Shlomi Cohen

Endoscopic ultrasonography in pediatric patients with gastrointestinal disorders.

Background: Endoscopic ultrasound is a diagnostic tool for evaluation of gastrointestinal diseases in adults, but in children the use of endoscopic ultrasound is limited. This study retrospectively evaluates endoscopic ultrasound indications in, safety in, and impact on children. Patients and Methods: We reviewed the data of all of the pediatric patients (<18 years old) that underwent endoscopic ultrasound in our institution. The main goal was to evaluate the impact of endoscopic ultrasound in this patient population. Significant impact was defined as a new diagnosis or treatment attributed to the endoscopic ultrasound examination. Results: Thirty-two children (21 boys, 11 girls) at mean age 12 ± 5 years; (range = 1.5–18 years) underwent endoscopic ultrasound during a period of 6 years. The pancreas and biliary tract were examined in 19 children, esophagus in 8, and the stomach and rectum in 2 children each. Only 1 child had endoscopic ultrasound for duodenal indication. The indications in the pancreas and biliary tract group were recurrent pancreatitis in 9 children, cyst or mass in 6 children, and obstructive jaundice in 4 children. Indications in the esophagus group were stenosis in 4 children, and suspected duplication and esophageal mass in 2 children each. We used conscious sedation in 18 children and unconscious sedation in 12. Two children underwent endoscopic ultrasound with no anesthesia at all. In 7 cases, endoscopic ultrasound–guided fine-needle aspiration was performed. The procedure was successful in all of the patients with no complications. Endoscopic ultrasound changed the diagnosis or therapy in 14 cases. Conclusions: Endoscopic ultrasound is an effective tool in the evaluation of pediatric gastrointestinal patients, mostly with pancreatobiliary or esophageal disorders. Endoscopic ultrasound is a safe procedure with a significant impact in almost half of the children examined.

FOXP3 expression in duodenal mucosa in pediatric patients with celiac disease.

Objective: It was the aim of this study to evaluate the number of 2 lymphoid subpopulations, CD8+ cells and FOXP3+, in the duodenum mucosa from pediatric celiac patients. Methods: Tissue sections prepared from paraffin-embedded biopsies of the descending duodenum of 61 celiac patients with Marsh grade 1 (M1), M2 and M3 disease and biopsies from 21 age-matched non-celiac (NC) patients were immunohistostained with anti-CD8 or FOXP3 antibodies. Results: The histological Marsh grade correlated with the mean number of FOXP3+ cells in the lamina propria (LP) mucosa (8.9 ± 1.1, 6.8 ± 2.4, 24.5 ± 2.6 and 31.1 ± 2.8 for NC, M1, M2 and M3 biopsies, respectively; p < 0.001). Using a cutoff point of 15 cells, 95% of NC and 88% of M1 biopsies had a mean of <15 FOXP3+ cells compared with 14% for M2 and 13% for M3 biopsies. The number of FOXP3+ cells in the epithelial mucosa also correlated with transglutaminase type 2 serum levels from the celiac patients. Unlike the FOXP3+ cells, CD8+ lymphocytes were present in both LP and surface epithelial mucosa and significantly different only in the LP mucosa of the M2 and M3 groups. Conclusion: The number of FOXP3+ cells is substantially increased in the mucosa of celiac patients at advanced stages. Characterization of the activity of these cells in celiac and in other inflammatory bowel diseases will enable us to understand the significance of these cells in celiac disease.

The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis-like phenotype and early onset cancer

Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis‐like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12–14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis‐like group, two subjects had already developed high‐grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory.

Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity

Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1.

Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN.

