Gian Luigi de’Angelis

Relationship between CARD15, SLC22A4/5, and DLG5 polymorphisms and early-onset inflammatory bowel diseases: An Italian multicentric study

BACKGROUND Inflammatory bowel disease (IBD) has been associated with several polymorphisms in genes likely involved in innate immune responses and integrity of epithelial mucosal barrier. A major role in adult Crohns disease (CD) has been defined for 3 polymorphisms in the CARD15 gene, whereas variants in the SLC22A4, SLC22A5, and DLG5 genes could have a minor contribution to IBD susceptibility. METHODS We analyzed a panel of 6 polymorphisms within these genes in 227 Italian early-onset IBD patients (134 CD, 93 ulcerative colitis [UC]; age at diagnosis <or=18 years) and 166 unaffected control subjects. RESULTS Each CARD15 variant was found to be independently associated with CD. After the genotypes at the 3 polymorphisms were combined, 37.3% patients carried at least 1 variant compared with 9.2% control subjects (odds ratio, 5.87; 95% CI 3.11-11.1; P < 0.001). The combined frequency of CARD15 variants was also higher in UC children compared with control subjects (14% vs 9.2%), but this difference was not significant. However, CARD15 variants were associated with earlier onset of UC, and the mutation rate was significantly higher in UC patients with onset at or before 6 years of age compared with control subjects (27.6% vs 9.2%) (odds ratio = 3.76; 95% CI 1.42-9.94; P = 0.01). CARD15 variants also were associated with ileal CD involvement and a higher rate of extraintestinal manifestations in UC. Allele and genotype frequencies at SLC22A and DLG5 polymorphisms were not significantly different between cases and controls. CONCLUSIONS Our results demonstrate that in the Italian population, the major CARD15 polymorphisms are associated with susceptibility to early-onset CD and with ileal involvement and suggest a previously unreported association with very early-onset, severe UC.

Short- and long-term efficacy of endoscopic balloon dilation in Crohn’s disease strictures

AIM To evaluate short- and long-term efficacy of endoscopic balloon dilation in a cohort of consecutive patients with symptomatic Crohns disease (CD)-related strictures. METHODS Twenty-six CD patients (11 men; median age 36.8 year, range 11-65 years) with 27 symptomatic strictures underwent endoscopic balloon dilation (EBD). Both naive and post-operative strictures, of any length and diameter, with or without associated fistula were included. After a clinical and radiological assessment, EBD was performed with a Microvasive Rigiflex through the scope balloon system. The procedure was considered successful if no symptom reoccurred in the following 6 mo. The long-term clinical outcome was to avoid surgery. RESULTS The mean follow-up time was 40.7 ± 5.7 mo (range 10-94 mo). In this period, forty-six EBD were performed with a technical success of 100%. No procedure-related complication was reported. Surgery was avoided in 92.6% of the patients during the entire follow-up. Two patients, both presenting ileocecal strictures associated with fistula, failed to respond to the treatment and underwent surgical strictures resection. Of the 24 patients who did not undergo surgery, 11 patients received 1 EBD, and 13 required further dilations over time for the treatment of relapsing strictures (7 patients underwent 2 dilations, 5 patients 3 dilations, and 1 patient 4 dilations). Overall, the EBD success rate after the first dilation was 81.5%. No difference was observed between the EBD success rate for naive (n = 12) and post-operative (n = 15) CD related strictures (P > 0.05). CONCLUSION EBD appears to be a safe and effective procedure in the therapeutic management of CD-related strictures of any origin and dimension in order to prevent surgery.

FOXE1 and SYNE1 Genes Hypermethylation Panel as Promising Biomarker in Colitis-associated Colorectal Neoplasia

