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Background: Childhood leukaemias express novel, clonotypic fusion genes that may already be present at birth before the clinical manifestation of leukaemia. Exposure of the fetus to diagnostic x rays is reported to increase the risk of childhood leukaemia, and may do so by generating leukaemic fusion genes. Advances in neonatal medicine in the past decade that have extended the limits of viability of preterm babies down to 23 weeks of gestation have resulted in the increased use of diagnostic x rays to monitor neonatal progress.Aim: To investigate whether exposure of very preterm infants to diagnostic x rays in the neonatal period leads to the development of leukaemic fusion genes.Methods: Peripheral blood samples were collected at birth from very preterm infants (23-30 weeks gestation) and following exposure to diagnostic x rays at intervals of two weeks, until discharge. Cord blood samples from normal full term infants served as controls. Total RNA was extracted from the blood and the expression of the fusion genes TEL-AML1, MLL-AF4, and BCR-ABL, characteristic of three subtypes of childhood leukaemia, was investigated in the preterm and full term infant samples using a nested reverse transcriptase polymerase chain reaction method. Serial pre- and post-x ray samples from 42 preterm babies, pre-x ray samples from an additional 46 preterm infants, and cord blood samples from 100 normal full term infants were screened for fusion gene transcripts.Results: No leukaemic fusion gene transcripts were detected in preterm infants following exposure to diagnostic x rays. A BCR-ABL transcript was identified in a single preterm infant prior to x ray exposure. TEL-AML1 transcripts were detected in cord blood samples from two full term infants. MLL-AF4 transcripts were not detected in any of the pre- or full term infants tested.Conclusions: Exposure of the preterm infants to x rays in this small series and at the doses used for diagnostic purposes did not induce leukaemic fusion gene expression, but we cannot exclude the possibility that a small proportion of preterm infants may be unusually sensitive to x rays. [ABSTRACT FROM AUTHOR]

The aim was to produce evidence-based guidelines on mouth care for children, teenagers and young adults receiving chemotherapy and/or radiotherapy. Systematic reviews were undertaken and research was graded according to the methods of the Scottish Intercollegiate Guidelines Network. Where no relevant research was identified, an opinion-gathering process was undertaken. 'Best practice' recommendations were developed with regard to appropriate dental care and basic oral hygiene. An evaluation of oral assessment tools identified seven which had been assessed for reliability and/or validity. Only Eilers' Oral Assessment Guide was felt to be relevant for daily clinical practice. A variety of interventions have been used for the management of oral mucositis, candidiasis, xerostomia and herpes simplex virus; few are supported by research evidence. Careful oral management of children treated for cancer can improve the quality of life during treatment. The guidelines have the potential to improve patient care by promoting interventions of proven benefit and discouraging use of ineffective or potentially harmful practices which may result in adverse patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Treatment of cancer is increasingly more effective but is associated with short and long term side effects. Oral side effects remain a major source of illness despite the use of a variety of agents to prevent them. One of these side effects is oral mucositis (mouth ulcers)., Objectives: To evaluate the effectiveness of prophylactic agents for oral mucositis in patients with cancer receiving treatment, compared with other potentially active interventions, placebo or no treatment., Search Strategy: The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched. Reference lists from relevant articles were scanned and the authors of eligible studies were contacted to identify trials and obtain additional information. Date of most recent searches: June 2006: CENTRAL (The Cochrane Library 2006, Issue 2)., Selection Criteria: Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone with cancer receiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral mucositis; outcomes - prevention of mucositis, pain, amount of analgesia, dysphagia, systemic infection, length of hospitalisation, cost and patient quality of life., Data Collection and Analysis: Information regarding methods, participants, interventions and outcome measures and results were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Collaboration statistical guidelines were followed and risk ratios (RR) calculated using random-effects models., Main Results: Two hundred and seventy-seven studies were eligible. One hundred and eighty-eight were excluded for various reasons, usually as there was no useable information on mucositis. Of the 89 useable studies all had data for mucositis comprising 7523 randomised patients. Interventions evaluated were: acyclovir, allopurinol mouthrinse, aloe vera, antibiotic pastille or paste, benzydamine, beta carotene, calcium phosphate, camomile, Chinese medicine, chlorhexidine, etoposide, folinic acid, glutamine, granulocyte/macrophage colony-stimulating factor (GM-CSF), histamine gel, honey, hydrolytic enzymes, ice chips, iseganan, keratinocyte GF, misonidazole, pilocarpine, pentoxifylline, povidone, prednisone, propantheline anticholinergic, prostaglandin, sucralfate, systemic antibiotic clarithromycin, traumeel, zinc sulphate. Of the 33 interventions included in trials, 12 showed some evidence of a benefit (albeit sometimes weak) for either preventing or reducing the severity of mucositis. Interventions where there was more than one trial in the meta-analysis finding a significant difference when compared with a placebo or no treatment were: amifostine which provided minimal benefit in preventing mild and moderate mucositis RRs = 0.95 (95% confidence interval (CI) 0.92 to 0.98) and 0.88 (95% CI 0.80 to 0.98); Chinese medicine showed a benefit at all three dichotomies of mucositis with RR values of 0.44 (95% CI 0.20 to 0.96), 0.44 (95% CI 0.33 to 0.59) and 0.16 (95% CI 0.07 to 0.35) for increasing levels of mucositis severity; hydrolytic enzymes reduced moderate and severe mucositis with RRs = 0.52 (95% CI 0.36 to 0.74) and 0.17 (95% CI 0.06 to 0.52); and ice chips prevented mucositis at all levels RRs = 0.64 (95% CI 0.50 to 0.82), 0.38 (95% CI 0.23 to 0.62), and 0.24 (95% CI 0.12 to 0.48). Other interventions showing some benefit with only one study were: benzydamine, calcium phosphate, etoposide bolus, honey, iseganan, oral care, zinc sulphate. The general reporting of RCTs, especially concealment of randomisation, was poor. However, the assessments of the quality of the randomisation improved when the authors provided additional information., Authors' Conclusions: Several of the interventions were found to have some benefit at preventing or reducing the severity of mucositis associated with cancer treatment. The strength of the evidence was variable and implications for practice include consideration that benefits may be specific for certain cancer types and treatment. There is a need for well designed and conducted trials with sufficient numbers of participants to perform subgroup analyses by type of disease and chemotherapeutic agent.

