Biliary and duodenal complications after « en bloc¼ liver-small bowel transplantation in children. A single center cohort study.

BACKGROUND: The technique of « en bloc¼ liver and small bowel transplantation (L-BT) spares a biliary anastomosis, but does not protect against biliary complications. We analyze biliary and duodenal complications (BDC) in our pediatric series. METHODS: Between 1994 and 2020, 54 L-BT were performed in 53 children. The procurement technique included in situ vascular dissection and pancreatic reduction to the head until 2009 (group A). Thereafter, the whole pancreas was recovered (group B). RESULTS: Nine BDCs occurred in 8/53 (15%) patients (7 in group A and 1 in group B): leak of the donor's duodenal stump (2), stenosis of the extra-pancreatic bile duct (5), and intra-pancreatic bile duct stenosis (2). Median delay for diagnosis of stricture was 8 months (4-168). Interventional radiology was successful in one child only, the others required reoperations. Two patients died, of biliary cirrhosis or cholangitis, 15-month and 12-year post-L-BT. One was listed and liver re-transplanted 13 years post-L-BT. At last follow-up, two patients only had normal liver tests and ultrasound. CONCLUSION: BDC after L-BT can cause severe morbidities. Pancreatic reduction might increase this risk. Early surgical complications or chronic pancreatic rejection might be co-factors. Early diagnosis and treatment are key to the long-term prognosis.

Tumor rupture in hepatoblastoma: A high risk factor?

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.

Establishing local diagnostic reference levels for pediatric percutaneous transhepatic cholangiography interventions and optimizing the routine practice.

BACKGROUND: Liver-transplanted, immunosuppressed pediatric patients undergoing repeated percutaneous transhepatic cholangiography (PTC) require optimized exposure to ionizing radiation. OBJECTIVE: To establish local diagnostic reference levels (DRL) for pediatric PTC and investigate the routine use of X-ray equipment. MATERIALS AND METHODS: The study retrospectively analyzed data collected between October 2016 and June 2018 from a single center performing PTC. We collected exposure parameters including kerma area product (PKA), air kerma at patient entrance reference point (Ka,r) and fluoroscopy time via a dose archiving and communication system. Local diagnostic reference levels were derived as the 50th percentile of the distributions while considering published recommended weight groups. We investigated exposure variability with procedure complexity and with technical parameters recovered from the radiation dose structured report. RESULTS: The analysis included 162 PTC procedures performed in 64 children: 58% male, average age 6 years (range 39 days to 16 years) and weight 24 kg (range 3-60 kg). Local DRLs for weight groups 0-5 kg, 5-15 kg, 15-30 kg, 30-50 kg and 50-80 kg were, respectively, 6 cGy.cm2, 22 cGy.cm2, 68 cGy.cm2, 107 cGy.cm2 and 179 cGy.cm2 in PKA. Local DRLs per weight group were also established for intermediate and complex procedures. Radiation dose structured report analysis highlighted good local practice with efficient collimation, low fluoroscopy pulse rate, no magnification and limited use of radiographic acquisitions. Meanwhile, table and detector positioning and tube projection could still be optimized. PKA correlated significantly with the number of acquisitions and tube-to-table distance. CONCLUSION: We established local DRLs for children undergoing PTC.

Diagnosis, treatment and outcome of hepatic venous outflow obstruction in paediatric liver transplantation: 24-year experience at a single centre.

