High Risk Neuroblastoma Study 1.8 of SIOP-Europe (SIOPEN)
- Conditions
- Neuroblastoma
- Interventions
- Registration Number
- NCT01704716
- Lead Sponsor
- St. Anna Kinderkrebsforschung
- Brief Summary
This is a randomized study of the European SIOP Neuroblastoma Group (SIOPEN) in high-risk neuroblastoma (stages 2, 3, 4 and 4s MYCN-amplified neuroblastoma, stage 4 MYCN non amplified \> 12 months at diagnosis).
The protocol consists of a rapid, dose intensive induction chemotherapy, peripheral blood stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour and immunotherapy (R4 randomization - isotretinoin and ch14.18/CHO (Dinutuximab beta, Qarziba ®).), with or without s.c. aldesleukin (IL-2)). Patients diagnosed after the closure of R3 randomization will not be R4 randomized. For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as continuous infusion as standard of care outside of controlled trials. ch14.18/CHO received marketing authorization by EMA in May 2017 (Qarziba ®).
In the induction phase, all patients receive Rapid COJEC following the result of the R3 randomization which was closed on June 8th, 2017 after inclusion of 630 patients as planned.
Following induction treatment peripheral blood stem cell harvest (PBSCH) is performed and complete excision of the primary tumour will be attempted.
Patients with an inadequate metastatic response to allow BuMel MAT followed by PBSCR at the end of induction should receive 2 TVD (Topotecan, Vincristine, Doxorubicin) cycles.
After Rapid COJEC induction, localized patients will proceed to consolidation. Patients aged 12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without segmental chromosomal alterations (SCAs) are thought to have a good prognosis and will stop treatment after induction therapy and surgery to the primary tumour.
Consolidation consists of BuMel MAT based on the results of the R1 randomization followed by peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour.
The R2 immunotherapy randomization using ch14.18/CHO as 8 hour infusion on 5 consecutive days ( total dose (100mg/m²) with or without aldesleukin (IL-2) alternated with isotretinoin (13-cis-RA) is closed.
The amended R4 immunotherapy randomization using ch14.18/CHO as continuous infusion (total dose 100mg/m² over 10 days) with or without aldesleukin (IL-2) alternated with isotretinoin (13-cis-RA) has accrued according to plan with results pending awaiting data maturity and DMC approval.
- Detailed Description
In this protocol the term high-risk neuroblastoma refers to children with either
* disseminated disease (INSS stage 4: about 40 to 50% of all neuroblastoma) over the age of one or
* INSS stage 2 and 3 disease with amplification of the MycN proto-oncogene Between 10% and 20% of children with stage 3 and occasional patients with stage 2 disease are characterized by amplification of the MycN gene in their tumours. This biological characteristic has clearly been shown to be associated with a greater risk of relapse and death from disease progression. These patients may benefit from very aggressive treatment and, based on this hypothesis, they are included in this protocol. Infants (\< 12 months at diagnosis) with MYCN amplified tumors are included.
Children with this type of presentation and age represent the largest neuroblastoma subgroup. Their prognosis remains poor in most cases and our ability to predict the clinical course and the outcome of the individual patient is modest.
Primary objectives:
R0 randomization: R0 was opened with the study activation in February 2002 and closed in November 2005. The randomized use of G-CSF during COJEC induction resulted in the recommendation of the prophylactic use of G-CSF to prevent episodes of febrile neutropenia (Ladenstein R, Valteau-Couanet D, Brock P, et al. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul 20;3516-24).
R1 randomization: R1 was opened with the study activation in February 2002 and closed in 10/2010 following the results showing significant superiority of myeloablative therapy (MAT) with busulfan and melphalan over continuous infusion of carboplatin, etoposide and melphalan (CEM). BuMel is now the standard MAT (Ladenstein R, Pötschger U, Pearson ADJ, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomized, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017 Apr;500-14).
R2 randomization: R2 was activated in November 2006 (13-cis retinoic acid +/- chimeric ch14.18/CHO antibody), modified in July 2009 and suspended in August 2013. R2 randomization tested the hypothesis that immunotherapy with ch14.18/CHO and subcutaneous aldesleukin (IL-2, Proleukin®), following MAT and autologous stem cell transplantation, in addition to differentiation therapy with 13-cis retinoic acid, will improve 3-year EFS in patients with high-risk neuroblastoma (ASCO 2016: Ladenstein R, et al J Clin Oncol 34, 2016 (suppl; abstr 10500)).
