Vuuren, A.J. van

Cost-effectiveness of one versus two sample faecal immunochemical testing for colorectal cancer screening (Article)

2013-05-01T00:00:00Z

Objective The sensitivity and specificity of a single faecal immunochemical test (FIT) are limited. The performance of FIT screening can be improved by increasing the screening frequency or by providing more than one sample in each screening round. This study aimed to evaluate if two-sample FIT screening is cost-effective compared with one-sample FIT. Design The MISCANecolon microsimulation model was used to estimate costs and benefits of strategies with either one or two-sample FIT screening. The FIT cut-off level varied between 50 and 200 ng haemoglobin/ml, and the screening schedule was varied with respect to age range and interval. In addition, different definitions for positivity of the two-sample FIT were considered: at least one positive sample, two positive samples, or the mean of both samples being positive. Results Within an exemplary screening strategy, biennial FIT from the age of 55-75 years, one-sample FIT provided 76.0-97.0 life-years gained (LYG) per 1000 individuals, at a cost of $259000-264000 (range reflects different FIT cut-off levels). Two-sample FIT screening with at least one sample being positive provided 7.3-12.4 additional LYG compared with one-sample FIT at an extra cost of $50000-59 000. However, when all screening intervals and age ranges were considered, intensifying screening with one-sample FIT provided equal or more LYG at lower costs compared with two-sample FIT. Conclusion If attendance to screening does not differ between strategies it is recommended to increase the number of screening rounds with one-sample FIT screening, before considering increasing the number of FIT samples provided per screening round.

Precore and core promoter mutants are associated with higher HBeAg seroconversion but low disease remission rates in HBV patients treated with nucleos(t)ide analogues (Article)

2013-05-01T00:00:00Z

HBeAg seroconversion in HBV patients is considered an important event. We determined precore (PC) and base core promoter (BCP) mutations in 137 HBeAg-positive nucleos(t)ide analogues (NA) treated patients by INNO-LiPA HBV PreCore assay (Innogenetics). The majority of patients with nongenotype A had PC/BCP mutants present at baseline (P = 0.02). During 29 months of therapy, 45 patients achieved HBeAg seroconversion. Probability of HBeAg seroconversion was higher in patients with PC and/or BCP mutants (P = 0.01). After HBeAg seroconversion, patients with BCP mutants had more HBeAg relapse (P = 0.07), and PC mutants less often achieved HBV DNA < 2000 IU/mL (P = 0.07).

Long-term follow-up of hepatitis B e antigen-negative patients treated with peginterferon α-2a: Progressive decrease in hepatitis B surface antigen in responders (Article)

2012-09-01T00:00:00Z

OBJECTIVE: Peginterferon (PEG-IFN) is considered as a first-line treatment option for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We aimed to evaluate the long-term response to PEG-IFN in HBeAg-negative patients. METHODS: All patients enrolled in the PARC study who completed the treatment phase were eligible for this long-term follow-up (LTFU) study. Patients received PEG-IFN α-2a (180 μg weekly)±ribavirin (1000-1200 mg daily) for 48 weeks and had at least one additional LTFU visit after the initial follow-up period of 24 weeks (mean duration 2.1±0.2 years). Retreated patients were considered nonresponders. RESULTS: Of 117 patients who completed the treatment phase, 79 (68%) were included in this LTFU study. Among 19 patients with a combined response at 24 weeks after treatment [initial responders; hepatitis B virus DNA<10 000 copies/ml (<1714 IU/ml) and normal alanine aminotransferase], 12 (63%) sustained this response through LTFU. Three additional patients showed such a response at LTFU, resulting in a total of 15 (19%) combined responders at LTFU. A marked decrease in the serum hepatitis B surface antigen (HBsAg) levels was observed in initial responders, resulting in HBsAg clearance in 26% of the patients (6% of all LTFU participants). CONCLUSION: About one-third of HBeAg-negative patients with a response to PEG-IFN at 24 weeks after treatment subsequently had a relapse during 2 years of follow-up. Despite the limited overall efficacy of PEG-IFN, patients responding to PEG-IFN treatment showed a marked decrease in serum HBsAg, resulting in a high rate of HBsAg clearance, which indicates the need for predictors of response to PEG-IFN in HBeAg-negative disease.

