Publications by authors named "Christophe Chardot"

69 Publications

Phenotypic switch of smooth muscle cells in paediatric chronic intestinal pseudo-obstruction syndrome.

J Cell Mol Med 2021 Mar 3. Epub 2021 Mar 3.

PhyMedExp, Université de Montpellier, CNRS, INSERM, Montpellier, France.

Smooth Muscle Cells (SMC) are unique amongst all muscle cells in their capacity to modulate their phenotype. Indeed, SMCs do not terminally differentiate but instead harbour a remarkable capacity to dedifferentiate, switching between a quiescent contractile state and a highly proliferative and migratory phenotype, a quality often associated to SMC dysfunction. However, phenotypic plasticity remains poorly examined in the field of gastroenterology in particular in pathologies in which gut motor activity is impaired. Here, we assessed SMC status in biopsies of infants with chronic intestinal pseudo-obstruction (CIPO) syndrome, a life-threatening intestinal motility disorder. We showed that CIPO-SMCs harbour a decreased level of contractile markers. This phenotype is accompanied by an increase in Platelet-Derived Growth Factor Receptor-alpha (PDGFRA) expression. We showed that this modulation occurs without origin-related differences in CIPO circular and longitudinal-derived SMCs. As we characterized PDGFRA as a marker of digestive mesenchymal progenitors during embryogenesis, our results suggest a phenotypic switch of the CIPO-SMC towards an undifferentiated stage. The development of CIPO-SMC culture and the characterization of SMC phenotypic switch should enable us to design therapeutic approaches to promote SMC differentiation in CIPO.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.16367DOI Listing
March 2021

Quality of life in long term survivors of pediatric intestinal transplantation compared with liver transplantation and home parenteral nutrition: A prospective single-center pilot study.

Pediatr Transplant 2021 Feb 16:e13982. Epub 2021 Feb 16.

Gastroenterology-Hepatology-Nutrition Unit, Hôpital Necker-Enfants Malades, Paris, France.

Health-related quality of life (HRQOL) after intestinal transplantation (IT) is important, as many psychological troubles have been reported in these patients on the long term. Our aim was to assess and compare HRQOL of patients after IT to patients after liver transplantation (LT) or on home parenteral nutrition (HPN) for intestinal failure. A cross-sectional study included patients and their parents between 10 and 18 years of age, on HPN for more than 2 years, or who underwent IT or LT, with a graft survival longer than 2 years. Quality of life was explored by Child Health Questionnaire. Thirteen children-parents dyads after IT, 10 after LT, and eight children on HPN completed the survey. Patients were a median age of 14 years old, a median of 10 years post-transplantation or on HPN. Patients after IT scored lower than patients after LT or on HPN in "social limitations due to behavioral difficulties" and in "behavior." They scored higher than those on HPN in "global health." Parents of children after IT scored lower than those after LT in many domains. No relevant correlation with clinical data was found. Our study showed the multi-level impact of IT on quality of life of patients and their parents. It highlights the importance of a regular psychological follow-up for patients, but also of a psychological support for families. Helping the patients to overcome the difficulties at adolescence may improve their mental health in adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13982DOI Listing
February 2021

Dysregulation of the NRG1-ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans.

J Clin Invest 2021 Jan 26. Epub 2021 Jan 26.

Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France.

Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system with an incidence of 1/5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in eight individuals variably associating HSCR, CIPO, peripheral neuropathy and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis and intestinal smooth muscle abnormalities. The cell-type-specific ErbB3 and ErbB2 function was further analysed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using RT-qPCR on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing either wild-type or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies including intestinal dysmotility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI145837DOI Listing
January 2021

Arterial abnormalities identified in kidneys transplanted into children during the COVID-19 pandemic.

Am J Transplant 2020 Dec 21. Epub 2020 Dec 21.

INSERM U1163, Institut Imagine, Paris, France.

Graft artery stenosis can have a significant short- and long-term negative impact on renal graft function. From the beginning of the COVID-19 pandemic, we noticed an unusual number of graft arterial anomalies following kidney transplant (KTx) in children. Nine children received a KTx at our center between February and July 2020, eight boys and one girl, of median age of 10 years. Seven presented Doppler features suggesting arterial stenosis, with an unusual extensive pattern. For comparison, over the previous 5-year period, persistent spectral Doppler arterial anomalies (focal anastomotic stenoses) following KTx were seen in 5% of children at our center. We retrospectively evidenced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in five of seven children with arterial stenosis. The remaining two patients had received a graft from a deceased adolescent donor with a positive serology at D0. These data led us to suspect immune postviral graft vasculitis, triggered by SARS-CoV-2. Because the diagnosis of COVID-19 is challenging in children, we recommend pretransplant monitoring of graft recipients and their parents by monthly RT-PCR and serology. We suggest balancing the risk of postviral graft vasculitis against the risk of prolonged dialysis when considering transplantation in a child during the pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.16464DOI Listing
December 2020

Long-term kidney and liver outcome in 50 children with autosomal recessive polycystic kidney disease.

Pediatr Nephrol 2020 Nov 9. Epub 2020 Nov 9.

Department of Gastroenterology-Hepatology-Nutrition, Reference Center for Biliary Atresia and Cholestatic Genetic Diseases, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France.

Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by congenital hepatic fibrosis and cystic kidney disease. Lack of data about long-term follow-up makes it difficult to discuss timing and type of organ transplantation. Our objectives were to evaluate long-term evolution and indications for transplantation, from birth to adulthood.

Methods: Neonatal survivors and patients diagnosed in postnatal period with ARPKD between 1985 January and 2017 December from 3 French pediatric centers were retrospectively enrolled in the study.

Results: Fifty patients with mean follow-up 12.5 ± 1 years were enrolled. ARPKD was diagnosed before birth in 24%, and at mean age 1.8 years in others. Thirty-three patients were < 1 year of age at first symptoms, which were mostly kidney-related. These most often presented high blood pressure during follow-up. Portal hypertension was diagnosed in 29 patients (58%), 4 of them with bleeding from esophageal varices. Eight patients presented cholangitis (> 3 episodes in three children). Liver function was normal in all patients. Nine children received a kidney transplant without liver complications. A 20-year-old patient received a combined liver-kidney transplant (CLKT) for recurrent cholangitis, and a 15-year-old boy an isolated liver transplant for uncontrollable variceal bleeding despite portosystemic shunt.

