Microsatellite instability in sporadic colon carcinomas has no independent prognostic value in a Belgian study population

Pathological stage is currently the most important determinant of colorectal cancer prognosis. Hence, identification of additional prognostic markers is warranted. This study aimed to analyse the prognostic relevance of microsatellite instability (MSI) in 241 colon and 90 rectal tumours, using a mononucleotide loci multiplex PCR assay and immunohistochemistry. Thirty (12.4%) colon tumours and one rectal tumour showed MSI. Although MSI was associated with proximal location and poor differentiation, no survival benefit was observed. The prognostic value of stage and differentiation was confirmed in this study. Analysis by stage revealed a longer overall (stage II/III) and disease free survival (stage II) for patients with well differentiated tumours. In addition, age and distal localisation were related to longer overall survival in stage II tumours. In conclusion, our findings show an association of MSI in sporadic colon tumours and certain clinical features; however, they do not suggest a survival benefit for MSI tumours

Spatiotemporal imaging and pharmacokinetics of fluorescent compounds in zebrafish eleuthero-embryos after different routes of administration

Abstract Zebrafish (Danio rerio) is increasingly used to assess the pharmacological activity and toxicity of compounds. The spatiotemporal distribution of seven fluorescent alkyne compounds was examined during 48 h after immersion (10 µM) or microinjection (2 mg/kg) in the pericardial cavity (PC), intraperitoneally (IP) and yolk sac (IY) of 3 dpf zebrafish eleuthero-embryos. By modelling the fluorescence of whole-body contours present in fluorescence images, the main pharmacokinetic (PK) parameter values of the compounds were determined. It was demonstrated that especially in case of short incubations (1–3 h) immersion can result in limited intrabody exposure to compounds. In this case, PC and IP microinjections represent excellent alternatives. Significantly, IY microinjections did not result in a suitable intrabody distribution of the compounds. Performing a QSPkR (quantitative structure-pharmacokinetic relationship) analysis, LogD was identified as the only molecular descriptor that explains the final uptake of the selected compounds. It was also shown that combined administration of compounds (immersion and microinjection) provides a more stable intrabody exposure, at least in case of a prolonged immersion and compounds with LogD value > 1. These results will help reduce the risk of false negative results and can offer an invaluable input for future translational research and safety assessment applications

Microsatellite instability in Belgian sporadic colon carcinomas has no independent prognostic value in a Belgian study population

Pathological stage is currently the most important determinant of colorectal cancer prognosis. Hence, identification of additional prognostic markers is warranted. This study aimed to analyse the prognostic relevance of microsatellite instability (MSI) in 241 colon and 90 rectal tumours, using a mononucleotide loci multiplex PCR assay and immunohistochemistry. Thirty (12.4%) colon tumours and one rectal tumour showed MSI. Although MSI was associated with proximal location and poor differentiation, no survival benefit was observed. The prognostic value of stage and differentiation was confirmed in this study. Analysis by stage revealed a longer overall (stage II/III) and disease free survival (stage II) for patients with well differentiated tumours. In addition, age and distal localisation were related to longer overall survival in stage II tumours. In conclusion, our findings show an association of MSI in sporadic colon tumours and certain clinical features; however, they do not suggest a survival benefit for MSI tumours

Acute Lower Gastrointestinal Bleeding in Crohn's Disease: Characteristics of a Unique Series of 34 Patients. Belgian Ibd Research Group

OBJECTIVE: Acute lower gastrointestinal bleeding is a rare complication of Crohn's disease, which represents a diagnostic and therapeutic challenge. The aim of this study was to define epidemiological characteristics and therapeutic options of hemorrhagic forms of Crohn's disease. METHODS: Thirty-four cases of hemorrhagic forms of Crohn's disease were studied retrospectively. Acute lower gastrointestinal hemorrhage was defined as acute rectal bleeding originating in diseased bowel and requiring a transfusion of at least 2 units of red blood cells within 24 h. Upper gastrointestinal tract hemorrhage or anal lesions and postoperative bleeding were excluded. RESULTS: Mean age at time of hemorrhage was 34.2 +/- 14 yr. Mean duration of disease before the hemorrhage was 5.6 +/- 6 yr. The hemorrhage occurred during a flare up of the disease in 35% of cases. The hemorrhage revealed Crohn's disease in 23.5% of cases. The hemorrhage was more frequent in colonic disease (85%) than in isolated small bowel disease (15%) (p < 0.0001). The origin of bleeding was identified in 65% of cases, by colonoscopy (60%), by angiography (3 patients), or at surgery (1 patient). The bleeding lesion was an ulcer in 95% of cases, most often in the left colon. The treatment was surgical in 20.5% (colectomy in 36%), endoscopical (7 patients, including 5 successes), or medical. Hemorrhage recurred in 12 patients (35%) within a mean time of 3 yr (4 days-8 yr), requiring surgery in 3 cases. No death was observed. CONCLUSIONS: This study performed in a series characterized by a nonsurgical recruitment, the largest to date, shows that hemorrhagic forms of Crohn's disease may reveal disease in 23.5%, occurs in quiescent Crohn's disease in two-thirds of cases. Given the potential efficacy of endoscopical or medical treatment, as well as the absence of mortality, a conservative approach may be suggested as first-line therapy in the majority of patients

