S. Branchereau

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.

Transcriptional profiling of pure fibrolamellar hepatocellular carcinoma reveals an endocrine signature

Fibrolamellar hepatocellular carcinoma (FLC) is a rare subtype of liver cancer occurring mostly in children and young adults. We have shown that FLC comprises two separate entities: pure (p‐FLC) and mixed‐FLC (m‐FLC), differing in clinical presentation and course. We show that p‐FLCs have a distinct gene expression signature different from that of m‐FLCs, which have a signature similar to that of classical hepatocellular carcinomas. We found p‐FLC profiles to be unique among 263 profiles related to diverse tumoral and nontumoral liver samples. We identified two distinct molecular subgroups of p‐FLCs with different outcomes. Pathway analysis of p‐FLCs revealed ERBB2 overexpression and an up‐regulation of glycolysis, possibly leading to compensatory mitochondrial hyperplasia and oncocytic differentiation. Four of the sixteen genes most significantly overexpressed in p‐FLCs were neuroendocrine genes: prohormone convertase 1 (PCSK1); neurotensin; delta/notch‐like EGF repeat containing; and calcitonin. PCSK1 overexpression was validated by immunohistochemistry, yielding specific, diffuse staining of the protein throughout the cytoplasm, possibly corresponding to a functional form of this convertase. Conclusion: p‐FLCs have a unique transcriptomic signature characterized by the strong expression of specific neuroendocrine genes, suggesting that these tumors may have a cellular origin different from that of HCC. Our data have implications for the use of genomic profiling for diagnosis and selection of targeted therapies in patients with p‐FLC. (Hepatology 2014;59:2228–2237)

Outcome of central hepatectomy for hepatoblastomas

BACKGROUND/PURPOSE Central hepatoblastomas (CHBL) involving liver segments (IV + V) or (IV + V + VIII) are in contact with the portal bifurcation. Their resection may be achieved by central hepatectomy (CH) with thin resection margins on both sides of the liver pedicle, by extended right or left hepatectomy with thin resection margins on one side, or by liver transplantation with thick free margins. The aim of this study is to assess the operative and postoperative outcome of CH for hepatoblastoma. METHODS This was a retrospective monocentric study of 9 patients who underwent CH for CHBL between 1996 and 2008. RESULTS The operative time was 4 hours 50 minutes (2 hours 20 minutes to 7 hours), vascular clamping lasted 30 minutes (0-90 minutes), and the amount of blood cell transfusion was 250 mL (0-1800 mL). Two patients had biliary leakage requiring percutaneous drainage. Median follow-up time was 27 months (14-120 months). All of 8 nonmetastatic patients are alive and disease-free; 1 metastatic patient died of recurrent metastases at last follow-up. Although 3 of 9 patients had surgical margins less than 1 mm, none, including the patients who died from metastases, had local recurrence. CONCLUSIONS Our study demonstrates the feasibility of CH for CHBL without operative mortality or local recurrence. Central hepatectomy is an alternative to extensive liver resections in selected patients.

Meso‐Rex bypass for extrahepatic portal vein obstruction in children

Meso‐Rex bypass (MRB) and portosystemic surgical shunt (PSS) are both used to treat extrahepatic portal vein obstruction (EHPVO) in children. The aim of this study was to analyse the outcome of MRB and PSS to select patients who could benefit from a prophylactic MRB.

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.

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.

SFCP P-063 - Pièges du diagnostic et traitement des sarcomes indifférenciés du foie

Objectifs Resultats des Sarcomes indifferencies du foie (SIF) selon la presence ou non d’une chimiotherapie neoadjuvante protocolaire (CNAP) ou d’une chirurgie d’emblee (CE). Etude mono centrique retrospective. Resultats 13 patients, âge 8 ans [11 mois -16 ans], 10 douleurs abdominales, 5 saignement intratumoral, 2 ruptures peritoneales. Toutes les lesions etaient uniques, non metastatiques, solides et kystiques, mesurant 14 [6–19] cm. Six ont eu une CE: 5 diagnostic errone (3 hamartomes mesenchymateux, 1 hematome, 1 lymphangiome kystique) 1croissance rapide de la tumeur. 7 ont eu une CNAP, diminution du diametre tumoral de 40% [0–60%] avec 90% a 100% de necrose tumorale(anapath). Chirurgie: 7 hepatectomies droites, 1 lobectomie droite ; 3 hepatectomies centrales, 2 hepatectomies gauches. 3 resections incompletes dans le groupe CE et aucune dans le groupe CNAP. Complications : 1 greffe hepatique suite a un Budd Chiari (CE), 1 plaie des voies biliaires (CNAP).1/7 patient avec CNAP a eu une radiotherapie pour rupture au diagnostic compare a 3/6 avec CE.1/6 avec CE a eu une recidive locale. Conclusion Le SIF est un diagnostic differentiel de l’hamartome mesenchimateux. Il faut eviter la chirurgie d’emblee afin d’eviter la recidive et la radiotherapie post operatoire.

