Publications by authors named "Mark Brougham"

13 Publications

  • Page 1 of 1

Impacts of platinum-based chemotherapy on subsequent testicular function and fertility in boys with cancer.

Hum Reprod Update 2020 Nov;26(6):874-885

MRC Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.

Background: Children with cancer often face infertility as a long-term complication of their treatment. For boys, compromised testicular function is common after chemotherapy and currently there are no well-established options to prevent this damage. Platinum-based agents are used to treat a wide variety of childhood cancers. However, platinum agents are not currently included in the cyclophosphamide equivalent dose (CED), which is used clinically to assess the risks to fertility posed by combination chemotherapy in children with cancer.

Objective And Rationale: This was a systematic search of the literature designed to determine the evidence for effects of platinum-based cancer treatment on the prepubertal human testis in relation to subsequent testicular function and fertility.

Search Methods: PubMed and EMBASE were searched for articles published in English between 01 January 1966 and 05 April 2020 using search terms including 'cancer treatment', 'chemotherapy', 'human', 'prepubertal', 'testis', 'germ cells', 'testosterone' and related terms. Abstracts were screened and full-text articles were obtained for those that met the three major inclusion criteria (age ≤12 years at treatment, exposure to platinum-based chemotherapeutic and measure of reproductive function). Screening of bibliographies for full-text articles was used to identify additional studies.

Outcomes: Our initial search identified 1449 articles of which 20 (1.3%) studies (n = 13 759 males) met all inclusion criteria. A control group (healthy individuals or siblings) was included for 5/20 (25%) studies. A total of 10/20 (50%) studies provided sub-analysis of the relative gonadotoxicity of platinum-based agents.The primary outcome measures were: pregnancies and fatherhood; semen analysis; and hormonal function. For pregnancies and fatherhood, three studies (n = 10 453 males) reported negative associations with platinum-agents, including the largest (n = 5640) controlled study (hazard ratio = 0.56, P = 0.0023), whilst two other studies (n = 1781) with platinum sub-analysis reported no association. For semen analysis (based on World Health Organization criteria), platinum-based chemotherapy was associated with azoospermia in one study (n = 129), whilst another (n = 44) found no association and the remainder did not perform platinum-based sub-analysis. For hormone analysis, conflicting results were obtained regarding potential associations between platinum-based agents and elevated FSH (a proxy for impaired spermatogenesis); however, the majority of these studies were based on low numbers of patients receiving platinum-based chemotherapy.

Wider Implications: Overall, these results indicate that platinum-based chemotherapy should be included in clinical calculators, for example CED, used to determine gonadotoxicity for childhood cancer treatment. These findings have important implications for clinicians regarding counselling patients and their carer(s) on fertility risk, guiding requirements for fertility preservation strategies (e.g. testicular tissue cryopreservation) and modification of treatments to reduce or eliminate the risk of infertility in childhood cancer survivors.
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http://dx.doi.org/10.1093/humupd/dmaa041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600277PMC
November 2020

Nutritional screening and assessment of paediatric cancer patients: A quality improvement project (baseline results).

Clin Nutr ESPEN 2020 08 27;38:242-252. Epub 2020 Apr 27.

Child Life and Health, University of Edinburgh, EH9 1UW, UK; Department of Sports and Health Sciences, College of Environment and Life Sciences, St Luke's Campus, University of Exeter, UK. Electronic address:

Background: The department of Haematology and Oncology at the Royal Hospital for Sick Children (RHSC) in Edinburgh have developed their own nutritional standards specific to paediatric cancer. We aimed to audit the current nutritional practice in anthropometry, nutritional biochemistry and malnutrition screening for paediatric cancer patients against nutritional standards to identify areas for nutritional-practice improvement and progress nutrition-related clinical outcomes.

Methods: A Clinical audit was conducted >20 weeks between 2015 and 2017 in three data collection locations (inpatient (IP), day-care (DC), or outpatient (OP)) at RHSC. We included patients aged 0-18 years and undergoing treatment for diagnosed malignant childhood cancer (ICCC-3 or Langerhans Cell Histiocytosis). Data were collected by analysing documentation and observing clinical practice for frequency and mode of administration of anthropometry, malnutrition screening, nutritional biochemistry and resulting documentation completion. Results were presented as descriptive statistics and stratified by percentage of standard met (100%, 99-70%, <70%).

Results: 185 audited patient records (22 IP, 54 DC and 109 OP) were analysed. The areas which were <70% of the standard were: height and weight documentation for DC; head-circumference for IP; arm anthropometry assessment for all locations; initial PYMS screening and re-screening in IP; malnutrition screening in DC and OP; and initial assessment and re-assessment for serum vitamins D, A, E, B and parathyroid hormone levels.

