Seeking consent to tissue banking: a survey of health professionals in childhood cancer.

To identify the views of health professionals working in childhood cancer on seeking consent to tissue banking from potential donors. Self-completion questionnaires sent to 553 UK paediatric oncology health professionals. The response rate was 60%. Respondents (100%) were in favour of using tissue samples from children with cancer for research. A substantial minority (30%) had concerns about the impact of the law on their professional role in relation to tissue banking. Almost all (90%) reported that both the parent(s) and the child, if able, should be asked for consent, though the UK Human Tissue Act provides that a competent child's consent is sufficient. Most (94%) supported 'generic' rather than 'specific' consent. Barriers to obtaining consent included: (1) timing of the approach to families; (2) availability of suitable staff; (3) sensitivity of the issues; (4) difficulties of managing the process; and (5) problems of maintaining a paper trail. Many would welcome training on seeking consent. Personal knowledge and relationships with families are often seen as important in guiding the proper approach to consent rather than formalized rules. There is widespread support among health professionals for tissue banking in childhood cancer. In sensitive situations, disciplined exercise of professional discretion might better deliver on aspirations for regulation than rigid procedures.

Reporting of prognostic markers: current problems and development of guidelines for evidence-based practice in the future.

Prognostic markers help to stratify patients for treatment by identifying patients with different risks of outcome (e.g. recurrence of disease), and are important tools in the management of cancer and many other diseases. Systematic review and meta-analytical approaches to identifying the most valuable prognostic markers are needed because (sometimes conflicting) evidence relating to markers is often published across a number of studies. To investigate the practicality of this approach, an empirical investigation of a systematic review of tumour markers for neuroblastoma was performed; 260 studies of prognostic markers were identified, which considered 130 different markers. The reporting of these studies was often inadequate, in terms of both statistical analysis and presentation, and there was considerable heterogeneity for many important clinical/statistical factors. These problems restricted both the extraction of data and the meta-analysis of results from the primary studies, limiting feasibility of the evidence-based approach.Guidelines for reporting the results of primary prognostic marker studies in cancer, and other diseases, are given in order to facilitate both the interpretation of individual studies and the undertaking of systematic reviews, meta-analysis and, ultimately, evidence-based practice. General availability of full individual patient data is a necessary step forward and would overcome the majority of problems encountered, including poorly reported summary statistics and variability in cutoff level, outcome assessed and adjustment factors used. It would also limit the problem of reporting bias, although publication bias will remain a concern until studies are prospectively registered. Such changes in practice would help important evidence-based reviews to be conducted in order to establish the most appropriate prognostic markers for clinical use, which should ultimately improve patient care.

A systematic review of molecular and biological markers in tumours of the Ewing's sarcoma family.

The aims of this study were to perform the first systematic review of molecular and biological tumour markers in tumours of the Ewing's sarcoma family (ESFT), and evaluate the current evidence for their clinical use. A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. Papers were independently assessed for tumour markers used in the screening, diagnosis, prognosis or monitoring of patients with ESFT. Eighty-four papers studying the use of 70 different tumour markers in ESFT's were identified. Low-quality, inconsistent reporting limited meta-analysis to that of prognostic data for 28 markers. Patients with tumours lacking S-100 protein expression have a better overall survival (OS) (hazard ratio (HR)=0.41, 95% confidence interval (CI) 0.19, 0.89) than those with expression; patients with high levels of serum LDH had a worse OS and disease-free survival (DFS) (OS: HR=2.92, CI 2.16, 3.94, DFS: HR=3.38, 95% CI 2.28, 4.99); patients with localised disease and tumours expressing type 1 EWS-FLI1 fusion transcripts had an improved DFS compared with those with other fusion transcript types (HR=0.17, 95% CI 0.079, 0.37). The knowledge base formed should facilitate more informative future research. Improved statistical reporting and large, multicentre prospective studies are advocated.

Childhood cancer and users' views: a critical perspective.

The understanding of users' views of childhood cancer services has been hampered by several important problems. First, this area has been dominated by the tradition of psycho-oncology, with its overly narrow focus on the psychopathological sequelae of chronic childhood illness. Second, a set of inappropriate and undertheorized assumptions has prevailed about the nature of childhood and children's experiences of illness and children's ability to articulate and report on these. Third, the roles, responsibilities and experiences of parents of children with cancer have been unhelpfully conceptualized and underinvestigated. Finally, there has been a lack of suitable methods for making progress with empirical research in this area. In this paper, we argue that interpretive perspectives and associated methods can offer much to those seeking more insightful and better-informed approaches to the views of users of childhood cancer services. We offer some specific examples of where such approaches have already demonstrated considerable promise, showing, for example, that the parenting role is distinctive and should not be assumed to be interchangeable, theoretically or practically, with that of a carer. We conclude by identifying areas where both empirical research and theoretical development are needed.

