Galectin-3 is a marker of favorable prognosis and a biologically relevant molecule in neuroblastic tumors.

Childhood neuroblastic tumors are characterized by heterogeneous clinical courses, ranging from benign ganglioneuroma (GN) to highly lethal neuroblastoma (NB). Although a refined prognostic evaluation and risk stratification of each tumor patient is becoming increasingly essential to personalize treatment options, currently only few biomolecular markers (essentially MYCN amplification, chromosome 11q status and DNA ploidy) are validated for this purpose in neuroblastic tumors. Here we report that Galectin-3 (Gal-3), a ß-galactoside-binding lectin involved in multiple biological functions that has already acquired diagnostic relevance in specific clinical settings, is variably expressed in most differentiated and less aggressive neuroblastic tumors, such as GN and ganglioneuroblastoma, as well as in a subset of NB cases. Gal-3 expression is associated with the INPC histopathological categorization (P<0.001) and Shimada favorable phenotype (P=0.001), but not with other prognostically relevant features. Importantly, Gal-3 expression was associated with a better 5-year overall survival (P=0.003), and with improved cumulative survival in patient subsets at worse prognosis, such as older age at diagnosis, advanced stages or NB histopathological classification. In vitro, Gal-3 expression and nuclear accumulation accompanied retinoic acid-induced cell differentiation in NB cell lines. Forced Gal-3 overexpression increased phenotypic differentiation and substrate adherence, while inhibiting proliferation. Altogether, these findings suggest that Gal-3 is a biologically relevant player for neuroblastic tumors, whose determination by conventional immunohistochemistry might be used for outcome assessment and patient's risk stratification in the clinical setting.

p53-mediated delayed NF-κB activity enhances etoposide-induced cell death in medulloblastoma.

Medulloblastoma (MB) is an embryonic brain tumour that arises in the cerebellum. Using several MB cell lines, we have demonstrated that the chemotherapeutic drug etoposide induces a p53- and caspase-dependent cell death. We have observed an additional caspase-independent cell death mechanism involving delayed nuclear factor κB (NF-κB) activity. The delayed induction was controlled by a p53-dependent transcription step and the production of death receptors (especially CD95/Fas). We further demonstrated that in both MB and glioblastoma (GM) cell lines, in which the p53 pathway was not functional, no p65 activation could be detected upon etoposide treatment. MB cell lines that have mutations in p53 or NF-κB are either less sensitive (NF-κB mutant) or even completely resistant (p53 mutant) to chemotherapeutic intervention. The optimal cell death was only achieved when both p53 and NF-κB were switched on. Taken together, our results shed light on the mechanism of NF-κB activation by etoposide in brain tumours and show that the genetic background of MB and GM cells determines their sensitivity to chemotherapy and has to be taken into account for efficient therapeutic intervention.

Peripheral T-cell lymphoma in a five year old.

We report a case presenting with persistent pyrexia that led to the diagnosis of peripheral T-cell lymphoma, a rare malignancy in childhood. The case illustrates diagnostic conundrums in a patient who is not responding as expected to treatment.

Efficacy of carboplatin given in a phase II window study to children and adolescents with newly diagnosed metastatic soft tissue sarcoma.

AIM: The activity of carboplatin was evaluated in a phase II window study in previously untreated children with metastatic soft tissue sarcoma. METHODS: Children with poor-risk metastatic disease (over 10 years and/or with bone/bone marrow involvement) treated in the SIOP MMT 98 study were scheduled to receive two courses of intravenous carboplatin (area under curve [AUC] of 10), 21 days apart. RESULTS: Sixteen eligible patients were entered into the rhabdomyosarcoma (RMS) group. Response (complete remission or partial remission) was seen in five children (31%, 95% confidence interval (CI) 14-56%). Ten eligible patients with other soft tissue sarcomas were recruited into the non-RMS group. Two responses (20%, 95% CI 6-51%) were seen. Toxicity in both groups was predictable nausea, vomiting and marrow suppression and there were no toxic deaths. CONCLUSION: Single-agent carboplatin at AUC of 10 has an acceptable toxicity profile but only moderate efficacy in poor-risk metastatic soft tissue sarcoma.

Adaptive dosing and platinum-DNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours.