Continuous interferon-α,2b infusion in combination with ribavirin for chronic hepatitis C in treatment-experienced patients (Article)

2012-06-05T00:00:00Z

Background: Sustained virological response (SVR) rates in previous non-responders to pegylated interferon (PEGIFN)-α and ribavirin for chronic HCV remain low (∼10%). We hypothesize that continuous subcutaneous delivery of fully potent interferon (IFN)-α2b via an external pump will lead to stable blood concentrations and thereby prevent subtherapeutic trough levels associated with viral breakthrough. The aims of the study were to assess safety, tolerability and virological response in patients who were previous PEG-IFN-α/ribavirin non-responders. Methods: We randomized 30 HCV genotype 1 (n=24) and genotype 4 (n=6) patients to receive 6, 9 or 12 million units (MU) IFN-α2b daily by continuous subcutaneous administration using an insulin pump (MiniMed® 508; Medtronic Inc., Minneapolis, MN, USA) in combination with ribavirin (1,000-1,600 mg) for 48 weeks. Results: The magnitude of viral decline in the 12 MU group after 4 weeks of treatment was 2.67 log HCV RNA compared with 1.21 and 1.27 log HCV RNA in the 9 and 6 MU groups, respectively (P=0.001). In the intention-to-treat analysis, the SVR rate was 20% (6/30). The perprotocol SVR rate was 25% (6/24), of which four out of six patients in the high-dose arm achieved SVR. Adverse events appeared dose-dependent, were mostly mild-to-moderate and were typical of IFN therapy. Five patients developed irritation and/or abscesses at the injection site. Six serious adverse events were reported in five patients. Conclusions: Continuous delivery of IFN-α2b can induce a strong dose-dependent viral suppression. This could be an effective approach in conjunction with, or as lead-in therapy prior to, treatment with a direct antiviral agent.

Are fecal immunochemical test characteristics influenced by sample return time a population-based colorectal cancer screening trial (Article)

2012-01-01T00:00:00Z

Objectives: Fecal immunochemical tests (FIT) are preferred over guaiac-based fecal occult blood testing as colorectal cancer (CRC) screening tool. However, hemoglobin (Hb) degradation over time may influence FIT outcome. We therefore evaluated the effect of sample return time on FIT performance characteristics in a population-based CRC screening trial. Methods: A representative random sample of the Dutch population (n=17,677), aged 50-74 years, was invited for FIT screening (OC-Sensor Micro; cutoff 50 ng Hb/ml). Sample return time was defined as the interval in days between fecal sampling and FIT laboratory delivery. Moreover, a random sample of positive FITs were selected to be stored at room temperature and re-tested every 3-4 days. Results: In total, 8,958 screenees fulfilled our inclusion criteria. The mean sample return time was 3 days (±3). Overall, 792 screenees (8.8%) had a positive test. Between the sample return time groups, the positivity rate (PR) varied between 7.7 and 9.0%. No statistically significant associations were found between PR or detection rate (DR) and the different sample return time groups (P value=0.84 and 0.76, respectively). For the laboratory experiment, 71 positive FITs were stored at room temperature and re-tested with standard intervals. The mean daily fecal Hb decrease was 5.88% per day (95% confidence interval 4.78-6.96%). None of the positive FITs became negative before 10 days after fecal sampling. Conclusions: This population-based CRC screening trial demonstrates that both the PR and DR of FITs do not decrease with prolonged sample return times up to 10 days. This means that a delay in sending the FIT back to the laboratory, of up to at least 1 week, does not necessitate repeat sampling in case of a negative test result. These data support the use of FIT-based screening as a reliable tool for nationwide CRC screening programs.