Background:Colitis-associated colorectal cancer affects individuals with inflammatory bowel disease (IBD) more often and earlier than cancer in the general population. Colonoscopy provides the surveillance gold standard. Changes to the surveillance intervals depending on endoscopic activity have been made, given data demonstrating that this is an important predictor of future dysplasia or cancer, but adjuvant, noninvasive clinical tools are still warranted to improve surveillance outcomes and to assist in management and interpretation of dysplasia. Methylation markers may be able to do this. Methods:SYNE1, FOXE1, NDRG4, and PHACTR3 genes were screened using methylation-specific PCR that permit the methylation status of the genes to be determined directly on biopsies. Ninety-three patients with long-standing IBD undergoing a cancer surveillance program, and 30 healthy controls were studied. These included colorectal adenocarcinomas on a background of IBD of various stages (n = 25), IBD-associated dysplastic lesions (n = 29), adenomas arising on a background of ulcerative colitis (n = 8), samples from patients with no evidence of dysplasia or cancer but long-standing IBD (n = 31), and symptomatic patients found to have normal colonoscopy (controls) (n = 30). Results:Gene promotor hypermethylation of SYNE1 and FOXE1 genes varied significantly between the groups and was increasingly likely with increased disease severity. Neither occurred in controls, whereas promotor hypermethylation was detected in biopsies of 60% of patients with colitis-associated colorectal cancer for FOXE1 and 80% for SYNE1. Promotor hypermethylation of either gene was highly significantly different between the groups overall. Conclusions:FOXE1 and SYNE1 hypermethylation markers demonstrated significantly increased expression in neoplastic tissue. Promoter methylation analysis of these genes might be a useful marker of neoplasia in long-standing IBD.

Primary Antimicrobial Susceptibility Changes in Children with Helicobacter pylori Infection over 13 Years in Northern Italy.

The eradication therapy of Helicobacter pylori (H. pylori) infection is still a challenge for gastroenterologists. One of the main causes of failure in H. pylori eradication is the antibiotic resistance mainly to clarithromycin. Culture from biopsies is maybe the most used method among the antimicrobial susceptibility techniques. In this study, we compared the antimicrobial susceptibility changes in children with H. pylori infection over 13 years and we confirmed that clarithromycin resistance has been increased (16% versus 26%) though with no statistically signficant value. Therefore, clarithromycin should not be used in empiric treatment of H. pylori eradication therapy in children, but its use should be limited only to children with known antimicrobial susceptibility. On the other hand, metronidazole resistance has decreased over this time period in statistically significant manner (56% versus 33%, p = 0.014). Furthermore, ampicillin resistance has been confirmed to be very rare (3% versus 0%) in children with H. pylori infection. In conclusion, in H. pylori infection, if we do not know the antibiotic susceptibility of patients, we should recommend an eradication therapy based on the local distribution of antibiotic resistance rates trying to limit the therapeutic failures.

A Role for Pathogenesis-Related Proteins in Poly-Sensitized Allergic Patients with Eosinophilic Esophagitis: Clinical and Endoscopic Features

Objective: Eosinophilic Esophagitis (EoE) is a chronic inflammatory disease of the esophagus often associated with atopy. Most EoE patients are poly-sensitized to inhalant and food allergens. Sensitization to pan-allergens is also frequent but their role in EoE is unclear. The aim of the study was to investigate the role of sensitization toward pathogenesis-related proteins (PR) in patients with EoE, and its relationship with clinical and endoscopic features. Methods: A group of poly-sensitized patients was retrospectively analyzed, and clinical, endoscopic, and histological differences were compared between patients’ sensitized and non-sensitized to PR-10 proteins. Results: Dysphagia was more frequent in patients sensitized to PR-10 compared with non-sensitized subjects (83% vs. 42%, p=0.032) while other presenting symptoms did not significantly differ between the two groups. The mean esophageal eosinophil peak was significantly higher in PR-10-sensitized patients (p=0.047). As far as endoscopic findings were concerned, no difference was found between the two groups. Conclusion: Sensitization to plant-food allergens such as PR-10 proteins seems relevant in poly-sensitized patients suffering from EoE and needs to be evaluated in order to test the result of an appropriate elimination diet.

Cancer and Dysplasia Surveillance

Colorectal cancer (CRC) and dysplasia surveillance are of paramount importance in the long-term management of inflammatory bowel disease (IBD). Chronic inflammation and immunosuppressive therapy represent risk factors. It has not yet been established which are the treatments at major risk; therefore, studies on long-term surveillance are awaited. Specific genetic mutations seem to have a role too. Although dysplastic lesions usually develop in the adult age, they must be taken into account by pediatricians. The risk to develop dysplastic lesions is mainly related to ulcerative colitis (UC), but also Crohn’s disease (CD) has to be strictly followed up.