BACKGROUND: Hepatic venous outflow obstruction after paediatric liver transplantation is an unusual but critical complication. OBJECTIVES: To review the incidence, diagnosis and therapeutic modalities of hepatic venous outflow obstruction from a large national liver transplant unit. MATERIALS AND METHODS: During the period from October 1992 to March 2016, 917 liver transplant procedures were performed with all types of grafts in 792 children. Transplants suspected to have early or delayed venous outflow obstruction were confirmed by percutaneous venography or surgical revision findings. Therapeutic intervention, recurrence and outcome were evaluated. RESULTS: Twenty-six of 792 children (3.3%) experienced post-transplant hepatic venous outflow obstruction. These patients had been diagnosed from 1 day to 8.75 years after transplantation. Six occurred during the early post-transplant period; in three of them, the graft was lost. Seventeen patients were initially treated by balloon angioplasty with success; 11 of these experienced recurrences. Four stents were implanted; one was complicated by definitive occlusion. Three of the five surgical revisions were successful. The initial stenosis involved the inferior vena cava in 10 grafts, in isolation or associated with hepatic vein involvement. Mean follow-up was 79 months after transplantation. Eight grafts were lost. CONCLUSION: Acute postoperative hepatic venous outflow obstruction was associated with poor prognosis. Diagnostic venography should be performed if there is any suspicion of venous outflow obstruction, even if first-line examinations are normal. Stenosis frequently involved the inferior vena cava. Angioplasty was a safe and efficient treatment for venous outflow obstruction despite frequent recurrence.

The porta hepatis microcyst: an additional sonographic sign for the diagnosis of biliary atresia.

OBJECTIVES: To describe and evaluate an additional sonographic sign in the diagnosis of biliary atresia (BA), the microcyst of the porta hepatis, in comparison with previously described signs. METHODS: Ultrasound performed in 321 infants (mean age 55 days) with cholestasis were retrospectively analyzed. BA was surgically confirmed in 193 patients and excluded in 128. US evaluated gallbladder type (1: normal; 2: consistent with BA; 3: suspicious), triangular cord sign (TCS), microcyst and macrocyst, polysplenia syndrome, portal hypertension, and bile duct dilatation. T test and Pearson χ2 test were used to compare US signs between the two groups, followed by univariate regression analysis. RESULTS: The highest specificity and sensitivity for BA (p < 0.001) were respectively obtained with non-visible gallbladder (100 %-13 %), macrocyst (99 %-10 %), polysplenia (99 %-11 %), microcyst (98 %-20 %), type 2 gallbladder (98 %-34 %), and TCS (97 %-30 %). Combination of signs (macro or microcyst; cyst and no bile duct dilatation; microcyst and/or TCS; type 2 gallbladder and/or cyst) provided better sensitivities (25-49 %) with similar specificities (95-98 %) (p < 0.001). On univariate analysis, the single US signs most strongly associated with BA were polysplenia (odds ratio, OR 16.3), macrocyst (OR 14.7), TCS (OR 13.4) and microcyst (OR 8). CONCLUSIONS: Porta hepatis microcyst is a reliable US sign for BA diagnosis. KEY POINTS: • The porta hepatis microcyst is a specific sign of biliary atresia. • It was found in 31 (16.1 %) of 193 patients with biliary atresia. • Its specificity was 98 % (p < 0.001). • High frequency transducer and color Doppler can show the porta hepatis microcyst.

Abdominal Arterial Anomalies in Children With Alagille Syndrome: Surgical Aspects and Outcomes of Liver Transplantation.

OBJECTIVES: Angiogenic defects secondary to gene mutations of JAG1 and NOTCH2, causing arterial anomalies in Alagille syndrome (AGS), are well described in the literature. The study analyzes the frequency of abdominal arterial anomalies in children with AGS with an emphasis on outcomes following liver transplantation (LT). METHODS: Between 1988 and 2013, 242 children with AGS were treated at our institution. We performed a retrospective analysis of 55 who underwent LT during the study period. Preoperative abdominal arterial findings, operative reports, arterial reconstruction technique, and early as well as late complications following LT were reviewed specifically focusing on arterial thrombosis. RESULTS: Twenty-five patients had preoperative imaging available for analysis. Twelve of these patients showed celiac trunk stenosis (48.0%), 2, a superior mesenteric artery stenosis (8.0%) and one a stenosis of both renal arteries. Twenty patients (36.3%) underwent standard hepatic reconstruction using the native recipient hepatic artery. Thirty-five patients (63.7%) underwent aortic conduit reconstruction (ACR) from the infrarenal aorta using donor arterial conduits. Hepatic artery thrombosis occurred in 9 patients (16.3%). This number was higher in the standard arterial anastomosis group 7/20 (35.0%) than in those with ACR 2/35 (5.7%, P = 0.0079). CONCLUSIONS: In this series, children with AGS pretransplant have a high prevalence of abdominal arterial anomalies. Preoperative abdominal vascular imaging makes it possible to anticipate whether or not a classical arterial revascularization can be performed or whether an ACR is required.

DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis.

Neonatal sclerosing cholangitis (NSC) is a rare biliary disease leading to liver transplantation in childhood. Patients with NSC and ichtyosis have already been identified with a CLDN1 mutation, encoding a tight-junction protein. However, for the majority of patients, the molecular basis of NSC remains unknown. We identified biallelic missense mutations or in-frame deletion in DCDC2 in four affected children. Mutations involve highly conserved amino acids in the doublecortin domains of the protein. In cholangiocytes, DCDC2 protein is normally located in the cytoplasm and cilia, whereas in patients the mutated protein is accumulated in the cytoplasm, absent from cilia, and associated with ciliogenesis defect. This is the first report of DCDC2 mutations in NSC. This data expands the molecular spectrum of NSC, that can be considered as a ciliopathy and also expands the clinical spectrum of the DCDC2 mutations, previously reported in dyslexia, deafness, and nephronophtisis.

Feasibility and Diagnostic Accuracy of Supersonic Shear-Wave Elastography for the Assessment of Liver Stiffness and Liver Fibrosis in Children: A Pilot Study of 96 Patients.

PURPOSE: To evaluate the feasibility of using supersonic shear-wave elastography (SSWE) in children and normal values of liver stiffness with the use of control patients of different ages (from neonates to teenagers) and the diagnostic accuracy of supersonic shear wave elastography for assessing liver fibrosis by using the histologic scoring system as the reference method in patients with liver disease, with a special concern for early stages of fibrosis. MATERIALS AND METHODS: The institutional review board approved this prospective study. Informed consent was obtained from parents and children older than 7 years. First, 51 healthy children (from neonate to 15 years) were analyzed as the control group, and univariate and multivariate comparisons were performed to study the effect of age, transducer, breathing condition, probe, and position on elasticity values. Next, 45 children (from 1 month to 17.2 years old) who underwent liver biopsy were analyzed. SSWE measurements were obtained in the same region of the liver as the biopsy specimens. Biopsy specimens were reviewed in a blinded manner by a pathologist with the use of METAVIR criteria. The areas under the receiver operating characteristics curve (AUCs) were calculated for patients with fibrosis stage F0 versus those with stage F1-F2, F2 or higher, F3 or higher, and F4 or higher. RESULTS: A successful rate of SSWE measurement was 100% in 96 patients, including neonates. Liver stiffness values were significantly higher when an SC6-1 probe (Aixplorer; SuperSonic Imagine SA, Aix-enProvence, France) was used than when an SL15-4 probe (Aixplorer) was used (mean ± standard deviation, 6.94 kPa ± 1.42 vs 5.96 kPa ± 1.31; P = .006). There was no influence of sex, the location of measurement, or respiratory status on liver elasticity values (P = .41-.93), although the power to detect such a difference was low. According to the degree of liver fibrosis at liver biopsy, 88.5%-96.8% of patients were correctly classified, with AUCs of 0.90-0.98 (95% confidence interval [CI]: 0.8, 1.0). The AUC for patients with stage F0 versus stage F1-F2 was 0.93 (95% CI: 0.87, 0.99). CONCLUSION: SSWE allows accurate assessment of liver fibrosis, even in children with early stage (F1-F2) disease, and the choice of transducer influences liver stiffness values.

