Papers by Stavroula Koilakou
Journal of Crohn's and Colitis Supplements, 2008
Aim: Crohn' s Disease (CD) has been linked to different functional deficiencies of antimicrobial ... more Aim: Crohn' s Disease (CD) has been linked to different functional deficiencies of antimicrobial defensins. Ileal CD is characterized by reduced expression of α-defensins (HD5, HD6). The mechanism is a compromised WNT/Tcf4 stem cell differentiation pathway and-in some cases-a mutation in NOD2. Colonic CD is mediated by an attenuated induction of β-defensins (HBD2, HBD3) which is due to a gene copy number polymorphism. Little is known about the effect of common drugs on innate immunity, especially in vivo. Herein, we aimed to address if current treatments of CD influence the defensin expression in clinical samples. Methods: Biopsies were collected from inflamed CD tissue of the small (n=55) and large intestine (n=45). RNA expression levels from defensins (HD5, HD6, HBD1, HBD2, HBD3) and cytokines (Il1β, Il-6, Il-8, Il-10, ICAM1, TNF-α) were quantified by real-time RT-PCR with external standards. Samples were arranged into groups with high or low Il-8 (moderate or severe) since this is a good marker for histological inflammation. After retrospective analysis of treatment we surrogated the samples according to the use of steroids (ileum n=31, colon n=24), azathioprine (ileum n=10, colon n=9) and 5-Asa (ileum n=16, colon n=15). Results: In small intestinal CD patients neither steroids, nor azathioprine, nor 5Asa seemed to have any effect on αand βdefensin expression. Some cytokines seemed to be decreased but none of the changes were significant. As reported earlier, the expression of Paneth cell α-defensins was independent of the degree of inflammation and did not correlate with Il-8. Similarly, in the colon, inducible β-defensin levels were unchanged with or without current treatments (HBD2, HBD3) and equally expressed in all inflamed samples. As reported earlier, the constitutive β-defensin HBD1 was decreased in case of severe inflammation (compared to mild inflammation) and seemed to be up regulated by steroids in this group (p=0.0087). Interestingly, the anti-inflammatory cytokine Il-10 showed a similar pattern with increased expression (p=0.0173) in severely inflamed tissue and steroid treatment. Conclusions: As tested in a clinical setting using retro-perspective analysis of inflamed CD samples, the currently used standard treatment (Azathioprine, 5Asa, steroids) did not influence the overall defensin expression. As reported earlier within CD samples as well as inflammatory ileal controls (UC pouchitis), the degree of inflammation it self did not change the gene expression of antimicrobial Paneth cell defensins. Hopefully, additional future drugs aimed at restoring the host-microbe balance at the intestinal mucosa will be identified.
Acta gastro-enterologica Belgica
Microsatellite instability seems to play a significant role in colorectal carcinogenesis, as it i... more Microsatellite instability seems to play a significant role in colorectal carcinogenesis, as it is reported to occur in HNPCC patients as well as in a proportion of sporadic cases. The aim of this study was to examine the presence of microsatellite instability in relation to other commonly observed genetic abnormalities and clinicopathological characteristics of sporadic and inherited colorectal cancers. One hundred and three sporadic colorectal adenocarcinomas and 9 adenocarcinomas from HNPCC patients were histologically evaluated. The presence of microsatellite instability was investigated at six loci. K-ras and p53 mutations, p53 LOH, hMLH1 expression and methylation status were examined as well. Statistical analysis was performed to define possible correlations of the observed genetic alterations with the clinicopathological characteristics of the analysed tumors. High-grade microsatellite instability was found in 14% of sporadic adenocarcinomas and in 78% of adenocarcinomas fro...
Hepato-gastroenterology
The genetic pathways of gallbladder cancer are not yet well defined, since the contribution of ge... more The genetic pathways of gallbladder cancer are not yet well defined, since the contribution of genetic abnormalities, clarified in other organs, remains questionable. Our aim was to evaluate the role of microsatellite instability in this organs carcinogenesis. We investigated a group of 20 gallbladder carcinomas from Greek patients with regard to alterations in length of the BAT-26 mononucleotide marker--as an indicator of microsatellite instability. The findings were correlated with the presence of p53 and ras mutations, alterations of the bax and TGF-beta RII genes and tumors' clinicopathological features. Polymerase chain reaction and electrophoretic analysis in a non-denaturating 25% polyacrylamide gel was performed for the detection of BAT-26 size variations. None of our specimens showed microsatellite instability at the BAT-26 marker. BAT-26, an indicator of high-level microsatellite instability, may not be sufficient, when used alone, for determining the microsatellite in...
