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Summary: Although announcement of the risks related to treatment has become a general rule in the healthcare relationship, doctors, nurses and parents of severely ill children tend to feel uncomfortable in relation to this mandatory information. The work conducted by the AP–HP Espace éthique working party in collaboration with parents, healthcare personnel and a philosopher demonstrates the need to announce these risks, even beyond the legal framework, while bearing in mind the difficulties and hazards inherent to changes in legislation and by observing the philosophical values that subtend this legislation. Faced with the broad range of diverse and complex risks, the working party proposes a classification of risks and hierarchisation of the difficulties encountered by the doctor during this announcement, which is difficult to make, and difficult to hear, as intimately related to the child''s quality of life. The very concept of the probability of a risk raises concepts that are difficult to accept: chance, randomness, and uncertainty. Informing the patient involves hearing as much as talking, listening as much as explaining and requires availability, time, space and an ability to listen to the patient. This article proposes several good practice guidelines designed to consolidate the therapeutic alliance by sharing the uncertainty of the risk and allowing the various partners to remain actors. Nonconfiscation of knowledge by doctors does not lead to a loss or transfer of their responsibility, but allows decisions to be taken in the context of the alliance, while taking the risks into account. [Copyright &y& Elsevier]

Abstract: The objective of a phase I trials in paediatrics is to determine the recommended dose of a new treatment in children while evaluating its toxicity. These trials are proposed when no effective curative treatment is available. The probability of a benefit in terms of disease control is certainly very low, but greater than zero. On the basis of the work conducted by an Assistance publique-Hôpitaux de Paris Espace éthique group in collaboration with parents, healthcare personnels and a philosopher, phase I therapeutic trials can be considered to be an ethically acceptable proposal provided the criteria and risks of inclusion in such a trial are clearly defined. This article discusses the main elements of this process and is designed to provide guidelines for healthcare personnel and parents. The need for an information provided gently but honestly, the importance of a sufficient time to think about the proposed trial, a two-sided dialogue and partnership between the various actors, and the priority given to the child''s best interest, as should always be the case, constitute the decisive elements to guide the proposed inclusion in a phase I trial. These conditions help to ensure that a decision is reached which appears to be morally founded for all parties, while allowing the child to remain alive up until the end, i.e. a human being capable of relating. This decision allows parents and healthcare personnel to retain a good self-image; if the child dies, it is by keeping their self-esteem that parents can live with their bereavement and healthcare personnel can reinvest in other patients. [Copyright &y& Elsevier]

Abstract: Retinoblastoma is the most frequent eye tumor in children, with an incidence of 1/15 000 births. Sixty per cent are unilateral: the median age at diagnosis is 2 years and most of these forms are not hereditary. Retinoblastoma is bilateral in 40%: the median age at diagnosis is 1 year. All bilateral and multifocal unilateral forms are hereditary. Hereditary retinoblastoma constitutes a cancer predisposition syndrome: a subject carrying a constitutional RB1 gene mutation has a greater than 90% risk of developing retinoblastoma, but is also at increased risk of developing secondary cancers. The 2 most frequent revealing symptoms are leucocoria and strabismus. Diagnosis is made by fundoscopy. US, MRI, CT scans may contribute to diagnosis. Management of patients with retinoblastoma must take into account the various aspects of the disease: the visual risk, the possibly hereditary nature of the disease and the life-threatening risk. Enucleation is still often necessary in unilateral disease; adjuvant treatment is decided according to the histological risk factors. Conservative treatment of at least 1 eye is possible in most of the bilateral cases: laser alone or combined with chemotherapy, cryotherapy and brachytherapy. The indication for external beam radiotherapy should be restricted to large ocular tumors and diffuse vitreous seeding because of the risk of late effects, including secondary sarcoma. Long-term follow-up and early information to retinoblastoma patients regarding the risk of second primary tumors and transmission is actually important. [Copyright &y& Elsevier]

Copyright of EMC-Pediatrie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Childhood cancer is a relatively rare disease, representing just 1% of all malignancies. Within Europe, this represents some 12,000 new cases each year, with approximately 1600 a year in the United Kingdom and 1800 in France. International collaboration in phase III trials of childhood cancer has been the norm for many years, traditionally within Europe, but, largely because of organisational considerations, phase I and II trials have only been conducted on a national basis. With overall cure rates in the region of 70%, relatively few children are available for these early drug trials. Access to new drugs is also a major problem. Against this background, a United Kingdom (UK)/French `new agent'' collaboration was established, expanding subsequently into a wider European grouping. This paper documents the history of that collaboration, the outcomes and future challenges. [Copyright &y& Elsevier]

Copyright of IBS, Immuno-analyse & Biologie Specialisee is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of EMC-Ophtalmologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Individual dosing of carboplatin based on drug monitoring was performed within a multi-centric phase I study based on high AUC-levels in children. Twelve patients (aged 3–17 years old) have been included: 3, 5, and 4 patients at the overall target ultrafilterable carboplatin AUC of 20, 25, or 30 mg/ml×min, respectively. Carboplatin was administered as a daily 60-min infusion, repeated on five consecutive days. The initial daily dose corresponding to the three first days was calculated according to the carboplatin clearance (CL) predicted from patients’ characteristics (body weight, serum creatinine and nephrectomy status). Three blood samples were taken per patient. The individual CL were estimated by MAP (maximum a posteriori approach) Bayesian method implemented in the MP-K program. The doses for day 4 and 5 was adjusted in order to obtain the overall target AUC. Drug monitoring led to a change in the carboplatin dose (overall administered dose versus overall dose planned) ranging from −41% to +45%. Pharmacokinetics were performed at day 5 for 7/12 children: mean relative change between day 1 and day 5 was −11% showing a statistically significant, but limited, decrease of CL from day 1 to day 5. The percentage of difference between the observed and target overall AUC ranged between −7% and +14%. Three patients (one at each AUC level) who were previously treated with cisplatin experienced dose-limiting hearing loss. In conclusion, drug monitoring and dose adjustment is needed for the control of carboplatin plasma exposure when administering high doses of carboplatin in children. [Copyright &y& Elsevier]

Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival. [Copyright &y& Elsevier]

Background TRK fusions are oncogenic drivers of a variety of tumors, many of which can involve the central nervous system (CNS). Larotrectinib is an FDA-approved selective TRK inhibitor for the treatment of TRK fusion cancer (Drilon et al. NEJM 2018). Here we report on the clinical activity of larotrectinib in an expanded set of TRK fusion-positive primary CNS tumors. Methods Patients with primary CNS tumors harboring an NTRK gene fusion detected by local molecular testing who were treated with larotrectinib in two clinical trials (NCT02637687 and NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO). Data cutoff: February 19, 2019. Results 18 patients with various histological types of glial tumors (11 high grade, 4 low grade, 3 unknown) were identified. The patients had gene fusions involving NTRK2 (n = 13), NTRK1 (n = 3) and NTRK3 (n = 2). Median age was 10.5 years (range 1.3–79.0); 14 patients were pediatric (< 18). In 14 evaluable patients, the objective response rate was 36% (2 CR [pending confirmation], 3 PR), with responses seen in high- and low-grade disease and across histologies. Nine patients had SD. The 24-week disease control rate was 71%. The duration of treatment ranged from 0.03+ to 16.6+ months. Conclusions Larotrectinib is active in patients with TRK fusion cancer with intracranial disease. Objective responses and durable disease control were seen in primary CNS tumors of various grades and histologies. These results further support expanded testing for NTRK gene fusions in patients with primary CNS tumors. Clinical trial identification NCT02637687 and NCT02576431. Legal entity responsible for the study Bayer. Funding Bayer. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

The central neurotoxicity of cytotoxic drugs depends on their ability to cross the blood-brain barrier (BBB). The drugs with the highest neurotoxicity are therefore those that cross the BBB most easily: alkylating agents (metabolites of cyclophosphamide and ifosfamide, thiotepa and high-dose melphalan), busulfan, platinum derivatives, aracytine and methotrexate. Apart from aracytine-induced cerebellar toxicity, the clinical signs suggestive of chemotherapy neurotoxicity are relatively nonspecific: altered level of consciousness, seizures, behavioural disorders and motor deficits. Nevertheless, a good knowledge of the various neurological syndromes likely to occur can allow them to be attributed to a drug-induced cause. However, as patients may be receiving several potentially neurotoxic treatments (chemotherapy, concomitant drugs, neurosurgery, radiotherapy), it is difficult to formally confirm the responsibility of the drug, which should only be considered after confirming the absence of radiological and metabolic abnormalities. A specific antagonist treatment can be administered in rare cases (ifosfamide-induced encephalopathy). [Copyright &y& Elsevier]

Infection-related outcomes associated with asplenia or impaired splenic function in childhood cancer survivors (CCS) remain understudied. Splenectomy and splenic radiation have been previously found to be risk factors regarding late infection-related mortality but few data exist concerning overall infections. Late infection-related morbidity and mortality was evaluated in the FCCSS cohort including 7670 5-year CCS diagnosed before the age of 21 treated before 2001 using data registered in the national medical database. Using a radiotherapy treatment planning system the dose distribution on different organs had been calculated on CT-based phantom. 4259 CCS had received radiotherapy, 5762 chemotherapy, and 87 splenectomy. Between 2006-2018: 580 patients were hospitalized at least once for bacterial infection, and 110 patients had severe sepsis or septic shock. 1493 late death are recorded, with an infectious cause in 3.8%(n=57). In a multivariate analysis, spleen irradiation was found to be a risk factor for infection (RR1.8-2.0[CI95%1.2-2.9]), non-significantly modified by radiotherapy, if considered as a binary variable, (RR1.7[CI95%1.4-2.0]) nor lung irradiation (RR1.7-2.1[CI95%1.3-3.2]) nor pituitary irradiation (RR1.5-1.9[CI95%1.1-3.2]).The risk was not related to the dose received to the spleen nor to the volume of spleen involved. Gender, age at diagnosis and chemotherapy were not found to play a significant role in the risk of infection. These results were not altered when considering any regular antibiotic prophylaxis nor vaccine therapy. When analyzing the risk of death by infection, the average dose to the spleen was a risk factor, from doses < 5 Gy, with an increased risk depending on the dose received, as well as a dose > 30 Gy on the pituitary gland. Splenic radiation was found to significantly increase the risk of late infection-related mortality but not of late severe infection. Nevertheless these data should be taken with caution as 45.6% of the deaths with an infectious cause were patients with a second progressive cancer. The dose to the pituitary gland was also a risk factor that may suggest a link with a hormonal deficit, possibly adrenal, that may increase the risk of decompensation during an infection. This hypothesis must be explored secondarily. [ABSTRACT FROM AUTHOR]