Conclusions: Long-term outcome in patients with ARPKD is heterogeneous, and in this cohort did not depend on age at diagnosis except for blood pressure. Few patients required liver transplantation. Indications for liver or combined liver-kidney transplantation were limited to recurrent cholangitis or uncontrollable portal hypertension. Liver complications after kidney transplantation were not significant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-020-04808-9DOI Listing
November 2020

Tumor rupture in hepatoblastoma: A high risk factor?

Pediatr Blood Cancer 2020 09 3;67(9):e28549. Epub 2020 Jul 3.

Gustave Roussy, Department of Children and Adolescents Oncology, Université Paris-Saclay, Villejuif, France.

Background: Hepatoblastoma tumor rupture is a high-risk criterion in the SIOPEL 3/4 protocol. Little is known about the outcome of these children.

Methods: Radiological signs of possible tumor rupture, defined as peritoneal effusion, peritoneal nodules, or hepatic subcapsular hematoma, were reported in 24 of 150 patients treated for hepatoblastoma in France from January 2000 to December 2014 after central radiological expert review.

Results: Twenty-two patients with available clinical data were included (nine PRETEXT-I/II, six PRETEXT-III, seven PRETEXT-IV, and five had lung metastases). Five patients had a subcapsular hematoma only, and 17 patients had intraperitoneal rupture (subcapsular hematoma and peritoneal effusion). A hepatic biopsy was performed in 19 patients. Intraperitoneal rupture occurred before biopsy in 12 and after biopsy in three (including one with prebiopsy subcapsular hematoma) (missing data: two). All patients were treated with chemotherapy, with high-risk regimens including cisplatin or carboplatin and doxorubicin in 19 and cisplatin or carboplatin alone in three. Liver surgery was performed in 20 patients (including three liver transplants). Fifteen patients (68%) achieved complete remission. With a median follow-up of 5.5 years, 11 events occurred (six progressions and three relapses, including three peritoneal progressions/relapses, one surgical complication, and one second cancer) and eight patients died. One of eight patients with no other high-risk criterion had a relapse. The three-year event-free survival and overall survival rates were 49.6% (95% CI = 30-69) and 68.2% (40-84), respectively.

Conclusions: Tumor rupture is predictive of poor prognosis with risk of peritoneal progression/relapse. However, it should not be a contraindication for liver transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28549DOI Listing
September 2020

Beyond 10 years, with or without an intestinal graft: Present and future?

Am J Transplant 2020 10 3;20(10):2802-2812. Epub 2020 May 3.

Department of Pediatric Gastroenterology, Hepatology and Nutrition, Necker-Enfants Malades Hospital, University of Paris, Paris, France.

Long-term outcomes in children undergoing intestinal transplantation remain unclear. Seventy-one children underwent intestinal transplantation in our center from 1989 to 2007. We report on 10-year posttransplant outcomes with (group 1, n = 26) and without (group 2, n = 9) a functional graft. Ten-year patient and graft survival rates were 53% and 36%, respectively. Most patients were studying or working, one third having psychiatric disorders. All patients in group 1 were weaned off parenteral nutrition with mostly normal physical growth and subnormal energy absorption. Graft histology from 15 late biopsies showed minimal abnormality. However, micronutrient deficiencies and fat malabsorption were frequent; biliary complications occurred in 4 patients among the 17 who underwent liver transplantation; median renal clearance was 87 mL/min/1.73 m . Four patients in group 1 experienced late acute rejection. Among the 9 patients in group 2, 4 died after 10 years and 2 developed significant liver fibrosis. Liver transplantation and the use of a 3-drug regimen including sirolimus or mycophenolate mofetil were associated with improved graft survival. Therefore, intestinal transplantation may enable a satisfactory digestive function in the long term. The prognosis of graft removal without retransplantation is better than expected. Regular monitoring of micronutrients, early psychological assessment, and use of sirolimus are recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.15899DOI Listing
October 2020

Early Bacterial Infections After Pediatric Liver Transplantation in the Era of Multidrug-resistant Bacteria: Nine-year Single-center Retrospective Experience.

Pediatr Infect Dis J 2020 08;39(8):e169-e175

From the Service de réanimation et surveillance continue médico-chirurgicales pédiatriques, Hôpital Necker Enfants Malades, AP-HP, Université de Paris, Paris, France.

Background: Early bacterial infection is a major and severe complication after liver transplantation (LT). The rise of antimicrobial resistance, especially extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE), is a growing concern for these patients. This study aimed to assess the epidemiology of early bacterial infections in a pediatric population, including those caused by multidrug-resistant (MDR) pathogens, and to identify risk factors for infection.

Methods: We conducted a monocentric retrospective study including 142 consecutive LTs performed in 137 children between 2009 and 2017.

Results: Ninety-three bacterial infections occurred after 67 (47%) LTs. Among the 82 isolated pathogens, the most common was Klebsiella pneumoniae (n = 19, 23%). Independent risk factors for early bacterial infection were low weight [odds ratio (OR) = 0.96; 95% confidence interval (CI): 0.9-0.99; P = 0.03] and the presence of a prosthetic mesh (OR = 2.4; 95% CI: 1.1-5.4; P = 0.046). Sixty-one children (45%) carried MDR bacteria and 16 infections were caused by MDR pathogens, especially ESBL-producing K. pneumoniae (n = 12). ESBL-PE stool carriage was associated with ESBL-PE infection (OR = 4.5; 95% CI: 1.4-17.4; P = 0.02). Four children died from an infection, three due to ESBL-producing K. pneumoniae.