Discordance between HCV RNA assays for week 24 HCV RNA determination during pegylated interferon-α/ribavirin treatment for chronic hepatitis C (Article)

2011-09-12T00:00:00Z

Background: The development of more sensitive HCV RNA assays might necessitate re-evaluation of the rules for stopping treatment (for example, HCV RNA negativity at week 24 during treatment with pegylated interferon-αand ribavirin for chronic hepatitis C). The aim of this study was to assess discordance between the week 24 HCV RNA test results of two PCR-based assays (Amplicor and Taq- Man) and the transcription-mediated amplification (TMA) HCV RNA qualitative assay. Methods: A total of 89 week 24 samples that were negative using PCR-based assays during treatment were retested with the TMA qualitative assay to investigate discordance between tests results. All week 24 samples were HCV RNA negative by Amplicor or by TaqMan. Results: Of the 89 patients, 46 (52%) achieved sustained virological response (SVR). Viral breakthrough or relapse occurred in 43 patients (48%). All 89 HCV RNA negative week 24 samples were retested with the qualitative TMA assay. Eleven out of 89 samples had detectable HCV RNA (12%). All patients with detectable HCV RNA experienced breakthrough or relapse (negative predictive value 100%). Of the 78 patients with undetectable HCV RNA at week 24 using the TMA assay, 46 achieved SVR. This resulted in a positive predictive value (PPV) of 59% for the TMA assay compared with a PPV of 52% for the PCR-based assays. Conclusions: All patients with detectable HCV RNA at week 24 using the TMA assay eventually relapsed. On the basis of these results, the use of this more sensitive HCV RNA assay could lead to the prevention of unnecessary treatment.

Serum HBsAg decline during long-term potent nucleos(t)ide analogue therapy for chronic hepatitis B and prediction of HBsAg loss (Article)

2011-08-01T00:00:00Z

Nucleos(t)ide analogues strongly inhibit viral replication in chronic hepatitis B (CHB) infection, but knowledge of their long-term effect on serum hepatitis B surface antigen (HBsAg) levels and HBsAg loss is lacking. Seventy-five CHB patients with virological response (VR) to ETV or TDF were included. HBsAg decline 2 years after VR was most pronounced in HBeAg-positive patients. Age, alanine aminotransferase, and HBeAg loss were associated with HBsAg decline in HBeAg-positive patients. Predicted median time to HBsAg loss was 36 years for HBeAg-positive and 39 years for HBeAg-negative patients. Thus, most patients treated with ETV and TDF will probably need decades of therapy to achieve HBsAg loss.

Comparison of non-invasive assessment to diagnose liver fibrosis in chronic hepatitis B and C patients (Article)

2011-07-01T00:00:00Z

Objective. Chronic viral hepatitis B and C cause liver fibrosis, leading to cirrhosis. Fibrosis assessment is essential to establish prognosis and treatment indication. We compared seven non-invasive tests, separately and in combination, in chronic hepatitis patients to detect early stages of fibrosis according to the Metavir score in liver biopsy. Material and methods. Galactose and methacetin breath tests (GBT and MBT), biomarkers (hyaluronic acid (HA), aspartate aminotransferase platelet ratio index (APRI), FibroTest, and Fib-4) and transient elastography (TE) were evaluated in 89 patients. Additionally, 31 healthy controls were included for evaluation of breath tests and biomarkers. Results. Serum markers (HA, APRI, FibroTest, and Fib-4) and elastography significantly distinguished non-cirrhotic (F0123) from cirrhotic (F4) patients (p < 0.001, p = 0.015, p < 0.001, p = 0.005, p = 0.006, respectively). GBT, HA, APRI, FibroTest, Fib-4, and TE detected F01 from F234 (p = 0.04, p = 0.011, p = 0.009, p < 0.001, p < 0.001, and p < 0.001, respectively). A combination of different tests (TE, HA, and FibroTest) improved the performance statistically, area under the curve (AUC) = 0.87 for F234, 0.92 for F34, and 0.90 for F4. Conclusion. HA, APRI, FibroTest, Fib-4, and TE reliably distinguish non-cirrhotic and cirrhotic patients. Except for MBT, all tests discriminate between mild and moderate fibrosis. As single tests: FibroTest, Fib-4, and TE were the most accurate for detecting early fibrosis; combining different non-invasive tests increased the accuracy for detection of liver fibrosis to such an extent and thus might be acceptable to replace liver biopsy.