Retinoblastoma is the most common paediatric neoplasm of the retina, and one of the earliest model of cancer genetics since the identification of the master tumour suppressor gene RB1. Tumorigenesis has been shown to be driven by pathogenic variants of the RB1 locus, but also genomic and epigenomic alterations outside the locus. The increasing knowledge on this "mutational landscape" is used in current practice for precise genetic testing and counselling. Novel methods provide access to pre-therapeutic tumour DNA, by isolating cell-free DNA from aqueous humour or plasma. This is expected to facilitate assessment of the constitutional status of RB1 , to provide an early risk stratification using molecular prognostic markers, to follow the response to the treatment in longitudinal studies, and to predict the response to targeted therapies. The aim of this review is to show how molecular genetics of retinoblastoma drives diagnosis, treatment, monitoring of the disease and surveillance of the patients and relatives. We first recap the current knowledge on retinoblastoma genetics and its use in every-day practice. We then focus on retinoblastoma subgrouping at the era of molecular biology, and the expected input of cell-free DNA in the field. [ABSTRACT FROM AUTHOR]

Retinoblastoma is the most common intraocular malignancy of infancy with an incidence of 1/15,000 births. Sixty percent of retinoblastomas are unilateral, with a median age at diagnosis of 2 years, and in most cases they are not hereditary. Retinoblastoma is bilateral in 40% of cases, with an earlier median age at diagnosis of 1 year. All bilateral and multifocal unilateral forms are hereditary and are part of a genetic cancer predisposition syndrome. All children with a bilateral or familial form, and 10-15% of children with a unilateral form, constitutionally carry an RB1 gene mutation. The two most frequent symptoms at diagnosis are leukocoria and strabismus. Diagnosis is made by fundoscopy, with ultrasound and magnetic resonance imaging (MRI) contributing both to diagnosis and assessment of the extension of the disease. Treatment of patients with retinoblastoma must take into account the various aspects of the disease (unilateral/bilateral, size, location), the risks for vision, and the possible hereditary nature of the disease. The main prognostic aspects are still early detection and adapted coverage by a multidisciplinary, highly specialized team. Enucleation is still often necessary in unilateral disease; the decision for adjuvant treatment is made according to the histological risk factors. The most important recent therapeutic advances concern conservative treatment, which is proposed for at least one of the two eyes in most bilateral cases: laser alone or in combination with chemotherapy, cryotherapy, or brachytherapy. Recently, the development of new conservative techniques of treatment, such as intra-arterial selective chemotherapy perfusion and intravitreal injections, aims at preserving visual function in these children and decreasing the number of enucleations and the need for external beam radiotherapy. The vital prognosis related to retinoblastoma is now excellent in industrialized countries, but long-term survival is still related to the development of secondary tumors, mainly secondary sarcoma. Retinoblastoma requires multidisciplinary care as well as a long-term specialized follow-up. Early counseling of patients and their family concerning the risk of transmission of the disease and the risk of development of secondary tumors is necessary. [ABSTRACT FROM AUTHOR]

Résumé Introduction Les enfants et adolescents atteints de cancer sont pris en charge en France par des équipes pluri-professionnelles au sein de centres spécialisés d’onco-hématologie pédiatrique, labellisés par l’Institut national du cancer, qui travaillent en réseau avec des centres de pédiatrie de proximité. Le diplôme inter-universitaire d’oncologie pédiatrique (DIUOP) propose une formation à l’onco-hématologie maligne pédiatrique comprenant un enseignement théorique, un stage dans un service validant et un projet de recherche soutenu devant un jury. Méthode Nous avons adressé un questionnaire aux diplômés pour connaître leur situation professionnelle actuelle et avons recherché sur PubMed tous les articles publiés. Résultats De 2000 à 2011, le DIUOP a formé 290 médecins spécialistes : 242 pédiatres, 21 chirurgiens et 19 radiothérapeutes, 8 ayant une autre spécialité telle que l’imagerie, l’hématologie ou l’anatomo-pathologie. Quatre-vingt-douze étaient titulaires d’un diplôme obtenu à l’étranger : en Europe (50 %), en Afrique et au Proche-Orient (42 %) et en Amérique du Sud (8 %). Cent quatre-vingt-dix-sept des 266 diplômés (74 %) ont répondu au questionnaire. Quatre-vingt-dix pour cent prenaient en charge des enfants et adolescents atteints de cancer. Pour ceux exerçant en France, ils travaillaient principalement dans les établissements impliqués dans l’organisation des soins définie par la circulaire DHOS (Direction de l’hospitalisation et de l’organisation des soins) de 2004. Soixante-neuf articles, soit un mémoire sur 4, avaient été publiés dans une revue avec un facteur d’impact médian de 3,5 (0–22,6) dont 85 % en langue anglaise. Conclusion Le DIUOP est la seule formation européenne en langue française offrant une formation professionnalisante, multidisciplinaire, de qualité et complète aux spécialistes impliqués dans la prise en charge des cancers de l’enfant et de l’adolescent. Summary Introduction According to the European Society of Pediatric Oncology (SIOPE) standard of care guidelines, high-quality care of children and adolescents with cancer needs to be delivered by well-trained multidisciplinary teams in specialist centers working with designated shared-care local centers in a so-called hub-and-spoke model. The Diplôme Inter-Universitaire d’Oncologie Pédiatrique (DIUOP) is the only European training program in pediatric oncology in French for all physicians involved in care of patients with pediatric malignancies. In agreement with the SIOPE syllabus, the DIUOP is composed of training courses (120 h), on-site practical training in a specialist center, and a research project to be defended before an examining board. Method All graduates received a questionnaire to describe their current professional position. A comprehensive PubMed analysis retrieved all papers published form DIUOP research projects. Results From 2000 to 2011, 290 physicians were trained: 242 pediatricians, 21 surgeons, and 19 radiation therapists. Eight had another specialty including imaging, hematology, and pathology. Ninety-two were initially trained outside of France: 50% in Europe (mainly in Italy, Belgium, and Switzerland), 42% in Africa and the Middle East, and 8% in South America. Of the 266 graduates, 74% answered the questionnaire, and 90% of them take care of children and adolescents with cancer. Sixty-nine articles, i.e., one out of four research projects, were published in 34 journals with a median impact factor of 3.5 (0–22.6), 85% in English. Conclusion DIUOP is the only French-speaking European education program providing a high-quality, professionalizing, and comprehensive multidisciplinary training program for French and international specialists taking care of children and adolescents with cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Usual dose-finding methods in oncology are sequential. Accrual is suspended after each group of patients to assess toxicity before increasing the dose. An adapted Continual Reassessment Method (CRM) and Rolling 6 (R6) method, designed to avoid this suspension of accrual in pediatric oncology, are compared with the traditional 3+3 design. Study design and setting: The competing performances were evaluated in a simulation study integrating the temporal dimension, and a phase I trial was reanalyzed. We compared methods for various interpatient arrival times and dose-toxicity relations, in terms of distribution of final recommendations, number of skipped children and duration of trials. Results: R6 and CRM can be safely implemented to limit trial suspensions, especially when mean interpatient arrival time is short. CRM was found to be more efficient than algorithm-based methods (44% of good recommendations vs. 38%) but moderately increased the risk of overtreatment. The R6 design included more patients at suboptimal doses. The design with the shortest study duration depended on the number of dose to escalate before the target. Conclusion: These new methods can reduce the number of skipped patients, but only provide limited gain in terms of ability to select the right dose. New designs are needed. [Copyright &y& Elsevier]