Conclusion: Baseline nutritional practice was successfully established, identifying areas for practice improvement in the RHSC Paediatric Oncology and Haematology Department; this will be implemented in the next step of the audit to optimise patient care.
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http://dx.doi.org/10.1016/j.clnesp.2020.04.003DOI Listing
August 2020

Embryonal precursors of Wilms tumor.

Science 2019 12;366(6470):1247-1251

Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.
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http://dx.doi.org/10.1126/science.aax1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914378PMC
December 2019

Detection of Circulating and Disseminated Neuroblastoma Cells Using the ImageStream Flow Cytometer for Use as Predictive and Pharmacodynamic Biomarkers.

Clin Cancer Res 2020 01 25;26(1):122-134. Epub 2019 Nov 25.

Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.

Purpose: Circulating tumor cells (CTCs) serve as noninvasive tumor biomarkers in many types of cancer. Our aim was to detect CTCs from patients with neuroblastoma for use as predictive and pharmacodynamic biomarkers.

Experimental Design: We collected matched blood and bone marrow samples from 40 patients with neuroblastoma to detect GD/CD45 neuroblastoma CTCs from blood and disseminated tumor cells (DTCs) from bone marrow using the Imagestream Imaging flow cytometer (ISx). In six cases, circulating free DNA (cfDNA) extracted from plasma isolated from the CTC sample was analyzed by high-density single-nucleotide polymorphism (SNP) arrays.

Results: CTCs were detected in 26 of 42 blood samples (1-264/mL) and DTCs in 25 of 35 bone marrow samples (57-291,544/mL). Higher numbers of CTCs in patients with newly diagnosed, high-risk neuroblastoma correlated with failure to obtain a complete bone marrow (BM) metastatic response after induction chemotherapy ( < 0.01). Nutlin-3 (MDM2 inhibitor) treatment of blood and BM increased p53 and p21 expression in CTCs and DTCs compared with DMSO controls. In five of six cases, cfDNA analyzed by SNP arrays revealed copy number abnormalities associated with neuroblastoma.

Conclusions: This is the first study to show that CTCs and DTCs are detectable in neuroblastoma using the ISx, with concurrently extracted cfDNA used for copy number profiling, and may be useful as pharmacodynamic biomarkers in early-phase clinical trials. Further investigation is required to determine whether CTC numbers are predictive biomarkers of BM response to first-line induction chemotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0656DOI Listing
January 2020

Nutritional status of children and adolescents with cancer in Scotland: A prospective cohort study.

Clin Nutr ESPEN 2019 08 17;32:96-106. Epub 2019 May 17.

Child Life and Health, University of Edinburgh, Edinburgh EH9 1UW, UK; Department of Paediatric Haematology and Oncology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK.

Background And Aims: Malnutrition (under and overnutrition) in paediatric cancer patients during and after treatment increases short and long-term side-effects; however, factors contributing to malnutrition and patterns of change in nutritional status are still unclear. The aims were to investigate the prevalence of malnutrition, patterns of change in nutritional status and factors contributing to malnutrition in Scottish paediatric cancer patients.

Methods: A prospective cohort study of Scottish children aged <18 years, diagnosed with and treated for cancer between Aug 2010 and Jan 2014 was performed. Clinical and nutritional data were collected at defined periods up to 36 months. Measurements of weight and height/length and arm anthropometry (mid-upper arm circumference (MUAC) and triceps skin-fold thickness (TSF)) were collected. Body composition was estimated from arm anthropometry using Frisancho's references and bio-electrical impedance (BIA). Malnutrition was defined according to UK BMI curves; undernutrition (<2.3rd centile; -2 SD), overweight (≥85th < 95th centile; ≥+1.05 SD < 1.63 SD) and obese (≥95th centile; ≥1.63 SD). We performed descriptive statistics and multilevel analysis. p < 0.05 was considered statistically significant.

Results: Eighty-two patients [median (IQR) age 3.9 (1.9-8.8) years; 56% males] were recruited. At diagnosis, the prevalence of undernutrition was 13%, overweight 7% and obesity 15%. TSF identified the highest prevalence of undernutrition (15%) and the lowest of obesity (1%). BMI [p < 0.001; 95% CI (1.31-3.47)] and FM (BIA) [p < 0.05; 95% CI (0.006-0.08)] significantly increased after 3 months of treatment, whilst FFM (BIA) [p < 0.05; 95% CI (-0.78 to (-0.01))] significantly decreased during the first three months and these patterns remained until the end of the study. High-treatment risk significantly contributed to undernutrition during the first three months of treatment [p = 0.04; 95% CI (-16.8 to (-0.4))] and solid tumours had the highest prevalence of undernutrition [BMI (17%)].

