Françoise Schmitt

Tolerance and efficacy of preventive gastrostomy feeding in pediatric oncology.

Malnutrition in pediatric oncology remains underestimated, although having a negative impact on outcome. Enteral nutrition (EN) using percutaneous endoscopic gastrostomy (PEG) may prevent or reverse malnutrition consequences. We aimed to evaluate both efficacy and safety of early EN during tumors treatment in children.

Hereditary pancreatitis in children: surgical implications with special regard to genetic background.

PURPOSE Hereditary pancreatitis (HP) is the primary etiology of chronic pancreatitis during childhood, progressing through recurrent episodes of acute pancreatitis and finally leading to pancreatic insufficiencies. Hereditary pancreatitis is because of mutations of the cationic trypsinogen (PRSS1) gene. Some other genes, such as SPINK1 or CFTR, have been associated with familial idiopathic chronic pancreatitis. The aim of our study was to clearly define diagnostic and therapeutic strategies for HP patients, through an analysis of our study group and a review of the literature. METHODS All children admitted from 1995 to 2007 with a final diagnosis of hereditary pancreatitis were restrospectively included in the study. We analyzed all medical records with special attention given to cases involving genetic screening (PRSS1, SPINK1, and CFTR genes). RESULTS Ten children were included. Eight had HP with PRSS1 mutation, 2 of them without a familial history of chronic pancreatitis. The 2 others patients had SPINK1 mutations. Three HP patients were operated on for acute complications of pancreatitis and are well with a mean follow-up of 5.5 years. No patient had pancreatic insufficiencies or weight loss. CONCLUSIONS Hereditary pancreatitis is associated with severe pancreatitis, with a greater risk of developing pancreatic cancer. It must therefore be diagnosed correctly and treated to prevent its considerable complications.

Evolution of Exchangeable Copper and Relative Exchangeable Copper through the Course of Wilson's Disease in the Long Evans Cinnamon Rat

Background Wilsons disease (WD) is an inherited disorder of copper metabolism leading to liver failure and/or neurological impairment. Its diagnosis often remains difficult even with genetic testing. Relative exchangeable copper (REC) has recently been described as a reliable serum diagnostic marker for WD. Methodology/Principal Findings The aim of this study was to validate the use of REC in the Long Evans Cinnamon (LEC) rat, an animal model for WD, and to study its relevance under different conditions in comparison with conventional markers. Two groups of LEC rats and one group of Long-Evans (LE) rats were clinically and biologically monitored from 6 to 28 weeks of age. One group of LEC rats was given copper-free food. The other groups had normal food. Blood samples were collected each month and different serum markers for WD (namely ceruloplasmin oxidase activity, exchangeable copper (CuEXC), total serum copper and REC) and acute liver failure (serum transaminases and bilirubinemia) were tested. Every LEC rat under normal food developed acute liver failure (ALF), with 40% global mortality. Serum transaminases and bilirubinemia along with total serum copper and exchangeable copper levels increased with the onset of acute liver failure. A correlation was observed between CuEXC values and the severity of ALF. Cut-off values were different between young and adult rats and evolved because of age and/or liver failure. Only REC, with values >19%, was able to discriminate LEC groups from the LE control group at every time point in the study. REC sensitivity and specificity reached 100% in adults rats. Conclusions/Significance REC appears to be independent of demographic or clinical data in LEC rats. It is a very simple and reliable blood test for the diagnosis of copper toxicosis owing to a lack of ATP7B function. CuEXC can be used as an accurate biomarker of copper overload.

A new surgical approach to improve gene transfer in liver using lentiviral vectors.