Helicobacter Pylori Infection: We Should Always Verify the Intrafamilial Transmission

Background and Aims: Helicobacter pylori infection is one of the most common gastrointestinal infections in humans; it affects about 30% of people in developed countries and about 80% in developing ones. The majority of patients acquire the infection during childhood and the intrafamilial transmission is considered one of the most important routes of infection. The aim of this study was to assess the intrafamilial transmission rate among family members of index subjects. Methods: We have suggested all patients H. pylori-positive (99 patients, symptomatic index subjects) diagnosed during 18 months (Sep 2011-Dec 2012) to screen their family members by stool antigen test (SAT) and, when positive, to perform upper gastrointestinal endoscopy. Results: Through SAT we identified 126 patients belonging to 41 households of 99 initial index subjects, therefore 41 index subjects (41.4%) had at least one family member affected. The entire population studied included 225 H. pylori-positive patients: 99 index subjects (symptomatic) and 126 family members diagnosed by SAT screening and histological examination by gastroscopy. Of these, 103 patients (81.7%) were considered slightly symptomatic (mild clinical history until then not important enough to perform further diagnostic study) and 23 patients (18.3%) were totally asymptomatic. Conclusions: In the spread of H. pylori infection, the intrafamilial transmission is an important route of contamination; besides the known mother-to-child dyad, also the transmission among family members plays a considerable role and it should be always verified.

P93 Situs viscerum inversus and apple peel atresia: a rare association. case report

Background and aims Duodenal atresia is a relatively common anomaly and its frequency ranges from 1 in 3000 to 5000 live births. Association of duodenal atresia with situs viscerum inversus is rare and fewer than 20 patients have been reported in literature. Methods We present a sub-Saharan 1 years old female baby, born at 31 weeks with prenatal diagnosis of situs viscerum inversus with dextrocardia, ventricular septal defect, ductus venous agenesis, duodenal atresia and intestinal malrotation. We considered risk factors, clinical and surgical management, complications and evolution of this rare association. Results A 31 weeks female baby was born by emergency caesarean section for cardiotocographic changes. Her mother history was positive for pre-gestational diabetes on insulin therapy and for Streptococcus beta-haemolytic infection. Incomplete intrapartum amplicillin prophylaxis was made. The baby weighed 2300 g and her Apgar scores were 5 and 5, needing non-invasive ventilation with nCPAP. Because of suspected intestinal obstruction, parental nutrition was started one day after birth and a radiological examination was performed showing the mirror image of a double-bubble configuration of duodenal atresia. She underwent laparotomy at 6 days of life, confirming situs inversus and intestinal necrosis secondary to volvulus on common mesentery (apple peel type 3b): duodeno-cecal anastomosis with saving the ileocecal valve was performed. Histology of the surgical specimen confirmed the transmural necrosis. Six days after, enteral nutrition was progressively introduced with good tolerance and weight gain; parental nutrition was continued with subsequent cholestasis needing the modification of the lipid composition. At 3 months of age, she underwent a Bianchi intestinal lengthening procedure and cholecystectomy. The onset of post-surgical duodenal stenosis two months after required one endoscopic pneumatic dilation (8–10 mm) and a gastrostomy button was placed too. Upper endoscopies performed 1 month and 6 months later were normal. Enteral and parental nutrition was continued and the oral feeding was gradually introduced. Conclusions Duodenal atresia and situs inversus are rare combinations. Outcome is good with appropriate multidisciplinary management and follow-up. Maternal diabetes could be factor risk of laterality, as suggested in literature.

Cutaneous Leishmaniasis with Long Duration and Bleeding Ulcer

Leishmaniasis may cause visceral, cutaneous and/or mucocutaneous diseases. Cutaneous and mucocutaneous forms are caused by a single celled parasite transmitted by sand fly bites. Although the cutaneous form of the disease is often self-limiting, it results in significant scarring and can spread to more invasive, mucocutaneous disease. Therefore, treatment may be considered to prevent these complications. We describe a case report of cutaneous leishmaniasis contracted in a healthy man in Italy (Emilian Apennines). This cutaneous ulcer healed only with intralesional injection of meglumine antimoniate. After about 18 and 30 months a scar area is still present and no satellite lesion appeared. We have had no side effects or complications due to therapy.

A Giant Congenital Lobular Capillary Haemangioma

Lobular capillary haemangioma is a relatively common benign mucocutaneous lesion in paediatric age. The etiopathogenesis is not very clear, but it seems that lesions originate de novo from a process of lobular vascular proliferation that appears to be neoplastic. Congenital onset is usually very rare; it happens only in 1.1% in literature. We report a case of a newborn with a giant congenital lobular capillary haemangioma of the head (left occipital region) which increased rapidly with superficial ulcers in the early days of life. The baby was operated on by full-thickness excision using the linear closure technique; this treatment allows histological examination, ensures the most efficacy aesthetic results and gives the lowest recurrence rate.