Search

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]

The article discusses about dumbbell neuroblastoma. According to the article, preoperative chemotherapy is recommended in dealing with dumbbell neuroblastomas which are considered to be unresectable tumors. It is reported that the pre-natal diagnosis of a dumbbell neuroblastoma was effectively administered through premature delivery succeeded by chemotherapy.

Chemotherapy plays a key role in the treatment of cancer in children. Thanks to its efficacy, three out of four children can now be cured. Nevertheless, 25% of paediatric cancer patients go uncured, and chemotherapy-induced long-term side effects justify the continued development of new agents and strategies to fight childhood cancer, including the investigation of off-patent drugs, which are administered on a daily basis in paediatric oncology. In this context, we review the specific characteristics of children compared to adults and the reasons for expanding pharmacological research that focuses on paediatric oncology. Such research is now encouraged and supported by European legislation and new international organisations, such as the consortium, Innovative Therapies for Children with Cancer (ITCC). [ABSTRACT FROM AUTHOR]

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]

Aims: To assess parental understanding and memorisation of the information given when seeking for consent to their child's participation to clinical research, and to identify the factors of significant influence on parents' decision making process.Methods: Sixty eight parents who had been approached for enrolling their child in a clinical oncology or HIV study were asked to complete an interview. Their understanding was measured by a score which included items required to obtain a valid consent according to French legislation.Results: Items that were best understood by parents were the aims of the study (75%), the risks (70%), the potential benefits to their child (83%), the potential benefits to other children (70%), the right to withdraw (73%), and voluntariness (84%). Items that were least understood were the procedures (44%), the possibility of alternative treatments (53%), and the duration of participation (39%). Less than 10% of the parents had understood all these points. Ten parents (15%) did not remember that they had signed up for a research protocol. Thirty three parents (48%) reported no difficulty in making their decision. Twenty four parents (38%) declared that they made their decision together with the investigator; 26 (41%) let the physician decide. Fifty four parents (78%) felt that the level of information given was satisfactory.Conclusion: There was an apparent discrepancy between parents' evaluation of the adequacy of the information delivered and evaluation of their understanding and memorisation. The majority of parents preferred that the physician take as much responsibility as possible in the decision making process. [ABSTRACT FROM AUTHOR]

Aims: To assess parental understanding and memorisation of the information given when seeking for consent to their child's participation to clinical research, and to identify the factors of significant influence on parents' decision making process. Methods: Sixty eight parents who had been approached for enrolling their child in a clinical oncology or HIV study were asked to complete an interview. Their understanding was measured by a score which included items required to obtain a valid consent according to French legislation. Results: Items that were best understood by parents were the aims of the study (75%), the risks (70%), the potential benefits to their child (83%), the potential benefits to other children (70%), the right to withdraw (73%), and voluntariness (84%). Items that were least understood were the procedures (44%), the possibility of alternative treatments (53%), and the duration of participation (39%). Less than 10% of the parents had understood all these paints. Ten parents (15%) did not remember that they had signed up for a research protocol. Thirty three parents (48%) reported no difficulty in making their decision. Twenty four parents (38%) declared that they made their decision together with the investigator; 26 (41%) let the physician decide. Fifty four parents (78%) felt that the level of information given was satisfactory. Conclusion: There was an apparent discrepancy between parents' evaluation of the adequacy of the information delivered and evaluation of their understanding and memorisation. The majority of parents preferred that the physician take as much responsibility as possible in the decision making process. [ABSTRACT FROM AUTHOR]

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]

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]

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m[sup2]). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity. [ABSTRACT FROM AUTHOR]

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]

