Sophie Branchereau

Hepatic Stem-like Phenotype and Interplay of Wnt/β-Catenin and Myc Signaling in Aggressive Childhood Liver Cancer

Hepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.

Laparoscopic Left Lateral Sectionectomy in Living Donors: Safety and Reproducibility of the Technique in a Single Center

Background Data and Objective:Left lateral sectionectomy for liver transplantation in children performed through laparoscopy is an innovative procedure that was developed by considering our acquired experience in both laparoscopic liver resection and graft harvesting in living donors. The main goal was to minimize donor morbidity while preserving the abdominal wall. Herein, we report the technical feasibility and reproducibility, and compared it with open liver resection (OLR). Methods:Sixteen successive donors underwent a laparoscopic liver resection (LLR) from 2001 to 2005. They were compared with 14 other donors who underwent a standard open liver resection (OLR) during a first period (1998–2004). First, this report describes the technical features of laparoscopic resection. Second, perioperative morbidity and graft characteristics were compared according to the use or not of the laparoscopic approach. Results:Laparoscopic harvesting was successfully performed in 15 of 16 cases in an intention-to-treat basis. One conversion was required to ensure the quality of the laparoscopic repair of a left portal vein injury occurring during the pedicle dissection. No specific complication related to laparoscopy was observed. As compared with OLR, the operation was longer (320 ± 67 vs. 244 ± 55 minutes, P < 0.005). The blood loss was significantly lower in the LLR group (18.7 ± 44.2 vs. 199.2 ± 185.4 mL, P < 0.005). The morbidity rate was similar in both groups (18.7% in LLR vs. 35.7% in OLR). One donor in the LLR group experienced a bile leak treated by redo laparoscopy. Grafts were anatomically similar irrespective of the use of laparoscopy. The duration of hospital stay and use of self-infused morphine pump was not different between the 2 groups. Conclusion:Left lateral section harvesting by laparoscopy is a safe and reproducible procedure, allowing to obtain similar grafts as compared with laparotomy and can therefore be recommended to transplant centers that have previous experience in laparoscopic liver resection.

Activation of β-catenin in epithelial and mesenchymal hepatoblastomas

Wnt/β-catenin signaling is frequently activated in cancer cells by stabilizing mutations of β-catenin or loss-of-function mutations of the APC tumor suppressor gene. We have analysed the role of β-catenin in the pathogenesis of hepatoblastoma (HB), an embryonic liver tumor occurring mainly in children under 2 years of age. Sequence analysis of the β-catenin NH2-terminal domain in 18 epithelial and mixed HBs revealed missense mutations in the GSK3β phosphorylation motif or interstitial deletions in 12 tumors (67%). In the remaining cases, no truncating mutation of APC could be evidenced. Immunohistochemical analysis of β-catenin in 11 HBs demonstrated nuclear/cytoplasmic accumulation of the protein in all tumors analysed, with predominant nuclear β-catenin immunostaining in undifferentiated cells. Membranous β-catenin localization was preserved only in fetal-type tumoral hepatocytes and was associated with E-cadherin expression. Moreover, we show that β-catenin is aberrantly overexpressed in a large spectrum of tumor components, including hepatocyte-like cells at various differentiation stages and heterologous elements such as squamous, osteoid and chrondroid tissues, and in occasional other mesenchymally-derived cells. These data strongly suggest that activation of β-catenin signaling is an obligatory step in HB pathogenesis, and raise the possibility that it interferes with developmental signals that specify different tissue types at early stages of hepatic differentiation.

ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history

Progressive familial intrahepatic cholestasis (PFIC) types 1 and 2 are characterized by normal serum gamma‐glutamyl transferase (GGT) activity and are due to mutations in ATP8B1 (encoding FIC1) and ABCB11 (encoding bile salt export pump [BSEP]), respectively. Our goal was to evaluate the features that may distinguish PFIC1 from PFIC2 and ease their diagnosis. We retrospectively reviewed charts of 62 children with normal‐GGT PFIC in whom a search for ATP8B1 and/or ABCB11 mutation, liver BSEP immunostaining, and/or bile analysis were performed. Based on genetic testing, 13 patients were PFIC1 and 39 PFIC2. The PFIC origin remained unknown in 10 cases. PFIC2 patients had a higher tendency to develop neonatal cholestasis. High serum alanine aminotransferase and alphafetoprotein levels, severe lobular lesions with giant hepatocytes, early liver failure, cholelithiasis, hepatocellular carcinoma, very low biliary bile acid concentration, and negative BSEP canalicular staining suggest PFIC2, whereas an absence of these signs and/or presence of extrahepatic manifestations suggest PFIC1. The PFIC1 and PFIC2 phenotypes were not clearly correlated with mutation types, but we found tendencies for a better prognosis and response to ursodeoxycholic acid (UDCA) or biliary diversion (BD) in a few children with missense mutations. Combination of UDCA, BD, and liver transplantation allowed 87% of normal‐GGT PFIC patients to be alive at a median age of 10.5 years (1‐36), half of them without liver transplantation. Conclusion: PFIC1 and PFIC2 differ clinically, biochemically, and histologically at presentation and/or during the disease course. A small proportion of normal‐GGT PFIC is likely not due to ATP8B1 or ABCB11 mutations. (HEPATOLOGY 2010)