R3 randomization: R3 was opened in June 2011 and tests the hypothesis that modified N7 induction regimen will improve the metastatic response rates or event free survival (EFS) as compared to Rapid COJEC. As of June 8th, 2017 R3 randomization reached the target of 630 randomized patients as planned. There was no difference in event free survival rate between both regimens (Rapid COJEC and modified N7), but modified N7 had a significantly higher grade 3 and 4 toxicity profile. Therefore, Rapid COJEC is maintained as the SIOPEN standard induction treatment with G-CSF support based on the results of the R0 randomization open from 2002 top 2005 This change has been implemented in amendment 8 of the protocol.
R4 randomization: R4 was activated in April 2014. The SIOPEN long term infusion (LTI) ch14.18/CHO trial successfully lowered the toxicity profile by prolonging the infusion time of the same total ch14.18/CHO antibody dose of 100 mg/m² to 10 days of continuous infusion in relapsed /refractory patients. Hence the HRNBL1/SIOPEN study committee wished to implement this more favorable immunotherapy dosing schedule for the time till the induction question R3 was answered and the HRNBL1/SIOPEN trial may be closed. Considering the high R2 dropout rate of patients unable to receive all immunotherapy cycles in the IL-2 s.c. combination treatment arm and not observing this effect in the current SIOPEN LTI trial, it is suggested to address the IL-2sc dose in the new R4. Therefore the potential synergistic effect of sc IL-2 will be addressed again with 50% of the original s.c. IL-2 dose. The IL-2sc dose will hence be reduced to 3 x 106 IU IL-2/m2/day s.c. in the HR-NBL1/SIOPEN R4 amendment instead of 6 x 106 IU IL-2/m2/day s.c as used in the SIOPEN LTI trial. In the second week of each IT course s.c.IL-2 will be given on days 2, 4, 6, 8, 10 in parallel to the ch14.18/CHO ctn infusion and not during the first 5 days in week 2 as scheduled in the SIOPEN LTI trial. R4 randomization is closed for patients diagnosed after June 8th, 2017, the closure date of R3 randomization. For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as continuous infusion (total dose 100 mg/m² over 10 days) as standard of care outside of controlled trials without scIL-2. The ch14.18/CHO monoclonal antibody received marketing authorization by EMA in May 2017 (dinutuximab beta, Qarziba®).
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 3300
-
• Established diagnosis of neuroblastoma according to the International Neuroblastoma Staging System (INSS).
-
Age below 21 years.
-
High risk neuroblastoma defined as either:
- INSS stage 2, 3, 4, and 4s with MYCN amplification, or
- INSS stage 4 without MYCN amplification aged > 12 months at diagnosis
-
Patients who have received no previous chemotherapy except for one cycle of etoposide and carboplatin (VP16/Carbo). In this situation patients will receive Rapid COJEC induction and the first Rapid COJEC cycle may be replaced by the first cycle VP16/Carbo (etoposide / carboplatin).
-
Written informed consent, including agreement of parents or legal guardian for minors, to enter a randomised study if the criteria for randomisation are met.
-
Tumour cell material available for determination of biological prognostic factors.
-
Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
-
Registration of all eligibility criteria with the data centre within 6 weeks from diagnosis.
-
Provisional follow up of 5 years.
-
National and local ethical committee approval.