Conclusions: This study confirmed a shift toward a predominance of Gram-negative early bacterial infections after pediatric LT. The risk factors for infection were low weight and the presence of a prosthetic mesh. ESBL-PE stool carriage was associated with ESBL-PE infection. Adapted antimicrobial prophylaxis and personalized antibiotherapy are mandatory to reduce infection prevalence and mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/INF.0000000000002662DOI Listing
August 2020

Long-term outcome of methylmalonic aciduria after kidney, liver, or combined liver-kidney transplantation: The French experience.

J Inherit Metab Dis 2020 03 11;43(2):234-243. Epub 2020 Feb 11.

Reference Center of Inherited Metabolic Diseases, Hôpital Universitaire Necker-Enfants Malades, APHP, Imagine Institute, Filière G2M, MetabERN, INEM, University Paris Descartes, Paris, France.

Organ transplantation is discussed in methylmalonic aciduria (MMA) for renal failure, and poor quality of life and neurological outcome. We retrospectively evaluated 23 French MMA patients after kidney (KT), liver-kidney (LKT), and liver transplantation (LT). Two patients died, one after LKT, one of hepatoblastoma after KT. One graft was lost early after KT. Of 18 evaluable patients, 12 previously on dialysis, 8 underwent KT (mean 12.5 years), 8 LKT (mean 7 years), and 2 LT (7 and 2.5 years). At a median follow-up of 7.3 (KT), 2.3 (LKT), and 1.0 years (LT), no metabolic decompensation occurred except in 1 KT. Plasma and urine MMA levels dramatically decreased, more after LKT. Protein intake was increased more significantly after LKT than KT. Enteral nutrition was stopped in 7/8 LKT, 1/8 KT. Early complications were frequent after LKT. Neurological disorders occurred in four LKT, reversible in one. Five years after KT, four patients had renal failure. The metabolic outcomes were much better after LKT than KT. LKT in MMA is difficult but improves the quality of life. KT will be rarely indicated. We need more long-term data to indicate early LT, in the hope to delay renal failure and prevent neurodevelopmental complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jimd.12174DOI Listing
March 2020

Management of Biliary Atresia in France 1986 to 2015: Long-term Results.

J Pediatr Gastroenterol Nutr 2019 10;69(4):416-424

Observatoire Français de l'Atrésie des Voies Biliaires et Centre de Référence Atrésie des Voies Biliaires-Cholestases Génétiques, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris.

Objectives: This study analyses the prognosis of biliary atresia (BA) in France since 1986, when both Kasai operation (KOp) and liver transplantation (LT) became widely available.

Methods: The charts of all patients diagnosed with BA born between 1986 and 2015 and living in France were reviewed.

Results: A total of 1428 patients were included; 1340 (94%) underwent KOp. Total clearance of jaundice (total bilirubin ≤20 μmol/L) was documented in 516 patients (39%). Age at KOp (median 59 days, range 6-199) was stable over time. Survival with native liver after KOp was 41%, 35%, 26%, and 22% at 5, 10, 20, and 30 years, stable in the 4 cohorts. 25-year survival with native liver was 38%, 27%, 22%, and 19% in patients operated in the first, second, third month of life or later, respectively (P = 0.0001). Center caseloads had a significant impact on results in the 1986 to 1996 cohort only. 16%, 7%, 7%, and 8% of patients died without LT in the 4 cohorts (P = 0.0001). A total of 753 patients (55%) underwent LT. Patient survival after LT was 79% at 28 years. Five-year patient survival after LT was 76%, 91%, 88%, and 92% in cohorts 1 to 4, respectively (P < 0.0001). Actual BA patient survival (from diagnosis) was 81%. Five-year BA patient survival was 72%, 88%, 87%, and 87% in cohorts 1986 to 1996, 1997 to 2002, 2003 to 2009, and 2010 to 2015, respectively (P < 0.0001).

Conclusions: In France, 87% of patients with BA survive nowadays and 22% reach the age of 30 years without transplantation. Improvement of BA prognosis is mainly due to reduced mortality before LT and better outcomes after LT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000002446DOI Listing
October 2019

Clostridium difficile: A Frequent Infection in Children After Intestinal Transplantation.

Transplantation 2020 01;104(1):197-200

Hôpital Necker-Enfants Malades Assistance Publique-Hôpitaux de Paris, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Université Paris Descartes - Sorbonne Paris Cité, Paris, France.

Background: Organ transplantation (Tx) is a risk factor for Clostridium difficile infection (CDI). After intestinal transplantation (ITx), few data are available on the impact of this graft infection and the possible induction of rejection.

Methods: We included retrospectively all children after ITx in our unit, with at least 1 year of graft survival. All samples positive for Clostridium difficile (CD) and its toxin were considered.

Results: Among the 57 ITx recipients (60 Txs), 22 children (39%) developed culture-proven CDI, 12 after isolated small bowel Tx, 9 after liver-small bowel Tx, and 1 after multivisceral Tx. Twenty patients had diarrhea, 8 bloody stools, 4 fever, and 1 hypothermia. Nine were hospitalized for an average of 6.5 days (2-20) and 4 with severe dehydration. Nine (40%) had received antibiotics for an average of 19 days (7-60) before CDI. Two patients were asymptomatic. CDI was treated with metronidazole in 12 children, vancomycin in 6, and both in 3. Three children presented mild-to-severe rejections. Two patients presented concomitantly CDI and rejection. The third patient presented a rejection with severe complications 4 years after CDI. Recurrence of toxinogenic CD was observed in 9 children, in 7 associated with clinical symptoms. During the last follow-up, the stool number was the same as before CDI except for 1 patient with ongoing infection.

Conclusions: CDI is more prevalent in children after ITx compared with other organ Tx; it is most often symptomatic but mildly or moderately severe. Standard antibiotics efficiently control the symptoms. Induction of rejection is a rare event.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000002795DOI Listing
January 2020

germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures.

Oncoimmunology 2019;8(6):e1583547. Epub 2019 Mar 28.

Centre de Recherche des Cordeliers, Functional Genomics of Solid Tumors laboratory, Sorbonne Université, Inserm, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France.