Background: Treatment of cancer is increasingly effective but is associated with short and long term side effects. Oral side effects, including oral candidiasis, remain a major source of illness despite the use of a variety of agents to treat them., Objectives: To assess the effectiveness of interventions for the treatment of oral candidiasis for patients with cancer receiving chemotherapy or radiotherapy or both., Search Strategy: Computerised searches of Cochrane Oral Health Group and PaPaS Trials Registers, CENTRAL, MEDLINE, EMBASE, CINAHL, CANCERLIT, SIGLE and LILACS were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches: June 2006: CENTRAL (The Cochrane Library 2006, Issue 2)., Selection Criteria: All randomised controlled trials comparing agents prescribed to treat oral candidiasis in people receiving chemotherapy or radiotherapy for cancer. The outcomes were eradication of oral candidiasis, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and patient quality of life., Data Collection and Analysis: Data were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. Risk ratios were calculated using random-effects models., Main Results: Nine trials involving 658 patients, satisfied the inclusion criteria and are included in this review. Only two agents, each in single trials, were found to be effective for eradicating oral candidiasis. A drug absorbed from the gastrointestinal tract, ketoconazole, was more beneficial than placebo in eradicating oral candidiasis (risk ratio (RR) = 3.61, 95% confidence interval (CI) 1.47 to 8.88) and clotrimazole, at a higher dose of 50 mg was more effective than a lower 10 mg dose in eradicating oral candidiasis, when assessed mycologically (RR = 2.00, 95% CI 1.11 to 3.60). Of the five trials included in these meta-analyses, three were at high risk of bias and two of moderate risk of bias. Another trial demonstrated no statistically significant difference between a 10 mg dose of the partially absorbed drug, clotrimazole, and placebo. No differences were found when comparing different absorbed drugs; and comparing absorbed drugs with drugs which are not absorbed., Authors' Conclusions: There is weak and unreliable evidence that the absorbed drug, ketoconazole, may eradicate oral candidiasis and that a higher dose of the partially absorbed drug, clotrimazole, may give greater benefit than a lower 10 mg dose, however, researchers may wish to prevent rather than treat oral candidiasis. Further well designed, placebo-controlled trials assessing the effectiveness of old and new interventions for treating oral candidiasis are needed.

Background: Treatment of cancer is increasingly effective but associated with short and long term side effects. Oral side effects, including oral mucositis (mouth ulceration), remain a major source of illness despite the use of a variety of agents to treat them., Objectives: To assess the effectiveness of interventions for treating oral mucositis or its associated pain in patients with cancer receiving chemotherapy or radiotherapy or both., Search Strategy: Computerised searches of Cochrane Oral Health Group's Trials Register; Cochrane Pain, Palliative and Supportive Care Group's Trials Register; CENTRAL; MEDLINE and EMBASE were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches June 2006: CENTRAL (The Cochrane Library 2006, Issue 2)., Selection Criteria: All randomised controlled trials comparing agents prescribed to treat oral mucositis in people receiving chemotherapy or radiotherapy or both. Outcomes were oral mucositis, time to heal mucositis, oral pain, duration of pain control, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and quality of life., Data Collection and Analysis: Data were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation, blindness and withdrawals. Quality assessment was carried out on these three criteria. The Cochrane Oral Health Group statistical guidelines were followed and risk ratio (RR) values calculated using fixed effect models., Main Results: Twenty-six trials involving 1353 patients satisfied the inclusion criteria. Four agents, each in single trials, were found to be effective for improving (allopurinol RR 3.33, 95% confidence interval (CI) 1.06 to 10.49; granulocyte macrophage-colony stimulating factor RR 4.23, 95% CI 1.35 to 13.24; immunoglobulin RR 1.81, 95% CI 1.24 to 2.65; human placentral extract RR 4.50, 95% CI 2.29 to 8.86) or eradicating mucositis (allopurinol RR 19.00, 95% CI 1.17 to 307.63). Three of these trials were rated as at moderate risk of bias and one as at high risk of bias. The following agents were not found to be effective: benzydamine HCl, sucralfate, tetrachlorodecaoxide, chlorhexidine and 'magic' (lidocaine solution, diphenhydramine hydrochloride and aluminum hydroxide suspension). Six trials compared the time to heal and mucositis was found to heal more quickly with two interventions: granulocyte macrophage-colony stimulating factor when compared to povidone iodine, with mean difference -3.5 days (95% CI -4.1 to -2.9) and allopurinol compared to placebo, with mean difference -4.5 days (95% CI -5.8 to -3.2). Three trials compared patient controlled analgesia (PCA) to the continuous infusion method for controlling pain. There was no evidence of a difference, however, less opiate was used per hour for PCA, and the duration of pain was shorter. One trial demonstrated that pharmacokinetically based analgesia (PKPCA) reduced pain compared with PCA: however, more opiate was used with PKPCA., Authors' Conclusions: There is weak and unreliable evidence that allopurinol mouthwash, granulocyte macrophage-colony stimulating factor, immunoglobulin or human placental extract improve or eradicate mucositis. There is no evidence that patient controlled analgesia (PCA) is better than continuous infusion method for controlling pain, however, less opiate was used per hour, and duration of pain was shorter, for PCA. Further, well designed, placebo-controlled trials assessing the effectiveness of allopurinol mouthwash, granulocyte macrophage-colony stimulating factor, immunoglobulin, human placental extract, other interventions investigated in this review and new interventions for treating mucositis are needed.

