Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Towards a Standardized Classification of the Hepatobiliary Manifestations in Cystic Fibrosis (CFHBI): A Joint ESPGHAN/NASPGHAN Position Paper.

The broad spectrum of hepatobiliary involvement in cystic fibrosis (CF) has been commonly referred to as cystic fibrosis liver disease (CFLD). However, differences in the definitions of CFLD have led to variations in reported prevalence, incidence rates, and standardized recommendations for diagnosis and therapies. Harmonizing the description of the spectrum of hepatobiliary involvement in all people with CF (pwCF) is deemed essential for providing a reliable account of the natural history, which in turn supports the development of meaningful clinical outcomes in patient care and research. Recognizing this necessity, The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) commissioned and tasked a committee to develop and propose a systematic classification of the CF hepatobiliary manifestations to increase uniformity, accuracy, and comparability for clinical, registry, and research purposes. This report describes the committee's combined expert position statement on hepatobiliary involvement in CF, which has been endorsed by NASPGHAN and ESPGHAN. We recommend using CFHBI (Cystic Fibrosis Hepato-Biliary Involvement) as the updated term to describe and classify all hepatobiliary manifestations in all pwCF. CFHBI encompasses the current extensive spectrum of phenotypical, clinical, or diagnostic expressions of liver involvement observed in pwCF. We present a schematic categorization of CFHBI, which may also be used to track and classify the changes and development of CFHBI in pwCF over time. The proposed classification for CFHBI is based on expert consensus and has not been validated for clinical practice and research purposes. Achieving validation should be an important aim for future research.

Identification of Iatrogenic Perforation in Pediatric Gastrointestinal Endoscopy.

OBJECTIVES: Iatrogenic viscus perforation in pediatric gastrointestinal endoscopy (GIE) is a very rare, yet potentially life-threatening event. There are no evidence-based recommendations relating to immediate post-procedure follow-up to identify perforations and allow for timely management. This study aims to characterize the presentation of children with post-GIE perforation to better rationalize post-procedure recommendations. METHODS: Retrospective study based on unrestricted pooled data from centers throughout Europe, North America, and the Middle East affiliated with the Endoscopy Special Interest Groups of European Society for Paediatric Gastroenterology Hepatology and Nutrition and North American Society for Pediatric Gastroenterology Hepatology and Nutrition. Procedural and patient data relating to clinical presentation of the perforation were recorded on standardized REDCap case-report forms. RESULTS: Fifty-nine cases of viscus perforation were recorded [median age 6 years (interquartile range 3-13)]; 29 of 59 (49%) occurred following esophagogastroduodenoscopy, 26 of 59 (44%) following ileocolonoscopy, with 2 of 59 (3%) cases each following balloon enteroscopy and endoscopic retrograde cholangiopancreatography; 28 of 59 (48%) of perforations were identified during the procedure [26/28 (93%) endoscopically, 2/28 (7%) by fluoroscopy], and a further 5 of 59 (9%) identified within 4 hours. Overall 80% of perforations were identified within 12 hours. Among perforations identified subsequent to the procedure 19 of 31 (61%) presented with pain, 16 of 31 (52%) presented with fever, and 10 of 31 (32%) presented with abdominal rigidity or dyspnea; 30 of 59 (51%) were managed surgically, 17 of 59 (29%) managed conservatively, and 9 of 59 (15%) endoscopically; 4 of 59 (7%) patients died, all following esophageal perforation. CONCLUSIONS: Iatrogenic perforation was identified immediately in over half of cases and in 80% of cases within 12 hours. This novel data can be utilized to generate guiding principles of post-procedural follow-up and monitoring. PLAIN LANGUAGE SUMMARY: Bowel perforation following pediatric gastrointestinal endoscopy is very rare with no evidence to base post-procedure follow-up for high-risk procedures. We found that half were identified immediately with the large majority identified within 12 hours, mostly due to pain and fever.

Safety of endoscopic retrograde cholangiopancreatography in the pediatric population: a multicenter study.