PURPOSE Metabolic inherited liver diseases are attractive targets for gene therapy. Recombinant lentiviruses are very powerful viral vectors able to infect nonmitotic cells. We wanted to develop a new surgical approach to improve gene transfer in adult liver using low viral doses. MATERIALS AND METHODS Adult rats were injected with 2.108 infectious particles of lentiviral vectors encoding the green fluorescent protein marker gene under control of a liver-specific promoter transthyretin. In the control group (n = 5), gene delivery was performed by inflow intraportal injection. In the surgical group (n = 5), liver was completely excluded from systemic circulation before viral injection in infrahepatic vena cava with high pressure. RESULTS At day 9, transduction efficiency was 14.35% in the surgical group 3 and 0.39% in the control group (P = .016). At month 2, the number of transduced hepatocytes decreased in the most part of rats, except in half of rats in the surgical group. Antibodies against green fluorescent protein were detected in all rats at month 2, except one in the surgical group. CONCLUSIONS We developed a new surgical approach allowing an efficient transduction of hepatocytes in adult rats using lentivirus at low viral doses. We have now to control the immune response to permit long-term expression of transgene.

Rapid and reliable diagnosis of Wilson disease using X-ray fluorescence

Wilsons disease (WD) is a rare autosomal recessive disease due to mutations of the gene encoding the copper‐transporter ATP7B. The diagnosis is hampered by the variability of symptoms induced by copper accumulation, the inconstancy of the pathognomonic signs and the absence of a reliable diagnostic test. We investigated the diagnostic potential of X‐ray fluorescence (XRF) that allows quantitative analysis of multiple elements. Studies were performed on animal models using Wistar rats (n = 10) and Long Evans Cinnamon (LEC) rats (n = 11), and on human samples including normal livers (n = 10), alcohol cirrhosis (n = 8), haemochromatosis (n = 10), cholestasis (n = 6) and WD (n = 22). XRF experiments were first performed using synchrotron radiation to address the elemental composition at the cellular level. High‐resolution mapping of tissue sections allowed measurement of the intensity and the distribution of copper, iron and zinc while preserving the morphology. Investigations were further conducted using a laboratory X‐ray source for irradiating whole pieces of tissue. The sensitivity of XRF was highlighted by the discrimination of LEC rats from wild type even under a regimen using copper deficient food. XRF on whole formalin‐fixed paraffin embedded needle biopsies allowed profiling of the elements in a few minutes. The intensity of copper related to iron and zinc significantly discriminated WD from other genetic or chronic liver diseases with 97.6% specificity and 100% sensitivity. This study established a definite diagnosis of Wilsons disease based on XRF. This rapid and versatile method can be easily implemented in a clinical setting.

What prenatal ultrasound features are predictable of complex or vanishing gastroschisis? A retrospective study

To evaluate prenatal ultrasound parameters as prognostic factors for complex and vanishing gastroschisis.

Early postpartum gastric band slippage after bariatric surgery in an adolescent obese girl

We report here a case of a rarely described complication of laparoscopic adjustable gastric banding (LAGB), slippage during the postpartum period, after LAGB had been performed in an adolescent obese girl. The LAGB had been placed after one year of clinical survey initiated at the age of 16. Maximal pre-operative body mass index (BMI) was 48.5 kg.m−2 and obesity was associated with insulin resistance. Before pregnancy, there was a loss of 17 Kg (final BMI = 41.5 kg.m−2) and a resolution of insulin resistance. The patient became pregnant 21 months after LAGB, and whole pregnancy and delivery were uneventful for both mother and fetus. Six weeks after delivery, the patient suddenly complained for total food intolerance, due to a band slippage, leading to removal of the band. Slippage is now a rare complication of LAGB, but can happen during pregnancy and the postpartum period as well.