Safety Assessment of Compounds after In Vitro Metabolic Conversion Using Zebrafish Eleuthero Embryos

Zebrafish-based platforms have recently emerged as a useful tool for toxicity testing as they combine the advantages of in vitro and in vivo methodologies. Nevertheless, the capacity to metabolically convert xenobiotics by zebrafish eleuthero embryos is supposedly low. To circumvent this concern, a comprehensive methodology was developed wherein test compounds (i.e., parathion, malathion and chloramphenicol) were first exposed in vitro to rat liver microsomes (RLM) for 1 h at 37 °C. After adding methanol, the mixture was ultrasonicated, placed for 2 h at -20 °C, centrifuged and the supernatant evaporated. The pellet was resuspended in water for the quantification of the metabolic conversion and the detection of the presence of metabolites using ultra high performance liquid chromatography-Ultraviolet-Mass (UHPLC-UV-MS). Next, three days post fertilization (dpf) zebrafish eleuthero embryos were exposed to the metabolic mix diluted in Danieau's medium for 48 h at 28 °C, followed by a stereomicroscopic examination of the adverse effects induced, if any. The novelty of our method relies in the possibility to quantify the rate of the in vitro metabolism of the parent compound and to co-incubate three dpf larvae and the diluted metabolic mix for 48 h without inducing major toxic effects. The results for parathion show an improved predictivity of the toxic potential of the compound.status: publishe

Maintenance therapy for ulcerative colitis has no impact on changes in the extent of ulcerative colitis

Background and aim: Although the efficacy of maintenance remission therapy in ulcerative colitis (UC) has been proved in many studies, little is known about its possible effect on the extent of the disease. The aim of the present multicenter Belgian study was to evaluate the potential role of UC maintenance therapy on the colonic extension of the disease. Materials and methods: A total of 98 patients, 56 males, 42 females, mean age 52 years, range 22-82 years, from 12 medical centers in Belgium, with an acute exacerbation of well-established, endoscopically and histologically proven left-sided UC, were included. The colonic extension was endoscopically determined at the time of the initial diagnosis and at the actual flare-up. The mean duration of UC was 93 + 72 months, median was 84 months, and range was 3-372 months. Active smoking was reported in only 7% of patients, while the majority were no-smokers (63%) or ex-smokers (30%). The median colonic extension at the time of initial diagnosis was 25 cm, range 2-70 cm from the anal merge. Sixty-six percent of the patients had quiescent disease without flare-ups during last year. The χ2-test was used for statistical analysis. Results: 29/98 (29.6%) patients had not used any maintenance therapy in the last 3 months before the actual exacerbation. The most commonly used maintenance therapy was 5-ASA (43%), while combined therapy with 5-ASA, corticosteroids or immunosuppresives (mainly azathioprine) in all possible combinations was reported by 29.6% of patients. The extent of UC had not changed in 50.7% and 51.7% of patients, respectively, with and without maintaining therapy (NS, p = 0.99). Some degree of regression was observed in, respectively, 21.7% and 20.7% (NS, p = 0.99), and some degree of extension in, respectively, 27.5% and 27.6% (NS, p = 0.99). Furthermore, no relationship was found between changes in colonic extent and type of maintaining therapy, smoking habits or disease activity during the last year before the acute exacerbation. A tendency of beneficial effect of maintenance therapy on disease extent was observed in patients with continuous active disease of short duration. Conclusions: According to this multicenter study, maintenance remission therapy for left-sided UC was not found to have a statistically significant effect on colonic extension. Further long-term studies are necessary to confirm these results. © 2007 European Crohn's and Collitis Organisation.info:eu-repo/semantics/publishe

Safety Assessment of Compounds after In Vitro Metabolic Conversion Using Zebrafish Eleuthero Embryos

