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Paediatric oncology article annual research report 1998.pdf

Section of Paediatric

ICR Section of Paediatric Oncology, HaddowLaboratories, Sutton •Phase I/II clinical trial assessment of new Paediatric Oncology Unit, Sutton, including Relevance to the NHS Research and
Development Programme
strategies is a stated NHS priority area. As a leading group in the UK in investigational Chairman
•development of techniques for molecular Section is involved in single and multicentre diagnostics of childhood cancer which are (Consultant Paediatric Oncologist, Head of Unit) (on applicable to clinically obtainable biopsy studies evaluating new strategies and their subsequent application nationally. Quality of K Pritchard-Jones PhD FRCPE FRCPCH (acting care remains a priority and is an important consideration in the design of new clinical trials. We continue to expand our long-term “late effects” clinics, in order that medical and psychological problems in survivors may The clinical research programme is focused be appropriately evaluated and managed.
on improving the efficacy and tolerability of The role of local paediatric departments in programme is concentrated in the following the shared care of children with cancer is an •optimising drug scheduling and particularly area of further development. A project to •the role of the Wilms tumour gene (WT1) the application of dose escalation strategies, evaluate in detail the needs of the patients and their families and the extent to which peripheral blood stem cell (PBSC) rescue; local care provision can meet these needs is •development of optimal supportive care nearing completion. This is consistent with •identification of novel genes involved in care. Improvement of symptom relief is also •the biology of sarcomas with particular •evaluation of drug resistance modulation a priority area for the NHS and our clinical strategies in conjunction with in vitro children are therefore of direct relevance.
evaluation as part of a European collaborative Role of Wilms Tumour Gene, WT1 in
Haematopoiesis, Leukaemias and other
uricozyme to prevent tumour lysis syndrome Tumours [Project No.0708]
gene, WT1, is mutated in 10% of acute K Pritchard-Jones, L King-Underwood, J Renshaw, A␣ Baker, R Williams, N Tiffin; in collaboration with efficacy of this drug. In collaboration with Dr N␣ Hastie, MRC Human Genetics Unit, Edinburgh with a poor response to treatment. In vitro Source of funding: CRC, RMT Children’s Cancer Unit models are being developed to identify WT1 Carcinogenesis), we continue a prospective study to detect PAX-FKHR translocations in Mutational analysis of a larger series of acute alterations in WT1 function affects leukaemias has shown that WT1 mutation chemosensitivity. WT1 expression in bone the UK (the Paediatric Section Laboratory is leukaemias, where it is associated with primary haemopoietic progenitor cell, the presumed chemoresistance, but also in occasional cases target for leukaemogenesis. Models of the Future Aims
of lymphoblastic and biphenotypic leukaemias, Under the direction of Dr Kathy Pritchard- in both adults and children. The role of this overexpressed wild type WT1 have been Shipley, we will continue to concentrate our haemopoietic progenitor cells is now being changes in relapsed Wilms tumour has been tested in transgenic models. In vitro studies on initiated, using international collaboration to highlighted above. Our specific aims are: the effects of manipulating WT1 expression on build a collection of these rare specimens.
•a further evaluation of the function of WT1 chemosensitivity of both leukaemic and solid tumour cell lines are underway. Analysis of adult tissues in which the WT1 promoter is translocations in a large retrospective cohort active, using a β-galactosidase reporter gene in •the identification of novel genes involved in a transgenic murine model (in collaboration with Professor Nick Hastie) has revealed wider •a greater understanding of the biology of expression of WT1 in tissues of mesodermal detection of known characteristic molecular origin. Disregulation of WT1 expression in correlates with phenotype and a continued tumours arising from these tissues may be of universally, even to small needle biopsies, Role of WT1 in Myogenesis
resistance in addition to dose escalation, differentiation in early embryonic mesodermal described above. The dose finding study of cells. In vitro models using inducible isoforms of function in vivo using sestamibi and to wildtype and mutant WT1 are being developed detect variability in ifosfamide metabolism defined the dose limiting toxicity to be ataxia to identify target genes and pathways.
and uptake in tumours in vivo using and hepatic toxicity. This agent is now to go into Phase II evaluation. A Phase I study of Molecular Genetics of Relapsed Wilms
liposomal cisplatin in children was initiated.