Journal of Crohn's and Colitis Supplements, 2008
Poster Presentations never been performed in the Netherlands. Therefore, the objective of this st... more Poster Presentations never been performed in the Netherlands. Therefore, the objective of this study was to investigate whether there is a difference in the levels of stress, anxiety and depression between Dutch IBD and IBS patients. Methods: In this cross-sectional study, levels of anxiety, depression and stress of out-clinic patients with IBD (N=452) or IBS (N=127) were measured with the Hospital Anxiety and Depression Scale (HADS) and the Perceived Stress Scale (PSS). Multiple linear regression models were used to investigate the differences in levels of anxiety, depression and stress between IBD and IBS taking into account other patient characteristics. Results: The scores for HADS-anxiety, HADS-depression (square root) and PSS were 2.1 (CI = 1.4-2.8; p<0.000), 0.3 (CI = 0.2-0.6; p<0.000) and 2.8 (CI = 1.4-4.3; p<0.000) higher in those with IBS compared to IBD respectively. After adjustments for the confounding variables gender, actual complaints, (sexual) abuse and major life events, only a statistically significantly higher HADS-anxiety score was seen in IBS compared to IBD. Conclusions: In this study, IBS patients have higher levels of stress, depression and anxiety compared to IBD patients, which is the result of differences in characteristics between these two groups. Additionally, the higher level of anxiety seems to be influenced by IBS itself. Treatment with emphasis on stress, depression and anxiety relief may improve the quality of life in these patients.
Journal of Crohn's and Colitis Supplements, 2008
Poster Presentations never been performed in the Netherlands. Therefore, the objective of this st... more Poster Presentations never been performed in the Netherlands. Therefore, the objective of this study was to investigate whether there is a difference in the levels of stress, anxiety and depression between Dutch IBD and IBS patients. Methods: In this cross-sectional study, levels of anxiety, depression and stress of out-clinic patients with IBD (N=452) or IBS (N=127) were measured with the Hospital Anxiety and Depression Scale (HADS) and the Perceived Stress Scale (PSS). Multiple linear regression models were used to investigate the differences in levels of anxiety, depression and stress between IBD and IBS taking into account other patient characteristics. Results: The scores for HADS-anxiety, HADS-depression (square root) and PSS were 2.1 (CI = 1.4-2.8; p<0.000), 0.3 (CI = 0.2-0.6; p<0.000) and 2.8 (CI = 1.4-4.3; p<0.000) higher in those with IBS compared to IBD respectively. After adjustments for the confounding variables gender, actual complaints, (sexual) abuse and major life events, only a statistically significantly higher HADS-anxiety score was seen in IBS compared to IBD. Conclusions: In this study, IBS patients have higher levels of stress, depression and anxiety compared to IBD patients, which is the result of differences in characteristics between these two groups. Additionally, the higher level of anxiety seems to be influenced by IBS itself. Treatment with emphasis on stress, depression and anxiety relief may improve the quality of life in these patients.
American Journal of Gastroenterology, 2010
Letters to the Editor 231 the MCA technique to make anastomoses between various hollow viscera, s... more Letters to the Editor 231 the MCA technique to make anastomoses between various hollow viscera, such as gastrojejunostomy, choledochojejunostomy, or choledochoduodenostomy, without surgery have been well demonstrated (2). It would have been very diffi cult for us to operate upon this patient, because of intra-abdominal adhesion. Th e MCA technique is a very reasonable method, especially for patients, such as this, with a past history of operation.
