Het is echter wel schadelijk om overmatig te alcohol te drinken, zeker als u een infectie heeft. Dit komt de infectie eerder verergerd door het gebruik van alcohol antibiotica en ibuprofen samen Doorgaans worden ze voorgeschreven bij bacteriële infecties die om de één of andere reden niet uit zichzelf over gaan; ze doden dan de bacteriën.
Paediatric oncology article annual research report 1998.pdf
Section of Paediatric Oncology
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.
THE ROYAL MARSDEN NHS TRUST – THE INSTITUTE OF CANCER RESEARCH
Highlights of 1998
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. Rhabdomyosarcoma
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 DickThe Use of Penciclovir and Famciclovir in Chemotherapy [Project No.1288] Immunocompromised Children with
CR Pinkerton, JC Chisholm, G Dick, M LittleSuspected 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 DickRandomised 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 DickSingle 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, AAtra, 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,SVaidya; in collaboration with MO Leach,
CRC Clinical Magnetic Resonance Research Group
Background. Reducing immunosuppression not onlyreduces complications but also may lessen recurrent hepatitis Cvirus (HCV) infection after liver transplantation. Patients/Methods. HCV-infected cirrhotic patients randomised to tacrolimus monother-apy (MT) or triple therapy (TT) using tacrolimus 0.1 mg/kg/day,azathioprine 1 mg/kg/day, and prednisolone 20 mg/day, tapering overWe gratefully ackno
. Vocabulary and Phrases: 20% Directions: Choose one answer that best paraphrases the meaning of the underlined word or phrase in each sentence. ( (B) 1.That naughty boy often turns a deaf ear to my friendly advice. (B) 2.Smog may contain noxious elements, and may be a factor causing lung cancer. (C) 3.Smallpox has been practically rooted out in the civilized world. (A) 4.Some p