Predictors for neoplastic progression in patients with Barrett's esophagus: A prospective cohort study (Article)

2011-07-01T00:00:00Z

Objectives: Patients with Barrett's 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.

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

2011-06-01T00:00:00Z

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.

Diagnostic Yield Improves With Collection of 2 Samples in Fecal Immunochemical Test Screening Without Affecting Attendance (Article)

2011-04-01T00:00:00Z

Background & Aims: The fecal immunochemical test (FIT) is superior to the guaiac-based fecal occult blood test in detecting neoplasia. There are not much data on the optimal number of FITs to perform. We conducted a population-based trial to determine attendance and diagnostic yield of 1- and 2-sample FIT screening. Methods: The study included 2 randomly selected groups of subjects aged 50-74 years (1-sample FIT, n = 5007; 2-sample FIT, n = 3197). The 2-sample group was instructed to collect fecal samples on 2 consecutive days. Subjects were referred for colonoscopy when at least 1 sample tested positive (≥50 ng hemoglobin/mL). Results: Attendance was 61.5% in the 1-sample group (2979 of 4845; 95% confidence interval, 60.1%-62.9%) and 61.3% in the 2-sample group (1875 of 3061; 95% confidence interval, 59.6%-63.0%; P = .84). In the 1-sample group 8.1% tested positive, and in the 2-sample group 12.8% had at least 1 positive test outcome and 5.0% had 2 positive test outcomes (P < .05). When the mean from both test results in the 2-sample group was used, 10.1% had a positive test outcome (P < .05). The detection rates for advanced neoplasia were 3.1% in the 1-sample group, 4.1% in the 2-sample group with at least 1 positive test outcome, 2.5% when both test results were positive, and 3.7% among subjects with the mean from both test results being positive. Conclusions: There is no difference in attendance for subjects offered 1- or 2-sample FIT screening. The results allow for the development of efficient FIT screening strategies that can be adapted for local colonoscopy capacities, rather than varying the cut-off value in a 1-sample strategy.

Uptake of faecal immunochemical test screening among non-participants in a flexible sigmoidoscopy screening programme (Article)

2011-01-01T00:00:00Z

A Randomized Trial of Peginterferon α-2a With or Without Ribavirin for HBeAg-Negative Chronic Hepatitis B (Article)

2010-08-01T00:00:00Z

OBJECTIVES:Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients are at high risk of treatment relapse after any antiviral therapy. Combining peginterferon α-2a with ribavirin might improve sustained response rates.METHODS:Overall, 138 HBeAg-negative chronic hepatitis B patients were randomized to receive monotherapy (peginterferon α-2a 180 μg weekly plus placebo) or combination therapy (peginterferon α-2a weekly plus ribavirin 1,000 or 1,200 mg daily, depending on body weight) for 48 weeks. Post-treatment follow-up lasted 24 weeks. Analyses were based on the modified intention-to-treat population after exclusion of five patients.RESULTS:At the end of follow-up, 14 (20%) of 69 patients assigned to monotherapy and 10 (16%) of 64 assigned to combination therapy had a combined response (hepatitis B virus (HBV) DNA <10,000 copies/ml (<1,714 IU/ml) and a normal alanine aminotransferase level, P=0.49). At the end of treatment, more patients had a combined response (25 (36%) vs. 26 (41%) in the monotherapy and combination therapy group, respectively, P=0.60), but subsequently relapsed during follow-up. Serum HBV DNA and hepatitis B surface antigen (HBsAg) levels decreased during treatment (mean change at week 48 compared with baseline -3.9 vs. -2.6 log copies/ml, P<0.001 and -0.56 vs. -0.34 log IU/ml, P=0.23, respectively). HBV DNA levels relapsed after treatment discontinuation; HBsAg remained at end-of-treatment levels. In general, combination therapy was well tolerated, although it was associated with a higher risk of anemia and neutropenia.CONCLUSIONS:Treatment with peginterferon α-2a resulted in a limited sustained response rate in HBeAg-negative chronic hepatitis B patients. Addition of ribavirin did not improve response to therapy.Am J Gastroenterol advance online publication, 11 May 2010; doi:10.1038/ajg.2010.186.

Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels (Article)

2010-08-01T00:00:00Z

Peginterferon alfa-2a results in a sustained response (SR) in a minority of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). This study investigated the role of early on-treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg-negative patients receiving peginterferon alfa-2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow-up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa-2a, n = 53, versus peginterferon alfa-2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%). Conclusion: At week 12 of peginterferon alfa-2a treatment for HBeAg-negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on-treatment adjustments of peginterferon therapy for HBeAg-negative CHB.

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

2010-07-01T00:00:00Z

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 50-74 years) 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.

Immunochemical fecal occult blood test in a screening program for colorectal cancer [De immunochemische fecaaloccultbloedtest in een screeningsstudie naar colorectaal carcinoom] (Article)

2010-01-01T00:00:00Z

The Health Council of the Netherlands advised on a national screening program for colorectal cancer (CRC) in November last year. Studies have already shown that screening for CRC using the guaiac based fecal occult blood test (gFOBT) reduces mortality, and more recently, results have been published using the immunological FOBT (iFOBT). The gFOBT and iFOBT do not differ in their CRC-detection rate, however, more advanced adenomas are found using the iFOBT. While the iFOBT is a quantitative test, it offers the possibility of choosing different cut-off points. It appears that, both clinical and analytical, a cut-off point of 75 ng/ml can be used, if adequate capacity for colonoscopy is available.

Serum Markers and Intestinal Mucosal Injury in Chronic Gastrointestinal Ischemia (Article)

2010-01-01T00:00:00Z

Background: Diagnosing chronic gastrointestinal ischemia (CGI) is a challenging problem in clinical practice. Serum markers for CGI would be of great diagnostic value as a non-invasive test method. Aims: This study investigated serum markers in patients with well-defined ischemia. Furthermore, intestinal mucosal injury was also evaluated in CGI patients. Methods: Consecutive patients suspected of CGI were prospectively enrolled and underwent a diagnostic work-up consisting of gastrointestinal tonometry and either CT or MR angiography. Blood samples for analysis of intestinal fatty acid-binding protein (I-FABP), D-dimer, lactate dehydrogenase (LDH), leucocyte counts, C-reactive protein (CRP), and L-lactate were drawn before and after a standard meal. Intestinal mucosal injury was assessed with glutamine, citrulline and arginine in blood samples and compared to a sugar absorption test (SAT). Test reproducibility was validated in healthy subjects. Results: Forty patients and nine healthy subjects were included. Ischemia was diagnosed in 32 patients (80%). I-FABP, leucocyte counts, LDH, CRP, glutamine, citrulline, arginine and SAT levels did not differ between patients with and without ischemia. L-lactate concentration showed a significant elevation in ischemia patients as compared to non-ischemia patients. In ischemia patients, D-dimer levels showed a significant elevation postprandially as compared to D-dimer levels at baseline. However, these ischemia patients did not show intestinal mucosal injury. Conclusions: I-FABP, leucocyte counts, LDH and CRP levels are not clinically useful for the diagnosis of CGI. However, postprandial rises in L-lactate and D-dimer serum levels can serve as non-invasive indicators of CGI.

Screening for colorectal cancer: Randomised trial comparing guaiac-based and immunochemical faecal occult blood testing and flexible sigmoidoscopy (Article)

2010-01-01T00:00:00Z

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 CRCscreening 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 (Article)

2009-04-07T00:00:00Z

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 (n10 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%; P0.001), whereas the number needed to scope (NNscope) to find one screenee with advanced neoplasia was similar (2.2 vs 1.9; P0.69). 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.