The American Journal of Gastroenterology, 2009
Journal of Crohn's and Colitis, 2007
Background: The long-term effectiveness of azathioprine, in Crohn's disease (CD) patients remains... more Background: The long-term effectiveness of azathioprine, in Crohn's disease (CD) patients remains a matter of debate. This study aims at assessing the effectiveness and safety of azathioprine in patients treated continuously for less or more than 4 years. Methods: Patients with steroid-dependent Crohn's disease in remission on azathioprine (2-2.5 mg/kg) for between 2 and 8 years were assigned into two groups. Patients in Group A were being treated continuously for 2 to 4 years whereas patients in Group B for 4 to 8 years. Patients were followed every month for 1 year with physical examination and laboratory tests. Compliance with treatment was also assessed every month. Every 3 months the Crohn's Disease Activity Index (CDAI) was calculated and the quality of life (QOL) Inflammatory Bowel Disease Questionnaire (IBDQ) was completed. Colonoscopy with calculation of the Crohn's Disease Endoscopic Index of Severity (CDEIS) was performed at baseline and at the end of the study. The primary end point was relapse after 1 year. Secondary end points were safety of treatment, QOL, and endoscopic healing. Results: Fifty-eight patients were included in Group A and 42 in Group B. The relapse rates per protocol were 19.6% and 11.9%, respectively (p: not significant). There were no significant differences overall and at each time point of the study between the two treatment groups regarding compliance with and safety of treatment, CDAI, IBDQ, and CDEIS scores. Multifactorial analysis did not identify any factor influencing the remission of disease in any patient group. Conclusions: Long-term treatment with azathioprine of steroid-dependent Crohn's disease is efficacious and safe.
Inflammatory Bowel Diseases, 2007
Background: Patients with longstanding quiescent Crohn's disease on azathioprine usually maintain... more Background: Patients with longstanding quiescent Crohn's disease on azathioprine usually maintain an excellent quality of life but are also concerned about long-term safety. This may affect adherence to treatment. The aim of the present study was to assess the adherence to azathioprine in a cohort of patients with Crohn's disease in long-term remission. Methods: Thirty patients with Crohn's disease in remission on azathioprine for Ն48 months were enrolled in the study. All were asked to record the number of azathioprine tablets they consumed daily. Notes were kept every other month for 6 months. Adherence was defined as consumption of Ն80% of medication. Results: Most patients (18/28, 74.3%) were not adherent to treatment. The mean (ϮSD) daily dose of azathioprine in adherent and nonadherent patients was 145 Ϯ 45 mg and 102 Ϯ 20 mg, respectively. However, there were no significant differences between the 2 groups in the mean IBDQ score and mean Crohn's Disease Activity Index (CDAI) score, both throughout the entire study and at each time point of the study. Male gender, single status, and consumption of Ͼ5 concomitant medications were associated with nonadherence. Conclusions: Most patients with Crohn's disease in longstanding remission had low self-reported adherence to azathioprine. Both male gender and single status were associated with nonadherence to azathioprine, whereas disease factors were not related to self-reported adherence. Patients considered nonadherent to treatment maintained disease remission and a quality of life similar to patients who were adherent to treatment.
Inflammatory Bowel Diseases, 2009
Background: The effects of azathioprine (AZA) and budesonide (BUD) on mucosal healing and histolo... more Background: The effects of azathioprine (AZA) and budesonide (BUD) on mucosal healing and histologic remission of Crohn's disease (CD) are insufficiently studied. In this prospective study we evaluated the comparative effects of AZA and BUD on endoscopic and histologic activity in patients with steroid-dependent Crohn's ileocolitis or proximal colitis who had achieved clinical remission on conventional steroids. Methods: Patients were randomized to AZA (2.0-2.5 mg/kg a day) or BUD (6-9 mg a day) for 1 year. The study protocol included clinical examination, laboratory tests, calculation of the Crohn's Disease Activity Index (CDAI), completion of the Inflammatory Bowel Disease Questionnaire (IBDQ), at baseline and then every 2 months for 1 year. Ileocolonoscopy with regional biopsies was performed at baseline and then at the end of the study to assess mucosal healing and the histologic activity of CD. Results: Thirty-eight patients were randomized to AZA and 39 to BUD. At the end of the study 32 and 25 patients in the AZA and BUD groups, respectively, were in clinical remission (P ϭ 0.07). The Crohn's Disease Endoscopic Index of Severity (CDEIS) score fell significantly only in the AZA group (P Ͻ 0.0001). Complete or near complete healing was achieved in 83% of AZA-treated patients compared with only 24% of BUDtreated patients (P Ͻ 0.0001). Histologic activity as assessed by an average histology score (AHS) fell significantly only in the AZA group (P Ͻ 0.001 versus baseline) and was significantly lower than in the BUD group at the end of the study (P Ͻ 0.001). Eight patients in the AZA group were withdrawn for adverse events (n ϭ 6) or relapse of disease compared with 14 patients in the BUD group who were withdrawn for relapse of disease. Conclusions: In patients with steroid-dependent inflammatory Crohn's ileocolitis or proximal colitis who achieve clinical remission with conventional steroids, a 1-year treatment with AZA was superior to BUD in achieving and maintaining mucosal healing and histologic remission.