Hepatoblastoma (HB) is the most common liver cancer in children. We aimed to characterize HB related to (Adenomatous Polyposis Coli) germline mutation (APC-HB). This French multicentric retrospective study included 12 APC-HB patients under 5 at diagnosis. Clinical features of APC-HB were compared to the French SIOPEL2-3 cohort of HB patients. Molecular and histopathological analyses of APC-HB were compared to 15 consecutive sporadic HB treated at Bicêtre hospital from 2013 to 2015 (non-APC-HB). APC-HB patients have a peculiar spectrum of germline mutations, with no events in the main hotspot of classical mutations at codon 1309 ( < .05). Compared to sporadic HB, they have similar clinical features including good prognosis since all patients are alive in complete remission at last follow-up. APC-HB are mostly well-limited tumors with fetal predominance and few mesenchymal components. All APC-HB have an activated Wnt/β-catenin pathway without mutation, confirming that germline and somatic mutations are mutually exclusive ( < .001). Pathological reviewing identified massive intratumor tertiary lymphoid structures (TLS) containing both lymphocytes and antigen-presenting cells in all 11 APC-HB cases who received cisplatin-based neoadjuvant chemotherapy but not in five pre-chemotherapy samples (four paired biopsies and one patient resected without chemotherapy), indicating that these TLS are induced by chemotherapy ( < .001). Conclusion: APC-HB show a good prognosis, they are all infiltrated by cisplatin-induced TLS, a feature only retrieved in a minority of non-APC-HB. This suggests that C inactivation can synergize with cisplatin to induce an immunogenic cell death that initiates an anti-tumor immune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2019.1583547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492969PMC
March 2019

Microscopically positive resection margin after hepatoblastoma resection: what is the impact on prognosis? A Childhood Liver Tumours Strategy Group (SIOPEL) report.

Eur J Cancer 2019 01 5;106:126-132. Epub 2018 Dec 5.

Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, Paris, France.

Background: To evaluate the impact of a microscopically positive resection margin (microPRM) on the outcome of hepatoblastoma patients pretreated with chemotherapy.

Methods: Local recurrence and survival rates of 431 children treated in the SIOPEL 2 and 3 trials were analysed comparing 58 patients with microPRM with 371 who had a complete resection (CR) and who were then stratified by risk category. The tumour was standard-risk in 312 patients and high-risk (PRETEXT IV and/or extrahepatic disease and/or α-fetoprotein [AFP]<100 ng/ml) in 117 patients. All received cisplatinum-based neoadjuvant and postoperative chemotherapy as per protocol. Apart from one microPRM patient who went on to transplant, none received any additional local treatment.

Results: With a median follow-up of 67 months, local relapse occurred in 3/58 patients with microPRM (5%) and in 23/371 (6%) patients with CR. The 5-year overall survival (OS) was 91% (95% confidence interval [CI] 80%-96%) for the microPRM and 92% (95% CI 89%-95%) for the CR group. The 5-year event-free survival (EFS) was 86% (95% CI 74%-93%) for the microPRM and 86% (95% CI 82%-89%) for the CR group. Neither OS nor EFS was statistically significantly different between the two groups, neither overall nor when risk group stratified.

Conclusions: In the context of cisplatin-based chemotherapy, the presence of microPRM did not influence the outcome even without additional local treatment. Although CR remains the aim, microPRM does not necessitate mandatory second look surgery. A 'wait and see policy' is warranted if postoperative chemotherapy is administered and AFP levels and imaging become normal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2018.10.013DOI Listing
January 2019

Reiterative Radiofrequency Ablation in the Management of Pediatric Patients with Hepatoblastoma Metastases to the Lung, Liver, or Bone.

Cardiovasc Intervent Radiol 2019 Jan 22;42(1):41-47. Epub 2018 Oct 22.

Interventional Radiology Department, Gustave Roussy, Villejuif, 94805, France.

Background And Purpose: Conventional treatments of systemic chemotherapy and surgical resection for recurrent or metastatic hepatoblastoma (HB) may be inhibitive for the pediatric patient and family who have already been through extensive therapies. This single-institution case series evaluates the safety and efficacy of percutaneous radiofrequency ablation (RFA) in the management of metastatic HB.

Materials And Methods: Between March 2008 and February 2015, RFA was used as part of multidisciplinary management for HB recurrence or metastasis in 5 children (median 5.0 years old) in an attempt to provide locoregional control and preclude additional surgery. Combined local treatments of 38 metachronous metastases included surgical metastasectomy (14 lesions: 7 lung, 7 liver), percutaneous RFA (23 lesions: 21 lung, 1 liver, 1 bone), and stereotactic radiotherapy (1 liver lesion).

Results: For lesions treated with RFA (median diameter 6 mm, range 3-15 mm), local control was achieved in 22/23 metastases (95.6%) with median follow-up of 30.1 months after RFA (range 18.9-65.7). Median hospitalization was 3 days (2-7), with major complications limited to 1 pneumothorax requiring temporary small-caliber chest tube. Four children remain in complete remission with median follow-up of 67 months (range 41.2-88.8) after primary tumor resection, with mean disease-free survival of 31.7 months after last local treatment. One child succumbed to rapidly progressive disease 12 months after RFA (23.9 months after primary tumor resection).

Conclusion: RFA provides a safe and effective reiterative treatment option in the multidisciplinary management of children with metastatic HB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00270-018-2097-7DOI Listing
January 2019

Another point of view on 2017 PRETEXT.

Pediatr Radiol 2018 11 14;48(12):1817-1819. Epub 2018 Aug 14.

Department of Children and Adolescent Oncology, Gustave Roussy Cancer Campus, Villejuif, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00247-018-4227-4DOI Listing
November 2018

Long term outcomes of intestinal rehabilitation in children with neonatal very short bowel syndrome: Parenteral nutrition or intestinal transplantation.

Clin Nutr 2019 04 15;38(2):926-933. Epub 2018 Feb 15.