Complications of Congenital Portosystemic Shunts in Children: Therapeutic Options and Outcomes

Background and Objective: Congenital portosystemic shunts are rare vascular malformations that lead to severe complications. Their management is controversial. The aim of this study was to propose a clear definition of the risks and management of congenital portosystemic shunts in children according to our experience and a review of the literature. Patients and Methods: Twenty-two children with a complicated congenital portosystemic shunt were studied in our institution. When necessary, management included portal pressure measurement and portal vein angiography during an occlusion test and closure of the shunt by surgical and/or endovascular methods. Results: Five neonates with intrahepatic shunts presented with cholestasis that resolved spontaneously, and 17 older children presented with liver tumors (13) and/or hepatopulmonary syndrome (2), pulmonary artery hypertension (3), portosystemic encephalopathy (3), heart failure (1), and glomerulonephritis (1). The portosystemic shunt was extrahepatic (11) or intrahepatic (6). Portosystemic shunts were closed by endovascular methods in 5 children and surgically in 10, 4 of whom had portal pressure during occlusion above 35 mmHg and extremely hypoplastic or undetectable portal veins requiring banding of the fistula before closure. Shunt closure resulted in restoration of intrahepatic portal flow in all, with complete or partial regression of benign liver masses, and regression or stabilization of pulmonary, cardiac, neurological, and renal complications. Conclusions: Congenital portosystemic shunt carries risks of severe complications in children. Closure of a shunt persisting after age 2 years should be considered preventively. Intrahepatic portal flux restoration can be expected, even when intrahepatic portal veins are extremely hypoplastic or undetectable.

Congenital Portosystemic Shunts in Children: Recognition, Evaluation, and Management

Congenital portosystemic shunts are present in one in 30,000 children. Among the associated risks of severe complications are neonatal cholestasis, benign and malignant liver tumors, hepatopulmonary syndrome, portopulmonary hypertension, and encephalopathy. They can be detected on prenatal ultrasonograms, during the investigation of a positive galactosemia screening test in neonates or of a complication, or be found fortuitously on an abdominal ultrasound. Small intrahepatic shunts may resolve spontaneously within one year of age, but other shunts such as extrahepatic, persistent ductus venosus or persisting intrahepatic shunts, must be closed in one or two steps, by interventional radiology techniques or surgically. The plasticity of the intrahepatic portal system allows revascularization of the liver after shunt closure, even when no intrahepatic portal structures can be detected on imaging studies. This leaves little or no place for liver transplantation in the management of these children.

Conservative surgery plus brachytherapy treatment for boys with prostate and/or bladder neck rhabdomyosarcoma: a single team experience

PURPOSE The aim of this study is to report the results of a conservative surgery + brachytherapy treatment for boys with prostate and/or bladder-neck rhabdomyosarcoma avoiding total cystectomy or prostatectomy and external radiotherapy. PATIENTS From 1991 to 2007, 26 boys were operated for a residual mass after chemotherapy (1 for local relapse). All patients underwent a conservative surgical procedure, with bladder-neck and urethra preservation. Surgery was never microscopically complete. Brachytherapy was systematically performed after tumor resection, as a perioperative procedure, consisting of 2 loops encompassing the prostate and the bladder-neck area. A dose of 60 Gy was delivered with low dose rate. Bladder function was evaluated clinically and with urodynamic study for boys with abnormal continence. RESULTS Median age at operation was 23 months (9 months-11 years). Seventeen boys underwent a partial prostatectomy associated in 5 with a partial cystectomy. The remaining 9 patients underwent a partial cystectomy with no procedure at the level of the prostate. At a median follow-up of 4 years (10 months-14.5 years), 24 of 26 boys are alive. Only 1 patient relapsed locally out of the brachytherapy field and died. A second boy died from metastatic relapse. Only 1 patient with bladder dysfunction after treatment underwent a total cystectomy. Four patients are too young to be evaluated for bladder function (<4 years of age). Seven patients, aged 4 to 6 years, have daytime continence, 1 has diurnal dribbling. Among 11 boys older than 6 years, 9 (82%) are normally continent (3 after temporary dribbling), 2 have diurnal dribbling treated by bladder education. CONCLUSION Even if very long-term sequelae of brachytherapy cannot be evaluated, this conservative combined treatment may allow normal continence in nearly all patients, even after temporary diurnal incontinence and should be discussed as an alternative to external radiotherapy or radical surgery.

