Chris Jj Mulder

Novel approaches in the management of refractory celiac disease

Celiac disease is a gluten-sensitive enteropathy, which commits the patient to a life-long gluten-free diet. This is sufficient to treat the overwhelming majority of patients. However, a small group of these patients, mainly those diagnosed above 50 years of age, fails to improve histologically and clinically upon elimination of gluten from the diet. These patients are regarded as suffering from refractory celiac disease. In a subgroup of these patients a pre-malignant intraepithelial lymphocyte population can be detected in the small intestinal mucosa (type II). These patients are at a high risk of developing an enteropathy-associated T-cell lymphoma (50–60% within 4–6 years), which has a very poor prognosis and a 5-year survival of only 8%. The therapeutic challenge in these refractory celiac disease type II patients is targeting the aberrant intraepithelial lymphocytes to eventually prevent enteropathy-associated T-cell lymphoma development. Although management of these patients is difficult and therapeutic options are currently limited, novel treatment modalities are being explored.

Video capsule endoscopy in celiac disease: current clinical practice.

OBJECTIVE:u2003 A complete examination of the small intestine is possible by video capsule endoscopy (VCE). The aim of this study was to evaluate current indications for performing VCE in celiac disease.

Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas

BackgroundNonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas.MethodsQuantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples.ResultsIncreased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (pu2009<u20090.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (pu2009<u20090.05).ConclusionsMethylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations.

Abstract 4523: Stool proteomics reveals new candidate biomarkers for colorectal cancer screening

Background Colorectal Cancer (CRC) screening can save many lives. Many invitational large scale screening programs worldwide use stool tests like the fecal immunochemical tests (FIT), which detects human hemoglobin. Tumor-specific biomarkers have the potential to improve the performance of these tests but so far, no protein-based fecal test has proved better than the FIT. Although most biomarker discoveries are done in tumor-tissues, the presence and/or chemical nature of biomarkers may be different in samples that ultimately will be used for screening like stool. Measuring biomarkers directly in stool samples may therefore yield candidate CRC biomarkers that are stable in the fecal environment. Aim The aim of the present study was to identify tumor-specific protein based biomarkers for the early detection of CRC, by applying in-depth proteomics to stool samples from CRC patients and healthy controls. Material and method Stool samples were obtained from 10 subjects with negative colonoscopy and from 12 CRC patients. Proteins were analyzed by in-depth proteomics using gel electrophoresis and nano Liquid Chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Resulting MS/MS spectra were searched against the human IPI database (version 3.62). Proteins were analyzed by hierarchical cluster analysis and visualized in a heat map. Non-paired statistical analysis of spectral count data from human proteins was performed using a beta-binomial test. Verification of candidate biomarkers was performed by Selected Reaction Monitoring Mass Spectometry (SRM-MS). Results In total 830 human proteins were identified of which 221 were present at different levels in stool samples from CRC patients compared to control subjects. Of these, 134 proteins were significantly enriched in CRC. Unsupervised hierarchical cluster analysis revealed two clusters. One cluster contained nine CRC stool samples, the other cluster contained all ten control stool samples together with three CRC stool samples. SRM-MS analysis of selected candidate biomarkers on the same stool samples verified the results obtained by LC-MS/MS. Conclusion Proteome profiling on stool revealed 134 proteins significantly enriched in CRC compared to control stool samples, of which a sub set could be verified by SRM-MS. Validation in an independent series of stool samples collection (n=200) by SRM-MS is in process. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4523. doi:1538-7445.AM2012-4523

Limited Intra-Individual Variability in Hypoxanthine-Guanine Phosphoribosyl Transferase, Thiopurine S-Methyl Transferase, and Xanthine Oxidase Activity in Inflammatory Bowel Disease Patients During 6-Thioguanine Therapy

6-Thioguanine (6-TG) may be indicated in case of intolerance of or resistance to conventional thiopurines in the treatment of inflammatory bowel diseases (IBD). The aim of our study was to evaluate the intrapatient variability in the 6-TG metabolizing enzymes: hypoxanthine-guanine phosphoribosyl transferase (HGPRT), thiopurine S-methyl transferase and xanthine oxidase. We performed a pharmacokinetic study of 6-TG after oral and intravenous administration in IBD patients in remission. The enzyme activities were determined at baseline and 1 week after the initiation of 6-TG in red blood cells, peripheral blood mononuclear cells (PBMC) or plasma. From the results we conclude that HGPRT activity in erythrocytes decreases following the initiation of 6-TG therapy, which may imply that HGPRT is a rate limiting enzyme in 6-TG metabolism. Moreover, little intrapatient variability in enzyme activities was observed except for HGPRT activity in PBMC. These data may have implications in regard of future therapeutic drug monitoring.