Department of Pediatric Gastroenterology, Hepatology and Nutrition, Intestinal Failure Rehabilitation Center, Hôpital Universitaire Necker Enfants Malades, 149 rue de Sèvres, 75015 Paris, France; Faculté de Médecine, Universitè of Sorbonne-Paris-Cité, Paris Descartes, 15 Rue de l'École de Médecine, 75006 Paris, France.

Background & Aims: Intestinal rehabilitation is the preferred treatment for children with short bowel syndrome (SBS) whatever the residual bowel length, and depends on the accurate management of long-term parenteral nutrition (PN). If nutritional failure develops, intestinal transplantation (ITx) should be discussed and may be life-saving. This study aimed to evaluate survival, PN dependency and nutritional status in children with neonatal very SBS on PN or after ITx, in order to define indications and timing of both treatments.

Patients And Methods: This retrospective cross-sectional study enrolled 36 children with very SBS (<40 cm) who entered our intestinal rehabilitation program from 1987 to 2007.

Results: All the children on long-term PN (n = 16) survived with a follow-up of 17 years (9-20). Six of them were eventually weaned off PN. Twenty children underwent ITx: eight children died (40%) 29 months (0-127) after Tx. The others 12 patients were weaned off PN 73 days (13-330) after Tx. Follow-up after transplantation was 14 years (6-28). Seven out of 8 (88%) patients with a history of gastroschisis required ITx. Patients who required ITx had longer stoma duration.

Conclusion: Survival rate of children with very short bowel was excellent if no life-threatening complications requiring transplantation developed. Gastroschisis and delayed ostomy closure are confirmed as risk factor for nutritional failure. Intestinal rehabilitation may allow a total weaning of PN before adulthood. A follow-up by a multidisciplinary team is necessary to avoid PN complications in order to minimize indications for ITx.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clnu.2018.02.004DOI Listing
April 2019

Population pharmacokinetics of enoxaparin in early stage of paediatric liver transplantation.

Br J Clin Pharmacol 2018 06 23;84(6):1206-1214. Epub 2018 Mar 23.

EA7323, Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, Université Paris Descartes, Paris, France.

Aims: Preventing post-liver transplantation (LT) hepatic artery and portal vein thrombosis includes enoxaparin administration. Enoxaparin pharmacokinetics (PK) has not been investigated in children following LT. We described an enoxaparin PK model in 22 children the first week following LT.

Methods: Anti-Xa activity time-courses were analysed using a nonlinear mixed effects approach with Monolix version 2016R.

Results: Anti-Xa activity time-courses were well described by a one-compartment model with first order absorption and elimination. Bodyweight prior to surgery (BW ) and the related postoperative variation (BW(t)) were the main covariates explaining CL and V between subject variabilities. Parameter estimates were CL  = CL * (BW /70) ; V  = V * (BW(t)/70) ; where typical clearance (CL ) and typical volume of distribution (V ) were 1.23 l h and 14.6 l, respectively. Standard dosing regimens of 50 IU kg  12 h were insufficient to reach the target range of anti-Xa activity of 0.2-0.4 IU ml . Specifically, seven children (32%) never attained the target range during the whole period of treatment and all children were at least once underdosed. According to the final results, we simulated individualized dosing regimens within 4 h following the first administration. More than 100 IU kg  12 h are suggested to reach the target range of anti-Xa activity of 0.2-0.4 IU ml from the first day.

Conclusion: Thanks to this model, the initial and maintenance doses could be assessed to rapidly achieve the target range. Higher doses per kg, especially in the youngest children, are suggested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.13543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980405PMC
June 2018

Antibody-mediated rejection in pediatric small bowel transplantation: Capillaritis is a major determinant of C4d positivity in intestinal transplant biopsies.

Am J Transplant 2018 09 24;18(9):2250-2260. Epub 2018 Mar 24.

Pathology Department, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France.

The diagnostic criteria for antibody-mediated rejection (ABMR) after small bowel transplantation (SBT) are not clearly defined, although the presence of donor-specific antibodies (DSAs) has been reported to be deleterious for graft survival. We aimed to determine the incidence and prognostic value of DSAs and C4d in pediatric SBT and to identify the histopathologic features associated with C4d positivity. We studied all intestinal biopsies (IBx) obtained in the first year posttransplantation (N = 345) in a prospective cohort of 23 children. DSAs and their capacity to fix C1q were identified by using Luminex technology. Eighteen patients (78%) had DSAs, and 9 had the capacity to fix C1q. Seventy-eight IBx (22.6%) were C4d positive. The independent determinants of C4d positivity were capillaritis grades 2 and 3 (odds ratio [OR] 4.02, P = .047 and OR 5.17, P = .003, respectively), mucosal erosion/ulceration (OR 2.8, P = .019), lamina propria inflammation grades 1 and 2/3 (OR 1.95, P = .043 and OR 3.1, P = .016, respectively), and chorion edema (OR 2.16, P = .028). Complement-fixing DSAs and repeated C4d-positive IBx were associated with poor outcome (P = .021 and P = .001, respectively). Our results support that capillaritis should be considered as a feature of ABMR in SBT and identify C1q-fixing DSAs and repeated C4d positivity as potential markers of poor outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.14685DOI Listing
September 2018

Survival of children after liver transplantation for hepatocellular carcinoma.

Liver Transpl 2018 02;24(2):246-255

Research Group Epidemiological and Statistical Methods, Helmholtz Centre for Infection Research, Braunschweig, Germany.