-
Any negative answer concerning the inclusion criteria of the study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description R2: ch14.18/CHO plus Aldesleukin ch14.18/CHO Patients randomised to receive ch14.18/CHO plus Aldesleukin R4: cnt inf ch14.18/CHO ch14.18/CHO ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO R1: CEM MAT Melphalan The CEM MAT regimen uses three drugs: the dose of Carboplatin must be based on renal function with a target area under the concentration versus time curve (AUC) of 16.4 mg/ml.min, etoposide 350 mg/m2/course and melphalan 210 mg/m2/course R2: ch14.18/CHO ch14.18/CHO ch14.18/CHO is given at a dose of 20 mg/m2/day over five days every four weeks for five courses R4: cnt inf ch14.18/CHO plus Aldesleukin ch14.18/CHO ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO. In addition, Aldesleukin is given at a dose of 3 x 10e6 on days 1 to 5 and on days 9, 11, 13, 15, and 17 during ch14.18/CHO infusion R0: COJEC plus G-CSF Carboplatin Patients randomised to G-CSF during induction treatment (Rapid COJEC) received a single daily subcutaneous injection of 5 microgram/kg/day G-CSF (filgrastim) beginning 24 hours after the last chemotherapy dose. R0: COJEC plus G-CSF G-CSF Patients randomised to G-CSF during induction treatment (Rapid COJEC) received a single daily subcutaneous injection of 5 microgram/kg/day G-CSF (filgrastim) beginning 24 hours after the last chemotherapy dose. R0: COJEC Vincristine Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF R0: COJEC plus G-CSF Etoposide Patients randomised to G-CSF during induction treatment (Rapid COJEC) received a single daily subcutaneous injection of 5 microgram/kg/day G-CSF (filgrastim) beginning 24 hours after the last chemotherapy dose. R0: COJEC plus G-CSF Cisplatin Patients randomised to G-CSF during induction treatment (Rapid COJEC) received a single daily subcutaneous injection of 5 microgram/kg/day G-CSF (filgrastim) beginning 24 hours after the last chemotherapy dose. R0: COJEC plus G-CSF Cyclophosphamide Patients randomised to G-CSF during induction treatment (Rapid COJEC) received a single daily subcutaneous injection of 5 microgram/kg/day G-CSF (filgrastim) beginning 24 hours after the last chemotherapy dose. R0: COJEC Carboplatin Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF R0: COJEC Etoposide Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF R0: COJEC Cyclophosphamide Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF R0: COJEC Cisplatin Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF R1: BuMel MAT Busulfan The BuMel MAT regimen consists of oral administration of busulphan and the short i.v. infusion of melphalan. In July 2007 (amendment 3) oral busulfan was changed to i.v. Busulfan (Busilvex) R1: BuMel MAT Melphalan The BuMel MAT regimen consists of oral administration of busulphan and the short i.v. infusion of melphalan. In July 2007 (amendment 3) oral busulfan was changed to i.v. Busulfan (Busilvex) R1: CEM MAT Carboplatin The CEM MAT regimen uses three drugs: the dose of Carboplatin must be based on renal function with a target area under the concentration versus time curve (AUC) of 16.4 mg/ml.min, etoposide 350 mg/m2/course and melphalan 210 mg/m2/course R1: CEM MAT Etoposide The CEM MAT regimen uses three drugs: the dose of Carboplatin must be based on renal function with a target area under the concentration versus time curve (AUC) of 16.4 mg/ml.min, etoposide 350 mg/m2/course and melphalan 210 mg/m2/course R3: COJEC Induction Vincristine Rapid COJEC induction treatment is applied over ten weeks; three different courses are given every ten days: Course A (given on days 0 and 40): vincristine, carboplatin, and etoposide Course B (given on days 10, 30, 50, and 70): vincristine and cisplatin Course C (given on days 20 and 60): vincristine, etoposide, and cyclophosphamide R3: COJEC Induction Carboplatin Rapid COJEC induction treatment is applied over ten weeks; three different courses are given every ten days: Course A (given on days 0 and 40): vincristine, carboplatin, and etoposide Course B (given on days 10, 30, 50, and 70): vincristine and cisplatin Course C (given on days 20 and 60): vincristine, etoposide, and cyclophosphamide R3: COJEC Induction Etoposide Rapid COJEC induction treatment is applied over ten weeks; three different courses are given every ten days: Course A (given on days 0 and 40): vincristine, carboplatin, and etoposide Course B (given