Parents' accounts of obtaining a diagnosis of childhood cancer.

BACKGROUND: Quick diagnosis and treatment of cancers is a UK government priority. However, the process of arriving at a diagnosis of childhood cancer has been neglected in comparison with the attention given to cancers in adults. We investigated parents' narratives about the period before their child's diagnosis. METHODS: We undertook semistructured interviews with 20 parents whose children (aged 4-18 years) had a confirmed diagnosis of cancer or brain tumour. All interviews were recorded and fully transcribed. Dates of consultations and investigations were noted from children's medical records. Data were analysed by the constant comparison method. FINDINGS: The time before diagnosis is very significant for parents and might affect their adaptation and reaction to their child's diagnosis. Parents were first alerted to their child's illness by a range of signs and symptoms, and by behavioural and affective changes. These early symptoms were often vague, non-specific, and common, and some older children were reluctant to disclose symptoms. Ten families' accounts of this period before diagnosis included a dispute with doctors. Disagreements between parents and doctors about the seriousness of children's symptoms and the need for investigations occurred in both primary and secondary care. Some parents felt that doctors discounted their special knowledge of their child. INTERPRETATION: Parents' accounts offer valuable insights into their experiences of obtaining a diagnosis of childhood cancer and into possible sources of delays in this complex process. If delays are to be avoided or reduced, attention must be given to the different roles of parents, children, general practitioners, hospital specialists, and type of cancer. Our findings have important implications for policy, practice, and research, and for the management of childhood illnesses.

Murine macrophage mannose receptor promoter is regulated by the transcription factors PU.1 and SP1.

The mannose receptor (MR) is a transmembrane protein that functions primarily as a phagocytic receptor for a wide range of microorganisms. Its expression appears to be restricted to tissue macrophages and Langerhans cells. To gain an understanding of the regulation of the gene, we have isolated the 5' flanking sequence of the murine MR gene and have analyzed a 536-bp sequence upstream of the ATG start site for transcriptional activity. This sequence lacks a TATA box but contains an initiator (Inr) consensus element overlapping the single transcriptional start site. Transcription factor binding sites contained within this sequence include PU.1, Sp1, ETS, GATA, and MYB motifs. Serial 100-bp deletions of this promoter fragment fused to a luciferase reporter gene showed various patterns of activity when transfected into different cell types. In myeloid cells, sequence elements upstream of bp -300 appeared to have a silencing effect on promoter activity. Of the four potential PU.1 binding sites contained within the fragment, one site (at -164) bound the PU.1 factor most strongly, whereas the adjacent PU.1 site (at -177 bp) bound PU.1 to a lesser degree. Mutations of these sites decreased transcriptional activity but did not abolish it. However, promoter activity was abrogated when both the -164 bp PU.1 site and the adjacent -177 bp PU.1 site were mutated. In addition, mutation of the Sp1 site also significantly reduced promoter activity. Cotransfection studies in Drosophila Schneider cells indicated that PU.1 and Sp1 may function synergistically in transactivating the murine MR. This study indicates that MR gene expression is regulated in part by the interaction between the ubiquitously expressed factor Sp1 and the lymphoid/myeloid factor PU.1 and provides a basis for studying the regulation of this gene.

Progressive glomerular toxicity of ifosfamide in children.