Tumour [Project No.1494]
A pilot study of split high dose single agent K Pritchard-Jones, S Hing, L King-Underwood; in •evaluation of the role of molecular analysis collaboration with B Summergill, JM Shipley, Section of Molecular Carcinogenesis; N Sodha, Section of Cancer Genetics; P Grundy, National Wilms Tumour Study and this regimen has now gone into Phase III childhood leukaemias and solid tumours.
Group; UK Children’s Cancer Study Group Source of funding: RMT Children’s Cancer Unit Fund Although 85% of Wilms tumours can be cured fixed tissue, so that these genetic changes can A novel region of amplification of genetic by conventional means, the prognosis after be reliably detected in virtually all patients.
material at 13q32 has been defined in alveolar relapse is much poorer. Other than anaplastic Detection of MYCN amplification in histology associated with p53 mutation, there neuroblastoma is used in clinical management being analysed to refine the amplicon with the are few molecular markers to define this group.
aim of identifying expressed sequences in YACs involving the FKHR gene on 13q14 and either hybridisation analysis of a series of paired the PAX3 or PAX7 genes on 2q35 and 1p36 tumours from diagnosis and relapse to define respectively are associated with the alveolar Evaluation of Multidrug Resistance in
consistent molecular changes associated with Rhabdomyosarcoma Cell Lines
A Newman, WJ Anderson, K Pritchard-Jones; in collaboration with H Cocker, LR Kelland, H Coley, CRC embryonal subtype. However, nearly 30% of Genetic Susceptibility to Wilms Tumour –
Genetic Analysis of Familial Wilms Tumour
these translocations. A national study has been completed, in collaboration with the K Pritchard-Jones, L King-Underwood; in collaboration UKCCSG, which shows that the presence of a with MR Stratton, N Rahman, E Rapley, Section of have been shown to be effective in vitro in PAX3-FKHR translocation is a stronger overcoming drug resistance associated with predictor of adverse clinical outcome than Source of funding: CRC, RMT Children’s Cancer Unit overexpression of either the MDR1 or MRP histological subtypes. An ongoing prospective genes. However, defining which drug resistance We have localised a gene, FWT1, for familial analyses in tailoring clinical treatment to further efforts to pinpoint the gene by the especially when sample size is limiting. We are, classical approach of searching for additional therefore, developing RT-PCR-based assays to Characterisation of Biological Features of
recombination events have been hampered by quantitate gene expression in needle biopsies.
the rarity and genetic heterogeneity of this WJ Anderson, R Williams, N Tiffin, K Pritchard-Jones; in collaboration with JM Shipley, Section of Molecular penetrance of Wilms tumour in FWT1 carriers pathways involving protein kinase C.
is low. Therefore, we are undertaking allelic Source of funding: CRC, RMT Children’s Cancer Unit association studies in apparently sporadic cases of Wilms tumour to search for shared haplotypes to further narrow the FWT1 rhabdomyosarcoma is defined by allele loss at interval. Rare cases of familial Wilms tumour are due to the already known WT1 gene and rhabdomyosarcoma is defined by PAX-FKHR we have further defined a pedigree with familial translocations. Our studies of alterations of Phase I Dose Finding Study to Evaluate
Wilms tumour due to mutation in this gene.
Safety and Pharmacokinetic Interactions of
SDZ PSC833 when Administered with
Molecular Diagnostics of Childhood Cancers
Intravenous Etoposide in Paediatric Subjects
S Hing, A Gordon, WJ Anderson, K Pritchard-Jones; in with Relapsing and/or Refractory Solid
collaboration with JM Shipley, Section of Molecular Tumours [Project No.1203]
complex and overlapping. Mutations of the Source of funding: RMT Children’s Cancer Unit Fund, CR Pinkerton, K Pritchard-Jones, ST Meller, G Dick, cyclin-dependent kinase inhibitor p57 do not appear to be common in rhabdomyosarcoma.
