Gigi Veereman

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease

Children and adolescents with Crohns disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohns and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Prebiotics in infant formula

The gastrointestinal microbiota of breast-fed babies differ from classic standard formula fed infants. While mothers milk is rich in prebiotic oligosaccharides and contains small amounts of probiotics, standard infant formula doesn’t. Different prebiotic oligosaccharides are added to infant formula: galacto-oligosaccharides, fructo-oligosaccharide, polydextrose, and mixtures of these. There is evidence that addition of prebiotics in infant formula alters the gastrointestinal (GI) microbiota resembling that of breastfed infants. They are added to infant formula because of their presence in breast milk. Infants on these supplemented formula have a lower stool pH, a better stool consistency and frequency and a higher concentration of bifidobacteria in their intestine compared to infants on a non-supplemented standard formula. Since most studies suggest a trend for beneficial clinical effects, and since these ingredients are very safe, prebiotics bring infant formula one step closer to breastmilk, the golden standard. However, despite the fact that adverse events are rare, the evidence on prebiotics of a significant health benefit throughout the alteration of the gut microbiota is limited.

Pooled analysis of the surgical treatment for colorectal cancer liver metastases

Liver metastases in colorectal cancer patients decreases the expected 5 year survival rates by a factor close to nine. It is generally accepted that resection of liver metastases should be attempted whenever feasible. This manuscript addresses the optimal therapeutic plan regarding timing of resection of synchronous liver metastases and the use of chemotherapy in combination with resection of synchronous metachronous liver metastases. The aim is to pool all published results in order to attribute a level of evidence to outcomes and identify lacking evidence areas. A systematic search of guidelines, reviews, randomised controlled, observational studies and updating a meta-analysis was performed. Data were extracted and analysed. Data failed to demonstrate an effect of timing of surgery or use of chemotherapy on overall survival. Concomitant resection of liver metastases and the primary tumour may result in lower postoperative morbidity. Systemic peri-operative chemotherapy may improve progression free survival compared to surgery alone.

COMBINED IMPACT OF MUCOSAL DAMAGE AND OF CYSTIC FIBROSIS ON THE SMALL INTESTINAL BRUSH BORDER ENZYME ACTIVITIES

Abstract In 61 cystic fibrosis (CF) patients, the small intestinal mucosa was studied at the time of diagnosis before starting therapy. In 19 out of 61 patients, partial villous atrophy on light microscopy and shortened villi on stereomicroscopic examination were seen. On the biopsy specimens, maltase, sucrase, lactase and alkaline phosphatase activities were studied. Comparison of the enzymatic activities in CF patients having damaged mucosa and a group of patients having similar mucosal lesions of unspecified origin (UTID), reveals a significantly more pronounced decrease of the alkaline phosphatase activity (p<0.005) in the CF patients. This is in agreement with previous reported results in CF patients with normal mucosa. The abnormal mucosal findings could be due to the decreased neutralization of the gastric content delivered into the duodenum, the early inflammatory reaction present in the CF mucosa and/or to the impaired synthesis of membrane glycoproteins and enzymes secondary to the CFTR mutation.

Use of Placebo in Pediatric Inflammatory Bowel Diseases : A Position Paper From ESPGHAN, ECCO, PIBDnet, and the Canadian Children IBD Network

ABSTRACT Performing well-designed and ethical trials in pediatric inflammatory bowel diseases (IBD) is a priority to support optimal therapy and reduce the unacceptable long lag between adult and pediatric drug approval. Recently, clinical trials in children have been incorporating placebo arms into their protocols under conditions that created controversy. Therefore, 4 organizations (the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Crohns and Colitis Organization; the Canadian Children IBD Network; and the Global Pediatric IBD Network) jointly provide a statement on the role of placebo in pediatric IBD trials. Consensus was achieved by 94 of 100 (94%) voting committees’ members that placebo should only be used if there is genuine equipoise between the active treatment and placebo; for example, this may be considered in trials of drugs with new mechanisms of action without existing adult data, especially when proven effective alternatives do not exist outside the trial. Placebo may also be used in situations where it is an “add-on” to an effective therapy or to evaluate exit-strategies of maintenance therapy after long-term deep remission. It has been, however, agreed that no child enrolled in a trial should receive a known inferior treatment both within and outside the trial. This also includes withholding therapy in children who show clinical response after a short induction therapy. Given the similarity between pediatric and adult IBD regarding pathophysiology and response to treatments, drugs generally cannot be considered being in genuine equipoise with placebo if it has proven efficacy in adults. Continued collaboration of all stakeholders is needed to facilitate drug development and evaluation in pediatric IBD.

