Search

Purpose There is limited evidence to define the role of radiation therapy in children with metastatic rhabdomyosarcoma (mRMS). In the international BERNIE study, children with mRMS or non-RMS soft tissue sarcoma were randomized to receive standard chemotherapy with or without bevacizumab, with radiation therapy to all disease sites recommended after chemotherapy cycle 6. We retrospectively evaluated the impact of radiation therapy on survival in the mRMS cohort. Methods and Materials Patients were grouped according to the radiation therapy they received: radical, partial, or none. Radical irradiation was defined as radiation therapy delivered to all disease sites, unless a site was completely surgically resected. Partial irradiation was defined as radiation therapy to ≥1, but not all, disease sites. Landmark analysis excluded patients with an event before day 221. Overall survival (OS) and event-free survival (EFS) were modeled using Cox proportional hazards models. Results Of 102 patients with mRMS, 97 were included in the analysis for OS and 85 for EFS. Overall, 27 patients received radical irradiation, 46 partial irradiation, and 24 no irradiation. EFS was not significantly different among patient groups after adjustment for prognostic factors (hazard ratio [HR] = 0.520; P = .054 for any vs no irradiation). Radiation therapy was associated with improved OS compared with no radiation therapy (adjusted HR = 0.249; P = .00025), with OS being greater for radical versus partial irradiation (HR = 0.245; P = .039). The 3-year OS rate was 84%, 54%, and 23% for patients receiving radical, partial, and no irradiation, respectively. Radical treatment (surgery, irradiation, or both) of the primary site improved EFS and OS compared with no treatment. Conclusions These findings demonstrate variability in the application of radiation therapy for mRMS and support the routine use of radical treatment to the primary site. Radical irradiation to metastatic sites may further improve OS. The burden of such treatment should be balanced against prognosis; further studies are needed.

Background The current biomarkers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) have limited sensitivity/specificity for diagnosing malignant germ cell tumors (GCTs) and “marker-negative” patients require histological confirmation for diagnosis. However, GCTs at intracranial sites are surgically relatively inaccessible and biopsy carries risks. MicroRNAs from the miR-371~373 and miR-302/367 clusters are over-expressed in all malignant GCTs and, in particular, miR-371a-3p shows elevated serum levels at diagnosis for testicular disease. Methods Using our robust preamplified qRT-PCR methodology, we quantified miR-371a-3p levels in serum and cerebrospinal fluid (CSF) in a series of 4 representative clinical cases, 3 with intracranial malignant GCT and 1 with Langerhans cell histiocytosis (LCH), compared with appropriate control cases. Results Serum and/or CSF miR-371a-3p levels distinguished those with intracranial malignant GCTs from LCH and, if known in real time, could have helped clinical management. The benefits would have included (1) the only confirmatory evidence of an intracranial malignant GCT in 1 case, supporting clinical decision making; (2) early detection of intracranial malignant GCT in another, where an elevated CSF miR-371a-3p level preceded the histologically confirmed diagnosis by 2 years; and (3) confirmation of an intracranial malignant GCT relapse with an elevated serum miR-371a-3p level, where serum and CSF AFP and HCG levels were below thresholds for such a diagnosis. Conclusions This series highlights the potential for microRNA quantification to assist the noninvasive diagnosis, prognostication, and management for patients with intracranial malignant GCTs. Serum and CSF should be collected routinely as part of future studies to facilitate the extension of these findings to larger patient cohorts.

We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS). Eligible patients aged ≥6 months to

BACKGROUND: Wilms tumour is the most common childhood renal cancer and is genetically heterogeneous. While several Wilms tumour predisposition genes have been identified, there is strong evidence that further predisposition genes are likely to exist. Our study aim was to identify new predisposition genes for Wilms tumour. METHODS: In this exome sequencing study, we analysed lymphocyte DNA from 890 individuals with Wilms tumour, including 91 affected individuals from 49 familial Wilms tumour pedigrees. We used the protein-truncating variant prioritisation method to prioritise potential disease-associated genes for further assessment. We evaluated new predisposition genes in exome sequencing data that we generated in 334 individuals with 27 other childhood cancers and in exome data from The Cancer Genome Atlas obtained from 7632 individuals with 28 adult cancers. FINDINGS: We identified constitutional cancer-predisposing mutations in 33 individuals with childhood cancer. The three identified genes with the strongest signal in the protein-truncating variant prioritisation analyses were TRIM28, FBXW7, and NYNRIN. 21 of 33 individuals had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted (p=0·00098). We also found a strong association with the rare epithelial subtype of Wilms tumour, with 14 of 16 tumours being epithelial or epithelial predominant. There were no TRIM28 mutations in individuals with other childhood or adult cancers. We identified truncating FBXW7 mutations in four individuals with Wilms tumour and a de-novo non-synonymous FBXW7 mutation in a child with a rhabdoid tumour. Biallelic truncating mutations in NYNRIN were identified in three individuals with Wilms tumour, which is highly unlikely to have occurred by chance (p