Hospital-based studies have reported long delays in the diagnosis of paediatric brain tumours. Our objective was to describe the duration between onset of symptoms and diagnosis of medulloblastoma in children and study their clinical determinants in a population-based study. This retrospective cohort study included all paediatric medulloblastoma from a region of France from 1990 to 2005. The median interval from symptom onset until diagnosis for these 166 patients was 65 days and did not decrease during the study period. The most frequent manifestations were: vomiting (88%), headaches (79%), psychomotor regression (60% of children under 3 years), psychological symptoms (27%), strabismus (26%), and asthenia (25%). For one third of the children under 3 years, the diagnosis was made only after life-threatening signs of intracranial hypertension appeared. The prediagnosis interval was significantly longer (median 91 vs. 60 days, p = 0.001) in children with psychological symptoms (27%). Causes for intervals that exceeded the median (65 days) included inconsistent (25%) or late (36%) combination of headaches and vomiting, a period of spontaneous symptom remission (14%-20%), no (24%) or late (57%) neurological signs, psychological symptoms (35%), and a normal neurological examination (27%). Time to medulloblastoma diagnosis in children remains fairly long, despite advances in imaging. Primary-care physicians must be suspicious not only of suggestive neurological signs, but also of non-specific symptoms that persist or are multiple. A meticulous neurological examination and cerebral imaging for such patients might facilitate earlier diagnosis. [ABSTRACT FROM AUTHOR]

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children. [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]

Peripheral blood stem cells (PBSC) harvest may be difficult in young children. Extracorporeal separator line priming by red blood cells is usually required to improve haemodynamic tolerance and efficacy of collection. We present our experience with 24 children weighing less than 15?kg treated between January 1997 and September 1999, in whom we tried to avoid systematic blood priming. The median age and weight at the time of apheresis were 2.4 years and 12?kg, respectively. A total of 48 PBSC were performed. When haemoglobin was less than 12?g/dl, packed red cells were transfused before collection (40% of aphereses). The median cell yield per apheresis was 7.1 (2.2-30.6)x106/kg CD34+ cells and 16.0 (3.3-44.3)x105 CFU-GM/kg. Initial collection failed in three cases. Four children required an additional haematopoietic progenitor mobilization. This procedure allowed PBSC collection without transfusion in 37.5% of children, and was safe (two serious and five mild transient side effects) and effective (median CD34+ cells collected per child: 7.1x106/kg (4.6-30.6) and CFU-GM: 15.1x105/kg (4.7-44.3)). Despite their low weight, insertion of a femoral catheter was avoided in 43% of children.Bone Marrow Transplantation (2003) 31, 171-174. doi:10.1038/sj.bmt.1703825 [ABSTRACT FROM AUTHOR]

We report a 40-year-old patient with familial retinoblastoma also affecting his elder son, who developed multiple fibromas on the periungual or subungual areas of all the fingers. Molecular analysis disclosed a loss of heterozygosity for the RB1 gene in the larger tumour, with disappearance of the normal allele and persistence of the mutated allele only. The similarity of this observation with distal fibrous tumours encountered in other diseases with germline mutations of tumour-suppressor genes such as neurofibromatosis type 1, tuberous sclerosis and multiple endocrine neoplasia type 1 led to the hypothesis that multiple acral benign tumours with a fibrous component might be a cutaneous marker of tumour suppressor gene germline mutation with low sensitivity but high specificity. [ABSTRACT FROM AUTHOR]

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]

BACKGROUND Retinoblastoma (RB) is the most frequent eye tumour in children, with an incidence of 1 in 15–20 000 births. It accounts for 11% of all cancers in the first year of life. Except for the hereditary forms, its causes are not well-known. Studies have recently suggested an increased risk of RB among children born after IVF, but the relevant literature is sparse. We assessed the association between infertility treatment, subfertility and RB. METHODS We included all children living in France diagnosed with RB between 1 January 2000 and 31 December 2006 at the Institut Curie, the national reference centre for RB diagnosis and treatment. We used multiple logistic regression to compare them with a national sample of births in France in 1998 and 2003 (n = 28 170). RESULTS The study included 244 non-familial RB cases. The risk of RB increased with maternal age [adjusted odds ratio (adj OR) = 2.07, 95% confidence interval (CI) 1.33–3.22 at 35–39 years compared with younger than 25 years and adj OR = 2.42, 95% CI 1.22–4.81 at 40 years or older], but the associations with IVF (adj OR = 1.37, 95% CI 0.64–2.95) and ovarian stimulation or intrauterine insemination (adj OR = 1.35, 95% CI 0.77–2.38) were not statistically significant after adjustment for maternal age and tobacco use. Among women who had no infertility treatment, the risk of RB was significantly increased when time to pregnancy exceeded 24 months (adj OR = 2.02, 95% CI 1.17–3.48) compared with time to pregnancy ≤24 months. CONCLUSIONS Our study did not observe a significantly increased risk of RB associated with infertility treatment, in particular with IVF. But we did find an increased risk for women for whom time to pregnancy exceeded 24 months. [ABSTRACT FROM AUTHOR]