Abstract: Pediatric tumors still represent a formidable challenge despite the considerable therapeutical advances that have been reported for the past 30 years. This is largely related with the untowards side-effects of local therapy that are still acknowledged as the “price for cure”. In this setting, Proton therapy a sophisticated radiotherapeutical modality seems to represent a real breakthrough due to its unique ability to spare close and distant normal organs compared with modern photons techniques. We summarize in this paper current clinical and dosimetrical evidences including an update of the Orsay series on 108 children. [Copyright &y& Elsevier]

Summary: Medulloblastoma is one of the most common malignant childhood brain tumors. It is a primitive neuroectodermal tumor (PNET) and predominantly arises in the cerebellum and 4th ventricle. Most cases of medulloblastoma are sporadic, but some predisposition syndromes are known, such as SUFU and Gorlin syndromes. Most often intracranial hypertension reveals the disease typically with headache and vomiting. However, the frequent atypical presentation should not delay neuroradiological investigations. Brain and spinal MRI can establish the diagnosis of posterior fossa tumor and define the extent of the disease. CSF study completes the staging. Histologic examination of the tumor confirms the diagnosis of medulloblastoma. Patients are classified into 2 risk groups: standard-risk medulloblastoma, defined by nonmetastatic disease treated by total or subtotal tumor resection; and high-risk patients who have disseminated disease and/or residual disease. Tumor molecular genetic findings allow the use of emerging prognostic factors and may ultimately contribute to the development of targeted therapy. Current treatment in the oldest children combines surgical resection followed by radiotherapy and chemotherapy. The aim of recent studies was to increase survival and decrease sequelae by reducing CSI in older children with standard risk medulloblastoma. Treatment in younger patients is as much as possible restricted to surgery and chemotherapy. However, long-term sequelae after treatment for medulloblastoma remain frequent and the detection and treatment of those sequelae is an essential part of the follow-up of the patients. [Copyright &y& Elsevier]

Abstract: School achievement of children with brain tumors is hampered by progressive neurologic and cognitive sequelae. To help the children and their family, we have created in 1997 a multidisciplinary consultation together with Necker''s hospital. Material and methods: The study describes the organization of the consultation and analyses the files of 69 children seen between September 2001 and June 2002. Results and conclusion: The authors conclude that this consultation is an irreplaceable mean to coordinate the complex rehabilitation process of a child treated for a brain tumor. [Copyright &y& Elsevier]

Abstract: The aim of this study was to evaluate a chemotherapy strategy that avoids radiotherapy in first-line treatment of young children with high-grade glioma. A total of 21 children under 5 years of age received the BBSFOP protocol, comprising seven cycles of three drug pairs (carboplatin/procarbazine, cisplatin/etoposide and vincristine/cyclophosphamide) administered over a 16 month period. Radiotherapy was performed in case of recurrence/progression. Median age at diagnosis was 23 months. Histology was classified as World Health Organisation (WHO) grade III in 13 and grade IV in 8. Of the 13 children with a residual tumour, chemotherapy induced 2 partial responses (PR), 1 minor response (MR) and 1 stable disease (SD) with no recurrent disease. Five-year progression-free survival was 35% and 5-year overall survival was 59%, with a median follow-up of 5.2 years. At the last update, 12 children were alive (10 without radiotherapy). In conclusion, this study shows that an adjuvant chemotherapy first approach is safe and allows radiotherapy to be avoided in selected children. [Copyright &y& Elsevier]