Long term results of liver transplantation for Wilson’s disease: Experience in France

BACKGROUND & AIMS Liver transplantation (LT) is the therapeutic option for severe complications of Wilsons disease (WD). We aimed to report on the long-term outcome of WD patients following LT. METHODS The medical records of 121 French patients transplanted for WD between 1985 and 2009 were reviewed retrospectively. Seventy-five patients were adults (median age: 29 years, (18-66)) and 46 were children (median age: 14 years, (7-17)). The indication for LT was (1) fulminant/subfulminant hepatitis (n = 64, 53%), median age = 16 years (7-53), (2) decompensated cirrhosis (n = 50, 41%), median age = 31.5 years (12-66) or (3) severe neurological disease (n = 7, 6%), median age = 21.5 years (14.5-42). Median post-transplant follow-up was 72 months (0-23.5). RESULTS Actuarial patient survival rates were 87% at 5, 10, and 15 years. Male gender, pre-transplant renal insufficiency, non elective procedure, and neurological indication were significantly associated with poorer survival rate. None of these factors remained statistically significant under multivariate analysis. In patients transplanted for hepatic indications, the prognosis was poorer in case of fulminant or subfulminant course, non elective procedure, pretransplant renal insufficiency and in patients transplanted before 2000. Multivariate analysis disclosed that only recent period of LT was associated with better prognosis. At last visit, the median calculated glomerular filtration rate was 93 ml/min (33-180); 11/93 patients (12%) had stage II renal insufficiency and none had stage III. CONCLUSIONS Liver failure associated with WD is a rare indication for LT (<1%), which achieves an excellent long-term outcome, including renal function.

The Long‐Term Outcome of Hepatic Artery Thrombosis After Liver Transplantation in Children: Role of Urgent Revascularization

Hepatic artery thrombosis (HAT), one of the most severe complications of pediatric orthotopic liver transplantation (OLT), often compromises graft and/or child survival. Of 590 OLT performed in 516 children over a 20‐year period, 45 were complicated by early HAT, during the first 2 weeks after transplantation. Systematic Doppler ultrasonographic detection of HAT allowed successful surgical revascularization in 19 instances, resulting in a 20‐year graft survival rate of 77% versus 24% of cases when revascularization was not attempted or failed. A combination of surgical emergency revascularization, biliary interventional radiology, biliary surgery and/or retransplantation resulted in an 80% 20‐year patient survival rate, identical to that of transplanted children who did not experience early HAT. The majority of long‐term survivors with their initial graft had normal liver tests, no biliary dilation on ultrasonography and minimal or moderate fibrosis on liver histology. A failed attempt at revascularization did not significantly alter patient survival. Despite these encouraging results, for the children and their parents to overcome the entire process in terms of reoperations, repeated radiological interventions, number of hospitalizations and emotional stress, remains an ordeal of such magnitude that it justifies renewed efforts to progress in the prevention of this complication.

Congenital portosystemic shunts in children: a new anatomical classification correlated with surgical strategy.

Objective:To propose an anatomical classification of congenital portosystemic shunts (CPSs) correlating with conservative surgery. Background:CPSs entail a risk of life-threatening complications because of poor portal inflow, which may be prevented or cured by their closure. Current classifications based on portal origin of the shunt are not helpful for planning conservative surgery. Methods:Twenty-three patients who underwent at least 1 surgical procedure to close the CPSs were included in this retrospective study (1997–2012). We designed a classification according to the ending of the shunt in the caval system. We analyzed the results and outcomes of surgery according to this classification. Results:Two patients had an extrahepatic portosystemic shunt, 17 had a portacaval shunt [subdivided in 5 end-to-side–like portal-caval, 7 side-to-side–like portal-caval, and 5 H-shaped (H-type portal-caval)], 2 had portal-to-hepatic vein shunts (portohepatic), and 2 had a persistent ductus venosus. All extrahepatic portosystemic shunts, H-type portal-caval, portohepatic, and patent ductus venosus patients had a successful 1-stage ligation. All 5 end-to-side–like portal-caval patients had a threadlike intrahepatic portal venous system; a 2-stage complete closure was successfully achieved for 4 and a partial closure for 1. The first 2 side-to-side–like portal-caval patients had a successful 2-stage closure whereas the 5 others had a 1-stage longitudinal caval partition. All patients are alive and none needed a liver transplantation. Conclusions:Our classification correlates the anatomy of CPSs and the surgical strategy: outcomes are good provided end-to-side–like portal-caval shunts patients have a 2-stage closure, side-to-side portal-caval shunts patients have a 1-stage caval partition, and the others have a 1-stage ligation.