Hepatocellular carcinoma (HCC) in childhood differs from adult HCC because it is often associated with inherited liver disease. It is, however, unclear whether liver transplantation (LT) for HCC in childhood with or without associated inherited disease has a comparable outcome to adult HCC. On the basis of data from the European Liver Transplant Registry (ELTR), we aimed to investigate if there are differences in patient and graft survival after LT for HCC between children and adults and between patients with underlying inherited versus noninherited liver disease, respectively. We included all 175 children who underwent LT for HCC and were enrolled in ELTR between 1985 and 2012. Of these, 38 had an associated inherited liver disease. Adult HCC patients with (n = 79) and without (n = 316, matched by age, sex, and LT date) inherited liver disease served as an adult comparison population. We used multivariable piecewise Cox regression models with shared frailty terms (for LT center) to compare patient and graft survival between the different HCC groups. Survival analyses demonstrated a superior longterm survival of children with inherited liver disease when compared with children with HCC without inherited liver disease (hazard ratio [HR], 0.29; 95% CI, 0.10-0.90; P = 0.03) and adults with HCC with inherited liver disease (HR, 0.27; 95% CI, 0.06-1.25; P = 0.09). There was no survival difference between adults with and without inherited disease (HR, 1.05; 95% CI, 0.66-1.66; P = 0.84). In conclusion, the potential survival advantage of children with an HCC based on inherited disease should be acknowledged when considering transplantation and prioritization for these patients. Further prospective studies accounting for tumor size and extension at LT are necessary to fully interpret our findings. Liver Transplantation 24 246-255 2018 AASLD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lt.24994DOI Listing
February 2018

Extracorporeal Membrane Oxygenation Can Save Lives in Children With Heart or Lung Failure After Liver Transplantation.

Artif Organs 2017 Sep;41(9):862-865

Pediatric Intensive Care Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, Île-de-France, France.

The risk of cardiac or lung failure after liver transplantation (LT) is significant. In rare cases, the usual intensive care techniques fail to maintain organ oxygenation with a risk of multiorgan dysfunction. Although extracorporeal membrane oxygenation (ECMO) is a difficult and risky procedure, it can be proposed as life-saving. Four children with either acute pulmonary (three) or cardiac (one) failure after LT, and the criteria that decided the use of ECMO (level of ventilation and results, dosage of inotropic drugs, cardiac ultrasound, blood lactate) were retrospectively reported. These patients, 1-11 years old, were treated with either veno-arterial (three) or veno-venous (one) ECMO. Two experienced a full recovery, with 3 and 6 years of follow-up. Two died of systemic inflammatory response syndrome (SIRS) due to ECMO, and relapse of heart failure due to the underlying disease. Although our patients' survival was only 50%, we showed that ECMO can be useful in children after LT. It should be considered before the development of irreversible multiorgan failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/aor.12975DOI Listing
September 2017

Twenty-eight years of intestinal transplantation in Paris: experience of the oldest European center.

Transpl Int 2017 Feb;30(2):178-186

Pediatric Surgery, Necker-Enfants malades Hospital, Paris, France.

Our aim was to describe our achievements in pediatric intestinal transplantation (ITx) and define areas for improvement. After a period (1987-1990) of nine isolated small bowel transplants (SBTx) where only one patient survived with her graft, 110 ITx were performed on 101 children from 1994 to 2014: 60 SBTx, 45 liver-small bowel, four multivisceral (three with kidneys), and one modified multivisceral. Indications were short bowel syndrome (36), motility disorders (30), congenital enteropathies (34), and others (1). Induction treatment was introduced in 2000. Patient/graft survival with a liver-containing graft or SBTx was, respectively, 60/41% and 46/11% at 18 years. Recently, graft survival at 5/10 years was 44% and 31% for liver-containing graft and 57% and 44% for SBTx. Late graft loss occurred in 13 patients, and 7 of 10 retransplanted patients died. The main causes of death and graft loss were sepsis and rejection. Among the 55 currently living patients, 21 had a liver-containing graft, 19 a SBTx (17 after induction), and 15 were on parenteral nutrition. ITx remains a difficult procedure, and retransplantation even more so. Over the long term, graft loss was due to rejection, over-immunosuppression was not a significant problem. Multicenter studies on immunosuppression and microbiota are urgently needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tri.12894DOI Listing
February 2017

Cutaneous and Visceral Chronic Granulomatous Disease Triggered by a Rubella Virus Vaccine Strain in Children With Primary Immunodeficiencies.

Clin Infect Dis 2017 Jan 6;64(1):83-86. Epub 2016 Oct 6.

Biology of Infection Unit, Laboratory of Pathogen Discovery, Inserm U1117.

Persistence of rubella live vaccine has been associated with chronic skin granuloma in 3 children with primary immunodeficiency. We describe 6 additional children with these findings, including 1 with visceral extension to the spleen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciw675DOI Listing
January 2017

Preoperative risk factors for intra-operative bleeding in pediatric liver transplantation.

Pediatr Transplant 2016 Dec 29;20(8):1065-1071. Epub 2016 Sep 29.

Pediatric surgery unit, Hôpital Necker enfants malades, Paris, France.

This study analyzes the preoperative risk factors for intra-operative bleeding in our recent series of pediatric LTs. Between November 2009 and November 2014, 84 consecutive isolated pediatric LTs were performed in 81 children. Potential preoperative predictive factors for bleeding, amount of intra-operative transfusions, postoperative course, and outcome were recorded. Cutoff point for intra-operative HBL was defined as intra-operative RBC transfusions ≥1 TBV. Twenty-six patients (31%) had intra-operative HBL. One-year patient survival after LT was 66.7% (CI 95%=[50.2-88.5]) in HBL patients and 83.8% (CI 95%=[74.6-94.1]) in the others (P=.054). Among 13 potential preoperative risk factors, three of them were identified as independent predictors of high intra-operative bleeding: abdominal surgical procedure(s) prior to LT, factor V level ≤30% before transplantation, and ex situ parenchymal transsection of the liver graft. Based on these findings, we propose a simple score to predict the individual hemorrhagic risk related to each patient and graft association. This score may help to better anticipate intra-operative bleeding and improve patient's management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.12794DOI Listing
December 2016

Patient-derived mouse xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management.

Hepatology 2016 10 16;64(4):1121-35. Epub 2016 Jun 16.

XenTech, 4 rue Pierre Fontaine, Evry, France.

