Bruce Morland

• Consultant at Birmingham Children's Hospital NHS Foundation Trust

Liver tumors account for approximately 2% of all pediatric malignancies. Children with advanced stages of hepatoblastoma (HB) are cured only 50–70% of the time while children with advanced hepatocellular carcinoma (HCC) have a <20% 5-year overall survival. This scoping review was performed to highlight the paucity of rigorous, reliable data guiding...

PURPOSE Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). MATERIALS AND METHODS Patients age 1-21 years with RR-HRNB with adequate org...

Background and Aims Hepatoblastoma (HB) is the predominant form of pediatric liver cancer, though it remains exceptionally rare. While treatment outcomes for children with HB have improved, patients with advanced tumors face limited therapeutic choices. Additionally, survivors often suffer from long-term adverse effects due to treatment, including...

Background: Liver tumors are rare in children with histologic heterogeneity that makes diagnosis challenging. Systematic histopathological review, performed as part of collaborative therapeutic protocols, identified relevant histologic subtypes that are important to distinguish. The Children's Hepatic tumors International Collaboration (CHIC) was...

Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens. In this study, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB. Paired tumor and adjacent tissues from 31 HBs and a validation s...

Background and Aims: Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens, commonly cisplatin. Here, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB.Methods: Paired tumor and adjacen...

Background: The main pediatric liver tumors are hepatoblastoma (HB) and, to a lesser extent, pediatric hepatocellular carcinoma (HCC). HB appears at an early age (<3 years) while HCC is diagnosed mainly in older children (>8 years) or adolescents and it is usually associated to underlying metabolic diseases. HEM-NOS (Hepatocellular malignant neopla...

Childhood liver cancers hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are rare diseases but with a rising incidence. HEMNOS (Hepatocellular malignant neoplasm, not otherwise specified) is a recent entity with histopathological features of HB and HCC. Current chemotherapy treatments are effective to shrink tumor before surgery, nonetheless...

Background and Aims: Management of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative platin-based regimens, commonly cisplatin. Here, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in HB cell lines, organoids and murine models. Methods: Paire...

Background: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). Patients and meth...

This Clinical Practice Guideline provides key recommendations on the management of bone sarcomas. // Recommendations have been agreed following a consensus meeting of representatives from ESMO, EURACAN, GENTURIS and ERNPaedCan. // Authorship includes a multidisciplinary group of experts from different institutions and countries worldwide.

Importance Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric on...

Background This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours. Patients and methods Patients (aged 6 months to <18 years) with recurrent/refractory solid tumours received oral regorafenib once daily for 3 weeks on/1 week off. The...

Background Tyrosine kinase inhibitors have shown activity in osteosarcoma and might enhance the efficacy of chemotherapy. We aimed to determine the recommended phase 2 dose and antitumour activity of lenvatinib with etoposide plus ifosfamide in patients with refractory or relapsed osteosarcoma. Methods This multicentre, open-label, multicohort, ph...

Soft tissue sarcomas (STSs) comprise ∼80 entities defined by the World Health Organization (WHO) classification based on a combination of distinctive morphological, immunohistochemical and molecular features.1 These ESMO–EURACAN–GENTURIS (European Society for Medical Oncology; European Reference Network for Rare Adult Solid Cancers; European Refere...

Background & Aims: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for pati...

This study (NCT01288573) investigated plerixafor’s safety and efficacy in children with cancer. Stage 1 investigated the dosage, pharmacokinetics (PK), pharmacodynamics (PD), and safety of plerixafor + standard mobilization (G-CSF ± chemotherapy). The stage 2 primary endpoint was successful mobilization (doubling of peripheral blood CD34+ cell coun...

Background Post‐transplant malignancies, that is, lymphomas, are a recognized complication in intestinal transplant recipients but are mostly secondary to EBV infection. There is an increased risk for malignancies in unusual sites in intestinal transplant recipients as compared to other solid organ transplants and the general population. Objective...

Background BEACON-Neuroblastoma is a randomized phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status w...