Conclusions: Arm anthropometry (or BIA) alongside appropriate nutritional treatment that targets undernutrition initially and overnutrition at later stages should be implemented in routine clinical practice of paediatric cancer patients.
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http://dx.doi.org/10.1016/j.clnesp.2019.04.006DOI Listing
August 2019

Comparison of carboplatin versus cisplatin in the treatment of paediatric extracranial malignant germ cell tumours: A report of the Malignant Germ Cell International Consortium.

Eur J Cancer 2018 07 31;98:30-37. Epub 2018 May 31.

Department of Paediatric Haematology and Oncology, Royal Victoria Infirmary, Queen Victoria Rd, Newcastle Upon Tyne, Tyne and Wear, NE1 4LP, UK.

Purpose: To compare the outcomes of paediatric and adolescent extracranial malignant germ cell tumour (GCT) patients treated with either carboplatin or cisplatin on clinical trials conducted by the Children's Oncology Group (COG) and the Children's Cancer and Leukaemia Group (CCLG).

Methods: The Malignant Germ Cell International Consortium (MaGIC) has created a database of the GCT clinical trials conducted since 1983 by COG (United States, Canada and Australia), which used cisplatin-based regimens, and by CCLG (United Kingdom), which used carboplatin-based regimens. Using the parametric cure model, this study compared the overall 4-year event-free survival (EFS), stratified by age, stage, site and the a-priori defined MaGIC 'risk' groups: standard risk ((SR) 1 (EFS >80%; age <11 years), SR2 (EFS >80%, age ≥ 11y) and poor risk (PR) (EFS ≤ 70%, age ≥ 11y).

Results: Cisplatin-based therapy was used in 620 patients; carboplatin was used in 163 patients. In the overall multivariate cure model, the two regimens did not differ significantly (cisplatin: 4-year EFS 86%; 95% confidence interval (CI) 83-89% versus carboplatin 4-year EFS 86%; 95% CI 79-90%; p = 0.87). No significant differences were noted in stratified analyses by site, stage, age and MaGIC risk groups: SR1 (p = 0.20), SR2 (p = 0.55) or PR (p = 0.72) patients.

Conclusions: In these trials conducted contemporaneously, there is no significant difference in outcome observed overall, or any subset of patients, who were treated with regimens containing cisplatin versus carboplatin These results suggested sufficient equipoise to justify a randomised trial to evaluate the effectiveness of carboplatin versus cisplatin in the treatment of children, adolescents and young adults with standard risk GCT, which is currently underway.
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http://dx.doi.org/10.1016/j.ejca.2018.03.004DOI Listing
July 2018

Delayed diffuse cerebellar swelling after resection of medulloblastoma: case report and review of literature.

Childs Nerv Syst 2017 Nov 29;33(11):2047-2049. Epub 2017 Jun 29.

Royal Hospital for Sick Children, 9 Sciennes Rd, Edinburgh, EH9 1LF, UK.

Introduction: Delayed diffuse cerebellar swelling is a rare life-threatening complication following medulloblastoma resection.

Presentation: We present our experience of managing a 4-year-old who developed diffuse cerebellar swelling with upward herniation 41 days after resection of a large cell anaplastic medulloblastoma.

Conclusion: Emergency chemotherapy alone was sufficient in promoting regression of swelling and recovery from coma. Reports of similar cases are scant. Chemotherapy may be a critical component of treatment.
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http://dx.doi.org/10.1007/s00381-017-3496-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644696PMC
November 2017

5-Hydroxyvitamin D concentration in paediatric cancer patients from Scotland: a prospective cohort study.

Br J Nutr 2016 Dec 15;116(11):1926-1934. Epub 2016 Dec 15.

2Child Life and Health,University of Edinburgh,Edinburgh,EH9 1UW,UK.