Background: Treatment of cancer is increasingly more effective but is associated with short and long term side effects. Oral side effects remain a major source of illness despite the use of a variety of agents to prevent and treat them. One of these side effects is oral candidiasis., Objectives: To assess the effectiveness of interventions (which may include placebo or no treatment) for the prevention of oral candidiasis for patients with cancer receiving chemotherapy or radiotherapy or both., Search Strategy: Computerised searches of Cochrane Oral Health Group and PAPAS Trials Registers, CENTRAL, MEDLINE, EMBASE, CINAHL, CANCERLIT, SIGLE and LILACS were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches: June 2006: CENTRAL (The Cochrane Library 2006, Issue 2)., Selection Criteria: Trials were selected if they met the following criteria: design - random allocation of participants; participants - anyone receiving chemotherapy or radiotherapy treatment for cancer; interventions - agents prescribed to prevent oral candidiasis; primary outcome - prevention of oral candidiasis., Data Collection and Analysis: Data were recorded on the following secondary outcomes if present: relief of pain, amount of analgesia, relief of dysphagia, incidence of systemic infection, duration of stay in hospital (days), cost of oral care, patient quality of life, death, use of empirical antifungal treatment, toxicity and compliance. Information regarding methods, participants, interventions, outcome measures and results were independently extracted, in duplicate, by two review authors. The Cochrane Oral Health Group statistical guidelines were followed and risk ratios (RR) calculated using random-effects models. Potential sources of heterogeneity were examined in random-effects metaregression analyses., Main Results: Twenty-eight trials involving 4226 patients satisfied the inclusion criteria. Drugs absorbed and partially absorbed from the gastrointestinal (GI) tract were found to prevent oral candidiasis when compared to a placebo, or a no treatment control group, with RR for absorbed drugs = 0.47 (95% confidence interval (CI) 0.29 to 0.78). For absorbed drugs in populations with an incidence of 20% (mid range of results in control groups), this implies a NNT of 9 (95% CI 7 to 13) patients need to be treated to avoid one patient getting oral candidiasis. There was no significant benefit shown for drugs not absorbed from the GI tract., Authors' Conclusions: There is strong evidence, from randomised controlled trials, that drugs absorbed or partially absorbed from the GI tract prevent oral candidiasis in patients receiving treatment for cancer. There is also evidence that these drugs are significantly better at preventing oral candidiasis than drugs not absorbed from the GI.

Background: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS., Methods: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS., Results: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases., Conclusions: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.

The ability of topoisomerase 2 inhibitors to induce DNA breakage is well recognized. Previous studies, however, have concentrated on the effects on individual genes. The effects of etoposide on the MLL, RUNX1, and MLLT3 genes were simultaneously studied in the same hemopoietic cell population. We found MLL to be more susceptible to etoposide-induced cleavage than RUNX1 and MLLT3, with maximum cleavage at a lower drug concentration. A higher level of MLL than other gene cleavage was also detected after cellular exposure to all drug concentrations. Greater susceptibility to topoisomerase 2 inhibitor-induced cleavage may explain the more frequent involvement of MLL in treatment-related leukemogenesis.