833 Malignancies in Children Receiving Infliximab and Other Inflammatory Bowel Disease Therapies: An Inflammatory Bowel Disease Multicenter, Prospective, Long-Term Registry of Pediatric Patients (Develop) Registry Data

matched controls without IBD. Information including diagnosis, IBD type, IBD activity, IBD medications, proton pump inhibitor (PPI) use, hospitalizations and antibiotic use was recorded. Patients were followed with repeat fecal and serum samples obtained. Cytotoxic culture for CD along with PCR to detect the toxin B gene was conducted on stool. Pulsed field gel electrophoresis (PFGE) was performed to determine strain type. Enzyme-linked Immunosorbent Assay (ELISA) was used to determine immunoglobulin G, A andM responses to CD toxin A and B from serum. Results: The prevalence of CD carriage was significantly greater in patients with IBD (17%) compared with controls (3%) (p=0.012). PCR to detect the toxin B gene compared to the gold standard of cytotoxic culture had a sensitivity of 92% and specificity of 100%. No patients showed clinical evidence of active CD infection. Among patients with IBD, IBD type, disease activity, IBD therapy, antibiotic use and hospitalizations were not found to be associated with CD carriage. PPI use was significantly more frequent in patients with CD carriage (54% vs. 25%, p,0.05). PFGE identified 6 different North American Pulsed Field Type (NAP) strains that then varied over time. There was a significantly greater proportion of patients with a positive antibody response to toxin A with IBD (69%) vs. controls (53%) (p,0.05), with a parallel trend of increased IgG and IgA responses against both toxin A and toxin B in those with IBD. Conclusions: Our findings show that asymptomatic toxigenic CD carriage, likely acquired in the community, is increased in pediatric IBD outpatients compared with controls. A variety of NAP strains were identified and these changed over time in CD colonized patients. PPI use was associated with an increased risk of carriage. Antibody responses of patients with IBD to CD toxins were increased, potentially promoting asymptomatic colonization. Future studies are needed to identify risk factors for symptomatic CD in pediatric IBD.

41 Serious Infections and Associated Risk Factors in Patients Receiving Infliximab and Immunotherapies for Children With Inflammatory Bowel Disease: Develop Registry Data

all pts with PSC-IBD who underwent LT for non-cholangiocarcinoma indications at Mayo Clinic, Rochester from 1998-2008, with follow-up through 2012. Information on course of pre-transplant IBD, de novo IBD and colectomy was extracted. Progression of IBD was defined as need for escalation of medical therapy, as compared to pre-LT course. Risk factors for progression of IBD were identified using multivariate Cox proportional hazard analysis. Results: One hundred one pts with PSC underwent LT (mean age, 48 yrs; 62 males). Median follow-up (IQR) was 8.4 years (5.5-10.7). Of these, 80 pts had associated IBD (74 pts with ulcerative colitis, 6 pts with Crohns disease). Twenty-five pts underwent colectomy prior to LT (18 for medically-refractory IBD, 7 for colorectal neoplasia). Further analysis was restricted to 55 pts with PSC-IBD with intact colon at time of LT. Pre-LT, 32 pts had quiescent IBD requiring no therapy and 21 were maintained on 5-ASA. Post-LT, despite transplant-related immunosuppression, 26/55 (47.3%) required escalation of therapy, whereas 28/55 had a stable course (50.9%) and 1 patient (1.8%) improved (Table). One, 5and 10-year risk of progression of IBD was 10.9%, 36.4% and 45.4%, respectively. Thirteen pts underwent colectomy after LT (5 for medically-refractory IBD, 8 for colorectal neoplasia), with 1-, 5and 10-year risk of colectomy being 1.8%, 16.4% and 21.8%. On multivariate Cox proportional hazard analysis, use of tacrolimus (hazard ratio, 5.6; 95% CI, 1.1-103.4) was associated with progression of IBD, whereas recurrence of PSC (HR, 0.2; 95% CI, 0.1-0.6) was protective against progression of IBD. There was no association between progression of IBD and transplant(CMV infection/mismatch), immunosuppression-(use of mycophenolate, azathioprine or prolonged prednisone use), or IBD-related factors (pretransplant IBD activity, empirical initiation of 5-aminosalicylates within 4 months of LT). Eleven pts developed de novo IBD after LT, with 1-, 5and 10-year risk (among PSC pts without IBD after LT) being 4.8%, 38.1% and 47.6%. No specific transplant or immunosuppression-related risk factor was identified, including CMV infection. Conclusion: The cumulative probability of IBD flare requiring escalation of therapy after LT for PSC is 45% at 10 years, despite immunosuppression for LT. Recurrent PSC was associated with mild course of IBD after LT, similar to the observation that advanced PSC requiring LT is associated with a mild course of IBD pre-transplant.