Background Vedolizumab, an anti-integrin antibody, has proven to be effective in adults with inflammatory bowel disease [IBD], but the data in paediatrics are limited. We describe the short-term effectiveness and safety of vedolizumab in a European multi-centre paediatric IBD cohort. Method Retrospective review of children [aged 2-18 years] treated with vedolizumab from 19 centres affiliated with the Paediatric IBD Porto group of ESPGHAN. Primary outcome was Week 14 corticosteroid-free remission [CFR]. Results In all, 64 children were included (32 [50%] male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks [interquartile range 14-38; range 6-116]); 41 [64%] cases of ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U] and 23 [36%] Crohns disease [CD]. All were previously treated with anti-tumour necrosis factor [TNF] [28% primary failure, 53% secondary failure]. Week 14 CFR was 37% in UC, and 14% in CD [P = 0.06]. CFR by last follow-up was 39% in UC and 24% in CD [p = 0.24]. Ten [17%] children required surgery, six of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate [42% vs 35%; p = 0.35 at Week 22]. There were three minor drug-related adverse events. Only 3 of 16 children who underwent endoscopic evaluation had mucosal healing after treatment (19%). Conclusions Vedolizumab was safe and effective in this cohort of paediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared with patients with UC.

Propofol for pediatric colonoscopy: the experience of a large, tertiary care pediatric hospital.

Successful colonoscopy includes full visualization of the terminal ileum, especially in inflammatory bowel disease when ileal biopsy is essential. In children, higher levels of anxiety and lack of cooperation often necessitate a deeper level of sedation. The aim of this study was to evaluate the effectiveness of propofol compared with midazolam and fentanyl for colonoscopy, and in accomplishing ileal and cecal intubation in particular. This was a retrospective cohort study comparing the rates of successful colonoscopy in patients receiving propofol with those receiving midazolam/fentanyl. Complete, successful, colonoscopy to the terminal ileum was achieved in 78% of propofol patients compared with 66% of the midazolam/fentanyl group (P = 0.004). Endoscopy reaching the cecum, but not the terminal ileum, was achieved in 78% of propofol patients and 66% of midazolam/fentanyl patients. The use of propofol was associated with a statistically significant increase in the rate of successful colonoscopy reaching the terminal ileum.

Polyposis syndromes in children and adolescents: a case series data analysis.

Background Polyposis syndromes in children are distinct entities clinically and pathologically. These syndromes have multiple genetic characteristics, with development of polyps at various sites of the gastrointestinal (GI) tract, and are associated with an increased risk of colon cancer. They are relatively rare, and have mostly been characterized in the adult population, whereas little epidemiologic data have been reported in children. Aims The aim of this study was to summarize the pediatric experience collected over a period of 11 years on polyposis syndromes in three major Israeli tertiary centers. Patients and methods Medical records of children below 18 years old and their families, diagnosed with polyposis syndromes between 1999 and 2010, were reviewed. The data included disease presentation, genetic profile, surveillance, and treatment. Results Fifty patients with polyposis syndromes were identified. The most frequent syndrome was familial adenomatous polyposis (FAP) in 33 children (66%), of whom 25 children (75.7%) had a known mutation. The mean age at presentation was 10.6±3.9 years (range 4–17 years). Most children were examined because of a family history of a polyposis syndrome (42 children, 84%). Among symptomatic children (32 children), the most frequent complaint was rectal bleeding (42%), followed by abdominal pain (22%), intussusception (10%), and diarrhea (4%). The youngest symptomatic patient was 4 years old at presentation, with rectal bleeding. All patients underwent multiple colonoscopies and upper GI endoscopies according to specific guidelines. Thirteen children underwent colonic surgery (39%); nine children had FAP. Adenocarcinoma of the colon was diagnosed in a 12.5-year-old child. Conclusion In this cohort study, FAP was the most common type of polyposis syndrome diagnosed in this pediatric population. Colon cancer was present at the onset of symptoms in a 12.5-year-old patient with FAP. We therefore recommend strict adherence to the hereditary GI cancer guidelines to prevent morbidity and mortality in FAP and other inherited polyposis syndromes.

Once- Versus Twice-daily Mesalazine to Induce Remission in Paediatric Ulcerative Colitis: A Randomised Controlled Trial.