INTRODUCTION: The aims of this retrospective multicenter study were to assess the technical success and adverse events of endoscopic retrograde cholangiopancreatography (ERCP) procedures in children in French and Belgian centers. METHODS: All children aged 1 day to 17 years who underwent ERCP between January 2008 and March 2019 in 15 tertiary care hospitals were retrospectively included. RESULTS: 271 children underwent 470 ERCP procedures. Clinical long-term follow-up was available for 72 % of our patients (340/470 procedures). The median age at intervention was 10.9 years. ERCP was therapeutic in 90 % (423/470) and diagnostic in cases of neonatal cholestasis in 10 % of the patients. The most common biliary indication was choledocholithiasis; the most common pancreatic indication was chronic pancreatitis. Biliary cannulation was successful in 92 % of cases (270/294); pancreatic cannulation in 96 % of cases (169/176); and planned therapeutic procedures in 92 % of cases (388/423). The overall complication rate was 19 % (65/340). The most common complication was post-ERCP pancreatitis (PEP) in 12 % of cases (40/340) and sepsis in 5 % (18/340). On univariate analyses, pancreatic stent removal was protective against PEP (odds ratio [OR] 0.1, 95 % confidence interval [CI] 0.01 - 0.75; P = 0.03), and sepsis was associated with history of liver transplantation (OR 7.27, 95 %CI 1.7 - 31.05; P = 0.01). Five patients had post-ERCP hemorrhage and two had intestinal perforation. All complications were managed with supportive medical care. There was no procedure-related mortality. CONCLUSION: Our cohort demonstrates that ERCP can be performed safely with high success rates in many pancreaticobiliary diseases of children. The rate of adverse events was similar to that in previous reports.

Management and outcome of hepatic artery thrombosis after pediatric liver transplantation.

BACKGROUND: Pediatric LT are at particular risk of HAT, and its management still constitutes a matter of debate. Our purpose was to study predisposing factors and outcome of HAT post-LT, including the impact of surgical revisions on survival and biliary complications. METHODS: Among 882 primary pediatric LT performed between 1993 and 2015, 36 HAT were encountered (4.1%, 35 fully documented). Each HAT case was retrospectively paired with a LT recipient without HAT, according to diagnosis, age at LT, type of graft, and era. RESULTS: Five-year patient survivals were 77.0% versus 83.9% in HAT and non-HAT paired groups, respectively (P = .321). Corresponding graft survivals were 20.0% versus 80.5% (P < .001), and retransplantation rates 77.7% versus 10.7%, respectively (P < .001). One-year biliary complication-free survivals were 16.6% versus 83.8% in the HAT and non-HAT groups, respectively (P < .001). Regarding chronology of surgical re-exploration, only HAT cases that occurred within 14 days post-LT were re-operated, fourteen of them being explored within 7 days post-LT (revascularization rate: 6/14), versus two beyond 7 days (no revascularization). When revascularization was achieved, graft and biliary complication-free survival rates at 1 year were 33.3% and 22.2%, respectively, both rates being 0.0% in case of failure. CONCLUSIONS: The pejorative prognosis associated with HAT in terms of graft survival is confirmed, whereas patient survival could be preserved through retransplantation. Results suggest that HAT should be re-operated if occurring within 7 days post-LT, but not beyond.

Living donor liver transplantation for hepatic malignancies in children.

BACKGROUND: Living donor liver transplantation is a treatment option for unresectable hepatic tumors in children. METHODS: We enrolled 45 living donor transplantations performed between 1993 and 2018 for liver malignacies, which included hepatoblastoma (n = 33), hepatocellular carcinoma (n = 10), hepatic angiosarcoma (n = 1), and rhabdomyosarcoma (n = 1). RESULTS: No mortality or major morbidities were encountered in any donor, and the complication rate was 9%. In the hepatoblastoma group, 5-year overall and event-free survival rate in recipients was 87.4% and 75.8%, respectively, and mortality was significantly higher in patients after rescue transplantation (p = .001). Inferior vena cava replacement in these recipients appeared to be associated with reduced mortality (p = .034), but this was not confirmed when rescue patients were excluded (p = .629). In hepatocellular carcinoma group, both 5-year overall and event-free survival rates were 75.4% each, and invasion of hepatic veins was significantly associated with increased risk of recurrence and death (p = .028). The patient with rhabdomyosarcoma died from EBV-induced lymphoma 2 months after transplantation. The patient with angiosarcoma was in complete remission at the last follow-up. Overall, 5-year graft survival rate was 81.3%, and one patient underwent re-transplantation due to chronic rejection. CONCLUSIONS: Pediatric oncological liver transplantation has become a key player in the management of malignancies with cancer cure in 84% of patients in this series. Living donor liver transplantation for pediatric recipients with unresectable tumors might be a beneficial surgical option, which is technically safe for donors and recipients, thus, allowing timely planning according to chemotherapy protocols.

Intracranial Hypertension and Papilledema in a Large Cohort of Pediatric Patients With Alagille Syndrome.