Zebrafish-based platforms have recently emerged as a useful tool for toxicity testing as they combine the advantages of in vitro and in vivo methodologies. Nevertheless, the capacity to metabolically convert xenobiotics by zebrafish eleuthero embryos is supposedly low. To circumvent this concern, a comprehensive methodology was developed wherein test compounds (i.e., parathion, malathion and chloramphenicol) were first exposed in vitro to rat liver microsomes (RLM) for 1 h at 37 &#176;C. After adding methanol, the mixture was ultrasonicated, placed for 2 h at &#8722;20 &#176;C, centrifuged and the supernatant evaporated. The pellet was resuspended in water for the quantification of the metabolic conversion and the detection of the presence of metabolites using ultra high performance liquid chromatography-Ultraviolet-Mass (UHPLC-UV-MS). Next, three days post fertilization (dpf) zebrafish eleuthero embryos were exposed to the metabolic mix diluted in Danieau&#8217;s medium for 48 h at 28 &#176;C, followed by a stereomicroscopic examination of the adverse effects induced, if any. The novelty of our method relies in the possibility to quantify the rate of the in vitro metabolism of the parent compound and to co-incubate three dpf larvae and the diluted metabolic mix for 48 h without inducing major toxic effects. The results for parathion show an improved predictivity of the toxic potential of the compound

Prevalence of genotypic resistance among antiretroviral drug-naive HIV-1-infected patients in Belgium

Objectives: To estimate the prevalence and the evolution over time (1995-1998) of genotypic resistance to antiviral drugs in antiretroviral drug-naive HIV-1-infected patients in Belgium. Design: Belgian Aids Reference Laboratories provided retrospective samples and clinical data from antiretroviral drug-naive HIV-1-infected patients who visited the hospital for the first time in 1995 (n=45), 1997 (n=75) and 1998 (n=111). Genotypic resistance to the three available classes of drugs was monitored using the Line Probe Assay (Innogenetics, Gent, Belgium). Additionally, ARMS-151 was performed for scoring multinucleoside resistance. Results: The prevalence of genotypic resistance at baseline to nucleoside analogue reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were each between 10% and 20% for 1995, 1997 and 1998 without an increasing trend over time. For NRTIs, resistance mutations were mainly related to zidovudine in 1995, whereas in 1997 and 1998 baseline resistance was scored for zidovudine, lamivudine or for both drugs simultaneously. No patients displayed the multi-nucleoside resistance Q151M mutation. Baseline resistance mutations to protease inhibitors (Pls) did not rise significantly: 4.4% in 1995, 8% in 1997 and 9.9% in 1998. When scoring any resistance-related mutation, 26.6% displayed genotypic baseline resistance in 1995, 26.6% in 1997 and 31.5% in 1998. Discussion: The prevalence of genotypic baseline resistance to any drug, as scored with LiPA, in naive HIV-1 patients in Belgium is 29%, with baseline resistance mutations to one or several drugs from all available classes of antiviral drugs. The ability of LiPA to pick up minor variants could be an explanation for the higher overall prevalence we observe, when compared to recent estimates in other countries of 16.3% and 22%, which were based on sequencing methods. According to the European guidelines for resistance testing, resistance testing in Belgium before starting antiviral therapy should be considered.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Budesonide in Collagenous colitis: A Double-Blind Placebo-Controlled Trial With Histologic Follow-Up

Collagenous colitis (CC) is a well-described entity causing chronic diarrhea and characteristic histologic findings. Several treatment options have been suggested, but no controlled data are available. We conducted a placebo-controlled trial to show the clinical and histologic effects of budesonide in CC. Twenty-eight patients were randomly assigned to receive placebo (n = 14) or budesonide 9 mg daily (n = 14) for 8 weeks. Patients were evaluated clinically, and blinded biopsy specimens were analyzed from fixed locations at weeks 0 and 8. Clinical response was defined as a decrease of at least 50% in the disease activity score (number of bowel movements in the last 7 days). At week 8, nonresponders received open-label budesonide for the next 8-week period; responders discontinued treatment and were followed up. Three patients discontinued the study prematurely. Intention-to-treat analysis showed clinical response in 8 of 14 patients in the budesonide group compared with 3 of 14 responders for placebo (P = 0.05) after 8 weeks of blinded therapy, together with improved stool consistency. Histologically, there was no change in the mean thickness of the collagen band but a significant decrease of the lamina propria infiltrate in the budesonide group (P <0.001). Budesonide is efficacious in inducing short-term clinical response in CC with significant reduction of the histologic infiltrate in the lamina propri