INTRODUCTION: The International Society of Paediatric Oncology (SIOP) protocols recommend pre-operative chemotherapy appropriate for Wilms tumours (WT) in children with renal tumours aged ≥6 months, reserving biopsy for ‘atypical’ cases. The Children’s Cancer and Leukaemia Group (CCLG) joined the SIOP-WT-2001 study but continued the national practice of biopsy at presentation. METHOD: Retrospective study of concordance between locally reported renal tumour biopsies and central pathology review nephrectomy diagnoses of children enrolled by CCLG centres in SIOP-WT-2001 Study. RESULTS: Biopsy reports were available for 552/787 children with unilateral tumours. 36/552 (6.5%) were non–diagnostic: 2 normal tissue, 12 necrotic, 9 insufficient sample and 13 indeterminate results (disproportionately non-WTs). The sensitivity and specificity of biopsy to identify tumours that did not require SIOP empirical pre-operative chemotherapy were 86.0% and 99.6%, respectively. 13/548 (2.4%) biopsy results were discordant with nephrectomy; non-WTs other than renal cell carcinoma and clear cell sarcoma (CCSK) were poorly recognised. In children aged 6-119 months, 480/518 (91.6%) had WT or nephroblastomatosis. 5/518 (1%) had benign tumours, only one diagnosed on biopsy. Biopsy results correctly changed clinical management in 25/518 (4.8%), including identifying 19/20 CCSKs, but would have led to overtreatment in 5/518 (1%) or undertreatment in 4/518 (0.8%). In children aged ≥10 years, biopsy correctly changed management in 5/19 (26%) cases with no discordance. CONCLUSION: Biopsy is less effective at identifying non-WTs than WTs and rarely changes management in younger children. Biopsy should be reserved in SIOP protocols for children ≥10 years and in younger children with clinical or radiological features inconsistent with WT.

BACKGROUND There are global variations in radiotherapy approaches for icGCT. An understanding of patterns of disease recurrence correlated with radiation techniques and doses is important in standardising and improving the quality of radiotherapy using high-precision techniques. METHODS AND RESULTS Data from 20 patients with tumour recurrence after treatment within the SIOP GCT96 study in the UK were analysed. Seven (35%) patients had germinoma and 13 (65%) had non-germinoma. Twelve patients had local recurrence, 5 had metastatic and 3 had local and metastatic disease. Radiotherapy details were retrieved in only 8 patients (40%). Six patients had received focal radiotherapy and two craniospinal radiotherapy. Of the patients who received focal radiotherapy, 4 had recurrence within the radiation portal, one had periventricular recurrence and one had marker-positive recurrence with no radiological lesions. Both patients who received CSI recurred within the CSF space. The main reasons for poor retrieval of treatment details were difficulty in retrieving archived information and that the study was conducted during a period before PACS or electronic radiotherapy records. CONCLUSION This study highlights the importance prospective data collection and analysis to understand the patterns of recurrence in icGCT. Even within a prospective study, radiotherapy techniques varied between centres. There is therefore an urgent need for centralised radiological review and prospective radiotherapy quality assurance measures in future clinical trials.