Source of funding: RMT Children’s Cancer Unit Fund Analysis of Rhabdomyosarcoma by
prognostic value in a variety of childhood reversal agent PSC833 has defined the dose Comparative Genomic Hybridisation
cancers. We continue to develop methods for limiting toxicity to be ataxia and hepatic A Gordon, K Pritchard-Jones; in collaboration with JM␣ Shipley, Section of Molecular Carcinogenesis toxicity. This agent is now to go into Phase II amplification in small biopsy samples or using Source of funding: RMT Children’s Cancer Unit Fund THE ROYAL MARSDEN NHS TRUST – THE INSTITUTE OF CANCER RESEARCH Phase II Study of Oral Temozolomide
Randomised Trial of Prophylactic G-CSF in
Children with ALL following Intensification
CR Pinkerton, M Brada, E Bouffet, G Dick The Use of Penciclovir and Famciclovir in
Chemotherapy [Project No.1288]
Immunocompromised Children with
CR Pinkerton, JC Chisholm, G Dick, M Little Suspected or Confirmed Herpetic Infections
paediatric patients has led to a Phase II A Atra, M Little, J Mycroft, G Dick, T Devine This study, in collaboration with The Children’s evaluation in brain stem glioma and high grade Source of funding: RMT, SmithKline Beecham Hospital, Birmingham, demonstrated that the use of prophylactic G-CSF significantly reduced This project will evaluate Penciclovir and its the likelihood of hospital readmission and Phase I Study in Children with Advanced
oral equivalent Famciclovir, antiviral agents appeared to be a cost effective measure.
Cancer to Evaluate the Safety and
which may have an improved pharmacokinetic Pharmacokinetics of SPI-77
profile against Herpes infections in children.
Safety, Efficacy and Pharmacokinetics of
Durogesic in the Treatment of Paediatric
CR Pinkerton, E Bouffet, G Dick Randomised Trial Evaluating the Potential
Patients with Chronic Pain Requiring Long
Source of funding: RMT, Sequus Pharmaceuticals Inc Value of Prophylactic Oral Glutamine
Term Opioid Therapy [Project No.1242]
Supplementation to Ameliorate
liposomal cisplatin, this formulation permits Chemotherapy-induced Mucositis
significant dose escalation without increased K Pritchard-Jones, T Devine, JC Chisholm, A Norton; in toxicity. To date the dose limiting toxicity has collaboration with B Mooreland, Birmingham; R Skinner, patch-delivered analgesics in young children. It is potentially useful where oral medication is considerably higher doses can be given than poorly tolerated and may also avoid the major irradiation. In a double blind study involving A Second UKCCSG Phase I Pilot Study
Respiratory Viral Infections in Symptomatic
of Combined Chemotherapy and mIBG
radiotherapy with stem cell rescue or allogeneic Immunocompromised Children [Project No.1498]
Therapy in Neuroblastoma
marrow transplantation, orally administered CR Pinkerton, HC Underhill; in collaboration with glutamine failed to significantly reduce the M␣ Sharland, D Osrin, St George’s Hospital ST Meller, CR Pinkerton, VR McCready, S Chittenden This study documents the contribution of viral Influenza Immunisation of Immuno-
Combined Phase I Toxicity/Phase II
compromised Children [Project No.1178]
Immunological Response Study of an Anti-
and A Study of the Immunogenicity of
idiotypic Cancer Vaccine, 105AD7, in
Haemophilus influenzae Type B (Hib) and
The use of SR29142 for Prevention or
Osteosarcoma of Children and Young Adults
Pneumococcal Vaccines in Children on
Treatment of Hyperuricemia at Multiple
(CRC Protocol 92/30, PH1/062)
Chemotherapy for Leukaemia [Project No.1179]
Centres in Europe, Australiasia, and Asia
CR Pinkerton, JC Chisholm, T Devine; in collaboration K Pritchard-Jones; in collaboration with I Lewis, Leeds; with M Zambon, PHLS, Colindale; M Sharland, E Bouffet, K Pritchard-Jones, ST Meller, A Atra, L␣ Durrant, Nottingham; S Weeden, Cambridge These studies have demonstrated that despite Phase I Study of Intravenous Liposomal
Daunorubicin in Relapsed or Resistant Solid
children are capable of mounting an immune Tumours, a UKCCSG/SFOP Study
response to both Haemophilus influenzae type Ovarian Function in the Survivors of
B (Hib) and influenza. These data will provide a Childhood Leukaemia [Project No.1208]
E Bouffet, K Pritchard-Jones, ST Meller, A Atra, A Davidson, basis for a rational immunisation policy in This study involves the use of ultrasound Adjuvant Psychological Therapy for Families