Inflammatory Bowel Diseases, 2005
REFERENCES 1. Brenner HI, Fishman EK, Harris ML, et al. Musculoskeletal complications of Crohn&#x... more REFERENCES 1. Brenner HI, Fishman EK, Harris ML, et al. Musculoskeletal complications of Crohn's dis-ease. Orthopedics. 2000;23. 2. Denton ERE, Jamieson CP, Rankin SC. Case report: abscess of the adductor muscles of the thighan unusual complication of Crohn's ...
Experimental and Molecular Pathology, 2006
The molecular alterations involved in the pathogenesis of gallbladder cancer are not yet well def... more The molecular alterations involved in the pathogenesis of gallbladder cancer are not yet well defined. Our aim was to determine the microsatellite status of gallbladder carcinomas and its possible correlation with alterations in K-ras and p53 genes as well as the clinicopathological characteristics of these tumors. A group of 37 gallbladder carcinomas was analyzed for alterations in a proposed panel of mononucleotide and dinucleotide markers of microsatellite instability. Somatic frameshift mutations at repeated sequences in the coding regions of TGF-betaRII, Bax, hMSH3, hMSH6 were also examined. The findings were correlated with the presence of K-ras and p53 alterations, and tumors&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; clinicopathological features. Microsatellite instability and/or LOH was observed in 9 gallbladder carcinomas. Cases showing microsatellite instability displayed alterations only in dinucleotide markers and were classified as MSI-L carcinomas. A subset of gallbladder carcinomas is characterized by low-level instability, based on the analysis of the above mentioned panel of markers. The pathway of microsatellite instability seems to play a minor role in the pathogenesis of gallbladder cancer.
European Journal of Gastroenterology & Hepatology, 2009
Objectives Antibodies to infliximab may lead to loss of response to infliximab (IFX) in Crohn's d... more Objectives Antibodies to infliximab may lead to loss of response to infliximab (IFX) in Crohn's disease. Azathioprine (AZA) coadministration prevents the formation, whereas hydrocortisone (HC) premedication reduces the levels of antibodies to IFX. This pilot study aims at assessing the efficacy of these strategies to prevent loss of response to IFX. Methods Eligible patients had active steroid-dependent luminal Crohn's disease and received IFX (5 mg/kg at weeks 0, 2, and 6 for induction and then scheduled q8 week for remission maintenance). Patients were stratified in a 1 : 1 ratio to oral AZA (2-2.5 mg/kg/day, stratum A) or HC premedication (250 mg intravenously, stratum B). Stratum A included only patients naive to AZA; stratum B included both AZA naive and intolerant patients. Steroids were tapered within 6-8 weeks. Patients were followed up with monthly clinical assessments, laboratory tests, Crohn's Disease Activity Index calculations, adverse-events check up, and adherence to treatment. Results Overall, 23 patients received IFX/HC and 23 IFX/ AZA. There were no differences at baseline in any patientrelated or disease-related parameters. Seventeen (74%) patients on IFX/AZA completed the study; six patients were withdrawn for primary nonresponse (one patient), lost response to IFX (two patients), or AZA-related adverse events. Eighteen (78%) patients on IFX/HC completed the study; five patients were withdrawn for primary nonresponse (one patient), loss of response (two patients), or infusion reactions to IFX. No significant differences emerged between strata in clinical remission rates or lost response to IFX. Conclusion This prospective 2-year pilot study has not confirmed superiority of any available strategy to maintain the efficacy of IFX.
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Papers by Stavroula Koilakou