INTRODUCTION The outcome for children with relapsed or progressed brain tumours is poor. The aim of this project was to identify total number of children who have relapsed or progressed with Brain tumour and to determine the types of tumours, treatment offered and assess outcome. METHODS This is a retrospective study of all patients treated for relapsed or progressed brain tumours between 2007 and 2017 at the Royal Hospital for children. Patients were identified using the unit database. Clinical data included demographics, histologic diagnosis, treatment characteristics and outcome which was obtained from electronic records. RESULTS 46 children were included (22M:24F). The median age of diagnosis was 5 years. There were 16 histological subtypes of brain tumours: pilocytic astrocytoma (n=12, 26%), optic pathway glioma (n=4,7%), medulloblastoma (n=8, 17%), ependymoma (n=4, 9%), high grade glioma (n=3, 7%, DIPG (n=2, 4%) and others 13(32.2%). 28(61%) had relapsed at a median time of 18 months. Tumour progression occurred in 18(31%) at a median time of 21.5 months. Post-relapse or progression therapy included surgery (14, 30%), chemotherapy (17, 40%) and radiotherapy (5, 10.9%). 50% of the patients remain alive with 17(37%) being stable and 6(13%) with progression of disease. 50% had died of disease progression. CONCLUSIONS The relapse and or progression was seen 61% of patients. The commonest tumours in this cohort were pilocytic astrocytoma and medulloblastoma. Chemotherapy was the most used regimen followed by surgery and radiotherapy. Primary dissemination at the time of diagnosis was associated with poor prognosis.

Vandetanib has been shown to improve progression-free survival in adults with advanced medullary thyroid cancer. This article describes a pediatric patient with metastatic medullary thyroid cancer secondary to sporadic multiple endocrine neoplasia 2B, treated with vandetanib. At presentation, he had an inoperable primary tumor, with carotid encasement, and pulmonary metastases. Vandetanib induced a significant response: calcitonin and carcinoembryonic antigen levels both fell considerably, primary tumor maximal diameter decreased by 68%, and pulmonary metastases became no longer detectable. This allowed surgical resection of the primary tumor. The patient remains well after over 6 years of vandetanib therapy, with no treatment toxicity.

BACKGROUND: Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS: We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS: A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. CONCLUSIONS: The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).

Introduction : Advancements in the treatment of paediatric cancer in recent years, have led to significant improvements in survival. Despite this there is still a significant proportion of patients whose disease; progress despite treatment or recurs after treatment. The factors which determine survival in patients with progressive or recurrent disease are unclear at present. The aim of this study was to investigate the factors which determine prognosis in cases of recurrent or progressive paediatric cancer. Methods : All patients with a diagnosis of solid or CNS tumour, treated at Yorkhill hospital Glasgow between January 1 st 1999 and December 31 st 2009 were evaluated for this study. Of the 339 patients 124 had progressive or recurrent disease. 96 of the 124 cases had data available for analysis. Log rank testing was used to compare survival amongst different types of tumour. Multivariate cox proportional hazard tests were used to model the influence on risk of death of the investigated prognostic factors. Results : 52% of patients were female, 55% had solid tumour. 76 deaths occurred during follow up, all of which were cancer related. 76% of deaths occurred within a year of progression or recurrence and median overall survival time was 240 days. There were significant differences in the survival of different tumour types at initial diagnosis (p=0.048). The treatment patients received after progression or recurrence and the interval from completion of treatment to progression or recurrence were associated with risk of death (p

We describe a child with advanced, metastatic, inoperable medullary carcinoma of thyroid associated with multiple endocrine neoplasia 2B and rearranged during transfection mutation with a positive response to vandetanib treatment. He responded well with a fall in calcitonin levels and a reduction in size of the thyroid malignancy, lymph nodes, and pulmonary metastases. He has been on vandetanib for 4 years with good clinical and biochemical response. Vandetanib has a role in the treatment of patients including children with inoperable locally advanced and metastatic medullary carcinoma of thyroid. More information is needed on its use in children and long-term outcome.

Purpose: To assess the clinical activity of irinotecan as single drug in children with refractory or recurrent hepatoblastoma. Patients and methods: Four cycles of irinotecan were administered (20 mg/m(2)/day intravenous (i.v.) infusion on days 1-5 and 8-12, every 21 days) unless tumour progression occurred or resectability was achieved earlier. Tumour response was assessed according to modified SIOPEL and Response Evaluation Criteria In Solid Tumours (RECIST) criteria. Main end-points were best overall response rate (RR), early progression rate (EPR) and progression free survival (PFS). Results: Twenty-four eligible patients (median age 58.0 months; 19 boys) were enrolled in the study (11 relapses, 13 refractory diseases). Of the 23 evaluable patients six had an overall partial response, 11 stable disease and six progressive disease, of which four were early progression (RR: 26%, EPR: 17%). In eight patients the residual tumour could be completely resected; seven patients became tumour free. At last follow-up 12 patients were alive (six with no evidence of disease, six with disease). PFS at 1 year was 24%. Patients with relapse had a higher RR than patients with refractory disease (46% versus 8%) and patients with isolated lung lesions showed a better response than patients with other tumour localisations (50% versus 13%). The main grade 3-4 toxicities, diarrhoea and neutropenia, occurred in half of the patients. Conclusion: Irinotecan has a significant anti-tumour activity and acceptable toxicity in patients with relapsed hepatoblastoma and therefore should be considered for the treatment of these patients. Exploration of the role of irinotecan in the initial treatment of hepatoblastoma is warranted. (C) 2012 Elsevier Ltd. All rights reserved

10514Background: SIOPEL 6 is a phase III randomized trial in SR-HB which is defined as tumor extension limited to PRETEXT I, II or III, no portal or hepatic vein involvement, no intra-abdominal ext...