Unlabelled: Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Liver cancer occurrence in infancy, 1.5 for million children per year, falls far below the threshold of interest for dedicated drug development programs, and this disease is so rare that it is very difficult to gather enough children into a phase II clinical trial. Here, we present the establishment of an unprecedented preclinical platform of 24 pediatric liver cancer patient-derived xenografts (PLC-PDXs) from 20 hepatoblastomas (HBs), 1 transitional liver cell tumor (TCLT), 1 hepatocellular carcinoma, and 2 malignant rhabdoid tumors. Cytogenetic array and mutational analysis of the parental tumors and the corresponding PLC-PDXs show high conservation of the molecular features of the parental tumors. The histology of PLC-PDXs is strikingly similar to that observed in primary tumors and recapitulates the heterogeneity of recurrent disease observed in the clinic. Tumor growth in the mouse is strongly associated with elevated circulating alpha-fetoprotein (AFP), low rate of necrosis/fibrosis after treatment, and gain of chromosome 20, all indicators of resistance to chemotherapy and poor outcome. Accordingly, the ability of a tumor to generate PLC-PDX is predictive of poor prognosis. Exposure of PLC-PDXs to standards of care or therapeutic options already in use for other pediatric malignancies revealed unique response profiles in these models. Among these, the irinotecan/temozolomide combination induced strong tumor regression in the TCLT and in a model derived from an AFP-negative relapsing HB.

Conclusion: These results provide evidence that PLC-PDX preclinical platform can strongly contribute to accelerate the identification and diversification of anticancer treatment for aggressive subtypes of pediatric liver cancer. (Hepatology 2016;64:1121-1135).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.28621DOI Listing
October 2016

Outcome of home parenteral nutrition in 251 children over a 14-y period: report of a single center.

Am J Clin Nutr 2016 05 30;103(5):1327-36. Epub 2016 Mar 30.

Departments of Pediatric Gastroenterology, Hepatology and Nutrition, Paris Descartes University, Paris, France; and.

Background: Parenteral nutrition (PN) is the main treatment for intestinal failure.

Objective: We aimed to review the indications for home parenteral nutrition (HPN) in children and describe the outcome over a 14-y period from a single center.

Design: We conducted a retrospective study that included all children who were referred to our institution and discharged while receiving HPN between 1 January 2000 and 31 December 2013. The indications for HPN were divided into primary digestive diseases (PDDs) and primary nondigestive diseases (PNDDs). We compared our results to a previous study that was performed in our unit from 1980 to 2000 and included 302 patients.

Results: A total of 251 patients were included: 217 (86%) had a PDD. The mean ± SD age at HPN onset was 0.7 ± 0.3 y, with a mean duration of 1.9 ± 0.4 y. The indications for HPN were short bowel syndrome (SBS) (59%), PNDD (14%), congenital enteropathies (10%), chronic intestinal pseudo-obstruction syndromes (9%), inflammatory bowel diseases (5%), and other digestive diseases (3%). By 31 December 2013, 52% of children were weaned off of HPN, 9% of the PDD subgroup had intestinal transplantation, and 10% died mostly because of immune deficiency. The major complications of HPN were catheter-related bloodstream infections (CRBSIs) (1.7/1000 d of PN) and intestinal failure-associated liver disease (IFALD) (51 children; 20% of cohort). An increased rate of CRBSIs was observed compared with our previous study, but we saw a decreasing trend since 2012. No noteworthy deceleration of growth was observed in SBS children 6 mo after weaning off HPN.

Conclusions: SBS was the major indication for HPN in our cohort. IFALD and CRBSIs were potentially life-threatening problems. Nevertheless, complication rates were low, and deaths resulted mostly from the underlying disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3945/ajcn.115.121756DOI Listing
May 2016

Severe Skin Complications After Small Bowel Transplantation: Graft-Versus-Host Disease, DRESS, Virus, or Drug Toxicity?

Transplantation 2016 10;100(10):2222-5

1 Department of Paediatric Hepatogastroenterology-Nutrition, Assistance Publique, Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France. 2 Department of Dermatology, AP-HP, Necker-Enfants Malades Hospital, Paris Descartes University, Sorbonne Paris Cité, Paris, France. 3 Department of Pathology, AP-HP, Necker-Enfants Malades Hospital, Paris, France. 4 Department of Paediatric Immuno-Haematology and Microbiology Laboratory, AP-HP, Necker-Enfants Malades Hospital, Paris Descartes University, Sorbonne Paris Cité, Paris, France. 5 Department of Paediatric Surgery, AP-HP, Necker-Enfants Malades Hospital, Paris, France.

Background: Severe skin problems are uncommon after small bowel transplantation. Differential diagnosis includes drug reactions, infections, graft-versus-host disease (GVHD), and mixed diseases. Early diagnosis and treatment are determinant for prognosis.

Methods And Results: We describe 6 patients with severe cutaneous complications after small bowel transplantation, the work-up, final diagnosis, and evolution. Two patients died from chronic GVHD or unrecognized drug rash with eosinophilia and systemic symptoms, the others recovered completely. In 2 patients, drugs and viruses could be implicated, and in 1 patient may have hidden or triggered chronic GVHD. Viruses (human herpesvirus 6, Epstein-Barr virus, and cytomegalovirus) were suspected to trigger drug rash with eosinophilia and systemic symptoms or GVHD. The 2 cases of acute GVHD were reversed completely by increased immunosuppression and anti-interleukin-2 receptor antibody.

Discussion: In these severe cases, diagnosis is urgent and should include a careful evaluation of drug history, clinical presentation, biological investigations, infections, and toxic screening. A skin biopsy and chimerism study should be performed whenever possible. An early treatment is key to a positive outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TP.0000000000001131DOI Listing
October 2016

Biliary atresia: Clinical advances and perspectives.

Clin Res Hepatol Gastroenterol 2016 Jun 5;40(3):281-287. Epub 2016 Jan 5.