Background Lenvatinib (LEN) is a multikinase inhibitor of VEGFR1–3 and other targets. We report data from phase Ib dose-finding and phase II expansion cohorts of LEN + etoposide + ifosfamide in pts with r/r osteosarcoma. Methods Pts were aged 2 to ≤ 25 years with r/r osteosarcoma and <2 prior VEGF-targeted therapies. The phase Ib starting dose was...

Background: Higher incidence of posttransplant lymphoproliferative disorder (PTLD) is reported in the pediatric small bowel transplant (SBTx) population, which may be associated with more aggressive disease and poorer outcome as compared to liver transplant (LTx) recipients. We aim to compare the characteristics and outcome of PTLD in pediatric SB...

Purpose: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or p...

Background: To evaluate the impact of a microscopically positive resection margin (microPRM) on the outcome of hepatoblastoma patients pretreated with chemotherapy. Methods: Local recurrence and survival rates of 431 children treated in the SIOPEL 2 and 3 trials were analysed comparing 58 patients with microPRM with 371 who had a complete resect...

Primary bone tumours are rare, accounting for < 0.2% of malignant neoplasms registered in the EUROCARE (European Cancer Registry based study on survival and care of cancer patients) database. Different bone tumour subtypes have distinct patterns of incidence, and each has no more than 0.3 incident cases per 100 000 per year. Osteosarcoma (OS) and E...

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel)...

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 eff...

Dexrazoxane can prevent anthracycline-associated cardiotoxicity. However, in 2011, its use in children was contraindicated by the EMA over concerns of increased risk of infection, myelosuppression and second primary malignancies, and because its efficacy in children had not then been established. We review here the evidence published since 2011, wh...

Imaging is crucial in the assessment of children with a primary hepatic malignancy. Since its inception in 1992, the PRETEXT (PRE-Treatment EXTent of tumor) system has become the primary method of risk stratification for hepatoblastoma and pediatric hepatocellular carcinoma in numerous cooperative group trials across the world. The PRETEXT system i...

Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged...

EBV-CTL immunotherapy targets EBV antigens expressed by tumor cells in PTLD. Data on outcome of EBV-CTL in pSOT patients are limited. The aim of the study is to describe our experience with allogeneic, third-party EBV-CTL for the treatment of PTLD in pSOT patients in a single tertiary center. Retrospective review was performed of all pSOT patients...

Background: Pediatric retroperitoneal tumors in the renal bed are often large and heterogeneous, and their diagnosis based on conventional imaging alone is not possible. More advanced imaging methods, such as diffusion-weighted (DW) MRI and the use of intravoxel incoherent motion (IVIM), have the potential to provide additional biomarkers that coul...

Background: The purpose of this study was to evaluate clinical characteristics, treatment, and survival of children, who were diagnosed with hepatoblastoma (HB) in their first 6 months of age, enrolled in the SIOPEL 2 and 3 protocols. Methods: Seventy-nine patients, treated between 1994 and 2006, were analyzed after stratification into three age...

Cartilage–hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia characterized by short‐stature, sparse hair and impaired cellular immunity. We describe a young girl who was diagnosed with CHH based on the findings of recurrent infections, short stature with metaphyseal chondrodysplasia, and a confirmed bi‐allelic RMRP gene mutation. At 1...

New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed...

The Milan criteria were originally defined in the context of adult liver transplantation for patients with hepatocellular carcinoma and cirrhotic livers. The aim of the criteria was to select patients with small tumours and no disease spread who had a good chance of success, thus avoiding futile transplants. This objective was reached successfully....

10544 Background: LEN is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet-derived growth factor receptor α, RET, and KIT. LEN is approved in adults for radioiodine-refractory differentiated thyroid cancer (DTC) and in combination with everolimus in patients (pts) with advanced...

In the past decade, the landscape of drug development in oncology has evolved dramatically; however, this paradigm shift remains to be adopted in early phase clinical trial designs for studies of molecularly targeted agents and immunotherapeutic agents in paediatric malignancies. In drug development, prioritization of drugs on the basis of knowledg...