Overall survival from childhood malignancies has dramatically improved, with survival rates now reaching over 70 %. Although improvements in radiotherapy and surgery have reduced the late sequelae of curative therapy, chemotherapy still remains the mainstay of treatment for most childhood cancers. Nevertheless, some types of childhood cancer remain a difficult challenge, and for those who survive the burden of late effects can be considerable. The current paradigm for new cancer therapies is to increase our knowledge of the molecular basis of carcinogenesis, followed by the development of cancer-cell specific therapies. During the past 10 years, initiatives have been undertaken by paediatric oncologists to further promote the clinical evaluation of new anti cancer compounds in children within national academic paediatric groups. Through proper evaluation in collaborative clinical trials we will learn how best to use these new therapeutic approaches and improve the survival rates and reduce toxicity for children with cancer.

Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor, we conducted a genome-wide association study in 757 individuals with Wilms tumor (cases) and 1,879 controls. We evaluated ten SNPs in regions significantly associated at P5 × 10(-5) in two independent replication series from the UK (769 cases and 2,814 controls) and the United States (719 cases and 1,037 controls). We identified clear significant associations at 2p24 (rs3755132, P = 1.03 × 10(-14); rs807624, P = 1.32 × 10(-14)) and 11q14 (rs790356, P = 4.25 × 10(-15)). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate association signals at 5q14, 22q12 and Xp22.

Background Radiotherapy remains a widely accepted postoperative treatment modality for unresectable or recurrent low-grade glioma (LGG). However, there is increasing evidence to suggest that chemotherapy can delay and may obviate the need for radiotherapy in progressive/recurrent LGG. The majority of the published experience is in children with hypothalamic/optic chiasmatic lesions and little information is available regarding its use in LGG of the brainstem. Procedure We describe clinical characteristics and course of children with LGG of the brainstem who received carboplatin-based chemotherapy in two institutions over 10 years (1996–2006). This was a retrospective review of consecutively treated children with LGG of the brainstem (midbrain, pons, medulla, and upper cervical cord). Vincristine and carboplatin were first-line chemotherapy regimen used in all patients. Results In this series, there were 16 children (9 males) with median age at diagnosis of 4.2 years (range 0.5–8). Eight children were treated at diagnosis while the remaining eight received chemotherapy after either radiological progression or clinical deterioration. After a median follow-up of 57 months (range 20–136) from initiation of chemotherapy all children are alive and 11 remain progression free (1 complete response, 8 with partial response + minor response, and 2 stable diseases). Conclusions The efficacy of this chemotherapy regimen in this series supports its role in children with progressive unresectable LGG of brainstem. Pediatr Blood Cancer. 2010;55:471–477. © 2010 Wiley-Liss, Inc.

