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

Summary 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/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 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/m2 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/m2 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.

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.

Radiological treatment of common bile duct lithiasis in infancy

Abstractthe authors report a series of 10 infants aged from 20 days to 11 months, presenting with CBD lithiasis, explored and cured by radiological procedure. US showed BD dilatation in 9 cases, sludge in the GB in 5 and in the CBD in 2. Histological findings of cholangitis were present in 4 infants. PTC was performed by GB puncture in 6 and BD puncture in 4. There was evidence of a filling defect in CBD but no anatomical anomaly. Blackish concretions were removed through a side-holes catheter or pushed in the duodenum by washing with saline. An external drainage was left a few days to allow control cholangiogram. Three infants underwent subsequent surgery but no residual lithiasis was found. No recurrence has occurred with a follow-up ranging from 10 months to 7 years. Mechanisms of this entity are discussed.

Liver nodules after portal systemic shunt surgery for extrahepatic portal vein obstruction in children

BACKGROUND Liver nodules have been reported after portal systemic shunt surgery (PSSS) in animal experiments or in humans with liver cirrhosis. The aim of our study was to assess the incidence of liver nodules after surgery for extrahepatic portal vein obstruction (EHPVO) in children without associated liver disease. METHODS We retrospectively reviewed the charts of 45 children who had surgery from 1979 to 2005 for EHPVO in our institution, consisting of 38 PSSS and 7 portal reperfusion procedures (PRPs). We assessed the presence of liver nodules on ultrasonography. RESULTS Of 45 patients, 7 (15%) had liver nodules during a median of 80 months of follow-up. All the nodules occurred after PSSS. Five nodules were subjected to biopsy; we found 2 liver cell adenomas and 3 focal nodular hyperplasias. CONCLUSIONS In this study, liver nodules occurred in 18% of cases after PSSS for EHPVO in children and not after PRP. As many children have undergone PSSS throughout the world, the presence of liver nodules should be considered during the follow-up of those patients.

Prenatal and postnatal Ciliated Hepatic Foregut Cysts in infants.

PURPOSE Ciliated Hepatic Foregut Cyst (CHFC) is a rare congenital lesion arising from the embryonic foregut. Since squamous cell carcinomas arising from CHFC have been reported in adults, complete resection should be considered. We report our experience with CHFC. METHODS We reviewed the charts of 2 patients who had surgery after prenatal detection of a CHFC and 2 patients with postnatal diagnosis. RESULTS Two patients had antenatally detected liver cyst. Postnatal ultrasonography showed a cyst in segment IV, with wall calcifications and sediments. Bile ducts were encased in the wall of the cyst. They underwent central hepatectomy with double biliary diversion and uneventful post operative course. The two other patients underwent non anatomical resection of a cyst on the left lobe and in segment IV, found prior or during liver surgery. Pathology examination showed cysts filled with mucinous fluid, surrounded by an epithelium composed of ciliated cells. One case had a squamous metaplasia. CONCLUSION In infants, CHFC are found antenatally or incidentally. A solitary uni or mutilocular cyst with wall calcifications, sediments, located in the central liver segments should raise the diagnosis. Resection of large cysts in the central segments of the liver is challenging and biliary diversion should be considered.

Portal cavernoma in congenital hepatic fibrosis. Angiographic reports of 10 pediatric cases.

A retrospective pediatric study of 30 angiograms in congenital hepatic fibrosis (CHF) was undertaken to analyze the different aspects of the portal venous system in this disease. Besides the classical angiographic signs (hepatofugal veins and intrahepatic duplications), a hepatopetal venous network was present in ten children, contrasting with the patency of the portal venous system. Analysis of the medical charts for these ten patients showed that the clinical signs and outcome were similar to classical CHF. Liver biopsies were available in six cases and, in addition to the diagnostic features of CHF, demonstrated paucity or absence of portal venules. This unusual association of hepatopetal and hepatofugal collateral veins in an intrahepatic block could be explained by hypoplasia or thrombosis of portal venules. Thus, the association between hepatomegaly and hepatopetal collateral veins without portal obstruction should be suggestive of CHF.