Abstract: Aim: Improvement of EFS of children older than 3 years with high risk medulloblastoma. Methods: Between 1993 and 1999, 115 patients (3–18 years, mean 8 years) with high risk medulloblastoma were included. After surgery treatment consisted of chemotherapy (‘8in1’ and etoposide/carboplatin) before and after craniospinal radiotherapy. Results: Patients were staged using Chang-criteria (PF residue only, M1 and M2/M3) by local investigator as well as by central review panel (82.4% concordance). Chemotherapy was well tolerated without major delays in radiotherapy. With a mean follow up of 81 months (9–119), 5-year EFS was 49.8% and OS 60.1%. In detail according to subgroups EFS was 68.8% for PF residue only, 58.8% for M1 disease and 43.1% for M2/M3. Conclusion: M1 patients are legitimate high risk patients. Survival rates are still very low for high risk medulloblastoma patients and future trials should therefore focus on more intensive (chemotherapy/radiotherapy) treatment. [Copyright &y& Elsevier]

BACKGROUND: Morbidity and mortality are high in young children with medulloblastoma who receive craniospinal radiotherapy. We aimed to assess whether adjuvant treatment with protracted chemotherapy alone could replace radiotherapy. METHODS: We enrolled 79 children aged younger than 5 years who had had surgical resection of medulloblastoma onto a multicentre trial. Patients were treated with combination chemotherapy, which did not include methotrexate, for more than 16 months irrespective of the extent of disease. Early postoperative imaging defined three groups: R0M0 (no residual disease, no metastasis), R1M0 (radiological residual disease alone), and RXM+ (presence of metastases). Patients who did not relapse did not receive radiotherapy. Patients who relapsed or had disease progression received salvage treatment, which consisted of high-dose chemotherapy and stem-cell transplantation followed by local or craniospinal radiotherapy. For children classified as R0M0, the primary endpoint was 5-year overall survival and the secondary endpoint was 5-year progression-free survival. For children classified as R1M0 or RXM+, the primary endpoint was best radiological response and the secondary endpoints were 5-year overall survival and 5-year progression-free survival. Analyses were done by intention to treat. FINDINGS: Two of 15 patients classified as RXM+ and four of 17 patients classified as R1M0 had a complete radiological response. 5-year progression-free survival was 29% (95% CI 18-44) in the R0M0 group, 6% (1-27) in the R1M0 group, and 13% (4-38) in the RXM+ group. 5-year overall survival was 73% (59-84) in the R0M0 group, 41% (22-64) in the R1M0 group, and 13% (4-38) in the RXM+ group. In the R0M0 group, 5-year progression-free survival was 41% (26-58) for the 34 patients who underwent gross total resection compared with 0% for the 13 patients who had subtotal resection (relative risk 2.7 [1.3-5.6], p=0.0065). INTERPRETATION: Conventional chemotherapy alone can be used to cure children with non-metastatic medulloblastoma who have gross total resection confirmed by early radiological assessment, but is not sufficient for treatment of those with metastatic or incompletely resected medulloblastoma. Salvage treatment followed by posterior-fossa radiotherapy can effectively treat local relapses or progression. [ABSTRACT FROM AUTHOR]

Abstract: We report five paediatric cases of portal vein thrombosis (PVT) occurring during chemotherapy, observed in two institutions over an 8-year time period. These children aged 2.5–15 years were treated for Burkitt’s lymphoma, Ewing’s tumour, small cell bone tumour or medulloblastoma. PVT was diagnosed on colour Doppler ultrasonography (US). In four patients, thrombosis occurred 2–45 days after severe hepatic veno-occlusive disease (HVOD) secondary to intensive chemotherapy containing busulfan. In one case, PVT occurred in the absence of HVOD in a patient with pre-existing periportal lymphomatous infiltration. Four patients experienced persistent portal hypertension, which resulted in death in one. PVT during chemotherapy in children is a rare event and appears to be closely related to intensive chemotherapy containing busulfan and to be associated with HVOD. [Copyright &y& Elsevier]

Twenty experts, members of a French medical network devoted to neurofibromatosis 1 have elaborated recommendations for the management of the disease. Bibliography was obtained through a Medline of articles from 1966 to 1999 for the terms neurofibromatosis, NF1, neurofibroma and from textbooks. A consensual document was written taking into account extracted data. An annual careful clinical examination is recommended except in cases with complications. Screening investigations are not recommended due to the rarity of complications, generally symptomatic and easily detected during the clinical follow-up. The only controversial exception might be magnetic resonance imaging for early detection of optic pathway gliomas in young children. A co-ordinated follow-up in specialised multidisciplinary centres, providing patients with a rational management, is recommended. [ABSTRACT FROM AUTHOR]