Transient postprandial ischemia is associated with increased intestinal fatty acid binding protein in patients with chronic gastrointestinal ischemia (Article)

2009-03-01T00:00:00Z

Background Chronic gastrointestinal ischemia (CGI) is still a difficult diagnosis to make. Currently, the only diagnostic with an acceptable sensitivity for actual mucosal ischemia is gastrointestinal tonometry. However, tonometry is a cumbersome and invasive diagnostic test We are in need of a more simple, noninvasive test for diagnosing mucosal ischemia. A sensitive and early serum marker could be of great use in this setting. The aim of this study was to evaluate the use of promising serum markers for mucosal ischemia [intestinal fatty acid binding protein (I-FABP), D-lactate, and lipopolysaccharide] and compared findings with corresponding gastrointestinal tonometry measurements. Methods Patients referred for evaluation of CGI were included. All patients had visualization of abdominal arteries and gastrointestinal tonometry. Before, during, and after tonometry blood samples were drawn for measurements of serum markers. Results Forty-nine patients were eligible for evaluation. CGI was diagnosed in 24 (49%) patients. The baseline measurements showed a significant increase in I-FABP before exercise tonometry in the abnormal-response groups compared with the normal-response group, respectively, 0.45 and 1.3μg/I (P= 0.04). An abnormal response on meal tonometry was associated with increased I-FABP levels, 1, 2, and 4 h after tonometry, compared with the patients with a normal response, respectively, 1.26, 1.11, and 0.58 μg/I (P= 0.048, 0.01, and 0.03). The measurements of D-lactate and lipopolysaccharide were undetectable, or low, at all different points of time. Conclusion Transient postprandial mucosal ischemia, as detected with gastrointestinal tonometry, is associated with increased I-FABP levels, indicating epithelial damage. Late markers for mucosal ischemia remained negative.

Sustained HBeAg and HBsAg Loss After Long-term Follow-up of HBeAg-Positive Patients Treated With Peginterferon α-2b (Article)

2008-08-01T00:00:00Z

Background & Aims: The aim of this study was to evaluate the long-term sustainability of response in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with pegylated interferon (PEG-IFN) α-2b alone or in combination with lamivudine. Methods: All 266 patients enrolled in the HBV99-01 study were offered participation in a long-term follow-up (LTFU) study. Patients were treated with PEG-IFN α-2b (100 μg/wk) alone or in combination with lamivudine (100 mg/day) for 52 weeks. Initial response was defined as HBeAg negativity at 26 weeks posttreatment. For the LTFU study, patients had one additional visit after the initial study (mean interval, 3.0 ± 0.8 years). Results: Of 266 patients enrolled in the initial study, 172 (65%) participated in the LTFU study. At LTFU, HBeAg and hepatitis B surface antigen (HBsAg) negativity were observed in 37% and 11% of 172 patients, respectively. Sixty-four patients were classified as initial responders and 108 as nonresponders. Among the initial responders, sustained HBeAg negativity and HBsAg loss were observed in 81% and 30%, respectively. Significantly higher rates of HBeAg negativity were observed in genotype A-infected initial responders compared with those with genotype non-A (96% vs 76%; P = .06) as well as HBsAg loss (58% vs 11%; P < .001). Conclusions: HBeAg loss after treatment with PEG-IFN α-2b alone or in combination with lamivudine is sustained in the majority of patients and is associated with a high likelihood of HBsAg loss, particularly in genotype A-infected patients. Therefore, PEG-IFN α-2b remains an important treatment option in this era of nucleos(t)ide analogue therapy.

Migrant communities constitute a possible target population for primary prevention of Helicobacter pylori-related complications in low incidence countries (Article)