Background Trials in adults suggested that, in ulcerative colitis [UC], once-daily [OD] dosing of 5-ASA [5-amino salicylic acid] may be as or more effective than twice-daily [BD] dosing. In this induction of remission, investigator-blinded, randomised controlled-trial, we aimed to compare effectiveness and safety of once- versus twice-daily mesalazine in paediatric UC. Methods Children, aged 4-18 years with a PUCAI [Paediatric Ulcerative Colitis Activity Index] of 10-55 points at inclusion, were randomised in blocks of six with blinded allocation to OD or BD mesalazine, using a weight-based dosing table. The primary outcome was mean PUCAI score at Week 6. Results A total of 83/86 randomised children were eligible and analysed: 43 in the OD group and 40 in the BD group (mean age 14 ± 2.7 years, 43 [52%] males, 51 [62%] extensive colitis). The groups did not differ with regard to disease activity or any other parameter at baseline. There was no difference in median PUCAI score between the OD group and BD group at Week 6: 15 ( interquartile range [IQR] 5-40) versus 10 [0-40]; p = 0.48]. Response was seen in 25 [60%] OD versus 25 [63%] BD dosing [p = 0.78]. Proportion of children in remission [PUCAI < 10] at Week 6 was 13 [30%] OD versus 16 [40%] BD; p = 0.35]. Most adverse events were related to disease aggravation; the rates of serious adverse events were similar [p > 0.2]. Conclusions In this first randomised controlled trial in children, no differences were found between OD and BD dosing for any clinical outcome. Remission was achieved in 35% of children treated with mesalazine for active UC.

Lactose Breath Test in Children: Relationship Between Symptoms During the Test and Test Results.

Background: Lactose malabsorption affects 70% of the world population. The hydrogen breath test (HBT) is used clinically to test for this condition. The aim of our study was to describe the relationship between symptoms experienced before and during the HBT and test results. Methods: We included children who underwent the HBT in the pediatric gastroenterology unit at Dana-Dwek Childrens Hospital during a 6-month period. Previous symptoms and those experienced before and after the HBT were assessed using a questionnaire and a validated pain scale. Results: Ninety-five children were included in the study, and 66.3% had a positive HBT. Diarrhea and flatulence during the test were significantly more frequent in the group with a positive HBT compared to those with a negative test (31.7% vs. 9.4%, P = 0.016 and 69.8% vs. 40.6%, P = 0.006, respectively). The frequency of abdominal pain and bloating was similar. Conclusions: Diarrhea and flatulence during the HBT are the most specific symptoms of lactose intolerance. Abdominal pain should not be automatically attributed to lactose intolerance even in the presence of lactose malabsorption. Coupling the HBT with a real-time questionnaire facilitates interpretation of results and subsequent recommendations.

Conclusiveness of the Cochrane Reviews in Pediatric-Gastroenterology: a systematic analysis.

Aim To assess the conclusiveness of the Cochrane Reviews (CRs) in the field of Pediatric-Gastroenterology. We tested the hypotheses that (a) the majority of CRs are inconclusive, (b) the majority of CRs recognize the need for further studies, (c) the ability to reach a conclusion is dependent on both the number of studies and the number of patients. We also studied whether the conclusiveness of CRs changed over time. Methods We selected all CRs in the field of Pediatric-Gastroenterology available in the Cochrane library. Each CR was analyzed for the number of randomized clinical trials (RCTs) found, the number of RCTs included for analysis, the number of patients enrolled, the stated need for further studies, and the conclusiveness of the CR. Results Sixty-eight out of 85 CRs (80%) were conclusive. The percentage of articles included in conclusive studies was significantly higher than that in inconclusive ones (P<0.00001). Thus, the average number of RCTs retained in the analyses was significantly higher in conclusive CRs. The total number of patients in the RCTs retained for analysis was significantly higher in conclusive CRs (P<0.0001). The majority of inconclusive CRs (82.4%) recognized the need for further studies compared with 44.1% in conclusive ones (P=0.002). The percentage of conclusive CRs was not affected by the year of publication. Conclusion In the field of Pediatric-Gastroenterology, CRs appear to be a potent clinical tool that allows, in 80% of the cases, to reach a valid (from a clinical standpoint) conclusion, while emphasizing the weaknesses of available, published evidence and delineating future avenues of research.