Imaging features of undifferentiated embryonal sarcoma of the liver: a series of 15 children.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver is a rare malignant mesenchymal tumour occurring mostly in children ages 6-10 years. The discrepancy between its solid appearance on US and cystic-like appearance on CT has been described. OBJECTIVE: To study the imaging particularities and similarities among our cases of undifferentiated embryonal sarcoma and to report the errors in initial diagnoses. MATERIALS AND METHODS: We conducted a retrospective study of 15 children with undifferentiated embryonal sarcoma diagnosed or referred to our hospital during 1997-2015 and analysed the clinical, biological and imaging data. RESULTS: We identified eight boys and seven girls ages 9 months to 14 years. Ten children presented with abdominal pain. Alpha-fetoprotein was slightly increased in one. Initial US and CT had been performed for all, while additional MRI had been done in two children. Initial CT demonstrated a hypoattenuated mass in all. Rupture was seen in five and intratumoural bleeding in seven children. Tumour volumes reduced during neoadjuvant chemotherapy in 10 children. CONCLUSION: Undifferentiated embryonal sarcoma might be suggested in a non-secreting unifocal tumour with well-defined borders, fluid-filled spaces on US, hypoattenuation and serpiginous vessels on CT, and if there are signs of internal bleeding or rupture on CT or MRI.

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.

Obliterative portal venopathy: a study of 48 children.

Childhood obliterative portal venopathy presents at any age and may be genetic in origin. We report 48 children with obliterative portal venopathy, based on strict histologic criteria, investigated between 1972 and 2011. Diagnosis requires histology and is suggested by ultrasonography findings. Portal hypertension is the main complication but is absent in some cases. Prognosis is relatively good, but the detection of cardiopulmonary complications is essential.

Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study.

BACKGROUND: The objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma. METHODS: SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with either metastatic disease, tumour in all liver segments, abdominal extrahepatic disease, major vascular invasion, low α fetoprotein, or tumour rupture were eligible. Treatment consisted of preoperative chemotherapy (cycles A1-A3: cisplatin 80 mg/m(2) per day intravenous in 24 h on day 1; cisplatin 70 mg/m(2) per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m(2) per day intravenous in 24 h on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumour lesions if feasible (including liver transplantation and metastasectomy, if needed). Patients whose tumour remained unresectable received additional preoperative chemotherapy (cycle B: doxorubicin 25 mg/m(2) per day in 24 h on days 1-3 and 22-24, and carboplatin area under the curve [AUC] 10·6 mg/mL per min per day intravenous in 1 h on days 1 and 22) before surgery was attempted. After surgery, postoperative chemotherapy was given (cycle C: doxorubicin 20 mg/m(2) per day in 24 h on days 1, 2, 22, 23, 43, and 44, and carboplatin AUC 6·6 mg/mL per min per day in 1 h on days 1, 22, and 43) to patients who did not receive cycle B. The primary endpoint was the proportion of patients with complete remission at the end of treatment. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00077389. FINDINGS: We report the final analysis of the trial. 62 eligible patients (39 with lung metastases) were included and analysed. 60 (98%, 95% CI 91-100) of 61 evaluable patients (one child underwent primary hepatectomy) had a partial response to preoperative chemotherapy. Complete resection of all tumour lesions was achieved in 46 patients (74%). At the end of therapy, 49 (79%, 95% CI 67-88) of 62 patients were in complete remission. With a median follow-up of 52 months, 3-year event-free survival was 76% (95% CI 65-87) and 3-year overall survival was 83% (73-93). 60 (97%) patients had grade 3-4 haematological toxicity (anaemia, neutropenia, or thrombocytopenia) and 44 (71%) had at least one episode of febrile neutropenia. Other main grade 3 or 4 toxicities were documented infections (17 patients, 27%), anorexia (22, 35%), and mucositis (seven, 11%). One child died of fungal infection in neutropenia. Moderate-to-severe ototoxicity was documented in 31 (50%) patients. 18 serious adverse events (including two deaths) reflecting the observed side-effects were reported in the trial (the most common was ototoxicity in five patients). INTERPRETATION: The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma. FUNDING: Cancer Research UK and Cancer Research Switzerland/Oncosuisse.