The molecular effects of etoposide in haemopoietic cells suggest that mixed lineage leukaemia (MLL) abnormalities can be biomarkers of patient susceptibility to the genotoxic effects of topoisomerase 2 (topo 2) inhibitors. We have prospectively studied treatment-related MLL cleavage and rearrangement in serial samples from 71 children receiving chemotherapy, using Southern blot analysis and panhandle PCR. The results were related to patient demographics, treatment details and outcome. MLL cleavage was identified in six bone marrow samples from five patients 2-10 months after the start of therapy. There was no obvious relationship between the degree of MLL cleavage and cumulative dose or schedule of topo 2 inhibitors. Three children with low percentage (23-30%) cleavage remained well and two were still receiving treatment at study completion. One child with two consecutively positive samples and higher level of MLL cleavage (45-48%) died from treatment-related toxicities and relapsed leukaemia. A patient with haemophagocytic lymphohistiocytosis developed the highest level of MLL cleavage (50%) at 3 months and a treatment-related leukaemia with MLL rearrangement 6 months after the start of treatment. It would appear that some patients are inherently more susceptible to the genotoxic effect of topo 2 inhibitors. The degree and persistence of MLL cleavage may identify patients at risk.

Treatment-related acute myeloid leukaemia (t-AML) is a serious complication of topoisomerase 2 inhibitor therapy and is characterised by the presence of mixed lineage leukaemia (MLL) rearrangement. By molecular tracking, we were able to show that MLL cleavage preceded gene rearrangement by 3 months and before the clinical diagnosis of t-AML in a patient with haemophagocytic lymphohistiocytosis. This is the first report on the sequential detection of the two biomarkers in treatment-related leukaemogenesis.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder resulting from mutations in the NBS1 gene, which encodes for the DNA double strand break repair protein nibrin. NBS is clinically characterized by microcephaly, dysmorphic features, immunodeficiency, and increased susceptibility to malignancy, mainly of lymphoid origin. Here, we describe a 7-year-old girl with NBS who is homozygous for the NBS1 698del4 mutation. She had been diagnosed with perianal rhabdomyosarcoma (RMS) and experienced severe toxicity from chemotherapy. RMS arising perianally is extremely uncommon but has been previously described in two cases with NBS. The strong association of perianal RMS with NBS should, therefore, be considered when confronted with a perianal RMS, as this carries important clinical implications in terms of potential need for therapy modification and follow up investigations. In addition, it suggests a role for the NBS1 gene and the nibrin dependent pathway in the pathogenesis of RMS, especially those arising perianally.

The aim of the study was to establish current UK oral care practice for children with cancer. A telephone survey of all 22 United Kingdom Children's Cancer Study Group (UKCCSG) centres was undertaken. Nineteen (86%) of the centres reported using guidelines/protocols for mouth care. The use of routine preventive oral care therapies showed the greatest variation between centres. Four centres (18%) did not use any prophylactic oral care therapy other than basic oral hygiene, whereas seven (32%) routinely used a combination of three or more agents. Chlorhexidine was the most frequently administered prophylactic therapy (17/22 centres, 77%), followed by nystatin (11/22 centres, 50%). There was little variation in advice given to parents/patients on basic oral hygiene. Regarding dental check-ups, 9/22 centres (41%) recommended children to attend a hospital-linked dental clinic. Only at 8/22 centres (36%) did children undergo a dental check-up before commencing cancer treatment. The survey identified significant variation in preventive oral care therapies and dental check-ups at the UKCCSG centres. Attention needs to be given to establishing evidence based, effective strategies.

We have examined space-time clustering amongst cases of lymphoma in children, aged 0-14 years, using population-based data from the North West of England for the period 1954-2001. There was little or no evidence for space-time clustering amongst all the lymphomas or amongst those sub-groups identified in advance.

Concern about late adverse effects of cranial radiotherapy (XRT) has led to alternative approaches to eliminate leukaemia from the central nervous system (CNS) in childhood acute lymphoblastic leukaemia (ALL). The Medical Research Council UKALL XI trial recruited 2090 children with ALL between 1990 and 1997. Median follow-up is 7 years 9 months; event-free survival (EFS) and overall survival were 63.1% and 84.6%, respectively, at 5 years and 59.8% and 79.4% at 10 years. The isolated CNS relapse rate was 7.0% at 10 years. Patients were randomized for CNS-directed therapy within white blood cell (WBC) groups. For WBC <50 x 10(9)/l, high-dose intravenous methotrexate (HDMTX) (6-8 g/m2) with intrathecal methotrexate (ITMTX) was compared with ITMTX alone, and was significantly better at preventing isolated and combined CNS relapse, but non-CNS relapses were similar. There was no significant difference in EFS at 10 years, 64.1% [95% confidence interval (CI) 60.4-67.8] with HDMTX plus ITMTX, and 63.0% (95% CI 59.5-66.5) with ITMTX alone. For WBC >/=50 x 10(9)/l, HDMTX with ITMTX was compared with XRT and a short course of ITMTX. CNS relapses were significantly fewer with XRT, but there was a non-significant increase in non-CNS relapses. EFS was not significantly different, being 55.2% (95% CI 47.8-62.6) at 10 years with XRT and 52.1% (95% CI 44.8-59.4) with HDMTX plus ITMTX.