AIMS AND BACKGROUND: Ophthalmic abnormalities are amongst the 5 major criteria required for a diagnosis of Alagille syndrome (ALGS), of which embryotoxon, pseudopapilledema, and hypopigmented retinopathy are the most common. Papilledema with or without intracranial hypertension (ICHT) is rarely described. We report 9 pediatric cases of ALGS with bilateral papilledema, 5 of which were diagnosed with ICHT. METHODS: The ophthalmic data from 85 patients with clinically and/or genetically (n = 37) proven ALGS were reviewed. The study inclusion criteria were a positive diagnosis of ALGS and availability of ophthalmic follow-up data. Ophthalmic data from 40 patients after liver transplantation (LT) for other indications were also analyzed. RESULTS: Nine (13.0%) of the 69 patients meeting the inclusion criteria had papilledema. The neurological and neuroimaging results in all 9 patients were normal. These 9 patients were categorized into 4 groups: a nontransplant group (n = 1), a group with pretransplant papilledema persistent after LT (n = 2), a group with papilledema occurring after LT with spontaneous resolution (n = 1), and a group with papilledema and signs of ICHT after LT (n = 5). The patients with ICHT were treated with steroids alone (n = 1) or with acetazolamide (n = 4). A ventriculoperitoneal shunt was placed in 2 of the 5 cases because of progressive visual loss. Pseudopapilledema was present in 10 additional patients (14.5%, 10/69). One (2.5%) of the 40 patients without ALGS developed papilledema after LT. CONCLUSIONS: True ICHT may be underdiagnosed in patients with ALGS. Our findings underscore the need for close ophthalmic follow-up before and after LT in these patients.

Clinical Characteristics and Long-term Outcomes of Children With Fibrosing Pancreatitis.

OBJECTIVES: Fibrosing pancreatitis (FP) shares clinical features with autoimmune pancreatitis (AIP), although both entities have not been definitely linked. This study aimed to assess the presence of AIP criteria in an historic FP patient cohort and investigate the clinical features, management, and long-term outcomes of pediatric FP (P-FP). METHODS: Clinical data of 14 P-FP patients from Toronto and 42 P-FP cases from a literature review were collected and compared to pediatric AIP (P-AIP). Toronto P-FP patients were recontacted to assess their current health status using a brief questionnaire. RESULTS: Jaundice and abdominal pain were the symptoms at presentation in 44 of 56 (79%) and 50 of 56 (89%) P-FP patients, respectively. Common findings on cross sectional imaging were an enlarged pancreas head with narrowing of the distal common bile duct (51/54, 94%). Histopathology mainly showed gland fibrosis (39/39, 100%). Three of twelve (25%) P-FP patients had elevated IgG4 in serum. None of the patients were treated with corticosteroids, but some underwent surgical or endoscopic intervention. Toronto patients were followed for a median of 13.6 years (interquartile range: 2.9-22.8). Complications during follow-up included exocrine pancreatic insufficiency (3/14, 21%) and pancreatic gland atrophy (5/13, 38%); but none of the patients had disease relapse or developed diabetes type 3c. Five (5/14, 36%) patients developed other immune-mediated diseases over time. CONCLUSIONS: Clinical features of patients with P-FP resembled those recently described in a subgroup of P-AIP presenting with jaundice. Long-term outcome of these patients is generally good, with or without invasive interventions. As some patients may develop exocrine pancreatic insufficiency and/or other immune-mediated diseases, ongoing clinical monitoring is recommended.

Nasobiliary drainage prior to surgical biliary diversion in progressive familial intrahepatic cholestasis type II.

Progressive familial intrahepatic cholestasis (PFIC) can cause intense pruritus that is refractory to medical therapy. Surgical biliary diversion techniques, including partial internal biliary diversion (PIBD), have been developed over the years to relieve pruritus without requiring liver transplantation. No clinical or genetic features can currently predict postoperative pruritus response. We present three PFIC type 2 (PIFC 2) patients who underwent transient endoscopic nasobiliary drainage (NBD) prior to PIBD surgery. Two patients repeatedly responded to NBD and presented with complete pruritus resolution after subsequent PIBD. NBD failed technically in the third patient, and PIBD was partially successful. Mild post-endoscopic biological pancreatitis occurred in 2/6 NBD procedures and resolved spontaneously. The only adverse effect observed within 7 years post-PIBD was very mild transient osmotic diarrhea.Conclusion: Our limited data suggest that NBD is a safe and effective way to predict pruritus response before performing permanent biliary diversion surgery in PFIC patients. What is Known: • Surgical biliary diversion techniques have been developed to relieve intractable pruritus in progressive familial intrahepatic cholestasis (PFIC). • No clinical or genetic features can currently predict pruritus response to surgery. What is New: • Our data suggest that nasobiliary drainage could be a safe and effective tool to predict pruritus response to biliary diversion and avoid unnecessary surgery in PFIC patients.