Background: The SIOPEL 6 randomised phase III trial was designed to investigate the efficacy of sodium thiosulphate (STS) in reducing ototoxicity in patients receiving cisplatin monotherapy for standard-risk hepatoblastoma. Preliminary results from the trial recently presented at ASCO indicated comparable response rates between the two study arms. The trial has now completed patient recruitment, with final evaluation of hearing loss at ≥3.5 years of age awaited as the primary endpoint of the trial. As part of the clinical study, blood samples were collected pre-treatment and 24 hours following cisplatin administration, to investigate the potential impact of STS on the formation of platinum-DNA adduct levels in leucocytes. Patients and methods: Whole blood samples (5-10ml) were taken prior to cisplatin treatment and 24 hours following the start of a 6 hour cisplatin infusion, with STS administered 6 hours after the end of cisplatin administration in patients randomised to receive STS. Samples were collected in EDTA blood tubes and frozen at -20°C or -80°C prior to transport to Newcastle for analysis. DNA was isolated from whole blood using Qiagen DNA blood Maxi kits and the concentration of DNA in each sample quantified by UV absorption. DNA samples were diluted in 3.5% nitric acid and hydrolyzed overnight at 70°C. Platinum-DNA adduct levels were determined by ICP-MS analysis, with results expressed in units of nmoles platinum/g DNA. Results: Blood samples were collected from a total of 37 patients, with 22/37 (59%) patients having received cisplatin followed by STS and 15/37 (41%) patients cisplatin alone. A significant difference in median platinum-DNA adduct levels was observed in patients receiving cisplatin followed by STS (median: 6.7 nmol/g DNA; range: 4.2 - 14.0), as compared to patients receiving cisplatin alone (median: 13.5 nmol/g DNA; range: 4.3 - 165.7) (P = 0.0011). Conclusion: Results indicate that the formation and/or longevity of platinum-DNA adducts determined in whole blood samples collected 24 hours following cisplatin administration are influenced by the co-administration of STS, with significantly higher levels observed in patients receiving cisplatin alone. Bearing in mind the comparable response data reported between the two randomisation study arms, these data would indicate that platinum-DNA adduct formation in leucocytes may act as a surrogate marker, providing novel insights into the mechanism of the otoprotective effects of STS when used in combination with cisplatin. Acknowledgements: Work supported by Cancer Research UK, the North of England Children's Cancer Research Fund and the Experimental Cancer Medicine Centre Network. Citation Format: Gareth J. Veal, Milind Ronghe, Bruce Morland, Edward Neuwelt, Rudolf Maibach, Penelope Brock. Cisplatin-DNA adduct formation in patients receiving cisplatin +/- sodium thiosulphate (STS) in the SIOPEL 6 randomized phase III trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3194.

11054Background: Thephase II BERNIE study evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic RMS/NRSTS. Methods: Eligible patients...

Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the commonest childhood kidney cancer. In this study we analysed all five loci in 120 Wilms tumors. We identified epigenetic 11p15 abnormalities in 69% of tumors, 37% were H19 epimutations and 32% were paternal uniparental disomy (pUPD). We identified mutations of WTX in 32%, CTNNB1 in 15%, WT1 in 12% and TP53 in 5% of tumors. We identified several significant associations: between 11p15 and WTX (P=0.007), between WT1 and CTNNB1 (P less than 0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P less than 0.001). We next used these data to stratify Wilms tumor into three molecular Groups, based on the status at 11p15 and WT1. Group 1 tumors (63%) were defined as 11p15-mutant and WT1-normal; a third also had WTX mutations. Group 2 tumors (13%) were WT1-mutant. They either had 11p15 pUPD or were 11p15-normal. Almost all had CTNNB1 mutations but none had H19 epimutation. Group 3 tumors (25%) were defined as 11p15-normal and WT1-normal and were typically normal at all five loci (P less than 0.001). We also identified a novel clinical association between H19 epimutation and bilateral disease (P less than 0.001). These data provide new insights into the pattern, order, interactions and clinical associations of molecular events in Wilms tumor.

Brain stem tumors account for 10–15% of all primary childhood CNS tumors. Most of the brain tumors arising in the brain stem are gliomas. With recent advances in neuro-imaging, particularly the advent of magnetic resonance imaging (MRI) and careful correlation of clinical presentation, location, and growth pattern, it has become evident that brain stem tumors are a heterogeneous group of neoplasms, divisible into distinct subgroups, such as diffuse intrinsic pontine tumors and focal, dorsal exophytic, cervicomedullary tumors. Diffuse intrinsic pontine gliomas (DIPG) constitute 80% of the pediatric brain stem tumors. These tumors are typically highgrade gliomas and have uniformly poor prognosis.

Three children presenting with pain in the arm and variable neurological signs are described. Each child had several hospital visits before being accurately diagnosed with a soft-tissue sarcoma in the axillary fossa. All presented with increasing pain at rest or on shoulder movement, and with some evidence of neurological dysfunction in the upper limb. Two of the girls had unremitting night pain. Delays in diagnosis of sarcomas are common despite internationally agreed referral guidelines, which are readily accessible. In children with unusual upper limb neurological symptoms, it is essential to have a high index of suspicion, and examine the arm including the axilla, thoroughly, and refer them early for a specialist opinion.

Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor. We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.