on days 10, 30, 50, and 70): vincristine and cisplatin Course C (given on days 20 and 60): vincristine, etoposide, and cyclophosphamide R3: COJEC Induction Cisplatin Rapid COJEC induction treatment is applied over ten weeks; three different courses are given every ten days: Course A (given on days 0 and 40): vincristine, carboplatin, and etoposide Course B (given on days 10, 30, 50, and 70): vincristine and cisplatin Course C (given on days 20 and 60): vincristine, etoposide, and cyclophosphamide R3: COJEC Induction Cyclophosphamide Rapid COJEC induction treatment is applied over ten weeks; three different courses are given every ten days: Course A (given on days 0 and 40): vincristine, carboplatin, and etoposide Course B (given on days 10, 30, 50, and 70): vincristine and cisplatin Course C (given on days 20 and 60): vincristine, etoposide, and cyclophosphamide R3: Modified N7 Vincristine The modified N7 induction is a dose intense induction chemotherapy regimen including two putatively non cross-resistent drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E). R3: Modified N7 Etoposide The modified N7 induction is a dose intense induction chemotherapy regimen including two putatively non cross-resistent drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E). R3: Modified N7 Cisplatin The modified N7 induction is a dose intense induction chemotherapy regimen including two putatively non cross-resistent drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E). R3: Modified N7 Cyclophosphamide The modified N7 induction is a dose intense induction chemotherapy regimen including two putatively non cross-resistent drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E). R3: Modified N7 Doxorubicin The modified N7 induction is a dose intense induction chemotherapy regimen including two putatively non cross-resistent drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E). R4: cnt inf ch14.18/CHO plus Aldesleukin Aldesleukin ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO. In addition, Aldesleukin is given at a dose of 3 x 10e6 on days 1 to 5 and on days 9, 11, 13, 15, and 17 during ch14.18/CHO infusion R2: ch14.18/CHO plus Aldesleukin Aldesleukin Patients randomised to receive ch14.18/CHO plus Aldesleukin
- Primary Outcome Measures
Name Time Method Event Free Survival (R1: MAT therapy) Up to three years The primary endpoint was the event free survival (EFS) calculated from the date of the first R1 randomisation. The following was considered as event:
* disease progression or relapse
* death from any cause
* second neoplasm
Patients lost to follow up without event were considered at the date of their last follow up evaluation.
R1 has been closed in October 2010 following the results of R1 randomisation showing significant superiority for myeloablative therapy (MAT) with busulfan and melphalan (BuMel) in patients with high risk neuroblastoma over MAT with continuous infusion of carboplatin, etoposide and melphalan (CEM). BuMel is now the standard MAT.Event Free Survival (immunotherapy) Up to three years R2 randomisation comparing immunotherapy with ch14.18/CHO and 13-cis retinoic acid versus 13-cis retinoic acid alone was activated in November 2006. It was amended in July 2009 and compares immunotherapy with anti GD2 antibody ch14.18/CHO with or without aldesleukin (IL-2). Immunotherapy randomisation has been amended in 2014 (R4 randomisation). The ch14.18/CHO antibody is given as continuous Infusion and the randomisation has lasted until the necessary number of patients for R3 randomisation was reached
The primary endpoint is 3-year event free survival calculated from the date of the second randomisation. The following will be considered as events:
* disease progression or relapse
* death from any cause
* second neoplasm
Patients lost to follow up without event will be censored at the date of their last follow-up evaluation.Event free survival (R3: Induction therapy) Up to three years R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7.
The primary endpoint is event free survival calculated from the date of the R3-randomisation. The following will be calculated as events:
* disease progression or relapse
* death from any cause
* second neoplasm
Patients lost to follow up without event will be censored at the date of their last follow up evaluationComplete metastatic response (R3: Induction therapy) Up to 95 days R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7.