Novel insights into the assessment of risk of upper gastrointestinal bleeding in decompensated cirrhotic children.

OBJECTIVES: Cirrhotic children wait-listed for liver transplant are prone to bleeding from gastrointestinal varices. Grade 2-3 esophageal varices, red signs, and gastric varices are well-known risk factors. However, the involvement of hemostatic factors remains controversial because of the rebalanced state of coagulation during cirrhosis. METHODS: Children suffering from decompensated cirrhosis were prospectively included while being on waitlist. Portal hypertension was assessed by ultrasound and endoscopy. Coagulopathy was evaluated through conventional tests, thromboelastometry, and platelet function testing. The included children were followed up until liver transplantation, and all bleeding episodes were recorded. Children with or without bleeding were compared according to clinical, radiological, endoscopic, and biological parameters. In addition, validation of a predictive model for risk of variceal bleeding comprising of grade 2-3 esophageal varices, red spots, and fibrinogen level <150 mg/dL was applied on this cohort. RESULTS: Of 20 enrolled children, 6 had upper gastrointestinal bleeding. Significant differences were observed in fibrinogen level, adenosine diphosphate, and thrombin-dependent platelet aggregation. The model used to compute the upper gastrointestinal bleeding risk had an estimated predictive performance of 81.0%. Platelet aggregation analysis addition improved the estimated predictive performance up to 89.0%. CONCLUSIONS: We demonstrated an association between hemostatic factors and the upper gastrointestinal bleeding risk. A low fibrinogen level and platelet aggregation dysfunction may predict the risk of bleeding in children with decompensated cirrhosis. A predictive model is available to assess the upper gastrointestinal bleeding risk but needs further investigations. Clinicaltrials.gov number: NCT03244332.

Living-donor liver transplantation for mild Zellweger spectrum disorder: Up to 17 years follow-up.

Mild Zellweger spectrum disorder, also described as Infantile Refsum disease, is attributable to mutations in PEX genes. Its clinical course is characterized by progressive hearing and vision loss, and neurodevelopmental regression. Supportive management is currently considered the standard of care, as no treatment has shown clinical benefits. LT was shown to correct levels of circulating toxic metabolites, partly responsible for chronic neurological impairment. Of three patients having undergone LT for mild ZSD, one died after LT, while the other two displayed significant neurodevelopmental improvement on both the long-term (17 years post-LT) and short-term (9 months post-LT) follow-up. We documented a sustained improvement of biochemical functions, with a complete normalization of plasma phytanic, pristanic, and pipecolic acid levels. This was associated with stabilization of hearing and visual functions, and improved neurodevelopmental status, which has enabled the older patient to lead a relatively autonomous lifestyle on the long term. The psychomotor acquisitions have been markedly improved as compared to their affected siblings, who did not undergo LT and exhibited a poor neurological outcome with severe disabilities. We speculate that LT performed before the onset of severe sensorineural defects in mild ZSD enables partial metabolic remission and improved long-term clinical outcomes.

Recommendations for Diagnosis and Management of Autoimmune Pancreatitis in Childhood: Consensus From INSPPIRE.

OBJECTIVES: Autoimmune pancreatitis (AIP) represents a complex immune-mediated pancreas disorder. Pediatric AIP (P-AIP) is rare. We have recently summarized the characteristic features of P-AIP. We now aim to develop recommendation statements to standardize the diagnostic and therapeutic approach to P-AIP and facilitate future research in the field. METHODS: A panel of pediatric gastroenterologists participating in the International Study Group of Pediatric Pancreatitis: In search for a cuRE was formed to discuss and then vote on 15 recommendation statements. A consensus of at least 80% was obtained following 3 voting rounds and revision of the statements. RESULTS: We have now generated 15 statements to help standardize the approach to diagnosis and management of P-AIP. CONCLUSIONS: The first P-AIP recommendation statements developed by the International Study Group of Pediatric Pancreatitis: In search for a cuRE group are intended to bring standardization to the diagnosis and treatment of this rare childhood disorder. These statements may help guide a uniform approach to patient care and facilitate future research studies.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Autoimmune Pancreatitis in Children: Characteristic Features, Diagnosis, and Management.