Glomerular toxicity following ifosfamide (IFO) is not as well recognized as renal tubular damage. Following a case of ifosfamide-induced renal failure with histological evidence of glomerular changes, we undertook a retrospective study of all IFO-treated children to assess the extent and severity of its glomerular toxicity and to identify possible predisposing factors. Thirty-seven children with a follow-up of 6 months or more from the end of chemotherapy were studied. They were a median of 10.8 years old (range 3.25-18.5), had received a median of 54 g/m2 (range 9-135) of IFO, and had a median follow-up of 29 months (range 6-68). The criteria to identify glomerular dysfunction were raised plasma creatinine (Pc) values on two occasions or a low glomerular filtration rate (GFR) measured by Tc-99-DTPA clearance. Detailed assessment was carried out to identify other nephrotoxic influences in these children. Subjects in whom glomerular dysfunction could be causally linked to IFO were compared with the rest of the group for a variety of predisposing factors. Of eight children with glomerular dysfunction, two had other nephrotoxic influences and were excluded from further analysis. In six (17.1%) children, glomerular dysfunction appeared to be causally linked to IFO. Their median GFR was 61.9 ml/min/1.73 m2(range 33-85) and Pc was 123 mumol/l (range 85-216). Five of the six had normal glomerular function at the end of therapy and the raised Pc values were first noted 19, 21, 26, 29, and 36 months later. Children with glomerular toxicity had a significantly longer median follow-up (41.5 vs. 19 months; P = 0.04) than the rest of the group, suggesting late onset of this problem. They were older at the time of the study and had received nearly twice the dose of IFO, though the differences in age and dose did not reach statistical significance. The earliest signs of renal toxicity were seen in the index case, who had had prior nephrectomy. All affected children had coexistent and preceding tubular toxicity. The inadequacies of tests commonly used to assess glomerular function and the possibility of underestimation of dysfunction are discussed. Glomerular dysfunction following IFO is poorly recognized and evidence from this study of its later onset and progressive nature is a cause for concern. The index case is described with histological findings.

Increased circulating adhesion molecule concentrations in patients with the systemic inflammatory response syndrome: a prospective cohort study.

OBJECTIVE: To investigate the relationship between the soluble derivatives of endothelial adhesion molecules liberated by activated vascular endothelium and the development of the systemic inflammatory response syndrome and organ dysfunction in septic patients. DESIGN: Prospective cohort study with controls. SETTING: University hospital intensive care unit. PATIENTS: Healthy volunteers (controls, n = 85), patients with the systemic inflammatory response syndrome (n = 21), patients with systemic inflammatory response syndrome and organ dysfunction (n = 14), and miscellaneous, severely ill patients (n = 5). INTERVENTIONS: Plasma samples were collected from consecutive patients who satisfied the criteria for inclusion in the groups listed above. MEASUREMENTS AND MAIN RESULTS: The plasma was assayed by enzyme-linked immunosorbent assay (ELISA) for each of the three soluble adhesion molecules: sE-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. There were low basal amounts of these adhesion molecules in the healthy volunteers, while plasma concentrations of all three adhesion molecules were increased in the sepsis groups. The median soluble E-selectin concentration was higher in those patients with organ dysfunction compared with the concentrations in patients with uncomplicated sepsis (p < .01 at first and p < .001 when comparing peak values attained). No patient survived when the amount of soluble E-selectin was > 30 units/mL. CONCLUSIONS: Concentrations of circulating vascular endothelial adhesion molecules, especially soluble E-selectin, are increased in patients with systemic inflammatory response syndrome and these concentrations are more increased in patients with organ dysfunction. High plasma concentrations of soluble E-selectin were closely associated with multiple-organ dysfunction and death. Measurement of adhesion molecules, especially soluble E-selectin, might be used to advantage in the management of patients with sepsis.

Ifosfamide enantiomers: pharmacokinetics in children.

Ifosfamide, like other oxazaphosphorine drugs, is chiral and there is some evidence, mainly from animal studies, of stereo-selective differences in metabolism, excretion and cytotoxic activity between the two enantiomers. The pharmacokinetics of racemic ifosfamide (RAC-IFO), R-ifosfamide (R-IFO) and S-ifosfamide (S-IFO) were studied in five children who received intravenous therapy with racemic ifosfamide on 3 consecutive days. The clearance of S-IFO was greater than that of R-IFO. The clearance value at the end of the infusion was faster than the respective rate measured at the beginning of or during the ifosfamide regimens in four children and, therefore, suggests autoinduction of elimination of both enantiomers.

Cisplatin-resistant metastatic hepatoblastoma: complete response to carboplatin, etoposide, and liver transplantation.

A child with stage 4 hepatoblastoma failed to respond to treatment with cisplatin and adriamycin. She then showed a response to carboplatin with complete clearing of pulmonary metastases. Bilobar liver disease persisted, although significantly reduced in size. A liver transplant was subsequently performed and she remains in complete remission 36 months later. After the first course of carboplatin, there was a dramatic rise in alpha-feto protein which then fell exponentially. Carboplatin warrants further study in hepatoblastoma.

Interleukin-6 and its relationship to C-reactive protein and fever in children with febrile neutropenia.