Children with cancer are potentially at a high risk of plasma 25-hydroxyvitamin D (25(OH)D) inadequacy, and despite UK vitamin D supplementation guidelines their implementation remains inconsistent. Thus, we aimed to investigate 25(OH)D concentration and factors contributing to 25(OH)D inadequacy in paediatric cancer patients. A prospective cohort study of Scottish children aged 75 nmol/l). In all, eighty-two patients (median age 3·9, interquartile ranges (IQR) 1·9-8·8; 56 % males) and thirty-five controls (median age 6·2, IQR 4·8-9·1; 49 % males) were recruited. 25(OH)D inadequacy was highly prevalent in the controls (63 %; 22/35) and in the patients (64 %; 42/65) at both baseline and during treatment (33-50 %). Non-supplemented children had the highest prevalence of 25(OH)D inadequacy at every stage with 25(OH)D median ranging from 32·0 (IQR 21·0-46·5) to 45·0 (28·0-64·5) nmol/l. Older age at baseline (R -0·46; P<0·001), overnutrition (BMI≥85th centile) at 3 months (P=0·005; relative risk=3·1) and not being supplemented at 6 months (P=0·04; relative risk=4·3) may have contributed to lower plasma 25(OH)D. Paediatric cancer patients are not at a higher risk of 25(OH)D inadequacy than healthy children at diagnosis; however, prevalence of 25(OH)D inadequacy is still high and non-supplemented children have a higher risk. Appropriate monitoring and therapeutic supplementation should be implemented.
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http://dx.doi.org/10.1017/S0007114516004074DOI Listing
December 2016

Effects of pediatric cancer and its treatment on nutritional status: a systematic review.

Nutr Rev 2015 May 29;73(5):276-95. Epub 2015 Mar 29.

R. Revuelta Iniesta, I. Paciarotti, and J.M. McKenzie are with the Department of Dietetics, Nutrition and Biological Health Sciences, Queen Margaret University, Edinburgh, United Kingdom. R. Revuelta Iniesta, I. Paciarotti, and D.C. Wilson are with the Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom. F.H.M. Brougham is with the Department of Haematology and Oncology, Royal Hospital for Sick Children, Edinburgh, United Kingdom.

Context: Malnutrition in pediatric cancer is common worldwide, yet its prevalence and effects on clinical outcomes remain unclear.

Objective: The aim of this review was to evaluate primary research reporting the prevalence of malnutrition in pediatric cancer patients and to assess the effects of pediatric cancer and its treatment on nutritional status.

Data Sources: Electronic databases of MEDLINE, CINHAL, and PubMed were searched (January 1990-February 2013).

Study Selection: Studies of patients aged <18 years who were diagnosed with and treated for cancer and for whom measurements of anthropometry were reported and included. The primary outcome was the prevalence of malnutrition (undernutrition and overnutrition), expressed as body mass index (BMI), in children diagnosed with and treated for cancer.

Data Extraction: Evidence was appraised critically by employing the Critical Appraisal Skills Program tool, and data was extracted from original articles.

Data Synthesis: A total of 46 studies were included, most of which were considered to be of low quality on the basis of heterogeneity in both the criteria and the measurements used to define malnutrition. Undernutrition was identified by measuring BMI, weight loss, mid-upper arm circumference, and triceps skinfold thickness, while overnutrition was assessed using BMI. Overall, the prevalence of undernutrition ranged from 0% to 65% and overnutrition from 8% to 78%. Finally, undernutrition in pediatric cancer at diagnosis was associated with poor clinical outcomes in 6 of 9 studies.

Conclusion: The possibility of a high prevalence of malnutrition in childhood cancer, indicated by the studies reviewed, highlights the need for high-quality, population-based, longitudinal studies using standard criteria to identify malnutrition.
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http://dx.doi.org/10.1093/nutrit/nuu062DOI Listing
May 2015

Anti-Müllerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study.

J Clin Endocrinol Metab 2012 Jun 3;97(6):2059-67. Epub 2012 Apr 3.

Department of Pediatric Hematology and Oncology, Royal Hospital for Sick Children, 17 Millerfield Place, Edinburgh EH9 1LF, United Kingdom.

Context: Cytotoxic treatment may accelerate depletion of the primordial follicle pool, leading to impaired fertility and premature menopause. Assessment of ovarian damage in prepubertal girls is not currently possible, but Anti-Müllerian Hormone (AMH) is a useful marker of ovarian reserve in adults.

Objective: The objective of the study was to prospectively evaluate AMH measurement in children as a marker of ovarian toxicity during cancer treatment.

Design And Setting: This was a prospective, longitudinal study at a University Hospital.

Patients: Twenty-two females (17 prepubertal), median age 4.4 yr (range 0.3-15 yr), were recruited before treatment for cancer.

Main Outcome Measures: AMH, inhibin B, and FSH at diagnosis, after each chemotherapy course and during follow-up, were measured. Risk of gonadotoxicity was classified as low/medium (n = 13) or high (n = 9) based on chemotherapy agent, cumulative dose, and radiotherapy involving the ovaries.