Pediatric Hepatology Unit, hôpital Necker-Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France; UMR1163, Imagine Institute, hôpital Necker-Enfants-Malades, Paris, France. Electronic address:

Biliary atresia (BA) is a rare and severe inflammatory and obliterative cholangiopathy that affects both extra- and intrahepatic bile ducts. BA symptoms occur shortly after birth with jaundice, pale stools and dark urines. The prognosis of BA has dramatically changed in the last decades: before the Kasai operation most BA patients died, while nowadays with the sequential treatment with Kasai operation±liver transplantation BA patient survival is close to 90%. Early diagnosis is very important since the chances of success of the Kasai procedure decrease with time. The causes of BA remain actually unknown but several mechanisms including genetic and immune dysregulation may probably lead to the obliterative cholangiopathy. Current research focuses on the identification of blood or liver factors linked to the pathogenesis of BA that could become therapeutic targets and avoid the need for liver transplantation. No similar disease leading to total obstruction of the biliary tree exists in older children or adults. But understanding the physiopathology of BA may highlight the mechanisms of other destructive cholangiopathies, such as sclerosing cholangitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinre.2015.11.010DOI Listing
June 2016

Influence of donor-recipient CYP3A4/5 genotypes, age and fluconazole on tacrolimus pharmacokinetics in pediatric liver transplantation: a population approach.

Pharmacogenomics 2014 Jun;15(9):1207-21

Laboratory of Analytical Biochemistry, Cliniques Universitaires Saint-Luc & Louvain Centre for Toxicology & Applied Pharmacology (LTAP), UCL, Avenue Mounier 53, Box B1-52-12, 1200, Brussels, Belgium.

Aim: To characterize the effect of donor and recipient CYP3A4, CYP3A5 and ABCB1 genotypes as well as relevant patient characteristics on tacrolimus pharmacokinetics in pediatric liver transplantation.

Patients & Methods: Data from 114 pediatric liver transplant recipients were retrospectively collected during the first 3 months following transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling, including characterization of influential covariates.

Results: A two-compartment model with first order elimination best fitted the data. Estimates of apparent volume of the central compartment, intestinal clearance, hepatic clearance and intercompartmental clearance were 79 l, 0.01 l/h, 10.9 l/h and 105 l/h, respectively. Time post-transplantation, recipient age, donor CYP3A5 and CYP3A4 genotypes and fluconazole administration significantly influenced tacrolimus apparent clearance while bodyweight influenced volume of distribution.

Conclusion: The proposed model displayed acceptable fitting performances and enabled identification of statistically significant and clinically relevant covariates on tacrolimus pharmacokinetics in the early pediatric post liver transplantation period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/pgs.14.75DOI Listing
June 2014

Anastomotic ulcerations after intestinal resection in infancy.

J Pediatr Gastroenterol Nutr 2014 Oct;59(4):531-6

*Department of Pediatric Gastroenterology-Hepatology and Nutrition †Department of Pediatric Surgery and Transplantation, Hôpital Necker-Enfants Malades ‡Department of Pediatric Gastroenterology-Hepatology and Nutrition, Hôpital d'Enfants de Brabois, Vandoeuvre-les-Nancy, France.

Objective: Anastomotic ulceration (AU) is a rare complication after intestinal resection and anastomosis, described mostly in children. The main symptom is occult bleeding, leading to iron-deficiency anemia, which is life threatening.

Methods: The present survey reports a series of patients with AU after intestinal resection in infancy, focusing on predictive factors, medical and surgical treatment options, and long-term outcomes. Eleven patients (7 boys) born between 1983 and 2005 with AU after an intestinal resection and anastomosis in infancy were included in this retrospective review.

Results: The diagnosis of AU was often delayed for several years. No predictive factor (including the primary disease, the length of the remnant bowel, and the loss of the ileocaecal valve) could be identified. Numerous treatment options, including antibiotics and anti-inflammatory drugs, proved to be ineffective to induce prolonged remission. Even after surgical resection, relapses were observed in 5/7 children.

Conclusions: The mechanism leading to AU remains unknown. Contrary to previous reports with limited follow-up, no medical or surgical treatment could prevent recurrences. Because relapses may occur several years after treatment, long-term follow-up is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000000472DOI Listing
October 2014

MYO5B and bile salt export pump contribute to cholestatic liver disorder in microvillous inclusion disease.

Hepatology 2014 Jul 27;60(1):301-10. Epub 2014 May 27.

Department of Pediatric Gastroenterology and Hepatology, Necker Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes-Sorbonne Cité, Paris, France; INSERM, UMR 781, Université Paris Descartes-Sorbonne Cité, Institut Imagine, Paris, France.

Unlabelled: Microvillous inclusion disease (MVID) is a congenital disorder of the enterocyte related to mutations in the MYO5B gene, leading to intractable diarrhea often necessitating intestinal transplantation (ITx). Among our cohort of 28 MVID patients, 8 developed a cholestatic liver disease akin to progressive familial intrahepatic cholestasis (PFIC). Our aim was to investigate the mechanisms by which MYO5B mutations affect hepatic biliary function and lead to cholestasis in MVID patients. Clinical and biological features and outcome were reviewed. Pretransplant liver biopsies were analyzed by immunostaining and electron microscopy. Cholestasis occurred before (n = 5) or after (n = 3) ITx and was characterized by intermittent jaundice, intractable pruritus, increased serum bile acid (BA) levels, and normal gamma-glutamyl transpeptidase activity. Liver histology showed canalicular cholestasis, mild-to-moderate fibrosis, and ultrastructural abnormalities of bile canaliculi. Portal fibrosis progressed in 5 patients. No mutation in ABCB11/BSEP or ATP8B1/FIC1 genes were identified. Immunohistochemical studies demonstrated abnormal cytoplasmic distribution of MYO5B, RAB11A, and BSEP in hepatocytes. Interruption of enterohepatic BA cycling after partial external biliary diversion or graft removal proved the most effective to ensure long-term remission.

Conclusion: MVID patients are at risk of developing a PFIC-like liver disease that may hamper outcome after ITx. Our results suggest that cholestasis in MVID patients results from (1) impairment of the MYO5B/RAB11A apical recycling endosome pathway in hepatocytes, (2) altered targeting of BSEP to the canalicular membrane, and (3) increased ileal BA absorption. Because cholestasis worsens after ITx, indication of a combined liver ITx should be discussed in MVID patients with severe cholestasis. Future studies will need to address more specifically the effect of MYO5B dysfunction in BA homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.26974DOI Listing
July 2014