceptable. We therefore recommend that such letters are incorporated within the standard CRC-screening invitation process.

Does CDX2 expression predict Barrett's metaplasia in oesophageal columnar epithelium without goblet cells?

Background  Intestinal metaplasia (Barretts oesophagus), but not cardiac‐type mucosa in columnar‐lined oesophagus, is regarded as premalignant. As intestinal metaplasia and cardiac‐type mucosa are endoscopically indiscernible, it is difficult to take targeted samples from columnar‐lined oesophagus with consequently a risk of having undetected intestinal metaplasia.

Partial characterization of the DNA repair protein complex, containing the ERCC1, ERCC4, ERCC11 and XPF correcting activities

The nucleotide excision repair (NER) protein ERCC1 is part of a functional complex, which harbors in addition the repair correcting activities of ERCC4, ERCC11 and human XPF. ERCC1 is not associated with a defect in any of the known human NER disorders: xeroderma pigmentosum, Cockaynes syndrome or trichothiodystrophy. Here we report the partial purification and characterization of the ERCC1 complex. Immunoprecipitation studies tentatively identified a subunit in the complex with an apparent MW of approximately 120 kDa. The complex has affinity for DNA, but no clear preference for ss, ds or UV-damaged DNA substrates. The size of the entire complex determined by non-denaturing gradient gels (approximately 280 kDa) is considerably larger than previously found using size separation on glycerol gradients (approximately 120 kDa). Stable associations of the ERCC1 complex with other known repair factors (XPA, XPC, XPG and TFIIH complex) could not be detected.

Wat gebeurt er bij een allergie

Een allergie kan zich op elke leeftijd manifesteren. Allergische reacties kunnen optreden in de neus, ogen, longen, de huid en andere organen. Allergische aandoeningen komen veel voor. Dat betekent dat een groot aantal mensen met het verschijnsel allergie te maken heeft: huisartsen en medisch specialisten, bedrijfs- en verzekeringsartsen, en natuurlijk patienten in alle leeftijdsklassen. Om misverstanden bij patienten en artsen te voorkomen, moeten artsen over een duidelijke naamgeving voor allergische aandoeningen beschikken. In deze paragraaf beschrijven wij de terminologie zoals die in 2001 is herzien door een Europese groep specialisten. In 2003 is deze terminologie aangepast en overgenomen door de wereldorganisatie op allergiegebied (Johansson et al., 2004). De terminologie die hier wordt besproken, is bedoeld om te worden gebruikt door de dokter die allergische patienten ziet en behandelt. Daarom wordt hier niet ingegaan op immunologische indelingen als de bekende type I tot en met IV volgens Gell en Coombs (kader 1.5).