Complete metastatic response after induction is defined as:
* no skeletal uptake on mIBG
* Negative bone marrow aspirates (by cytomorphology) and trephines
* Absence of other metastatic sites
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (125)
Medical University in Gdansk
🇵🇱Gdansk, Poland
Children's University Hospital in Lublin
🇵🇱Lublin, Poland
University of Medical Sciences Poznan
🇵🇱Poznan, Poland
Women and Children´s Hospital
🇦🇺Adelaide, Australia
Lady Cilento Children´s Hospital
🇦🇺Brisbane, Australia
John Hunter Children's Hospital
🇦🇺Newcastle, Australia
Royal Children's Hospital Melbourne
🇦🇺Parkville, Australia
Sydney Children's Hospital
🇦🇺Sydney, Australia
Children´s Hospital Westmead
🇦🇺Westmead, Australia
St. Anna Kinderspital
🇦🇹Vienna, Austra, Austria
Univ.Klinik f. Kinder-u. Jugendheilkunde Innsbruck
🇦🇹Innsbruck, Austria
Landes- Kinderklinik Linz
🇦🇹Linz, Austria
Univ.-Klinik für Kinder- und Jugendheilkunde Graz
🇦🇹Graz, Austria
St. Johanns Spital LKH Salzburg
🇦🇹Salzburg, Austria
Cliniques universitaires St-Luc
🇧🇪Brussels, Belgium
Hôpital des Enfants
🇧🇪Brussels, Belgium
University Hospital Gent
🇧🇪Gent, Belgium
CHR Citadelle
🇧🇪Lüttich, Belgium
Clinique de l'Espérance
🇧🇪Montegnee, Belgium
University Hospital Motol
🇨🇿Prague, Czechia
Hopital d'Enfants Dijon
🇫🇷Dijon, France
CHU de Grenoble
🇫🇷Grenoble, France
CHR Pellegrin
🇫🇷Le Pellerin, France
Centre Oscar Lambret de Lille
🇫🇷Lille, France
CHR de Nantes
🇫🇷Nantes, France
CHU-Saint Etienne
🇫🇷Saint Etienne, France
Hopitaux de Marseille La Timone
🇫🇷Marseille, France
Hôpital Trousseau Paris
🇫🇷Paris, France
Hôpital American Memorial Hospital
🇫🇷Reims, France
Hôpital de Hautepierre
🇫🇷Strasbourg, France
Hôpital D'Enfants de Toulouse
🇫🇷Toulouse, France
Aghia Sophia Children's Hospital
🇬🇷Athens, Greece
PEPAGNH University Hospital
🇬🇷Heraklion, Greece
Madarász Children Hospital Budapest
🇭🇺Budapest, Hungary
University of Pecs
🇭🇺Pécs, Hungary
Dublin: OLHSC
🇮🇪Dublin, Ireland
University of Szeged
🇭🇺Szeged, Hungary
Rambam Medical Centre
🇮🇱Haifa, Israel
Schneider Children's Medical Center of Israel
🇮🇱Petah Tiqwa, Israel
Sheba Medical Center
🇮🇱Tel Aviv, Israel
Ospedale G. Salesi
🇮🇹Ancona, Italy
Universitŕ degli studi di Bari
🇮🇹Bari, Italy
Ospedale S. Orsola
🇮🇹Bologna, Italy
Azienda Ospedaliera di Cosenza
🇮🇹Cosenza, Italy
Azienda Ospedaliera A. Meyer
🇮🇹Firenze, Italy
Istituto Giannina Gaslini
🇮🇹Genua, Italy
Istituto Nazionale Tumori di Milano
🇮🇹Milano, Italy
Azienda Ospedal. Univ. di Modena
🇮🇹Modena, Italy
Ospedale dei Bambini, Palermo
🇮🇹Palermo, Italy
Sec. Univ. degli Studi di Napoli - Policlinico
🇮🇹Napoli, Italy
Clinica di Oncoematologia Pediatrica Padova
🇮🇹Padova, Italy
Policlinico San Matteo
🇮🇹Pavia, Italy
Azienda Ospedaliera Universitaria di Parma-Oncoematologia Pediatrica
🇮🇹Parma, Italy
Ospedale Civile Spirito Santo
🇮🇹Pescara, Italy
Ospedale "Infermi "
🇮🇹Rimini, Italy
Policlinico Borgo Roma
🇮🇹Roma, Italy
Ospedale Bambino Gesu
🇮🇹Rome, Italy
Casa Sollievo della Sofferenza
🇮🇹San Giovanni Rotondo, Italy
O.I.R.M. - S. Anna
🇮🇹Torino, Italy
Rikshospitalet
🇳🇴Oslo, Norway
Istituto per l'Infanzia "Burlo Garofolo"
🇮🇹Trieste, Italy
University Hospital of North-Norway
🇳🇴Tromso, Norway