imaging and hormone profiles and should shed of Children with Cancer – a Controlled Trial
medulloblastoma [Project No.0777] M Brada; light on the nature of endocrinological sequelae in collaboration with C␣ Bailey, St James Hospital, M Watson, L Edwards; in collaboration with ST Meller, (See Neuro-oncological Cancer Unit Chapter) Source of funding: RMT Children’s Cancer Unit Fund The Effect of Growth Hormone Replacement
•LMB 96 trial evaluating the possibility of Therapy in Childhood Onset Growth Hormone
(See Psychological Medicine in Healthcare reduction of chemotherapy dose and duration Deficient Patients, Previously Treated to
in B-cell Non-Hodgkin’s Lymphoma [Project Final Height (Hypopituitary Developmental
No.1322] CR Pinkerton, ST Meller, K Pritchard-Jones Outcome Study)
•International Society for Paediatric Oncology SIOPEL 3 liver tumour studies, hepatoblastoma Source of funding: RMT, Eli Lilly & Co Studies that Evaluate the Benefit of
and hepatocellular carcinoma (MREC/98/2/68) Increased Dose Intensity by Rapid Delivery of
High Dose Multi-agent Chemotherapy
•Protocol for the treatment of childhood anaplastic large cell lymphoma (SFOP/UKCCSG Adolescents’ Perceptions and Experience of
Protocol ALCL 98 HL 1998/03) (MREC8/5/32) [Project No.1640] K Pritchard-Jones, E Bouffet, Being Diagnosed with and Treated for Cancer
ST␣ Meller, A Atra, A Davidson, A Norton, G Dick [Project No.0987] CR Pinkerton, IR Judson, G Dick Single Arm Trials
This qualitative study aims to gain insight into Studies that Evaluate the Benefit of
the perceptions and experience of adolescents Additional Chemotherapy at Standard
with cancer using a semi-structured interview.
lymphoblastic leukaemia study evaluates the Scheduling
Adolescence is a period of development that role of intensified second line chemotherapy involves many different changes, which will be •European Intergroup Cooperative Ewing’s further complicated by a diagnosis of cancer.
[Project No.1184] CR Pinkerton, A Atra, ST Meller, The study will also examine the differences in being treated on adult or paediatric units, with •Germ Cell Tumour, GCT2 evaluates the role No.1164] CR Pinkerton, ST Meller, K Pritchard-Jones Study to Establish Whether the Needs of
Children with Cancer and their Families are
Trial [Project No.1399] ST Meller, CR Pinkerton, •A series of single arm chemotherapy trials are met within the Community Setting
underway for non-metastatic neuroblastoma.
•UK Acute Myeloid Leukaemia 12 Trial [Project J Mallett, J Thompson, R Anderson, RP A’Hern, M Patel, No.1159] ST Meller, CR Pinkerton, K Pritchard-Jones Source of funding: RMT Children’s Cancer Unit Fund Studies Evaluating other Treatment Variables
(See Patient Services Directorate in UKCCCR National Case Control Study of
Childhood Cancer
The role of pre-operative chemotherapy in The Transition from Inpatient to Outpatient –
What is this Period Like for the Parents of
CR␣ Pinkerton, ST Meller, K Pritchard-Jones Children with Cancer?
•International Society of Paediatric Oncology – should shed light on the various hypotheses of K Pritchard-Jones; in collaboration with S Kingdom, THE ROYAL MARSDEN NHS TRUST – THE INSTITUTE OF CANCER RESEARCH Constitutional Karyotype Analysis in Patients
with Neuroblastoma (UKCCSG Study NB 9604)
K Pritchard-Jones, ST Meller, CR Pinkerton This study aims to identify rare individuals with abnormalities to aid in identification of familial UK Children’s Cancer Study Group (UKCCSG)
Protocol for Collection and Banking Tumour
Specimens for Biological Studies
MRC Acute Lymphoblastic Leukaemia in
Children Trial ALL 97 [Project No.1399]
ST Meller, CR Pinkerton, K Pritchard-Jones, A Atra The predictive value of measuring cytotoxic metabolites of thiopurine drugs used in therapy of acute lymphoblastic leukaemia is being analysed prospectively on all patients in the Technetium MIBI (sestamibi) Imaging for the
In Vivo Evaluation of P-glycoprotein Activity
in Childhood Solid Tumours [Project No.1508]
CR Pinkerton, VR McCready, G Dick, ST Meller, Use of Magnetic Resonance Spectroscopy to
Detect Ifosfamide in Tissue and Tumour in
Children with Solid Tumours [Project No.1580]
E Bouffett, S Vaidya; in collaboration with MO Leach, CRC Clinical Magnetic Resonance Research Group


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