Angiographic Findings in Biliary Atresia

We present the angiographic findings of 46 patients with biliary atresia (BA). There were 25 males and 21 females, with a mean age of 22.5 months (range - 1.5 to 141 months). Hepatic and mesenteric angiography were obtained as part of a liver transplantation work-up or as part of the treatment of clinical events. All patients had a histological diagnosis of BA. The portal vein was patent in 43 patients, with a mean size of 4.1 mm, using the arterial catheter as comparison. Portal hepatopetal flow was observed in 20 patient and hepatofugal flow was observed in 21 patients. Presence of gastroesophageal varices was observed in 41 patients. The hepatic artery was enlarged in all patients. In all 46 patients studied, the intrahepatic peripheral hepatic artery branches presented with irregularities in contour, including encasement, strictures, dilatation and angulation, and images suggestive of peripheral occlusion. Angiographic vascular “tuft-like” blush surrounding the irregular or occluded peripheral arterial segments was observed in 40 patients. The injection of Microfil ® in one case showed a marked vascular proliferation within the portal tract, apparently derived from arterial and portal connections, filling the entire portal space. We conclude that the presence of angiographically demonstrable perivascular arterial tufts in the periphery of the hepatic arterial circulation is a common finding in cases of BA, and may be a characteristic diagnostic angiographic finding.

Hepatobiliary Intervention in Children

Various vascular and nonvascular hepatobiliary interventional radiology techniques are now commonly performed in children’s hospitals. Although the procedures are broadly similar to interventional practice in adults, there are important differences in indications and technical aspects. This review describes the indications, techniques, and results of liver biopsy, hepatic and portal venous interventions and biliary interventions in children.

Rhabdoid tumor of the liver: Report of 6 pediatric cases treated at a single institute

BACKGROUND Rhabdoid tumors (RTs) of the liver are rare, aggressive and nonsecreting malignancies occurring mainly during the first year of life. Definition of RT relies on characteristic morphology and on the inactivation of the SMARCB1 tumor suppressor gene. The aim of this study was to analyze clinical data, treatments and outcomes in our patients. PATIENTS AND METHODS 6 cases of patients treated in our institution for RT of the liver between January 2007 and January 2015 are reported. Variables examined included age at diagnosis, tumor stage, treatment and long-term survival. RESULTS Median age at diagnosis was 5months (range: 4-23). Normal for age serum AFP levels was observed in all patients. No patient presented with metastasis at diagnosis. The diagnosis of RT based on the loss of SMARCB1 was made early in 4 patients. The 2 others were initially diagnosed as nonsecreting hepatoblastomas. Median follow-up was 6years (range: 2-9). All patients received chemotherapy, with variable regimens depending on initial diagnosis, followed by surgical resection. Three patients (50%) died of disease. Two of them were mistaken for nonsecreting hepatoblastomas at diagnosis and had recurrence shortly after completion of treatment. The third one presented a cardiac right atrium thrombus. Three patients (50%) are long-term survivors; they received multimodal therapy including chemotherapy according to protocol EpSSG NRSTS consisting of doxorubicin and surgical removal of the tumor performed within 3months after diagnosis. One patient had adjuvant radiotherapy. CONCLUSION According to our results, search of SMARCB1 mutation or alternatively immunohistochemical assay for SMARCB1 in nonsecreting hepatoblastomas is mandatory to exclude RT. Chemotherapy according to EpSSG NRSTS protocol together with a surgical treatment seems justified to improve long-term survival. TYPE OF STUDY Retrospective study. LEVEL OF EVIDENCE Level IV.

Primary Hepatic Ewing Sarcoma With EWS-FLI1 RNA Transcript in a Child.

A 3-year-old white girl was diagnosed with hepatomegaly during a routine medical examination. Ultrasonography revealed a well-defined heterogenous mass in the segment 4 of the left hepatic lobe, measuring 70 50mm on computed tomography scan, with microcystic areas and poor contrast enhancement. The serum a-fetoprotein, lactate dehydrogenase, and liver enzyme levels were normal. An ultrasound-guided biopsy revealed a poorly differentiated small round-cell tumor. Because of the small sample size, further characterization was not possible. Five weeks later, partial hepatectomy of the anterior fourth segment was performed in a surgical reference center, with complete macroscopic resection of the 9cm tumor covered by a thin capsule. Histologic analysis confirmed an undifferentiated small round-cell tumor with rare perivascular pseudorosettes, which showed diffuse membranous CD99 expression and inconsistent paranuclear dot-like epithelial membrane antigen and CK19 staining. Margins were not cleared. Detection of the EWS-FLI1 fusion transcript by fluorescence in situ hybridization and reverse-transcription polymerase chain reaction confirmed the diagnosis of extraosseous Ewing sarcoma (EES) (Fig. 1). Medullary evaluation, thoracic computed tomography scan, Tc-99m