OBJECTIVES: Autoimmune pancreatitis (AIP) is an increasingly recognized disease entity, but data in children are limited. AIP presentation and outcome in children might differ from the adult experience. We aim to determine the characteristic features of AIP in children. METHODS: Data about clinical symptoms, imaging, histology, and treatment were collected using two sources: (i) a systematic literature search and (ii) the INSPPIRE database, the largest international multicenter study of pancreatitis in children and the Cliniques Universitaires St-Luc (CUSL) registry. RESULTS: We identified 48 AIP cases: 30 from literature review, 14 from INSPPIRE, and 4 from CUSL. The median age at diagnosis was 13 years (range 2-17 years). Abdominal pain (43/47, 91%) and/or obstructive jaundice (20/47, 42%) were the most common symptoms at diagnosis. Elevated serum IgG4 levels were only observed in 9/40 (22%) children. Cross-sectional imaging studies were abnormal in all children including hypointense global or focal gland enlargement (39/47, 83%), main pancreatic duct irregularity (30/47, 64%), and common bile duct stricture (26/47, 55%). A combination of lymphoplasmacytic inflammation, pancreatic fibrosis, and ductal granulocyte infiltration were the main histological findings (18/25, 72%). Children with AIP had a prompt clinical response to steroids. Complications of AIP included failure of exocrine (4/25, 16%) and endocrine (3/27, 11%) pancreas function. CONCLUSIONS: Pediatric AIP has a distinct presentation with features similar to type 2 AIP in adults. This comprehensive report on the largest group of children with AIP to date is expected to help with the diagnosis and management of this disease and pave the way for future research studies.

Retargeting of bile salt export pump and favorable outcome in children with progressive familial intrahepatic cholestasis type 2.

UNLABELLED: We investigated predictors of clinical evolution in progressive familial intrahepatic cholestasis type 2 patients and how they relate to bile salt export pump (BSEP) expression and its (re)targeting. Our retrospective study included 22 children with progressive familial intrahepatic cholestasis type 2. Clinical, biochemical, and histological characteristics were reviewed on admittance and following treatment with either ursodeoxycholic acid alone (10 mg/kg thrice daily, n = 19) or partial biliary diversion (n = 3). Immunostaining of BSEP was performed in 20 patients. Response to treatment was defined as normalization of pruritus, disappearance of jaundice, and alanine aminotransferase (ALT) levels <1.5 times the upper limit of normal. Ten of 22 patients were responders, and paired biopsies were available in six. De novo or retargeted canalicular expression of BSEP occurred in four of these six, two of whom exhibited baseline intracellular expression. Twelve of 22 were nonresponders and exhibited earlier onset of jaundice (<9 months), neonatal cholestasis, and higher ALT levels. An ALT >165 IU/L produced 72% sensitivity and 55% specificity in predicting nonresponse. Seven patients were still responding at last follow-up (median = 20 months, range 5-67 months). Three responders relapsed after 56, 72, and 82 months, respectively. Of nine surviving responders, median relapse-free survival time was 72 months (95% confidence interval 48-96 months) and 5-year relapse-free survival was 75% (95% confidence interval 33-100%). Intracellular BSEP at baseline was seen in six, of whom five were responders. Genetic analysis was performed in 17 of 22, confirming diagnosis in 13 (76%) and in four (24%) in whom only heterozygous mutation was identified. CONCLUSION: De novo or retargeted canalicular expression of BSEP occurs in treatment responders; children with late-onset presentation, lower ALT, and intracellular BSEP expression are likely to respond, at least transiently, to nontransplant treatment.

Evaluation of the Explorer Endoscopy Mask(©) for esogastroduodenoscopy in children: a retrospective study of 173 cases.

AIMS: The aim of this study was to evaluate the usability and safety of the Explorer Endoscopy Mask(®) (EM) as an alternative to endotracheal intubation in children undergoing elective esogastroduodenoscopy (EGD) under general anesthesia (GA). METHODS: This study was a retrospective observational study. The study was undertaken at the pediatric digestive endoscopy suite in the Cliniques universitaires Saint-Luc, Brussels, Belgium. We retrospectively analyzed the occurrence of minor and major airway-related adverse effects during pediatric EGD procedures performed under GA with the EM between June 2014 and March 2015. RESULTS: During the study period, 173 patients underwent EGD. Their mean age was 8.4 years (median: 9.1 years, range 4 months to 16 years). Mean duration of endoscopy (from insertion to removal of the endoscope) was 12.6 min (median: 12 min, range 3-47 min). The use of EM was uneventful in 159 (92%) cases. There were 24 airway-related adverse events in 14 children. Hypoxemia (SpO2 <90%) (13 events, 7.5%) was the most commonly encountered complication followed by laryngo- or bronchospasm (five events, 2.89%), cough (five events, 2.89%), and intubation (one event, 0.58%). No cases of regurgitation/aspiration were observed. CONCLUSIONS: Our data support the EM use in pediatric EGD. There were few transient respiratory adverse events which were easily solved with minor interventions.