Aims: To investigate the association of acute parvovirus B19 infection with new onset of acute lymphoblastic and myeloblastic leukaemia., Methods: Cerebrospinal fluid (CSF) samples from patients with acute myelogenous leukaemia (AML) at diagnosis (n = 2) and acute lymphoblastic leukaemia (ALL) at diagnosis (n = 14) were analysed for parvovirus B19 DNA by means of nested polymerase chain reaction. In addition, samples from patients with benign intracranial hypertension (BIH) (n = 10) and hydrocephalus (n = 13) were tested as controls., Results: Four leukaemia cases were positive-common ALL (n = 2), null cell ALL (n =1), and M7 AML (n = 1)-whereas all controls were negative (Yates corrected chi(2) value, 3.97; p = 0.046; odds ratio, 16.92; confidence interval, 1.03 to 77.18). All four patients were significantly anaemic, but none was encephalitic or had evidence of central nervous system leukaemia. In three of these patients, serum tumour necrosis alpha, interferon gamma, interleukin 6, granulocyte-macrophage colony stimulating factor (range, 34.93-3800.06 pg/ml), and macrophage chemoattractant protein 1 were detectable. All of these four patients carried at least one of the HLA-DRB1 alleles, which have been associated with symptomatic parvovirus B19 infection., Conclusion: Erythroid suppression and immune cell proliferation are both associated with B19 infection and may also be important in the pathogenesis of acute leukaemia.

The relationship between neonatal vitamin K received by the intramuscular (i.m.) route and the development of leukaemia or other cancers was investigated as part of a national case-control study of childhood cancer, using data abstracted from obstetric and neonatal records. The analyses included 2530 children diagnosed with cancer before 15 years of age, 1174 of whom had leukaemia and 4487 control children without cancer. Overall, 39% of cases and 42% of controls had records of i.m. vitamin K administration, while 24% of cases and 22% of controls had no record of whether or not they had received vitamin K. Using subjects who received i.m. vitamin K as the baseline group, our analyses found no association between the administration of i.m. vitamin K and either leukaemia or other cancers as a group. We conclude that there is no convincing evidence that neonatal vitamin K administration, irrespective of the route by which it is given, influences the risk of children developing leukaemia or any other cancer.

Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.

The aim of this paper was to study the geographical distribution of Wilms' tumours (WT) and soft-tissue sarcomas (STS) for 0-14 year olds included in a population-based registry from North West England during 1976-2000. Standardised morbidity ratios (SMRs) were calculated. Relationships between incidence rates and small area (ward) population density, ethnic composition, deprivation index and urban-rural status were examined using Poisson regression. There was a non-linear relationship between WT incidence and population density (P=0.008), with a higher incidence associated with wards with low deprivation scores (P=0.02); and which included a greater proportion of whites (P=0.01). For STS, a higher incidence was associated with wards with low deprivation scores (P=0.04); and which were 'more rural/less urban' (P=0.03). These results are consistent with a role for localised environmental exposures, in combination with lifestyle factors, in the aetiology of WT. For STS, there is some evidence for the involvement of environmental and/or lifestyle factors.

The extent to which genetic susceptibility contributes to the causation of childhood acute myeloid leukaemia (AML) is not known. The inherited bone marrow failure disorder Fanconi anaemia (FA) carries a substantially increased risk of AML, raising the possibility that constitutional variation in the FA (FANC) genes is involved in the aetiology of childhood AML. We have screened genomic DNA extracted from remission blood samples of 97 children with sporadic AML and 91 children with sporadic acute lymphoblastic leukaemia (ALL), together with 104 cord blood DNA samples from newborn children, for variations in the Fanconi anaemia group C (FANCC) gene. We found no evidence of known FANCC pathogenic mutations in children with AML, ALL or in the cord blood samples. However, we detected 12 different FANCC sequence variants, of which five were novel to this study. Among six FANCC variants leading to amino-acid substitutions, one (S26F) was present at a fourfold greater frequency in children with AML than in the cord blood samples (odds ratio: 4.09, P = 0.047; 95% confidence interval 1.08-15.54). Our results thus do not exclude the possibility that this polymorphic variant contributes to the risk of a small proportion of childhood AML.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23+/-+/-12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5+/-+/-5% vs 23.4+/-+/-4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88+/-+/-13 vs 46+/-14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64+/-+/-8% (high risk) vs 83+/-+/-6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.

The aetiology of most childhood solid tumours (other than central nervous system [CNS] tumours) is unclear. To investigate whether certain environmental exposures may be involved, we have analysed for space-time clustering using population-based data from North West England for the period 1954-98. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space, <5 km, and close in time, <1 year apart. Addresses at birth and at diagnosis were used. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. There was significant evidence of space-time clustering for Wilms' tumours (p = 0.03 and 0.04, using the geographical distance and nearest neighbour versions of the Knox test; and p = 0.07 and 0.03, using the geographical distance and nearest neighbour versions of the K-function method), and soft tissue sarcomas (p = 0.01, using both the geographical distance and nearest neighbour versions of the Knox test; and p = 0.001 and 0.002, using the geographical distance and nearest neighbour versions of the K-function method) based on time and location at birth, but not time and location at diagnosis. There was little or no evidence of space-time clustering amongst other diagnostic groups. These are the first results to demonstrate space-time clustering for childhood Wilms' tumours and soft tissue sarcomas. The results are consistent with environmental exposure hypotheses, relating to locations pre-natally or peri-natally., (Copyright 2003 Wiley-Liss, Inc.)