Haukeland University Hospital
🇳🇴Bergen, Norway
Medical University of Bydgoszcz
🇵🇱Bydgoszcz, Poland
Upper Silesian Centre of Child and Mother's Care
🇵🇱Katowice, Poland
Institute Mother and Child
🇵🇱Warschau, Poland
University Children's Hospital Ljubljana
🇸🇮Ljubljana, Slovenia
H. General de Alicante
🇪🇸Alicante, Spain
Hospital de Cruces
🇪🇸Bilbao, Spain
Hospital Vall d'Hebron
🇪🇸Barcelona, Spain
H. Monteprincipe
🇪🇸Madrid, Spain
H Central de Asturias
🇪🇸Oviedo, Spain
H. de Donostia Ntra. Sra. de Aranzazu
🇪🇸San Sebastián, Spain
Hospital 12 de Octubre
🇪🇸Madrid, Spain
H. C. U. de Salamanca
🇪🇸Salamanca, Spain
H. General de Galicia
🇪🇸Santiago De Compostela, Spain
Carlos Haya
🇪🇸Valencia, Spain
Hospital Virgen del Rocio
🇪🇸Sevilla, Spain
Hospital Infantil La Fe
🇪🇸Valencia, Spain
Queen Silvia's Children's Hospital
🇸🇪Göteburg, Sweden
H Clinico-Universitario
🇪🇸Zaragoza, Spain
CHUV
🇨🇭Lausanne, Switzerland
Childrens Hospital Linkoping
🇸🇪Linkoping, Sweden
Royal Belfast Hospital for Sick Children
🇬🇧Belfast, United Kingdom
Aberdeen: Royal Aberdeen Children's Hospital
🇬🇧Aberdeen, United Kingdom
Birmingham Children's Hospital
🇬🇧Birmingham, United Kingdom
Bristol Royal Hospital for Children
🇬🇧Bristol, United Kingdom
Glasgow Royal Hospital for Sick Children
🇬🇧Glasgow, United Kingdom
Leeds: St James's University Hospital
🇬🇧Leeds, United Kingdom
St Bartholomew's Hospital
🇬🇧London, United Kingdom
Addenbrooke's NHS Trust
🇬🇧Cambridge, United Kingdom
Liverpool: Alder Hey Children's Hospital
🇬🇧Liverpool, United Kingdom
Leicester Royal Infirmary
🇬🇧Leicester, United Kingdom
Great Ormond Street Hospital
🇬🇧London, United Kingdom
UCLH University College London Hospital
🇬🇧London, United Kingdom
Nottingham: Queen's Medical Centre
🇬🇧Nottingham, United Kingdom
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
Oxford: John Radcliffe Hospital
🇬🇧Oxford, United Kingdom
Newcastle: Royal Victoria Infirmary
🇬🇧Newcastle, United Kingdom
Sheffield Children's Hospital
🇬🇧Sheffield, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton, United Kingdom
Ospedale Regionale per le Microcitemie
🇮🇹Cagliari, Italy
Aarhus Universitetshospital
🇩🇰Aarhus, Denmark
National State Hospital
🇩🇰Copenhagen, Denmark
University Hospital of Odense
🇩🇰Odense, Denmark
Skejby Hospital
🇩🇰Skejby, Denmark
Institut Curie
🇫🇷Paris, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Ospedali Riuniti
🇮🇹Bergamo, Italy
Llandough Hospital
🇬🇧Cardiff, United Kingdom
Edinburgh Royal Hospital for Sick Children
🇬🇧Edinburgh, United Kingdom
Southampton General Hospital
🇬🇧Southhampton, United Kingdom
Complejo Hospitalario de Jaen
🇪🇸Jaen, Spain
H . Materno-Infantil Teresa Herrera
🇪🇸La Coruna, Spain
MITERA Hospital
🇬🇷Heraklion, Greece
Medical University of Bialystok
🇵🇱Bialystok, Poland
Childrens' Hospital in Chorzów
🇵🇱Chorzów, Poland
University Children's Hospital
🇨🇭Geneva, Switzerland
Ipofg-Crl
🇵🇹Lissabon, Portugal
"A&P Kyriakou" Children's Hospital
🇬🇷Athens, Greece
University of Debrecen
🇭🇺Debrecen, Hungary
Semmelweis University of Budapest
🇭🇺Budapest, Hungary
UZ Gasthuisberg
🇧🇪Leuven, Belgium
Wroclaw Medical University
🇵🇱Wroclaw, Poland
University Hospital F. D. Roosevelt
🇸🇰Banská Bystrica, Slovakia