Primary objective: Childhood craniopharyngioma, a benign tumour with a good survival rate, is associated with important neurocognitive and psychological morbidity, reducing quality--of--life (QoL). Method: This retrospective study analysed QoL, mood disorders, everyday executive functioning and disease's impact on family life in 29 patients (mean age at diagnosis 7 years 10 months (SD == 4.1); mean follow--up period 6 years 2 months (SD == 4.5)) treated for childhood craniopharyngioma by surgery combined with radiotherapy using proton beam. Assessment included a semi--structured interview and standardized scales evaluating self--report of QoL (Kidscreen 52) and depression (MDI--C) and proxy--reports of QoL (Kidscreen 52), executive functioning (BRIEF) and disease's impact (Hoare and Russel Questionnaire). Results: Twenty--three families answered the questionnaires completely. Overall QoL self--report was within the normal range. QoL proxy--report was lower than self--report. Eleven patients reported depression; 24-38%% had dysexecutive symptoms. A majority of families felt 'very concerned' by the disease. Depression and low parental educational level were associated with lower QoL and higher levels of executive dysfunction. Conclusion: Given the high morbidity of childhood craniopharyngioma, screening for psychosocial outcome, cognitive functioning, including executive functions, mood and QoL should be systematic and specific interventions should be developed and implemented. [ABSTRACT FROM AUTHOR]

AimsTo assess if systematic fundus screening according to an 'intensive' schedule alters ocular outcome and to propose fundus screening schedule guidelines for children related to a retinoblastoma patient.MethodsFor children with a positive family history of retinoblastoma, we perform fundus exams shortly after birth under general anaesthesia and then at regular intervals according to schedules based on the risk. Familial retinoblastoma cases seen at our institution from January 1995 to December 2004 were retrospectively classified as 'screened' or 'non-screened' (NS) and, among the 'screened' patients, as 'intensively screened' (IS) if screening matched our recommendations or 'non-intensively screened' (S). Groups were compared by Fisher exact test for categorical variables and Kruskal-Wallis test for continuous variables.ResultsAmong the 547 retinoblastoma patients managed at our institution during this period, 59 were familial cases. In all, 20 were in the NS group, 23 in the S group, and 16 in the IS group. The number of children enucleated was, respectively, 13, 2, and 0 (P<10−4); external beam radiation (EBRT) was required for, respectively, 6, 0, and 2 children (P<0.009). Chemotherapy burden and visual acuity were not significantly different between groups.ConclusionAn 'intensive' fundus screening schedule decreased the need for enucleation and EBRT. Therefore, despite the heavy burden of the screening schedule, we recommend physicians and health-care professionals to better inform and refer children with a family history of retinoblastoma for genetic counselling and proper fundus screening in specialized centres. [ABSTRACT FROM AUTHOR]

Overcoming childhood cancers is critically dependent on the state of research. Understanding how, with whom and what the research community is doing with childhood cancers is essential for ensuring the evidence-based policies at national and European level to support children, their families and researchers. As part of the European Union funded EUROCANCERCOMS project to study and integrate cancer communications across Europe, we have carried out new research into the state of research in childhood cancers. We are very grateful for all the support we have received from colleagues in the European paediatric oncology community, and in particular from Edel Fitzgerald and Samira Essiaf from the SIOP Europe office. This report and the evidence-based policies that arise from it come at a important junction for Europe and its Member States. They provide a timely reminder that research into childhood cancers is critical and needs sustainable long-term support. [ABSTRACT FROM AUTHOR]