The assessment of febrile neutropenia is problematic. C-reactive protein (CRP) values alone do not differentiate those patients with microbiologically documented infections from those with unexplained fevers. Plasma interleukin-6 (IL-6), measured by ELISA, was correlated with different diagnostic groups in 47 episodes of febrile neutropenia in children. Samples were collected daily from admission until resolution of fever. On admission, the median IL-6 value for gram-negative infections was 1610 pg/ml (range, 896-40,000), for gram-positive infections it was 138 pg/ml (range, 66-1045), and for unexplained fevers it was 50 pg/ml (range, 24-135, with a single high value of 665 pg/ml). These medians were significantly different (P less than .005). There was no significant difference in median CRP values. IL-6 values peaked 24-48 h before CRP values. There was a positive correlation of IL-6 with the presence of fever. Plasma IL-6 may be a more sensitive marker than CRP of acute infection and should prove useful in the assessment of fevers in these patients.

The intensive care unit in paediatric oncology.

There were 70 admissions from a regional paediatric oncology centre to the intensive care unit over a six and a half year period. Patients were divided into those with systemic infections (n = 19), respiratory infections (n = 15), metabolic effects (n = 9), tumour mass effects (n = 10), neurological complications (n = 8), and others (n = 9). The overall survival was 51%. Patients admitted with metabolic or tumour mass related effects had the best prognosis with a survival of 84%. If dialysis is required in this group of patients then continuous arteriovenous haemofiltration is recommended. Patients with systemic or respiratory infections comprised the main poor prognosis group with a survival of 26%. For patients with a systemic infection who required ventilation, the mortality was 100%. The outlook for patients with a generalised encephalopathy was also poor, with no neurologically intact survivors. The median APACHE-II (acute physiology and chronic health evaluation) score for patients who died was 27 and for survivors was 16. There is a need for close cooperation between staff of intensive care and paediatric oncology units. Alternative treatments should be considered for patients with systemic infections who require ventilation.

Measurement of dopamine, HVA and HMMA in untimed urine samples: establishment of age-related reference data in children.

We describe assays for homovanillic acid, hydroxymethylmandelic acid and dopamine that have proven practical and reliable during 3 years of routine use. Homovanillic and hydroxymethylmandelic acids were measured as trimethyl silyl derivatives by capillary gas chromatography. Dilution of samples prior to extraction was found to be necessary to achieve consistent recoveries of these acidic metabolites. Dopamine was assayed by high pressure liquid chromatography with electrochemical detection using an optimized method of catecholamine isolation that involved both ion exchange and alumina extraction. Untimed urine samples were collected from 140 hospitalized children. Age related reference data for the excretion of all three metabolites are reported. We suggest certain precautions that should be observed when using untimed samples and relating the results to creatinine excretion.

Familial microcephaly with normal intelligence in a patient with acute lymphoblastic leukemia.

The authors describe a family with two children with microcephaly and normal intelligence, in which acute lymphoblastic leukemia developed in one of the siblings. An autosomal recessive pattern of inheritance is suggested by the pedigree. This is consistent with the literature, which the authors reviewed. All of the patients have similar phenotypic features, with some demonstrating chromosomal instability. It is important to recognize this syndrome because of the increased risk of lymphoreticular malignancy.

Nasopharyngeal rhabdomyosarcoma and multiple lentigines syndrome: a case report.

An 8-year-old boy with multiple lentigines syndrome presented with a nasopharyngeal rhabdomyosarcoma. The tumour failed to respond to chemotherapy. This is a further association of rhabdomyosarcoma with a congenital syndrome.

Progressive renal toxicity due to ifosfamide.

A prospective and follow up study of renal tubular and glomerular function in 11 children receiving ifosfamide treatment was conducted. Each child received between four and 14 courses of ifosfamide, given as a continuous infusion of 3 g/m2 over 24 hours for two or three days. Evidence of renal toxicity was seen in all patients. There was a treatment related rise in urinary tubular markers (N-acetyl-glucosaminidase and alpha 1 microglobulin). Recovery was limited, so that by the fourth course of treatment all values remained abnormal. There was an associated treatment related reduction in plasma phosphate concentration. Urinary albumin also showed a treatment related rise, but with fewer abnormal values. Electrophoresis was used to confirm tubular or glomerular patterns. Glomerular toxicity was less severe and occurred in fewer patients. The follow up study showed persistence of tubular damage in all seven patients examined, and there was evidence of glomerular damage in five of the seven children. Children receiving ifosfamide need to be carefully monitored for renal toxicity both during treatment and at follow up.