Pediatric hepatic tumors are rare and demand a specialist multidisciplinary approach for successful management. Accurate staging and diagnostic work-up is essential to enable correct risk stratification for treatment. Despite the rarity of the tumor, international collaboration and prospective clinical trial activity has dramatically improved the s...

Objectives: Dose-finding trials are fundamental to develop novel drugs for children and adolescents with advanced cancer. It is crucial to maximise individual benefit, whilst ensuring adequate assessment of key study end-points. We assessed prognostic factors of survival in paediatric phase I trials, including two predictive scores validated in ad...

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....

10514 Background: 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 extrahepatic disease, AFP >100ng/ml and no metastases. A serious permanent side effect of cisplatin (Cis) therapy is bilateral high-frequency hearing loss...

Background: EE99R2Loc (ISRCTN61438620) was conducted in 12 countries, by 4 cooperative groups: GPOH, SFCE/GSF, UK-CCLG, and EORTC. It evaluated effects on event-free (EFS, main endpoint) and overall survival (OS) of BuMel compared to standard chemotherapy in ES presenting with localized disease and either a poor histologic response to induction che...

This document is an update of the British Sarcoma Group guidelines published in 2010. The aim is to provide a reference standard for the clinical care of patients in the UK with bone sarcomas. Recent recommendations by the European Society of Medical Oncology, The National Comprehensive Cancer Network and The National Institute for Health and Care...

IntroductionThe aim of this article is to present an experience of two prospective studies from the International Childhood Liver Tumor Strategy Group (SIOPEL 2 [S2] and SIOPEL [S3]) trials and to evaluate whether modified platinum- and doxorubicin-based chemotherapy is capable of increasing tumor resectability and changing patient outcomes.Methods...

Hepatoblastoma is a comparatively uncommon paediatric solid tumour, while hepatocellular carcinoma is very rare. The Paediatric Hepatic International Tumour Trial will be the single largest clinical trial undertaken in paediatric liver cancer patients as collaboration between the European Study Group for Paediatric Liver Tumours, Children’s Oncolo...

To promote early diagnosis of cancer, NICE published updated guidelines ‘Suspected cancer: recognition and referral – NICE guidelines NG 12 in June 20151. It is our opinion that the new guidelines on sarcomas need urgent review/update to provide clarity on recognition and referral and our response was published on 26th July 20152 Soft tissue lumps...

Liver tumors are relatively rare in childhood, but may be associated with a range of diagnostic, genetic, therapeutic, and surgical challenges sufficient to tax even the most experienced clinician. This article outlines the epidemiology, etiology, pathologic condition, initial workup, and management of hepatocellular carcinoma in children and adole...

Purpose: A phase I trial of AT9283 (a multitargeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumors, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics, and pharmacodynamic (PD) activity. Experimental design: AT9283 was administered as a 72-hour continuous intravenous inf...

Aim of the Review: To describe the significant improvement in the diagnosis, treatment and outcome of children diagnosed with hepatoblastoma (HB) that has occurred in the past four decades. Recent findings are mainly focused on lessons learned from the experiences of the Childhood Liver Tumors Strategy Group (SIOPEL). Important milestones were the...

The purpose of this national retrospective study was to evaluate the outcome in children with relapsed or primary refractory Hodgkin lymphoma [HL] after a primary chemotherapy alone treatment strategy. Between 2000 and 2005, 80 children with relapsed [n = 69] or primary refractory [n = 11] HL were treated on a standardized treatment protocol of 4-6...

The prognosis for patients with nonpulmonary metastatic Ewing sarcoma remains poor with survival in the order of 15-20%. The need to introduce effective new agents into clinical practice is clear. Based on a preclinical rationale of responses in xenografts and backed by a phase I study in children, the Euro-E.W.I.N.G consortium planned a phase II w...

Future advances in childhood cancer treatment will pivot on developing biology-driven new drug development pathways that build on current knowledge of oncogenic pathways; however, we need to address major barriers to accessing new drugs for clinical evaluation in childhood cancers. Through legislative change, substantial incentives to the pharmaceu...

To compare the incidence of acute histologically proven rejection in children who have had a liver transplant for hepatoblastoma with a control group of children transplanted for biliary atresia (EHBA). A retrospective case notes based study was performed. Twenty patients were identified with hepatoblastoma who were transplanted at a single unit be...

The objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma. SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with eithe...

The European Pediatric Medicine Regulation was launched in 2007 to provide better medicines for children. Five years later, the number of new anticancer drugs in early development in the pediatric population remains low and most children with cancer are still largely denied access to innovative drugs in Europe, as compared to the US. We analyzed in...

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 (20mg/m(2)/day intravenous (i.v.) infusion on days 1-5 and 8-12, every 21days) unless tumour progression occurred or resectability was achieved earlier. T...

9542 Background: AT9283, is a multi-targeted inhibitor, against Aurora A and B, JAK & ABL kinases. Aurora kinases are potential therapeutic targets in paediatric solid cancers. Methods: A phase I dose escalation study was performed using a 72 hour intravenous infusion repeated 3 weekly using a rolling 6 design for patients aged >2 to <19 years with...

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 P < 5 × 10(-5) in two independent replication s...

To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-...

To assess the efficacy of a standardised hybrid chemotherapy treatment programme for Hodgkin lymphoma (HL) in a national series of children and adolescents. The 381 assessable patients, treated between March 2000 and April 2005 in the United Kingdom Children's Cancer Study Group trial, were reviewed to evaluate overall survival (OS), disease free s...

Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lin...

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 EUR...

Systemic chemotherapy plays a fundamental role in the cure of children diagnosed with hepatoblastoma. In fact for them, the best chance of cure can be achieved only with a multidiscplinary approach that includes surgery and systemic chemotherapy. Cisplatin-based regimes have been repeatedly shown by the different study groups to be the most effecti...

Background/Purpose Remarkable advances in paediatric cancer research and treatment were achieved during the last decades: In industrialised nations, overall cure rates were raised from below 20% to over 75% during the last forty years. Randomised investigator-driven clinical trials have been the backbone of this progress so far. The EU Clinical Tri...

This multicenter phase I study aimed to establish the recommended dose (RD) of the epidermal growth factor receptor (EGFR) inhibitor erlotinib, given as monotherapy or with radiotherapy to children with malignant brain tumors. Group 1 included patients with refractory or relapsing brain tumors receiving erlotinib alone, and group 2 included newly d...

Parkes SE, Parke S, Manghan DC, Grimer RJ, Davies P, Morland BJ. Fifty years of paediatric malignant bone tumours in the West Midlands, UK, 1957–2006: incidence, treatment and outcome. Paediatric and Perinatal Epidemiology 2010. Malignant bone tumours in the paediatric age group (0–14 years) are uncommon; various aetiological theories exist and few...

Overall survival from childhood malignancies has dramatically improved, with survival rates now reaching over 70%. Nevertheless, some types of childhood cancer remain a difficult challenge, and for those who survive the burden of treatment can be considerable. The current paradigm for new cancer therapies is to increase our knowledge of the molecul...

These guidelines have been developed in order to provide an overview and a set of broad-based key recommendations for the management of patients with bone sarcomas in the UK. They have taken into consideration the most up-to-date scientific literature along with the recent recommendations by the European Society of Medical Oncology. The principles...

Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). Children with standard-risk hepatoblastoma who were younger than 16 years of age were eligible for inclus...

To explore imatinib efficacy and pharmacokinetics in children and adolescents with refractory/relapsing solid tumours, expressing imatinib-sensitive receptor tyrosine kinases. Exploratory study on imatinib in tumours expressing, at least, one of the receptors KIT or platelet-derived growth factor receptor (PDGFR). Standard radiological response eva...

EpidemiologyEtiologyPathologyMalignant tumorsBenign tumorsReferences

To evaluate the efficacy and safety of irinotecan in paediatric recurrent or refractory neuroblastoma. Thirty seven patients aged between 6 months and < or = 20 years, with relapsed or refractory neuroblastoma, received irinotecan at 600 mg/m(2) administered as a 60-min infusion, every 3 weeks. Tumour response was evaluated by conventional radiolog...

EpidemiologyAetiologyPathologyMalignant tumoursBenign tumours