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]

Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability. A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated. Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16–23 kg; 0.95 mg/kg for >23–34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3–17.2 years (median 5.6 years). No difference in AUC values was observed between weight strata (mean ± SD 1248 ± 205 μmol·min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900–1500 μmol·min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window. [ABSTRACT FROM AUTHOR]

Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability. A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated. Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16–23 kg; 0.95 mg/kg for >23–34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3–17.2 years (median 5.6 years). No difference in AUC values was observed between weight strata (mean ± SD 1248 ± 205 μmol·min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900–1500 μmol·min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window. [ABSTRACT FROM AUTHOR]

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]

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome’, as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m−2 for Group A and 100 mg m−2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.British Journal of Cancer (2006) 95, 571–580. doi:10.1038/sj.bjc.6603288 www.bjcancer.com Published online 1 August 2006 [ABSTRACT FROM AUTHOR]

Retinoblastoma is the most frequent malignant tumour in children with an incidence of 1 in 15,000 live births. Sixty per cent of retinoblastoma cases involve one eye (unilateral):median age at diagnosis is 2 years, and most of these forms are non-hereditary. Forty percent of retinoblastoma cases are bilateral: the median age at diagnosis is 1 year. All bilateral and multifocal unilateral forms are hereditary. Hereditary retinoblastoma is a cancer predisposition syndrome: the presence of a constitutional RB1 gene mutation in patients implies they have a greater than 90% chance of developing retinoblastoma. They also have an increased risk of developing other types of cancer. Leucocoria and strabismus are the most frequent revealing symptoms. Diagnosis is made by fundoscopy. US, MRI and CT scans may contribute to diagnosis. Treatment of patients with retinoblastoma should take into account the various aspects of the disease: the risk to vision, the possible hereditary nature of the disease, the life threatening risk. Enucleation is still often necessary in unilateral disease; adjuvant treatment might be given according to histological risk factors. Conservative treatmentmay be to at least one eye in most of bilateral cases: thermotherapy combined with chemotherapy, cryotherapy and brachytherapy. External beam radiation therapy should be restricted to large ocular tumours and diffuse vitreous seeding ocular because of the risk of late effects, including secondary sarcoma. Long term follow-up of patients with retinoblastoma is important, as well as information given at an early stage to them and their family about the risks of second primary tumours and of transmission to their off springs. [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: 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]

In order to assess the role of genetic predispositionin the induction of radiation-induced tumors, we performed statistical analysis on data from the literature and from our own Institute with regard to theage at onset and the latency period of osteosarcoma as the second primarytumor for retinoblastoma with or without subsequent radiotherapy. In retinoblastomasurvivors who subsequently developed osteosarcoma, the age at onset of retinoblastomawas young (average of 12 months) in both unilateral and bilateral forms. Thissuggests that all or almost all of the patients were genetically predisposedby a mutation of one allele of the RB1 gene. For retinoblastoma patients, osteosarcomas occurred 1.2 years earlier inside than outside the radiationfield. The latency period between radiotherapy and osteosarcoma onset was1.3 years shorter inside than outside the radiation field. Interestingly,a bimodal distribution of latency periods was observed for osteosarcomasarising inside, but not outside the radiation field: 40% occurred after ashort latency, while the latency of the remaining 60% was comparable to thatof osteosarcoma occurring outside the radiation field. This suggests thatdifferent mechanisms may be involved in radiocarcinogenesis. A radiation-inducedmutation of the second RB1 allele may be the cause of osteosarcomas occurring after a short delay, while other genes may be affected in those occurringafter a longer delay. [ABSTRACT FROM AUTHOR]