Background: Cisplatin (cDDP), when used either alone or, more often, in combination with other agents, especially adriamycin, achieves a high response rate in osteosarcoma. Its use, however, is limited by severe nephro- and neuro-toxicity. Second generation platinum compounds, most notably carboplatin (CBDCA), have been developed in order to attempt to reduce these dose-limiting toxicities, and thus improve the therapeutic ratio. Studies evaluating the role of combination CT containing CBDCA vs. cDDP have demonstrated differing results depending on the tumor type tested and its role in the treatment of osteosarcoma has yet to be clarified., Procedure: In this study, we compared the in vitro anti-tumor activity of cDDP and CBDCA in a panel of three human osteosarcoma cell lines (HOS, MG63, and U2OS)., Results: cDDP and CBDCA (0-20 micromol) showed marked variation in cytotoxicity among the three cell lines. EC(50) values for CBDCA in HOS and MG63 cells were approximately two-fold higher than for cDDP and the ratio of AUC(CBDCA) to AUC(cDDP) varied from 1.8 in the HOS cell line to 2.3 in the MG63 cell line. Exposure of MG63 and HOS cells to either cDDP or CBDCA (1.67 and 13.5 micromol) caused a G2/M cell cycle arrest by 24 hr. Also evident was a sub G1 peak indicative of cell death by apoptosis. U2OS cells were relatively resistant to the cytotoxic effects of both drugs, although a cell cycle arrest in response to DNA damage was observed. This suggests that unlike MG63 and HOS cells, U2OS cells have either a more efficient repair pathway for platinum-induced DNA damage or are able to evade apoptosis. Examination of apoptotic events and cellular recovery demonstrated that both an 8-16-fold higher concentration and longer treatment period for CBDCA compared with cDDP was required to produce equivalent cell death and a loss of the ability of single cell clones to form colonies in both the HOS and MG63, but not the U2OS cell line., Conclusions: Our findings suggest that CBDCA at a two- to four-fold higher concentration than cDDP has potential therapeutic activity in platinum sensitive osteosarcomas, particularly when cDDP cytotoxicity compromises therapeutic efficacy., (Copyright 2002 Wiley-Liss, Inc.)

In a previous study, we obtained preliminary evidence in a small series of patients (n = 63) suggesting that susceptibility to childhood common acute lymphoblastic leukaemia (c-ALL) was associated with an allele at the HLA-DPB1 locus, DPB1*0201. We have now tested this hypothesis by comparing the frequency of children with leukaemia (n = 982) who typed for specific DPB1 alleles and two groups of non-leukaemic children, one consisting of children with solid tumours, excluding lymphomas (n = 409), the other consisting of normal infants (n = 864). We found that significantly more children with c-ALL and T-ALL, but not pro-B ALL or acute non-ALL typed for DPB1*0201 as compared with children with solid tumours [odds ratio (OR), 95% confidence interval (CI) for c-ALL: 1.76, 1.20-2.56; T-ALL: 1.93, 1.01-3.80] and normal infants (OR, 95% CI for c-ALL: 1.83, 1.34-2.48; T-ALL: 2.00, 1.10-3.82). In childhood c-ALL, significantly more children than those with solid tumours or normal infants typed for DPB1 alleles coding specific polymorphic amino acids lining the antigen-binding site of the DPbeta1*0201 allotypic protein, suggesting that susceptibility to childhood c-ALL may be influenced by DPbeta ABS amino acid polymorphisms shared by DPbeta1*0201 and other DPbeta1 allotypes. These results point to a mechanism of c-ALL susceptibility that involves the presentation of specific antigenic peptides, possibly derived from infectious agents, by DPbeta1*0201-related allotypic proteins, leading to the activation of helper T cells mediating proliferative stress on preleukaemic cells.

Purpose: To investigate the G2 chromosomal radiosensitivity of patients with cancers diagnosed when the patients are less than 20 years of age. Earlier studies demonstrated an enhanced sensitivity in substantial proportions of patients with breast or colorectal cancer, and in early onset head and neck cancer cases. Heritability of chromosomal radiosensitivity in families of breast cancer patients was also demonstrated. It is suggested that elevated sensitivity in this assay could be a marker of genetic predisposition to cancer, mediated through inherited genetic determinants of low penetrance., Materials and Methods: Stimulated lymphocytes were exposed to 0.5 Gy X-rays in the G2-phase of the cell cycle and chromatid aberrations were scored in metaphase cells., Results: The assay was performed on 32 patients with early onset cancers (aged 0.5-19 years) of various types and their sensitivity was compared with that of 41 young normal controls (0.25-19 years) and 32 adult normals (20-60 years). The proportion of cases showing enhanced sensitivity in the three groups was 44, 15 and 10%, respectively. The difference between the young patients and normals was highly significant (p = 0.004)., Conclusions: The results suggest the possibility that a substantial proportion of early onset cancers are associated with the inheritance of predisposing genes of low penetrance. However, support for this hypothesis requires that the heritability of chromosomal radiosensitivity be demonstrated in family members. In addition, a larger study is now required to investigate the chromosomal radiosensitivity of specific early onset cancers.