2008-04-03T00:00:00Z

Objective. Pre-selection of individuals with epidemiological risk factors for Helicobacter pylori infection and atrophic gastritis could increase the efficiency of serologic screening to prevent peptic ulcer disease and gastric cancer in Western countries. The aim of this study was to determine the prevalence of and risk factors for H. pylori infection and atrophic gastritis in a migrant community in The Netherlands. Material and methods. Inhabitants from an urban district in Rotterdam, The Netherlands with a large proportion of immigrants were randomly selected. Information was collected on demographic factors, socio-economic status, lifestyle, history of dyspeptic symptoms and medication use. In addition, serologic H. pylori and CagA status and the presence of atrophic gastritis were evaluated. Results. In total, 288 subjects were included. Surinamese or Antillean, Turkish, Cape Verdian and Moroccan subjects were H. pylori-infected in 65%, 82%, 86% and 96% of cases, respectively, whereas the infection rate in Dutch subjects was 46% (all p<0.05). Within multivariate logistic regression analysis, ethnicity and number of persons in a household were identified as independent risk factors for H. pylori infection. In addition, mean pepsinogen I level and pepsinogen I/II ratio were significantly lower in subjects of non-Dutch origin as compared to Dutch subjects (both p<0.001). No Dutch subjects suffered from atrophic gastritis, as compared with 12 subjects of non-Dutch origin (p=0.13). Conclusions. The prevalence of H. pylori is high in migrant populations in The Netherlands. Furthermore, markers of atrophic gastritis are increased in subjects of foreign origin. Therefore, these migrant communities may constitute a target group for serologic screening to prevent H. pylori-related complications in Western countries.

Thiopurine-methyltransferase and inosine triphosphate pyrophosphatase polymorphism in a liver transplant recipient developing nodular regenerative hyperplasia on low-dose azathioprine (Article)

2008-01-01T00:00:00Z

The enzymes thiopurine-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are involved in thiopurine metabolism. We describe a liver transplant recipient who presented with liver enzyme abnormalities after 78 months of low-dose azathioprine (AZA) therapy (less than 1 mg/kg). No underlying etiology of these abnormalities was identified after extensive analysis including repeated liver biopsy. Fifteen years after transplantation, the patient presented with variceal bleeding, liver biopsy showed nodular regenerative hyperplasia (NRH). TPMT*3C genotype was found in the patient's lymphocytes and heterozygous ITPA (94C>A) genotype was found in both patient and donor liver. These findings further emphasize the importance of pharmacogenetics in predicting NRH and other adverse events during AZA therapy. Furthermore, a high index of suspicion with early detection of NRH is crucial, as improvement seems only to occur in patients with compensated liver disease. Liver biopsy and discontinuation of AZA are recommended in case of liver enzyme abnormalities or signs of portal hypertension.

Tumor pyruvate kinase isoenzyme type M2 and immunochemical fecal occult blood test: Performance in screening for colorectal cancer (Article)

2007-10-01T00:00:00Z

OBJECTIVES: Immunochemical fecal occult blood test (FOBT) and determination of tumor pyruvate kinase isoenzyme type M2 (TuM2-PK) in stool samples may be valuable new screening tools for colorectal cancer (CRC). The aim of this study was to compare the accuracy of fecal TuM2-PK testing with immunochemical FOBT in patients with CRC or adenomas. METHODS: A total of 52 patients with CRC were analyzed, 47 with colorectal adenomas, and 63 matched controls with a normal colonoscopy. Nineteen additional patients with inflammatory bowel disease were tested to determine influence of inflammation. Stool samples were analyzed with two immunochemical FOBTs, Immo-care and OC-Light, and with a commercial enzyme-linked immunosorbent assay for TuM2-PK. RESULTS: In patients with CRC, the sensitivity of TuM2-PK, Immo-care and OC-Light was respectively 85, 92 and 94%. In patients with adenomas, the sensitivity was respectively 28, 40 and 34%. Specificity for these tests was 90% for TuM2-PK and 97% for both immunochemical FOBTs. All tests showed a high positivity rate in patients with inflammatory bowel disease (79% for TuM2-PK and Immo-care, and 89% for OC-Light). CONCLUSION: Both immunochemical FOBTs appear valuable and are sensitive tests for CRC screening. TuM2-PK does not have supplemental value for screening for CRC because of a lower sensitivity and specificity. None of these tests is sensitive enough for detection of advanced adenomas. Patients with inflammatory bowel disease should be excluded from CRC screening when using immunochemical FOBT or TuM2-PK.