SFCP CO-73 - Tumeurs rhabdoïdes du foie : étude observationnelle de 5 cas pédiatriques

Objectifs Les tumeurs rhabdoides hepatiques (TRH) sont rares et agressives, survenant essentiellement chez les enfants de moins de 1 an. L’objectif de cette etude est de decrire les traitements recus et la survie de patients avec TRH. Patients et methode Il s’agit d’une etude unicentrique retrospective de 5 patients traites pour TRH entre le 1 er janvier 2007 et le 31 decembre 2013. Les variables etudiees ont ete l’âge au diagnostic, la presence de metastases, le traitement recu et la survie globale. Resultats L’âge median au diagnostic etait de 6 mois (4–23). Dans tous les cas, le diagnostic a ete histologique avec absence d’expression du gene INI1. Aucun n’enfant n’etait metastatique au diagnostic. Tous les patients ont eu de la chimiotherapie et de la chirurgie. Un seul a eu de la radiotherapie. Les 3 patients (60%) vivants ont tous recu de la doxorubicine et ont eu une chirurgie moins de 3 mois apres le diagnostic. Le recul median est de 9 mois (9–80). Conclusions La survie serait amelioree par une chimiotherapie intensive contenant de la doxorubicine et une chirurgie precoce.

SFCP CO-51 - Prise en charge unicentrique de 60 hernies de coupole diaphragmatique

Objectifs Etudier la correlation entre l’image antenatale et le devenir clinique des patients ayant une hernie de coupole diaphragmatique et analyser les resultats a court et moyen terme. Materiels et methodes Etude retrospective de 60 enfants de 2010 a 2013. Nous avons etudie le LHR prenatal, l’utilisation d’un plug tracheal, la technique chirurgicale, la duree d’hospitalisation, les complications et la survie globale. Resultats Le diagnostic antenatal a ete fait chez 49 enfants. Selon le LHR, 21 (43%) formes favorables, 15 (30%) intermediaires et 13 (27%) severes. Seize enfants ont eu un plug. La chirurgie a ete realisee chez 46 (77%) enfants, 13 ont eu un patch. La duree d’hospitalisation mediane etait de 25 jours (7–132). Trois patients sont rentres a domicile avec une nutrition enterale et 2 avec une oxygenotherapie temporaires. Sept patients ont eu une occlusion sur bride et 3 une recidive. Aucun geste de gastrostomie ou anti-reflux n’a ete pratique. Vingt (33%) enfants sont decedes: 9 (45%) formes severes, 8 (40%) intermediaires et 3 (15%) legeres. Le recul median est de 23,5 mois (4–47). Conclusions Le LHR semble etre un bon facteur pronostic. Meme si la mortalite reste severe, les complications associees a une faible morbidite permettent une qualite de vie satisfaisante.

SFCP CO-74 - Chirurgie des métastases hépatiques des néphroblastomes : expérience monocentrique

Introduction Les metastases hepatiques de nephroblastome (MHN) sont rares et leur prise en charge est specialisee. Materiel et methodes Etude monocentrique retrospective (1993–2010) incluant les patients (pts) ayant une chirurgie hepatique pour MHN. Resultats Dix pts ont ete identifies : 4 pts avec metastases synchrones, 6 pts metachrones (delai moyen de rechute de 23 mois [1–123]). Toutes touchaient le lobe hepatique droit. Elles etaient multiples 4 fois et unique 6 fois. Une atteinte pulmonaire etait associee chez 5 pts (dont les 4 synchrones). Localement, dans 40% des cas le stade de la tumeur etait I, II dans 40%, III dans 20%. Elle etait a droite chez 6 pts. Le geste chirurgical etait une chirurgie reglee pour 6 pts et une resection atypique pour 4. Un patient a necessite la pose d’un packing. Il n’y a pas eu de mortalite peroperatoire. La resection a ete microscopiquement complete pour 8 patients. Une chirurgie pulmonaire a ete faite chez 4 pts. 3 patients ont presente une rechute hepatique avec un delai moyen de 5 mois. Parmi eux, 2 sont decedes. La survie globale est de 80% dans cette serie. Conclusion Le pronostic des enfants ayant une resection complete des MHN persistant apres chimiotherapie est bon. Une prise en charge chirurgicale agressive est necessaire.