Long-term follow-up after retrosternal ileocolic esophagoplasty in two cases of long-gap esophageal atresia: why it is still a valid option as a rescue strategy

IntroductionEsophageal replacement surgery in children is sometimes necessary for long-gap esophageal atresia. Ileocolic esophagoplasty in the retrosternal space can serve as a good alternative technique in case of hostile posterior mediastinum. We present two cases of successful ileocolic transposition performed at 6 months of age.MethodsEsophageal replacement was performed through a midline laparotomy incision associated with a left cervical approach. The ileocolic transplant was pediculized on the right superior colic artery after ligating the right colic and ileocolic vessels. A retrosternal tunnel was created, and the ileocolic transplant pulled through it to reach the cervical region. Proximally, esophageal-ileal anastomosis and, distally, colonic–gastric anastomosis were performed. Ileocolic continuity was repaired.ResultsThere were no early postoperative complications. In both cases, the patients presented oral feeding difficulties during the first 6 postoperative months. Thereafter, full oral feeding was achieved, and both patients were clinically asymptomatic during the following 18 and 20 years, respectively, with satisfactory oral radiological assessments, showing no redundancy or inappropriate growth of the graft and no anastomotic stricture. Currently, these patients do not complain of dysphagia, pathological reflux, or respiratory symptoms.ConclusionWhen native esophagus preservation in long-gap esophageal atresia is estimated unfeasible, ileocolic transposition in the retrosternal space might be considered a good and safe option, particularly in those difficult cases after multiple previous surgical attempts and mediastinitis. This technique is putatively associated with a beneficial anti-reflux effect, thanks to the presence of the ileocecal valve, in preventing cervical peptic esophagitis. Long-term follow-up confirms that the transposed colon in the retrosternal space did not suffer any abnormal modification in size and growth

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

Inherited pancreatic exocrine insufficiency and pancreatitis: When children transition to adult care

Hereditary pancreatitis (HP) encompasses two distinct disease groups: the first manifests as congenital exocrine pancreatic insufficiency (EPI), and the second includes hereditary forms of pancreatitis. EPI represents the ultimate expression of gland function loss. Cystic fibrosis is by far the most frequent aetiology of early-onset EPI; genetics and a growing understanding of the disease mechanisms have paved the way for innovative and personalized treatment approaches. Efforts are ongoing to further decipher the pathophysiology and explore new therapies for other causes of EPI. HP occurs in patients carrying mutations in genes encoding digestive proteases or proteins playing an important role in proper pancreatic function and homeostasis. Improved sequencing techniques have led to the discovery of several causal and disease promoting genes. Most forms of HP have a paediatric onset but complications usually manifest during adulthood. Surveillance in experienced centres is mandatory to diagnose and address these complications in a timely manner

Characterization of human derived liver progenitor cells and mesenchymal stem cells for their risk of malignant transformation

The last decade, stem cell therapy has raised much hope to treat patients presenting a variety of end-stage diseases. These promising results are sustained by the physiologic role of stem cells in tissue development and repair. Despite the enthusiasm, essential stability questions may not be overlooked and need to be assessed on the route to clinic. In the present study, we analyzed, both in vitro and in vivo, the phenotype and genotype stability of stem/progenitor cells issued from human bone marrow, Wharton jelly and liver during long-term culture. We observed that the proliferation potential of stem/progenitor cells was variable between donors; and decreased with time in culture. Cells progressively displayed senescent features, which were however acquired earlier in progenitor cells compared to bone marrow and umbilical cord derived mesenchymal stem cells. Differential sensitivity to oxidative stress, related to hyperoxic culture conditions and overexposure to mitogens, may explain these differences. The phenotype characteristics of stem cells remained stable over time. UCMSC, BMMSC and ADHLPC were able to differentiate in hepatocyte-like cells; which was demonstrated by enhanced mature hepatic functionality features. Nevertheless, the hepatocyte-like differentiation potential was incomplete for all cell types as their phenotype remains chimerical for mesenchymal and hepatic epithelial markers. Furthermore, the ability to differentiate into multilineage seems to decrease with time. Umbilical cord and bone marrow derived mesenchymal stem cells had normal karyotypes and cell cycle regulation genes were appropriately upregulated according to senescence. Some ADHLPC cultures displayed random cytogenetic instability at later passages. Aneuploidy was most likely driven by culture stress. These findings were correlated to an early decrease in growth potential, upregulation of cell cycle regulation genes and premature senescence. Moreover, karyotypic changes do not confer selective growth advantage in vitro to cells that carry them. Instead, cells seem to undergo apoptosis. All these characteristics suggest that ADHLPC carrying cytogenetic instability demonstrate the capacity to regulate their cell cycle and induce premature senescence as a potent mechanism against transformation.(MED 3) -- UCL, 201

Survival benefit for individuals with constitutional mismatch repair deficiency syndrome and brain tumors who undergo surveillance protocol. a report from the international replication repair consortium

METHODS: We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS: Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION: These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors

Congenital etiologies of exocrine pancreatic insufficiency.

Congenital exocrine pancreatic insufficiency is a rare condition. In a vast majority of patients, exocrine dysfunction occurs as part of a multisystemic disease, the most prevalent being cystic fibrosis and Shwachman-Bodian-Diamond syndrome. Recent fundamental studies have increased our understanding of the pathophysiology of these diseases. Exocrine pancreatic dysfunction should be considered in children with failure to thrive and fatty stools. Treatment is mainly supportive and consists of pancreatic enzyme replacement and liposoluble vitamins supplementation

Stem and progenitor cells for liver regenerative medicine

Orthotopic liver transplantation is the gold standard treatment for end stage liver disease or inborn errors of liver metabolism. However organ shortage, severity of the surgical procedure and risks related to graft loss have stimulated the exploration of less invasive strategies. Liver cell transplantation has demonstrated short to medium-term efficacy in correcting inborn errors of metabolism and could offer a valuable bridging treatment for patients with acute liver failure awaiting liver transplant. However, hepatocyte transplantation in the clinic has shown important limitations including transient effect of donor cells, low proportion of engraftment and repopulation, poor resistance of hepatocytes to cryopreservation procedures and also shortage of procurement. Thus while hepatocyte transplantation remains a promising alternative to liver transplantation, replacement of hepatocytes by proliferating stem cells seems likely to circumvent many of the aforementioned obstacles. Building on the demonstration that various stem and progenitor cells can differentiate in vitro and in vivo into hepatocyte-like cells, these cells are now being investigated as an alternative to hepatocytes in liver regenerative medicine. In this study, we concentrate on cells sourced from human adult tissues only as the use of embryonic or fetal material still faces major ethical, safety and/or feasibility concerns. We summarize here the major progresses that have been achieved as regards the isolation and characterization of potential stem and progenitor cell candidates for liver cell therapies both from intra-and extra-hepatic sources. We also discuss animal transplantation data as well as considerations about the carcinogenic risk of such cell therapies. © 2012 The authors and IOS Press. All rights reserve