Results: Pretreatment AMH was detectable across the age range studied. AMH decreased progressively during chemotherapy (P < 0.0001) in both prepubertal and pubertal girls, becoming undetectable in 50% of patients, with recovery in the low/medium risk groups after completion of treatment. In the high-risk group, AMH became undetectable in all patients and showed no recovery. Inhibin B was undetectable in most patients before treatment and, with FSH, showed no clear relationship to treatment.

Conclusion: AMH is detectable in girls of all ages and falls rapidly during cancer treatment in both prepubertal and pubertal girls. Both the fall during treatment and recovery thereafter varied with risk of gonadotoxicity. AMH is therefore a clinically useful marker of damage to the ovarian reserve in girls receiving treatment for cancer.
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http://dx.doi.org/10.1210/jc.2011-3180DOI Listing
June 2012

Subfertility in children and young people treated for solid and haematological malignancies.

Br J Haematol 2005 Oct;131(2):143-55

Department of Paediatric Haematology and Oncology, Royal Hospital for Sick Children, Edinburgh, UK.

Children treated for cancer may exhibit impaired fertility in later life. A number of chemotherapeutic agents have been identified as being gonadotoxic, and certain treatment regimens are particularly associated with subsequent infertility. Radiotherapy can also cause gonadal damage, most notably after direct testicular or pelvic irradiation or following total body irradiation. Because of the varied nature of the cytotoxic insult, it can be difficult to predict the likelihood of infertility in later life. Currently, cryopreservation of spermatozoa, oocytes or embryos is the only method of preserving fertility in patients receiving gonadotoxic therapy. This is only applicable to postpubertal patients and can be problematic in the adolescent age group. At present there is no provision for the prepubertal child, although there are a number of experimental methods being investigated. However, in addition to the many scientific and technical issues to be overcome before clinical application of such techniques, a number of ethical and legal issues must also be addressed to ensure a safe and realistic prospect for future fertility in these patients.
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http://dx.doi.org/10.1111/j.1365-2141.2005.05740.xDOI Listing
October 2005

Male fertility following childhood cancer: current concepts and future therapies.

Asian J Androl 2003 Dec;5(4):325-37

Royal Hospital for Sick Children, 17 Millerfield Place, Edinburgh, EH9 1LW, UK.

Prepubertal boys treated for cancer may exhibit impaired fertility in later life. A number of chemotherapeutic agents have been identified as being gonadotoxic, and certain treatment regimens, such as that used for Hodgkin's disease, are particularly associated with subsequent infertility. Radiotherapy may also cause gonadal damage, most notably following direct testicular irradiation or total body irradiation. Because of the varied nature of the cytotoxic insult, it can be difficult to predict the likelihood of infertility in later life. Currently it is not possible to detect gonadal damage early due to the lack of a sensitive marker of gonadal function in the prepubertal age group. Semen cryopreservation is currently the only method of preserving fertility in patients receiving gonadotoxic therapy. This is only applicable to postpubertal patients and can be problematic in the adolescent age group. At present there is no provision for the prepubertal boy, although there are a number of experimental methods currently being investigated. By harvesting testicular tissue prior to gonadotoxic therapy, restoration of fertility could be achieved following treatment, either by germ cell transplantation or by in vitro maturation of the germ cells harvested. Alternatively, rendering the testes quiescent during cytotoxic treatment may protect the germ cells from subsequent damage. In addition to the many scientific and technical issues to be overcome prior to clinical application of these techniques, a number of ethical and legal issues must also be addressed to ensure a safe and realistic prospect for future fertility in these patients.
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December 2003

The late endocrine effects of childhood cancer treatment.

Pediatr Rehabil 2002 Oct-Dec;5(4):191-201

Department of Paediatric Haematology and Oncology, Royal Hospital for Sick Children, 17 Millerfield Place, Edinburgh, EH9 1LW, UK.

Whilst many children diagnosed with cancer can now realistically hope for long term survival, the consequences of cancer treatment can be particularly devastating as they enter adolescence and adulthood. Disruption of the endocrine system can result from such treatment, including growth hormone deficiency, problems in normal pubertal progression and thyroid dysfunction. Fertility can also be affected by cancer treatment received as a child, which can have a devastating impact as the patient enters adulthood. In addition, these children may encounter disorders of growth and bone metabolism due to both their initial disease and aspects of its treatment, resulting in further morbidity in later life. The aetiology and diagnosis of these problems are discussed in this review, along with therapeutic options in order to reduce their impact. Long term follow up and clinical vigilance in this patient group is vital. We must continue to strive towards improved survival from childhood cancer, but equally we must remain aware of the adverse effects of treatment, particularly in the long term, and must aim to reduce the impact of these effects as children enter adolescence and adult life.
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http://dx.doi.org/10.1080/1363849021000039407DOI Listing
May 2003