Genomic rearrangements involving NTRK1/2/3 result in constitutively active TRK fusion proteins that are oncogenic drivers in multiple pediatric and adult cancers. Larotrectinib is a selective TRK inhibitor approved by the FDA in 2018 for the treatment of any TRK fusion cancer based on a primary analysis in 55 patients from 3 clinical trials [Drilon et al. NEJM 2018]. For the first time, we now report median duration of response (DOR) data in this primary cohort, as well as updated data in an expanded cohort of 159 total TRK fusion patients treated with larotrectinib, with 153 (55 primary + 98 supplemental) evaluable for efficacy. Patients with TRK fusion cancer detected by local molecular profiling were treated with larotrectinib across 3 studies (NCT02122913, NCT02637687, and NCT02576431). Disease status was assessed by investigators using RECIST 1.1. Data cut-off was 19 February 2019. In the primary cohort of 55 patients with a median follow-up of 26 months, the median DOR in 44 patients with complete or partial responses was 35.2 months (95% CI 21.2–NE), with 17 progression events and 27 responses ongoing (range 1.6–44 months). The median PFS in the primary cohort was 25.8 months (95% CI 9.9–NE), with 27 patients having progressed. In the expanded combined dataset, the most common tumor types included soft tissue sarcoma (n = 36), infantile fibrosarcoma (n = 29), thyroid carcinoma (n = 26), salivary gland carcinoma (n = 21), and lung cancer (n = 12). The median age was 43 years, ranging from <1 month to 84 years; 33% <18 yr. The overall ORR was 79% (95% CI 72–85), with complete responses in 16%. Adverse events were primarily grade 1-2, with 13% of patients having had a grade 3-4 event related to larotrectinib. Only one patient discontinued due to an AE related to larotrectinib. These data confirm the marked tissue-agnostic efficacy and long durability of response in patients with TRK fusion cancer treated with larotrectinib. Larotrectinib continued to demonstrate a favorable long-term safety profile. Screening patients for NTRK gene fusions should be actively considered. NCT02122913, NCT02637687, NCT02576431. Editorial assistance was provided by Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer. Bayer. Bayer. D.M. Hyman: Advisory / Consultancy: Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer Pharmaceuticals, Genentech / F. Hoffmann-La Roche; Research grant / Funding (self): Loxo Oncology, Bayer Pharmaceuticals, PUMA Biotechnology, AstraZeneca. C.M. van Tilburg: Advisory / Consultancy: Novartis, Bayer. D.S.W. Tan: Advisory / Consultancy: Novartis, Merck Loxo AstraZeneca Roche Pfizer; Travel / Accommodation / Expenses: Pfizer Boehringer Ingelheim Roche; Honoraria (self): BMS, Takeda, Novartis, Roche, Pfizer; Research grant / Funding (self): Novartis, GSK, AstraZeneca. A.F. Farago: Research grant / Funding (self): Bayer, Loxo Oncology; Advisory / Consultancy: Bayer, Loxo Oncology. T.W. Laetsch: Advisory / Consultancy: Novartis, Bayer, Loxo, Lill; Research grant / Funding (self): Pfizer Novartis Bayer Loxo Abbvie Amgen Atara Biotherapeutics BMS Lilly Epizyme GSK Janssen Jubilant Pharmaceuticals Novella Clinical, Servier. S. Kummar: Honoraria (self): Bayer; Advisory / Consultancy: Bayer; Travel / Accommodation / Expenses: Bayer. F. Doz: Research grant / Funding (institution): BMS, Celgene; Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Bayer, BMS, Celgene, Loxo Oncology, Servier. U.N. Lassen: Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer. S.G. DuBois: Advisory / Consultancy: Loxo; Travel / Accommodation / Expenses: Loxo, Roche; Honoraria (self): Loxo; Research grant / Funding (self): Millennium, Merck, Novartis Roche Lilly Lilly Loxo BMS. R. McDermott: Travel / Accommodation / Expenses: Janssen-Cilag, Pfizer; Honoraria (self): Bayer, Sanofi, Janssen, Astellas, BMS, MSD, Pfizer, Novartis, Clovis; Research grant / Funding (self): Sanofi, Janssen, Bayer, Astellas. L. Mascarenhas: Research grant / Funding (institution): AstraZeneca, Eli Lilly. J.D. Berlin: Research grant / Funding (institution): PsiOxus, Bayer, EMD Serono, Symphogen, Roche/Genentech, Immunomedics, Novartis, Taiho, AbbVie (pharamcyclics), Boston Biomedical, FivePrime, Loxo, Incyte, Macrogenics; Honoraria (self): Nestle; Advisory / Consultancy: Rafeal, Seattle Genetics, EMD Serono, Bayer, eisai, Taiho, Armo,Gritstone, AstraZeneca, Celgene, Erytech. E.R. Rudzinski: Advisory / Consultancy: Bayer. M.C. Cox: Full / Part-time employment: Loxo Oncology. S. Nanda: Full / Part-time employment: Loxo Oncology. B.H. Childs: Full / Part-time employment: Bayer. A. Drilon: Advisory / Consultancy: Loxo Oncology/Bayer, Ignyta, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda/Ariad/Millenium, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Bayer, Tyra; Research grant / Funding (self): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Honoraria (institution): Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho; Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: MORE Health. D.S. Hong: Research grant / Funding (self): AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seatt; Travel / Accommodation / Expenses: Loxo, MiRNA, ASCO, AACR, SITC, Genmab; Advisory / Consultancy: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics; Shareholder / Stockholder / Stock options: Molecular Match, OncoResponse, Presagia Inc. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Genomic rearrangements involving neurotrophic tropomyosin receptor kinase 1, 2, or 3 (NTRK1/2/3) result in constitutively active tropomyosin receptor kinase (TRK) fusion proteins that are oncogenic drivers in multiple pediatric and adult cancers. Larotrectinib is a selective TRK inhibitor approved by the US Food and Drug Administration in 2018 for the treatment of TRK fusion cancer based on a primary analysis in 55 patients from 3 clinical trials [Drilon et al. NEJM 2018]. Here, we report median duration of response (DOR) data in the primary cohort and updated data in an expanded cohort of 159 patients with TRK fusion cancer treated with larotrectinib, with 153 (55 primary + 98 supplemental) evaluable for efficacy. Methods Patients with TRK fusion cancer detected by local molecular profiling were treated with larotrectinib across 3 studies (NCT02122913, NCT02637687, NCT02576431). Disease status was assessed by investigators using RECIST 1.1. Data cut-off was February 19, 2019. Results In the primary cohort of 55 patients with a median follow-up of 26 months, the median DOR in 44 patients with complete or partial responses was 35.2 months (95% CI 21.2–not evaluable [NE]), with 17 progression events and 27 responses ongoing (range 1.6–44 months). Median progression-free survival in the primary cohort was 25.8 months (95% CI 9.9–NE), with 27 patients having progressed. In the expanded combined dataset, the most common tumor types included soft tissue sarcoma (n = 36), infantile fibrosarcoma (n = 29), thyroid carcinoma (n = 26), salivary gland carcinoma (n = 21), and lung cancer (n = 12). Median age was 43 years, ranging from < 1 month to 84 years; 33% < 18 years. The overall response rate was 79% (95% CI 72–85), with complete responses in 16%. Adverse events were mostly grade 1–2; 13% of patients had a grade 3–4 event related to larotrectinib. Only one patient discontinued due to an adverse event related to larotrectinib. Conclusions These data confirm the marked tissue-agnostic efficacy and long durability of response in patients with TRK fusion cancer treated with larotrectinib. Larotrectinib demonstrated a favorable long-term safety profile. Screening patients for NTRK gene fusions should be considered. Clinical trial identification NCT02122913, NCT02637687, NCT02576431. Legal entity responsible for the study Bayer. Funding Bayer. Disclosure F. Doz: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (self): Celgene; Advisory / Consultancy: Bayer; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy: Servier. L. Mascarenhas: Speaker Bureau / Expert testimony: Bayer. J. Berlin: Research grant / Funding (institution): PsiOxus; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): AbbVie (pharamcyclics); Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): FivePrime; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Macrogenics; Honoraria (self): Nestle; Advisory / Consultancy: Rafeal; Advisory / Consultancy: Seattle Genetics; Honoraria (self): Eisai; Advisory / Consultancy: Taiho; Advisory / Consultancy: Armo. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Le neuroblastome (NB) est une tumeur pédiatrique maligne du système nerveux périphérique, caractérisée par une grande hétérogénéité clinique, évolutive et génétique, le plus souvent sporadique. De rares formes familiales sont décrites, compatibles avec une transmission dominante. Par ailleurs, des tumeurs neuroblastiques sont observées chez des patients porteurs d’autres anomalies de la crête neurale, comme la maladie de Hirschprung, le syndrome d’Ondine. Nous avons identifié le gène PHOX2B comme premier gène de prédisposition au NB. En effet, des mutations constitutionnelles de ce gène ont été caractérisées dans des formes familiales de NB ainsi que chez des patients présentant une association NB/maladie de Hirschsprung. Récemment, notre groupe et d’autres équipes ont identifié le gène ALK, (Anaplastic Lymphoma Kinase), comme gène de prédisposition au NB. Ce gène code pour un récepteur transmembranaire à activité tyrosine kinase. Des mutations somatiques du gène ALK ont par ailleurs été caractérisées dans des tumeurs sporadiques. L’identification de mutations constitutionnelles des gènes PHOX2B et ALK va permettre d’améliorer la prise en charge des familles à risque en proposant une surveillance adaptée aux enfants porteurs d’une mutation. [ABSTRACT FROM AUTHOR]