Children’s cancers are rare and account for 1% of all malignancies. Within Europe this represents some 12,000 new cases each year, with approximately 1,600 per year in the UK. In the UK, 1 in every 600 children under 15 years of age develop cancer. Although rare, childhood cancer is the second commonest cause of death in children between 1–14 years of age. These cancers are quite different from cancers affecting adults. Most adult tumors are carcinomas and are usually classified by their site of origin, whereas pediatric tumors occur in different parts of the body, look different under the microscope, and are classified by histological subtypes. Tumor types that are common to both adults and children, such as lymphomas and leukemia, differ in their biology, behavior, and prognosis and hence demand different treatment. They also respond differently to treatment. Some embryonal tumors presenting in infancy undergo spontaneous remission or maturation (e.g., Stage IVS neuroblastoma).

Thromboembolic disease (TED) is increasingly recognized as a major cause of morbidity and mortality in tertiary pediatrics. Children younger than 1 year of age and teenage girls are at greatest risk of thromboembolism. Although anticoagulation therapy is the treatment of choice for TED, the treatment strategy is often difficult, especially in children. Treatment relies largely on anticoagulation with heparin and warfarin. Recommendations for antithrombotic therapy in children have been loosely extrapolated from recommendations for adults; however, it is likely that optimal treatment of children with TED differs from adults because of important ontogenic features of hemostasis that affect both the pathophysiology of the thrombotic processes and the response to antithrombotic agents. Until recently, the primary treatment for TED has been unfractionated heparin (UFH) in conjunction with warfarin. Warfarin, the most commonly used oral anticoagulant, acts through inhibition of the vitamin K-dependent transcarboxylation reactions that convert precursors of clotting factors into their active form. Appropriate use of UFH and warfarin requires close patient monitoring and dosage adjustments to ensure tolerability and efficacy. In recent years, low molecular weight heparins (LMWH) have become available as alternatives to UFH and warfarin, for both the prevention and treatment of TED. Potentially, LMWH have significant advantages. They have superior pharmacokinetics, which results in minimal laboratory monitoring, offering important benefits to children with poor venous access. Based on available data, LMWHs are at least as effective and well tolerated as UFH, and are more convenient. Although LMWHs are more expensive than UFH, the expense is likely to be offset by savings from a reduced hospital stay.

TPS10094 Background: The SIOPEL 3 trial of Cis monotherapy and surgery in SR-HB showed a 3yr OS of 95% at 5 years. SR-HB is defined as tumor extension limited to PRETEXT I, II or III, no involvemen...

AIMS—To evaluate the pharmacokinetics of once daily (OD) gentamicin and its effectiveness as part of an OD regimen for the empirical treatment of febrile neutropenia in children with cancer. SUBJECTS—59 children aged 6 months to 16 years (mean (SD) 5.7 (4) years) with febrile neutropenia (neutrophil count < 0.5 × 109/l) after chemotherapy. METHODS—Over one year, 113 febrile neutropenic episodes were treated empirically with an OD antibiotic regimen of ceftriaxone (80 mg/kg; maximum 4 g) and gentamicin (7 mg/kg; infused over 60 minutes, no maximum). The patients were assessed after 48hours. RESULTS—86 of the 113 episodes settled with the first line antibiotic regimen. In 29 episodes, blood cultures identified a causative bacterial pathogen; for 17 of these, the first line antibiotic regimen was adequate; in four episodes, although the episode settled, ceftriaxone was replaced by a more appropriate antibiotic and OD gentamicin was continued; in the remaining eight episodes, a glycopeptide antibiotic was deemed necessary. There was no failure of treatment in organisms sensitive to gentamicin, including Pseudomonas aeruginosa. In 27 episodes (24%), resolution was obtained by the empirical introduction of a second line regimen of ceftazidime and a glycopeptide antibiotic, and/or amphotericin. Gentamicin concentrations were measured in 110 episodes and they were all below the 24 hour line indicating that there was no need to change the dosing interval. In two episodes (2%), serum creatinine rose transiently by more than 50% of the baseline concentration. Although there was no vestibular toxicity, three of 30 children who underwent pure tone audiometry reported high frequency hearing loss in one ear. CONCLUSION—OD gentamicin can be used safely and effectively to treat febrile neutropenia in children with cancer. When used for a short period (< 5 days), in children not receiving other nephrotoxic drugs and who have normal serum creatinine, serum gentamicin estimations are unnecessary.

10039 Background: SR-HB is defined as tumor extension limited to PRETEXT I, II or III, no portal, hepatic veins, or intra-abdominal extra-hepatic disease, AFP > 100ng/ml and no metastases. Cis can ...