Thoracic skeletal anomalies following surgical treatment of esophageal atresia. Lessons from a national cohort

INTRODUCTION Thoracotomy as surgical approach for esophageal atresia treatment entails the risk of deformation of the rib cage and consequently secondary thoracogenic scoliosis. The aim of our study was to assess these thoracic wall anomalies on a large national cohort and search for factors influencing this morbidity. MATERIALS AND METHODS Pediatric surgery departments from our national network were asked to send recent thoracic X-ray and operative reports for patients born between 2008 and 2010 with esophageal atresia. The X-rays were read in a double-blind manner to detect costal and vertebral anomalies. RESULTS Among 322 inclusions from 32 centers, 110 (34.2%) X-rays were normal and 25 (7.7%) displayed thoracic malformations, including 14 hemivertebrae. We found 187 (58.1%) sequelae of surgery, including 85 costal hypoplasia, 47 other types of costal anomalies, 46 intercostal space anomalies, 21 costal fusions and 12 scoliosis, with some patients suffering from several lesions. The rate of patients with these sequelae was not influenced by age at intervention, weight at birth, type of atresia, number of thoracotomy or size of the center. The rate of sequelae was higher following a classical thoracotomy (59.1%), whatever the way that thoracotomy was performed, compared to nonconverted thoracoscopy (22.2%; p=0.04). CONCLUSION About 60 % of the patients suffered from a thoracic wall morbidity caused by the thoracotomy performed as part of surgical treatment of esophageal atresia. Minimally invasive techniques reduced thoracic wall morbidity. Further studies should be carried out to assess the potential benefit of minimally invasive approaches to patient pulmonary functions and on the occurrence of thoracogenic scoliosis in adulthood. LEVELS OF EVIDENCE Level III retrospective comparative treatment study.

Bariatric surgery in adolescents with severe obesity: Review and state of the art in France

Severe obesity (body mass index>120% of BMI IOTF-30 cut off) and morbid obesity (BMI>140% of BMI IOTF-30 cut off) affect 5 to 10% of obese adolescents in France. Organic complications can be found in about 50% of these patients, and depressive symptoms in one-third of them. Finally, over 70% will suffer from adult morbid obesity associated with a marked increase in morbidity and mortality. However, the reversion of obesity strongly decreases, and may even cancels, these risks. In controlled randomized studies, lifestyle interventions have limited effectiveness on BMI in children (and none in adolescents). Bariatric surgery has been shown to have short-term effectiveness in adolescents with severe and morbid obesity: the average BMI loss after gastric banding was 11.6kg/m2 (95% confidence interval from 9.8 to 13.4), 16.6kg/m2 (95% confidence interval from 13.4 to 19.8) after bypass, and 14.1kg/m2 (95% confidence interval 10.8 to 17.5) after sleeve gastrectomy. The resolution of comorbidities was the main aim, as well as the improvement of quality of life. This is not a simple surgical intervention, and minor side effects have been reported in approximately 10-15% of teenagers who underwent surgery (more common with the gastric band), and severe side effects in nearly 1-5% (mainly with bypass). In France, recommendations regarding indications, the care pathway, multidisciplinary meetings, reference management structures and postoperative care have been published by the French National Health Authority (HAS) in 2016 to provide a framework for bariatric surgery in underage patients.

Transient Increase in Intrahepatic Pressure Mediates Successful Treatment of the Gunn Rat with Reduced Doses of Lentiviral Vector

Lentiviral vectors can stably transduce hepatocytes and are promising tools for gene therapy of hepatic diseases. Although hepatocytes are accessible to blood-borne viral vectors through fenestrations of the hepatic endothelium, improved liver transduction after delivery of vectors to the blood stream is needed. As the normal endothelial fenestration and lentiviral vectors are similar in size (150 nm), we hypothesized that a transient increase in hepatic blood pressure may enhance in vivo gene transfer to hepatocytes. We designed a simple surgical procedure, by which the liver is temporarily excluded from blood flow. Lentiviral vectors were injected in a large volume to increase intrahepatic pressure. We demonstrated that in the Gunn rat, a model of Crigler-Najjar disease, the administration of low vector doses (corresponding to a multiplicity of infection of 0.2) by this procedure resulted in therapeutic correction of hyperbilirubinemia, without toxicity. The correction was sustained for 10 months (end of study). The same vector amounts yielded only partial correction after intraportal delivery. We believe that this new and clinically applicable strategy may broaden the range of genetic liver diseases accessible to gene therapy.