Treatment Options and Outcomes of Pediatric IBDU Compared with Other IBD Subtypes: A Retrospective Multicenter Study from the IBD Porto Group of ESPGHAN.

Background:Inflammatory bowel disease unclassified (IBDU) is the rarest IBD subtype with treatment based on extrapolation from ulcerative colitis (UC) and Crohns disease (CD) studies. We compared IBDU treatment choices with other colonic IBDs and explored long-term outcomes. Methods:This was a multicenter retrospective longitudinal study of 23 centers of pediatric IBD with isolated colitis, including a mild ileitis consistent with backwash. Results:Of note, 797 children (median age: 11.6 years, range: 2–18.4) were included: 250 with CD, 287 with UC, and 260 with IBDU (median follow-up: 2.8 [interquartile range: 1.6–4.2] years). IBDU differed from UC with lower corticosteroid (154 [59%] versus 204 [71%]; P = 0.004) and higher exclusive enteral nutrition use (26 [10%] versus 2 [0.6%]; P < 0.0001). Compared to patients with CD, patients with IBDU received less exclusive enteral nutrition and immunomodulators (26 [10%] versus 93 [37%]; P < 0.0001 and 67 [26%] versus 129 [52%]; P < 0.0001, respectively) but more aminosalicylates (228 [88%] versus 159 [64%]; P < 0.0001). Biological treatment was significantly higher in CD (82 [34%]) than in IBDU and UC (24 [12%] and 47 [17%], respectively; P < 0.0001). At last follow-up, 135 (69%) patients with IBDU had remission/mild disease activity compared with 100 (46%; P < 0.0001) patients with CD and 174 (64%; P = 0.3) patients with UC. Four (2%) of 194 patients with IBDU underwent surgery compared with 22 (8%) of 270 patients with UC (P = 0.009) and 20 (8%) of 238 patients with CD (P = 0.008). Conclusions:Children with IBDU have a lower medication burden and lower surgery rates than other IBD subtypes. The disease course at follow-up is generally mild, supporting an initial trial with 5-ASA before using more aggressive therapies.

Public-private collaboration in clinical research during pregnancy, lactation, and childhood: Joint position statement of the early nutrition academy and the european society for pediatric gastroenterology, hepatology, and nutrition

ABSTRACT This position statement summarises a view of academia regarding standards for clinical research in collaboration with commercial enterprises, focussing on trials in pregnant women, breast-feeding women, and children. It is based on a review of the available literature and an expert workshop cosponsored by the Early Nutrition Academy and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Clinical research collaborations between academic investigators and commercial enterprises are encouraged by universities, public funding agencies, and governmental organisations. One reason is a pressing need to obtain evidence on the effects, safety, and benefits of drugs and other commercial products and services. The credibility and value of results obtained through public–private research collaborations have, however, been questioned because many examples of inappropriate research practice have become known. Clinical research in pregnant and breast-feeding women, and in infants and children, raises sensitive scientific, ethical, and societal questions and requires the application of particularly high standards. Here we provide recommendations for the conduct of public–private research collaborations in these populations. In the interest of all stakeholders, these recommendations should contribute to more reliable, credible, and acceptable results of commercially sponsored trials and to reducing the existing credibility gap.

Gastric Emptying of Liquids in Children.

Objectives: The present study was performed to determine normal values for gastric half-emptying time (t1/2GE) of liquids in healthy children. Methods: Gastric emptying (GE) of a standardized test milk-drink measured with 99mtechnetium scintigraphy and the 13C-acetate breath test (13C-ABT) was compared in 19 children ages between 4 and 15 years with upper gastrointestinal symptoms. The 13C-ABT was subsequently used to determine normal values for GE of the same liquid test meal in 133 healthy children ages between 1 and 17 years. Results: In the group of children with upper gastrointestinal symptoms, the results showed a significant correlation (r = 0.604, P = 0.0006) between t1/2GE measured with both techniques. In the group of healthy children, the results of t1/2GE showed that there was no influence of age, sex, weight, height, and body mass index on GE. Conclusions: Normal values for GE of a standardized test milk-drink in healthy children were determined with the 13C-ABT. This technique is considered reliable and is well accepted by the patients.