Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study. APPROACH AND RESULTS: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings. CONCLUSIONS: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.

Helicobacter pylori Infection in Pediatric Patients Living in Europe: Results of the EuroPedHP Registry 2013 to 2016.

OBJECTIVES: The aim of the study was to assess clinical presentation, endoscopic findings, antibiotic susceptibility and treatment success of Helicobacter pylori (H. pylori) infected pediatric patients. METHODS: Between 2013 and 2016, 23 pediatric hospitals from 17 countries prospectively submitted data on consecutive H. pylori-infected (culture positive) patients to the EuroPedHP-Registry. RESULTS: Of 1333 patients recruited (55.1% girls, median age 12.6 years), 1168 (87.6%) were therapy naïve (group A) and 165 (12.4%) had failed treatment (group B). Patients resided in North/Western (29.6%), Southern (34.1%) and Eastern Europe (23.0%), or Israel/Turkey (13.4%). Main indications for endoscopy were abdominal pain or dyspepsia (81.2%, 1078/1328). Antral nodularity was reported in 77.8% (1031/1326) of patients, gastric or duodenal ulcers and erosions in 5.1% and 12.8%, respectively. Primary resistance to clarithromycin (CLA) and metronidazole (MET) occurred in 25% and 21%, respectively, and increased after failed therapy. Bacterial strains were fully susceptible in 60.5% of group A, but in only 27.4% of group B. Primary CLA resistance was higher in Southern and Eastern Europe (adjusted odds ratio [ORadj] = 3.44, 95% confidence interval [CI] 2.22-5.32, P < 0.001 and 2.62, 95% CI: 1.63-4.22, P < 0.001, respectively) compared with Northern/Western Europe. Children born outside Europe showed higher primary MET resistance (ORadj = 3.81, 95% CI: 2.25-6.45, P < 0.001). Treatment success in group A reached only 79.8% (568/712) with 7 to 14 days triple therapy tailored to antibiotic susceptibility. CONCLUSIONS: Peptic ulcers are rare in dyspeptic H. pylori-infected children. Primary resistance to CLA and MET is markedly dependent on geographical regions of birth and residence. The ongoing survey will show whether implementation of the updated ESPGHAN/NASPGHAN guidelines will improve the eradication success.

Telogen effluvium as the first symptom of Crohn's disease in a child.

Crohn's disease usually manifests gastrointestinal symptoms, however in some cases the patient presents with prominent or even exclusive extraintestinal involvement. Alopecia has been reported as a complication of therapeutic agents used in the treatment of inflammatory bowel disease, and, in a few cases of adult patients, prior to the appearance of gastrointestinal symptoms. We present a 10 year-old-child with telogen effluvium that appeared one year before the diagnosis of Crohn's disease, as the first and only symptom at that time. Other systemic causes of hair loss such as micronutrient deficiencies, endocrine imbalance or chemical exposure were excluded. Eight months later the patient presented with mild iron deficiency and signs of social retraction, while two months before the final diagnosis of Crohn's disease other more characteristic alarming symptoms (mild fever, oral apthous ulcers, weight loss) were added to the clinical picture. Alopecia improved after remission of Crohn's disease, reappeared when the patient relapsed, and finally resolved gradually when complete remission of Crohn's disease was achieved. Telogen effluvium was the first symptom of Crohn's disease in a child, and, although this is a rare association, it should be considered as an extraintestinal manifestation of Crohn's disease.

Caroli's disease: Description of a case with a benign clinical course.

Caroli's disease is a rare congenital disorder characterized by cystic dilatation of the large in-trahepatic bile ducts. The most frequent complications due to biliary stasis are cholelithiasis, cholangitis and sepsis as well as an increased risk of cholangiocarcinoma. Patients may have a history of intermittent abdominal pain, pruritus and/or symptoms of cholangitis. It is rarely diagnosed in childhood. A 12-year-old boy with isolated Caroli's disease is described. This child presented at the age of 2 years, with 4 episodes of recurrent bacterial infections. Interestingly he remained asymptomatic for over 10 years, between the second and third episode. During the 4th episode, when he presented with fever and slight abdominal pain, the diagnosis was made on the basis of radiological findings: U/S, CT, MRI and especially with MRCP, in relation with a more typical picture, resembling cholangitis. Since then he has been followed-up systematically for ten years and remains in good clinical condition without further relapses and with unchanged radiological findings. This atypically benign course of Caroli's disease, with intermittent asymptomatic periods, without any treatment, is very rare.

Serum carnitine levels in childhood leukemia.

In patients with malignancies, the system of carnitine seems abnormally expressed. The serum total, free, and acyl carnitine levels in 40 children and adolescents with acute leukemia were determined using electrospray tandem mass spectrometry in 4 different phases of the disease: at the diagnosis, 1 year after the initiation of chemotherapy, at the end of treatment, and 2.4+/-1.668 years after the completion of chemotherapy. The age, sex, hemoglobin values, serum biochemistry, somatometric features of the patients, and the risk group of the disease were examined. Although the carnitine levels were found higher in patients compared with the control group from diagnosis to treatment completion, statistically significant decrease in carnitine levels was observed in patients within different phases of the disease especially during induction and consolidation treatment (phase A to B) for both free and total (P=0.023) carnitine. In addition, a statistically significant recovery in carnitine levels was observed between phase B (end of intensive chemotherapy) and D (some years after the completion of treatment) for free and total carnitine (P=0.054 and 0.035, respectively). No statistical correlation was documented between the carnitine levels and somatometric parameters or other variables studied. In conclusion, a significant transient decrease in the levels of carnitine during the treatment was observed in children with acute leukemia. Further studies are required to clarify the role of carnitine status in patients with malignancies and possibly the necessity of carnitine supplementation during chemotherapy administration.

3C syndrome with cryptorchidism and posterior embryotoxon.

We report a case of the 3C (cranio-cerebello-cardiac) syndrome, also known as Ritscher-Schinzel syndrome, a rare autosomal recessive disorder characterized by craniofacial, cerebellar, and cardiac anomalies. In addition to features previously reported the child had Wormian bones of the skull, intra-abdominal testes, and posterior embryotoxon that have not previously been reported as part of the 3C syndrome.