To investigate whether infections or other environmental exposures may be involved in the aetiology of childhood central nervous system tumours, we have analysed for space-time clustering and seasonality using population-based data from the North West of England for the period 1954 to 1998. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space, <5 km, and close in time, <1 year apart. Addresses at birth and diagnosis were used. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. Tests for heterogeneity and Edwards' test for sinusoidal variation were applied to examine changes of incidence with month of birth or diagnosis. There was strong evidence of space-time clustering, particularly involving cases of astrocytoma and ependymoma. Analyses of seasonal variation showed excesses of cases born in the late Autumn or Winter. Results are consistent with a role for infections in a proportion of cases from these diagnostic groups. Further studies are needed to identify putative infectious agents.

Background: Treatment of cancer is increasingly effective but associated with short and long-term side effects. Oral side effects, including oral mucositis (ulceration), remain a major source of illness despite the use of a variety of agents to treat them., Objectives: To assess the effectiveness of interventions for treating oral mucositis or its associated pain in patients with cancer receiving chemotherapy and/or radiotherapy., Search Strategy: Computerised searches of Cochrane Oral Health Group Specialised Register, CCTR, MEDLINE and EMBASE were undertaken. Reference lists from relevant articles were searched. Authors of eligible trials were contacted to identify trials and obtain additional information. Date of most recent searches: May 2001 (CCTR 2001, issue 3), Selection Criteria: All randomised controlled trials comparing agents prescribed to treat oral mucositis in people receiving chemotherapy and/or radiotherapy. Outcomes were oral mucositis, oral pain, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and quality of life., Data Collection and Analysis: Data were independently extracted, in duplicate, by two reviewers. Authors were contacted for details of randomisation, blindness and withdrawals. Quality assessment was carried out on these three criteria. Cochrane Oral Health Group statistical guidelines were followed and relative risk values calculated using fixed effects models as no significant heterogeneity was detected (P>0.1)., Main Results: Fifteen trials involving 876 patients satisfied the inclusion criteria. Two agents, each in single trials, were found to be effective for improving (allopurinol RR=0.63 95%CI 0.42 to 0.96) or eradicating mucositis (allopurinol RR=0.59 95%CI 0.42 to 0.84; vitamin E RR=0.38 95%CI 0.14 to 0.97). The following agents were not found to be effective: benzydamine HCl, sucralfate, tetrachlorodecaoxide, chlorhexidine and "magic" (lidocaine solution, diphenhydramine hydrochloride and aluminum hydroxide suspension). Three trials compared patient controlled analgesia (PCA) to the continuous infusion method for controlling pain. There was no evidence of a difference, however, less opiate was used per hour for PCA. One trial demonstrated that pharmacokinetically based analgesia (PKPCA) reduced pain compared with PCA, however more opiate was used with PKCA., Reviewer's Conclusions: There is weak and unreliable evidence that allopurinol mouthwash and vitamin E improves or eradicates mucositis. There is no evidence that patient controlled analgesia (PCA) is better than continuous infusion method for controlling pain, however, less opiate was used per hour for PCA. Further, well designed, placebo-controlled trials assessing the effectiveness of allopurinol mouthwash, vitamin E and new interventions for treating mucositis are needed.

Background: Treatment of cancer is increasingly effective but is associated with short and long-term side effects. Oral side effects, including oral candidiasis, remain a major source of illness despite the use of a variety of agents to treat them., Objectives: To assess the effectiveness of interventions for the treatment of oral candidiasis for patients with cancer receiving chemotherapy and or radiotherapy., Search Strategy: Computerised searches of Cochrane Oral Health Group Specialised Register, CCTR, MEDLINE and EMBASE were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information. Date of the most recent searches May 2001: (CCTR 2001, issue 3), Selection Criteria: All randomised controlled trials comparing agents prescribed to treat oral candidiasis in people receiving chemotherapy or radiotherapy for cancer. The outcomes were eradication of oral candidiasis, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and patient quality of life., Data Collection and Analysis: Data were independently extracted, in duplicate, by two reviewers. Authors were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The Cochrane Oral Health Group statistical guidelines were followed and relative risk values calculated using random effects models where significant heterogeneity was detected (P<0.1)., Main Results: Eight trials involving 418 patients, satisfied the inclusion criteria and are included in this review. Only two agents, each in single trials, were found to be effective for eradicating oral candidiasis. A drug absorbed from the gastrointestinal tract, ketoconazole, was more beneficial than placebo in eradicating oral candidiasis (RR=0.35 95%CI 0.20 to 0.61) and clotrimazole, at a higher dose of 50mg was more effective than a lower 10mg dose in eradicating oral candidiasis, when assessed mycologically (RR=0.47 95%CI 0.25 to 0.89). Another trial demonstrated no difference between a 10mg dose of the partially absorbed drug, clotrimazole, and placebo. No differences were found when comparing different absorbed drugs; and comparing absorbed drugs with drugs which are not absorbed., Reviewer's Conclusions: There is weak and unreliable evidence that the absorbed drug, ketoconazole, may eradicate oral candidiasis and that a higher dose of the partially absorbed drug, clotrimazole, may give greater benefit than a lower 10mg dose, however, researchers may wish to prevent rather than treat oral candidiasis. Further well designed, placebo-controlled trials assessing the effectiveness of old and new interventions for treating oral candidiasis are needed.