Introduction: la protonthérapie (PT) apporte un bénéfice par l’épargne qu’elle permet des tissus sains. Elle offre aussi la possibilité d’escalader la dose pour des tumeurs agressives. Sujets, Matériel et Méthode: 108 enfants ont été pris en charge entre 1994 et 2007 à Orsay par PT, pour tout (44) ou partie (64) de leur RT. Étaient sélectionnés : 1]craniopharyngiomes (33) ; 2]gliomes BG (15) ; 3]sarcomes osseux (34) ; 4]sarcomes des tissus mous (11) ; 5]« autres » (15). L’âge médian était de 11 ans et la dose administrée de 50 à 70 Gy Eq Co, en fractionnement classique. La préparation des malades a fait appel à une dosimétrie 3D (TDM/IRM haute définition fusionnées) et la mise en place à un positionnement stéréotaxique par « fiduciaires » implantés. Une AG a été effectuée dans 7 cas. Résultats: avec un suivi moyen de 28 mois, la SG/SSR selon Kaplan/Meier à 5 ans, s’établit pour l’ensemble du groupe, à (%) 88/72. Par sous-groupes, elles s’établissent à 1]100/71, 2]100/52, 3]92/85, 4]63/54, 5]64/55. La tolérance immédiate et à long terme a été jugée excellente. Conclusion: cette expérience clinique encourageante basée sur un équipement ancien sera prochainement complétée par l’utilisation d’un accélérateur compact + source isocentrique aux multiples possibilités nouvelles. [ABSTRACT FROM AUTHOR]