Clinical nutrition in the hepatogastroenterology curriculum

Gastroenterology (GE) used to be considered a subspecialty of internal medicine. Today, GE is generally recognized as a wide-ranging specialty incorporating capacities, such as hepatology, oncology and interventional endoscopy, necessitating GE-expert differentiation. Although the European Board of Gastroenterology and Hepatology has defined specific expertise areas in Advanced endoscopy, hepatology, digestive oncology and clinical nutrition, training for the latter topic is lacking in the current hepatogastroenterology (HGE) curriculum. Given its relevance for HGE practice, and being at the core of gastrointestinal functioning, there is an obvious need for training in nutrition and related issues including the treatment of disease-related malnutrition and obesity and its associated metabolic derangements. This document aims to be a starting point for the integration of nutritional expertise in the HGE curriculum, allowing a central role in the management of malnutrition and obesity. We suggest minimum endpoints for nutritional knowledge and expertise in the standard curriculum and recommend a focus period of training in nutrition issues in order to produce well-trained HGE specialists. This article provides a road map for the organization of such a training program. We would highly welcome the World Gastroenterology Organisation, the European Board of Gastroenterology and Hepatology, the American Gastroenterology Association and other (inter)national Gastroenterology societies support the necessary certifications for this item in the HGE-curriculum.

Splenic volume differentiates complicated and non-complicated celiac disease

Background Studies in small groups of patients indicated that splenic volume (SV) may be decreased in patients with celiac disease (CD), refractory CD (RCD) type II and enteropathy-associated T-cell lymphoma (EATL). Objective The objective of this article is to evaluate SV in a large cohort of uncomplicated CD, RCD II and EATL patients and healthy controls. Methods The retrospective cohort consisted of 77 uncomplicated CD (of whom 39 in remission), 29 RCD II, 24 EATL and 12 patients with both RCD II and EATL. The control group included 149 healthy living kidney donors. SV was determined on computed tomography. Results The median SV in the uncomplicated CD group was significantly larger than in controls (202 cm3 (interquartile range (IQR): 154–275) versus 183 cm3 (IQR: 140–232), pu2009=u20090.02). After correction for body surface area, age and gender, the ratio of SV in uncomplicated CD versus controls was 1.28 (95% confidence interval: 1.20–1.36; pu2009<u20090.001). The median SV in RCD II patients (118 cm3 (IQR 83–181)) was smaller than the median SV in the control group (pu2009<u20090.001). Conclusion This study demonstrates large inter-individual variation in SV. SV is enlarged in uncomplicated CD. The small SV in RCD II may be of clinical relevance considering the immune-compromised status of these patients.

Risks for lymphoma and gastrointestinal carcinoma in patients with newly diagnosed adult-onset celiac disease: Consequences for follow-up: Celiac disease, lymphoma and GI carcinoma

Background The association between celiac disease (CD) and the development of lymphoid and gastrointestinal (GI) malignancies have been reported. However, data are scarce yet needed to develop evidence-based follow-up programs. Objective The objective of this article is to assess relative (RR) and absolute risks of lymphoma and GI carcinoma for newly diagnosed patients. Methods A case-control design to determine RR was performed with cases (lymphoma or GI carcinoma) and controls (melanoma or basal cell carcinoma) diagnosed 1994–2014, retrieved from the Dutch nationwide population-based pathology database (PALGA). Within this population, individuals with histologically proven CD before or simultaneously diagnosed with the malignancy were identified. Results A total of 349/301,425 cases (0.1%) and 282/576,971 (0.05%) controls were diagnosed with CD. Risk of T-cell lymphoma, predominantly enteropathy-associated T-cell lymphoma (EATL), was strongly associated with CD diagnosis (RRu2009=u200935.8 (95% CI 27.1–47.4)). Although most often synchronously diagnosed, T-cell lymphoma RRu2009≥u20091 year after CD diagnosis was still elevated (RRu2009=u200912.7 (95% CI 7.6–21.3)). Other CD-associated malignancies were small bowel adenocarcinoma (RRu2009=u200911.9 (95% CI 8.2–17.2)) and esophageal squamous cell carcinoma (RRu2009=u20093.5 (95% CI 2.1–5.8)). Absolute risks were relatively low. Other types of lymphomas and GI carcinomas were not associated with CD. Conclusion Increased risk for specific malignancies in CD should alert physicians for EATL (both intestinal and extraintestinal) and small bowel adenocarcinoma in patients with CD diagnosed at ageu2009≥u200950 years.

High inter-individual variability of serum xanthine oxidoreductase activity in IBD patients

ABSTRACT Objectives: Thiopurines play an essential role in the management of inflammatory bowel diseases (IBD, i.e. Crohns disease and ulcerative colitis). Over the past decade, several strategies to optimize treatment with thiopurines have been evaluated, including co-administration of allopurinol, a xanthine-oxidoreductase (XO) inhibitor, to low-dose thiopurine therapy. We aimed to assess the inter-individual variability of XO-activity between IBD-patients. Methods: We assessed XO activity in serum of IBD-patients of two medical centers in The Netherlands using the Amplex® Red Xanthine/Xanthine Oxidase Assay Kit, which measures the superoxide formation in a coupled reaction to the red-fluorescent oxidation product, resofurine. Results: We observed a high inter-individual variability of XO-activity in 119 patients, with a median activity of 16 µU/ml/hour (range 1–85 µU/ml/hour). The XO-activity was influenced by gender (male 19.5 vs. female 14.0 µU/ml/hour, p < 0.01), patients age (Pearsons correlation r = 0.21, p = 0.02) and duration of IBD (r = 0.23, p = 0.01). The XO activity was not affected by the type of IBD, smoking status, body mass index or (type of) thiopurine use (p > 0.05). Conclusions: There is a high inter-individual variability of XO-activity in IBD-patients; XO-activity is positively associated with male gender and patients age.