Hepatic haemangioma-prenatal imaging findings, complications and perinatal outcome in a case series.

BACKGROUND: The clinical presentation of foetal hepatic haemangioma (HH) is highly variable, from asymptomatic to life-threatening. OBJECTIVE: The aim of this study was to describe foetal hepatic haemangioma and identify prognostic factors. MATERIALS AND METHODS: Antenatal and postnatal imaging studies, clinical and biological records of infants with antenatally diagnosed HH (2001-2009) were reviewed. RESULTS: Sixteen foetuses had one focal lesion, with a mean volume of 75 ml (5-240 ml). One had multifocal HH. Most presented as a focal well-delimited heterogeneous vascular mass. Four had associated cardiomegaly, five had cardiac failure. Eight of the nine foetuses with cardiac disorders were symptomatic at birth: cardiac failure with pulmonary hypertension (9), consumptive coagulopathy (8), compartmental syndrome (2). All received supportive medical treatment, four embolisation. Five of these died. The remaining eight had a normal cardiac status. Two became symptomatic after birth: one with a large porto-hepatic shunt and one with significant mass effect. Prenatal cardiac abnormality (univariate, P = 0.031), enlargement of more than one hepatic vein (P = 0.0351) and large volume (P = 0.0372) were associated with symptomatic disease. CONCLUSION: Hepatic haemangioma associated with prenatal cardiac disorders, large volume and more than one enlarged hepatic vein have poorer outcome and require specific perinatal multidisciplinary management.

Initial liver transplantation for unresectable hepatoblastoma after chemotherapy.

BACKGROUND: SIOPEL protocols have recommended liver transplantation for unresectable hepatoblastoma (HBL) after chemotherapy in absence of visible extrahepatic disease. METHODS: This retrospective single center study includes 13 children treated following SIOPEL 3 or 4 protocols who underwent orthotopic liver transplantation (OLT) for HBL between February 2001 and May 2009. RESULTS: Twelve patients had PRETEXT IV HBL, one had PRETEXT II P + HBL, two had pulmonary metastasis at diagnosis. Extra hepatic vascular involvement was present in seven patients (two vena cava, four main portal vein). Twelve patients received a deceased donor organ graft; wait time to OLT was 16 days (1-50 days). One patient received a living donor graft. Four patients did not undergo post-OLT chemotherapy because of major post-OLT surgical complications. Mean follow up was 3.1 years (1-5 years). Ten patients are alive, eight in first complete remission (CR), one is in second CR after two surgical pulmonary metastasis were removed, the latter is in second CR after a surgery for excision of two local recurrences and re-OLT for a secondary HBL in the first graft. Three patients died (two from tumor recurrence, one from cardiac failure after second OLT). Overall survival at 1 and 4 years was 100% and 83.3%. CONCLUSIONS: Application of SIOPEL protocols for treatment of HBL in a specialized multidisciplinary team with access to liver transplantation has resulted in excellent survival. Initial extrahepatic disease should not be considered a contraindication. Future refinements of the protocol need to be considered to reduce toxicity.

Widening spectrum of liver angiosarcoma in children.

OBJECTIVES: Liver hemangiomas are vascular tumors, which occur in the first months of life and carry risks of initial complications, but are considered to be benign histologically and to regress with time. Histologic studies suggest that a subtype, type 2 hemangioendothelioma, is akin to angiosarcoma and may have a severe long-term prognosis. We report 5 girls with type 2 hemangioendothelioma of the liver. METHODS AND RESULTS: Three children initially presented with classical infantile multinodular hemangioma, including cardiac and pulmonary complications and regression of tumors at age 1½ to 2½ years. All 3 experienced tumor relapse at ages 2½ to 3, leading to death at ages 2½ to 5. Tumor histology showed type 2 hemangioendothelioma. The other 2 children presented with liver tumors at ages 2 and 3 years. In 1, initial biopsy of a single tumor showed benign type 1 hemangioendothelioma, but surgical resection was followed by relapse in the remaining liver, lung metastases, and death. Whole tumor histology showed both type 1 and 2 lesions. In the other child, tumor biopsy showed type 2 lesions. She underwent liver transplantation and is alive without tumor recurrence 3 years later. CONCLUSIONS: Careful follow-up is necessary to detect late recurrence in infants with multinodular liver hemangiomas. Vascular liver tumors occurring after infancy are likely to be malignant. The high risk of relapse in the remaining liver suggests that if no metastases are detected, liver transplantation is preferable to surgical tumor resection in both situations.