Diagnostic and Therapeutic Roles of Endoscopic Ultrasound in Pediatric Pancreaticobiliary Disorders.

OBJECTIVES: The diagnostic role of endoscopic ultrasound (EUS) in children has only recently been demonstrated, and that also to a lesser extent than in adults. Data on the technique's therapeutic indications remain scarce. We therefore sought to evaluate diagnostic and interventional EUS indications, safety, and impact in children with pancreaticobiliary disorders. METHODS: We retrospectively reviewed our single pediatric center records, covering a 14-year period. RESULTS: From January 2000 to January 2014, 52 EUS procedures were performed in 48 children (mean age: 12 years; range: 2-17 years) with pancreaticobiliary disorders for the following indications: suspected biliary obstruction (n = 20/52), acute/chronic pancreatitis (n = 20), pancreatic mass (n = 3), pancreatic trauma (n = 7), and ampullary adenoma (n = 2). EUS was found to have a positive impact in 51 of 52 procedures, enabling us to avoid endoscopic retrograde cholangiopancreatography (ERCP) (n = 13 biliary; n = 6 pancreatic), focusing instead on endotherapy (n = 7 biliary; n = 14 pancreatic) or reorienting therapy toward surgery (n = 7). EUS-guided fine-needle aspiration was carried out on 12 patients for pancreatic tumor (n = 4), pancreatic cyst fluid analysis (n = 4), autoimmune pancreatitis (n = 2), and suspicion of biliary tumor (n = 2). A total of 13 therapeutic EUS procedures (11 children) were conducted, including 9 combined EUS-ERCP procedures (7 children, mean age: 8 years, range: 4-11 years), 3 EUS-guided pseudocyst drainage (2 children), and 1 EUS-guided transgastric biliary drainage. CONCLUSIONS: Our study reports on a large pediatric EUS series for diagnostic and therapeutic pancreaticobiliary disorders, demonstrating the impact of diagnostic EUS and affording insights into novel EUS and combined EUS-ERCP therapeutic applications. We suggest considering EUS as a diagnostic and therapeutic tool in the management of pediatric pancreaticobiliary diseases.

Differentiated umbilical cord matrix stem cells as a new in vitro model to study early events during hepatitis B virus infection.

UNLABELLED: The role of cell differentiation state on hepatitis B virus (HBV) replication has been well demonstrated, whereas how it determines cell susceptibility to HBV entry is far less understood. We previously showed that umbilical cord matrix stem cells (UCMSC) can be differentiated towards hepatocyte-like cells in vitro. In this study we infected undifferentiated (UD-) and differentiated (D-) UCMSCs with HBV and studied the infection kinetics, comparing them to primary human hepatocytes (PHHs). UD-UCMSCs, although permissive to viral binding, had a very limited uptake capacity, whereas D-UCMSCs showed binding and uptake capabilities similar to PHHs. Likewise, asialoglycoprotein receptor (ASGPR) was up-regulated in UCMSCs upon differentiation. In D-UCMSCs, a dose-dependent inhibition of HBV binding and uptake was observed when ASGPR was saturated with known specific ligands. Subsequent viral replication was shown in D-UCMSCs but not in UD-UCMSCs. Susceptibility of UCMSCs to viral replication correlated with the degree of differentiation. Replication efficiency was low compared to PHHs, but was confirmed by (1) a dose-dependent inhibition by specific antiviral treatment using tenofovir; (2) the increase of viral RNAs along time; (3) de novo synthesis of viral proteins; and (4) secretion of infectious viral progeny. CONCLUSION: UCMSCs become supportive of the entire HBV life cycle upon in vitro hepatic differentiation. Despite low replication efficiency, D-UCMSCs proved to be fully capable of HBV uptake. Overall, UCMSCs are a unique human, easily available, nontransformed, in vitro model of HBV infection that could prove useful to study early infection events and the role of the cell differentiation state on such events.