Objectif: Évaluer l’impact du traitement sur la prise de poids, la fonte tumorale et le délai avant irradiation. Méthode: 35 pts (âge médian 10 mois) ont reçu le BBSFOP qui consiste en l’alternance de 6 drogues pendant 16 mois. Résultats: 4 ont une NF1. Le diagnostic histologique est astrocytome pilocytique (19) ou astrocytome de bas grade NOS (4). 9 ont une dissémination leptoméningée. 18 ont reçu la totalité du protocole. La meilleure réponse a été BRP (2), RP (5), RO (5) MS(14) et MP(9). 13 ont pris du poids, sans corrélation avec la réponse. 34 ont ensuite progressé (délai médian: 22,5 mois [2-137]). 17 ont été irradiés (gain de temps médian : 54 mois [21-114]). La survie globale (SG) à 5 ans est de 83% [67-92], la survie sans événements (SSE) 8,6% [3-22] (suivi médian de 89 mois). 11 sont décédés (7 progressions tumorales et 4 toxicités des autres lignes). La SSE est moins bonne que celle des pts avec un GVO sans CD (34%), surtout pour les moins de 6 mois (p = 0,01), mais la SG est comparable. En fin de suivi, 10 sont obèses, 8 ont un déficit en GH et 19 ont des troubles pubertaires. Conclusion: le but de cette stratégie qui était de retarder l’irradiation a été atteint. La chimiothérapie est donc efficace dans le contrôle tumoral mais les résultats à long terme sont décevants. [ABSTRACT FROM AUTHOR]

Les tumeurs de la granulosa juvéniles (TGJ) se développent à partir du stroma gonadique et des cordons sexuels. Elles représentent 5 % des tumeurs ovariennes pédiatriques. L’objectif était de dégager les éléments cliniques et paracliniques importants à prendre en compte pour améliorer leur prise en charge. Sujets et Méthodes: Etude rétrospective monocentrique portant sur 12 patientes atteintes de TGJ, ayant un âge moyen au diagnostic de 6 ans [0-14 ans]. La période d’étude s’est étalée de 1994 à 2007 (recul moyen : 6 ans [3 mois–13 ans]). Les données anamnestiques, cliniques, biologiques, radiologiques, anatomopathologiques, moléculaires, thérapeutiques et l’évolution ont été recueillies. Résultats: Deux modes de présentation ont été mis en évidence, correspondant à deux tranches d’âge. Les signes endocriniens (hyperœstrogénie et hyper-androgénie) étaient au premier plan chez les patientes pré-pubères (n = 9) alors que le diagnostic a été posé devant une masse abdominale chez les patientes pubères (n = 3). Des signes de virilisation ont été trouvés dans 9 cas/12. L’inhibine B était un bon marqueur tumoral (élevé dans 6 cas/6). Le traitement a comporté une ovariectomie complète (11 cas), une tumorectomie (1 cas), une chimiothérapie (2 cas). Les TGJ avaient une double composante cellulaire (cellules de la granulosa et thécale), et une composante kystique (10 cas/12). L’analyse immuno-histochimique conforte le diagnostic. Une corrélation entre les signes endocriniens, les sécrétions et la taille tumorales ainsi que la présence d’une ascite a pu être décrite (dans la population pré-pubère). Il n’a pas été trouvé de lien entre la symptomatologie, le délai de prise en charge et le stade FIGO des tumeurs. Dans 2 cas/10, une mutation somatique R201C du gène codant pour la protéine Gαs était présente dans les cellules tumorales. Elle était associée à des critères macroscopiques (FIGO Ic) ou histologiques de gravité. Conclusions: Le diagnostic de TGJ doit être évoqué devant une puberté précoce et/ou une masse ovarienne avec élévation des taux sériques d’inhibine B. Grace à un diagnostic précoce et à un traitement chirurgical adapté complété par une chimiothérapie dans les formes agressives, le pronostic est excellent mais nécessite une surveillance prolongée. [Copyright &y& Elsevier]

Objectifs: étudier la compréhension par les parents de l’information reçue lors du recueil du consentement dans un essai clinique de phase 3 et les motivations de leur décision. Patients et Méthode: étude prospective, de janvier 2005 à septembre 2006. Ont été inclus dans cette étude tous les parents ayant eu dans les centres participants une proposition d’inclusion pour leur enfant dans le protocole Fralle 2000 (leucémie aigue lymphoblastique). Les parents étaient vus en entretien semi directif à deux reprises par une psychologue diplômée (1 mois-6 mois). Résultats: 51 parents ont été rencontrés et 43 entretiens réalisés. Trente cinq parents (81 %) pensaient que les informations étaient adaptées. Huit parents (19 %) ne savaient pas qu’il s’agissait d’un protocole de recherche. Seize parents (39 %) n’avaient pas compris le principe de la randomisation. La moitié des parents n’était pas capable d’expliquer le but ni le bénéfice potentiel pour leur enfant à participer à cet essai clinique. Quant à la notion d’alternative, elle était connue d’un tiers des parents. Vingtdeux parents (52 %) considéraient qu’ils « n’avaient pas eu le choix » de participer. Conclusion: Si les parents étaient satisfaits de la manière dont les informations leur avaient été données, leur compréhension était le plus souvent incomplète. [Copyright &y& Elsevier]