Renal safety in pediatric imaging: randomized, double-blind phase IV clinical trial of iobitridol 300 versus iodixanol 270 in multidetector CT.

BACKGROUND: It is debated whether iso-osmolar and low-osmolar contrast media are associated with different incidences of contrast medium-induced nephropathy (CIN) in patients with renal insufficiency. OBJECTIVE: To compare the incidence of CIN in children undergoing contrast-enhanced multidetector computer tomography (MDCT) with intravenous injection of low-osmolar (iobitridol, Xenetix® 300) or an iso-osmolar (iodixanol, Visipaque® 270) iodinated contrast medium. MATERIALS AND METHODS: One hundred forty-six children with normal renal function were included in this multicenter trial and underwent contrast-enhanced MDCT. The primary endpoint was the relative change in creatinine clearance from 48 h pre- to 72 h postcontrast medium administration using a noninferiority analysis in the intent-to-treat (ITT, n = 128) and per protocol (n = 68) populations. Secondary endpoints were incidence of CIN, global image quality, diagnostic efficacy and clinical safety. RESULTS: In the ITT population, the noninferiority of iobitridol over iodixanol was demonstrated. CIN incidence was 4.8% (three cases) with iobitridol and 10.6% (seven cases) with iodixanol (not significant). No statistically significant differences were observed for the secondary endpoints. CONCLUSION: Comparable satisfactory safety profiles were confirmed for both contrast media, with no significant difference in the incidence of CIN in children with normal renal function.

Efficient hepatocyte engraftment and long-term transgene expression after reversible portal embolization in nonhuman primates.

UNLABELLED: The feasibility of ex vivo gene therapy as an alternative to liver transplantation for the treatment of liver metabolic diseases needs to be analyzed in large animal models. This approach requires appropriate gene transfer vectors and effective hepatocyte engraftment. Lentiviral vectors have the ability to transduce nondividing differentiated cells, such as hepatocytes, and portal vein occlusion increases hepatocyte engraftment. We investigated whether reversible portal vein embolization combined with ex vivo lentivirus-mediated gene transfer is an effective approach for successful hepatocyte engraftment in nonhuman primates and whether the transgene remains expressed in the long term in transplanted hepatocytes in situ. Simian hepatocytes were isolated after left lobe resection, and the left and right anterior portal branches of animals were embolized with absorbable material. Isolated hepatocytes were labeled with Hoechst dye or transduced in suspension with lentiviruses expressing green fluorescent protein under the control of the human apolipoprotein A-II promoter and transplanted via the inferior mesenteric vein. The whole procedure was well tolerated. The embolized liver was revascularized within 2 weeks. The volume of nonembolized liver increased from 38.7% +/- 0.8% before embolization to 55.9% +/- 1% after embolization and hepatocytes significantly proliferated (10.5% +/- 0.4% on day 3 after embolization). Liver repopulation after transplantation with Hoechst-labeled hepatocytes was 7.4% +/- 1.2%. Liver repopulation was 2.1% +/- 0.2% with transduced hepatocytes, a proportion similar to that obtained with Hoechst-labeled cells, given that the mean transduction efficacy of simian hepatocyte population was 34%. Transgene expression persisted at 16 weeks after transplantation. CONCLUSION: We have developed a new approach to improve hepatocyte engraftment and to express a transgene in the long term in nonhuman primates. This strategy could be suitable for clinical applications.

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.