Nucleotide excision repair: ERCC1 and TFIIH complexes (Doctoral Thesis)

1995-06-28T00:00:00Z

DNA is the carrier of genetic information in living organisms. The information stored in the nucleotide sequence of DNA is transmitted to the offspring by generating identical copies of the parental DNA molecules. Damage in DNA can cause loss of genetic information. Nevertheless, the DNA is continuously subject to alterations, and its instability is likely one of the major factors in mutagenesis. The structure of DNA can be modified spontaneously by hydrolysis, oxidation, or by environmental factors such as ultra-violet (UV) light, X-rays, or numerous chemical agents. Replication of unrepaired DNA can cause genetic changes, which may affect proper functioning of proteins encoded by that DNA. As a result cellular malfunction, onset of carcinogenesis, inborn defects, or even cell death can occur. In addition, DNA damage can interfere with other essential metabolizing processes, like recombination or transcription, with deleterious consequences for the cell. In order to maintain the integrity of DNA, all organisms have evolved a complex network of mechanisms to prevent or repair DNA damage. The different pathways known are able to handle distillct classes of DNA damage.

Correction of xeroderma pigmentosum repair defect by basal transcription factor BTF2/TFIIH. (Article)

1994-01-01T00:00:00Z

ERCC3 was initially identified as a gene correcting the nucleotide excision repair (NER) defect of xeroderma pigmentosum complementation group B (XP-B). The recent finding that its gene product is identical to the p89 subunit of basal transcription factor BTF2(TFIIH), opened the possibility that it is not directly involved in NER but that it regulates the transcription of one or more NER genes. Using an in vivo microinjection repair assay and an in vitro NER system based on cell-free extracts we demonstrate that ERCC3 in BTF2 is directly implicated in excision repair. Antibody depletion experiments support the idea that the p62 BTF2 subunit and perhaps the entire transcription factor function in NER. Microinjection experiments suggest that exogenous ERCC3 can exchange with ERCC3 subunits in the complex. Expression of a dominant negative K436-->R ERCC3 mutant, expected to have lost all helicase activity, completely abrogates NER and transcription and concomitantly induces a dramatic chromatin collapse. These findings establish the role of ERCC3 and probably the entire BTF2 complex in transcription in vivo which was hitherto only demonstrated in vitro. The results strongly suggest that transcription itself is a critical component for maintenance of chromatin structure. The remarkable dual role of ERCC3 in NER and transcription provides a clue in understanding the complex clinical features of some inherited repair syndromes.

Evidence for a repair enzyme complex involving ERCC1, and the correcting activities of ERCC4, ERCC11 and the xeroderma pigmentosum group F. (Article)

1993-01-01T00:00:00Z

Nucleotide excision repair (NER), one of the major cellular DNA repair systems, removes a wide range of lesions in a multi-enzyme reaction. In man, a NER defect due to a mutation in one of at least 11 distinct genes, can give rise to the inherited repair disorders xeroderma pigmentosum (XP), Cockayne's syndrome or PIBIDS, a photosensitive form of the brittle hair disease trichothiodystrophy. Laboratory-induced NER-deficient mutants of cultured rodent cells have been classified into 11 complementation groups (CGs). Some of these have been shown to correspond with human disorders. In cell-free extracts prepared from rodent CGs 1-5 and 11, but not in a mutant from CG6, we find an impaired repair of damage induced in plasmids by UV light and N-acetoxy-acetylaminofluorene. Complementation analysis in vitro of rodent CGs is accomplished by pairwise mixing of mutant extracts. The results show that mutants from groups 2, 3, 5 and XP-A can complement all other CGs tested. However, selective non-complementation in vitro was observed in mutual mixtures of groups 1, 4, 11 and XP-F, suggesting that the complementing activities involved somehow affect each other. Depletion of wild-type human extracts from ERCC1 protein using specific anti-ERCC1 antibodies concomitantly removed the correcting activities for groups 4, 11 and XP-F, but not those for the other CGs. Furthermore, we find that 33 kDa ERCC1 protein sediments as a high mol. wt species of approximately 120 kDa in a native glycerol gradient.