Background: There has been speculation that increasing trends in incidence of childhood central nervous system tumors and infant neuroblastoma in the United States have been due to diagnostic improvements or reporting changes. To investigate whether or not such trends could be explained in this way in the U.K., the authors used population-based data from Northwest England to analyze incidence trends in childhood solid tumors., Methods: Cases were diagnosed during 1954-1998 and were grouped according to a morphology-based classification scheme. More than 95% of diagnoses were based on special histopathologic review. Tissue sections were retained, and diagnoses were rereviewed to ensure consistency in classification throughout the time period. Age-, gender- and period-specific incidence rates were calculated. Analyses were performed with chi-square tests and Poisson regression., Results: There was an overall increase in the incidence of all childhood solid tumors of 0.9% each year. A temporal increase was found in childhood brain tumors characterized by, in particular, annual increases of 1% in pilocytic astrocytoma, 1% in primitive neuroectodermal tumors, and 2.3% in miscellaneous gliomas. The incidence of germ cell tumors increased at a rate of 2.6% each year., Conclusions: These increases could not be attributed to changes in diagnostic practice, and it is unlikely that the increases were due to changes in reporting practice. Further, the restriction of the increases to certain groups, with stable rates in others, argued against the changes being artifactual. The authors concluded that the increases in incidence were likely to be real., (Copyright 2001 American Cancer Society.)

The spectrum and frequency of cancers associated with germline TP53 mutations are uncertain. To address this issue a cohort of individuals from 28 families with Li-Fraumeni syndrome, segregating germline TP53 mutations was established. Predicted cancers were estimated by applying age, morphology, site and sex-specific UK cancer statistics to person-years at risk. Observed and predicted cancers were compared and two-sided P-values calculated. Cancer types occurring to excess and showing P-values <0.02, were designated strongly associated with germline TP53 mutations. These were removed from the data and a second round of analyses performed. Cancer types with P-values <0.02 and 0.02-0.05 in the second round analyses were considered moderately and weakly associated respectively. Strongly associated cancers were: breast carcinoma, soft tissue sarcomas, osteosarcoma, brain tumours, adrenocortical carcinoma, Wilms' tumour and phyllodes tumour. Carcinoma of pancreas was moderately associated. Leukaemia and neuroblastoma were weakly associated. Other common carcinomas including lung, colon, bladder, prostate, cervix and ovary did not occur to excess. Although breast carcinoma and sarcomas were numerically most frequent, the greatest increases relative to general population rates were in adrenocortical carcinoma and phyllodes tumour. We conclude that germline TP53 mutations do not simply increase general cancer risk. There are tissue-specific effects.

The occurrence of childhood acute lymphoblastic leukemia (ALL) in 2 of 3 triplets provided a unique opportunity for the investigation of leukemogenesis and the natural history of ALL. The 2 leukemic triplets were monozygotic twins and shared an identical, acquired TEL-AML1 genomic fusion sequence indicative of a single-cell origin in utero in one fetus followed by dissemination of clonal progeny to the comonozygotic twin by intraplacental transfer. In accord with this interpretation, clonotypic TEL-AML1 fusion sequences could be amplified from the archived neonatal blood spots of the leukemic twins. The blood spot of the third, healthy, dizygotic triplet was also fusion gene positive in a single segment, though at age 3 years, his blood was found negative by sensitive polymerase chain reaction (PCR) screening for the genomic sequence and by reverse transcription-PCR. Leukemic cells in both twins had, in addition to TEL-AML1 fusion, a deletion of the normal, nonrearranged TEL allele. However, this genetic change was found by fluorescence in situ hybridization to be subclonal in both twins. Furthermore, mapping of the genomic boundaries of TEL deletions using microsatellite markers indicated that they were individually distinct in the twins and therefore must have arisen as independent and secondary events, probably after birth. These data support a multihit temporal model for the pathogenesis of the common form of childhood leukemia.

Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C-->T) and 1,298 (A-->C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07--0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20--1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.

In the last 20 years, the survival rate for children with acute lymphoblastic leukaemia (ALL) has markedly improved, largely owing to a decrease in relapses. However, children still die from complications of treatment and these are potentially preventable. We have analysed data from three large consecutive national protocols for ALL from 1980 to 1997 [Medical Research Council United Kingdom ALL (MRC UKALL) trials VIII, X and XI] to compare the incidence and causes of treatment-related deaths (TRD). The percentage of TRD has fallen from 9% to 2% (UKALL VIII to XI), largely as a result of a decrease in fatal infections. Deaths during induction have fallen from 3% to 1%, the main causes of death being bacterial, followed by fungal infection, while other causes, chiefly haemorrhage, have not declined. Remission deaths also decreased from 6% to 1%, particularly those deaths due to measles and pneumocystis carinii. More guidelines for surveillance and treatment of infections have been included within progressively more intensive protocols. Risk factor analysis showed increased TRD in patients with Down's syndrome, high leucocyte count and older age in UKALL XI. In contrast, the introduction of blocks of intensification was not associated with an increased death rate. While improved supportive care has reduced the incidence of TRD, there is still scope for further reduction by prompt treatment of suspected infection. Maintenance of herd immunity remains of vital importance in avoiding deaths from measles.