A pharmacokinetic-pharmacodynamic study was carried out to investigate the feasibility and potential importance of therapeutic monitoring following high-dose carboplatin treatment in children. High-dose carboplatin was administered over 3 or 5 days, with the initial dose based on renal function, to achieve target area under the plasma concentration-time curve (AUC) values of 21 or 20 mg ml(-1).min, respectively. Dose adjustment was carried out based on observed individual daily AUC values, to obtain the defined target exposures. Platinum-DNA adduct levels were determined in peripheral blood leucocytes and toxicity data were obtained. Twenty-eight children were studied. Based on observed AUC values, carboplatin dose adjustment was performed in 75% (21 out of 28) patients. Therapeutic monitoring resulted in the achievement of carboplatin exposures within 80-126% of target AUC values, as compared to estimated exposures of 65-213% of target values without dose adjustment. The carboplatin AUC predicted with no dose modification was positively correlated with pretreatment glomerular filtration rate (GFR) values. Higher GFR values were observed in those patients who would have experienced AUC values >25% above the target AUC than those patients attaining AUC values >25% below the target AUC, following renal function-based dosing. Platinum-DNA adduct levels correlated with observed AUC values on day 1 of carboplatin and increased over a 5-day course of treatment. Real-time monitoring of carboplatin pharmacokinetics with adaptive dosing is both feasible and necessary for the attainment of consistent AUC values in children receiving high-dose carboplatin treatment. Pharmacodynamic data suggest a strong correlation between carboplatin pharmacokinetics and the drug-target interaction.

Morphological and molecular assessment of apoptotic mechanisms in peripheral neuroblastic tumours.

Multiple defects in apoptotic pathways have been described in peripheral neuroblastic tumours (NTs). Mitosis-karyorrhexis index (MKI) is a reliable morphological marker identifying favourable and unfavourable NTs. The extent to which apoptotic processes contribute to determine the clinical significance of MKI is still undefined. Apoptosis was investigated in a series of 110 peripheral NTs by comparing MKI to immunohistochemical and molecular apoptotic features. High MKI was found in 55 out of 110 NTs (50%) and was associated with advanced stage (P = 0.007), neuroblastoma (NB) histological category (P = 0.024), MYCN amplification (P < 0.001), and poor outcome (P = 0.011). Overall survival probability was 45% in patients with high MKI compared to 73% in patients with low MKI. In the same 110 NTs, the expression of Bcl-2, Bcl-XL, Bax and Mcl-1 was studied by immunohistochemistry, but no significant associations were found with clinicohistological features. Microarray analysis of apoptotic genes was performed in 40 out of 110 representative tumours. No significant association was found between the expression of apoptotic genes and MKI or clinicohistological features. Proliferative activity was assessed in 60 out of 110 representative tumours using Ki67 immunostaining, but no significant correlations with MKI or clinicobiological features were found. In NTs, the combination of apoptosis and proliferation as expressed by MKI is a significant prognostic parameter, although neither of them is per se indicative of the clinicobiological behaviour and outcome.

Emergent embolisation to control severe haematuria in Wilms' tumour.

Wilms' tumour commonly presents with an abdominal mass and gross haematuria. Here, we present the novel application of paediatric renal arterial embolisation to control life-threatening haematuria in Wilms' tumour.

Oscillations in NF-kappaB signaling control the dynamics of gene expression.

Signaling by the transcription factor nuclear factor kappa B (NF-kappaB) involves its release from inhibitor kappa B (IkappaB) in the cytosol, followed by translocation into the nucleus. NF-kappaB regulation of IkappaBalpha transcription represents a delayed negative feedback loop that drives oscillations in NF-kappaB translocation. Single-cell time-lapse imaging and computational modeling of NF-kappaB (RelA) localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased IkappaBalpha transcription. Transcription of target genes depended on oscillation persistence, involving cycles of RelA phosphorylation and dephosphorylation. The functional consequences of NF-kappaB signaling may thus depend on number, period, and amplitude of oscillations.

Psychological and/or educational interventions for the prevention of depression in children and adolescents.

BACKGROUND: Depression is the fourth most important disease in the estimation of the burden of disease Murray 1996 and is a common problem with prevalence rates estimated to be as high as 8% in young people. Depression in young people is associated with poor academic performance, social dysfunction, substance abuse, suicide attempts, and completed suicide (NHMRC 1997). This has precipitated the development of programmes aimed at preventing the onset of depression. This review evaluates evidence for the effectiveness of these prevention programmes. OBJECTIVES: To determine whether psychological and/or educational interventions (both universal and targeted) are effective in reducing risk of depressive disorder by reducing depressive symptoms immediately after intervention or by preventing the onset of depressive disorder in children and adolescents over the next one to three years. SEARCH STRATEGY: The Cochrane Depression, Anxiety and Neurosis Group trials register (August 2002), MEDLINE (1966 to December Week 3 2002), EMBASE (1980 to January Week 2 2003), PsychInfo (1886 to January Week 2 2003) and ERIC (1985 to December 2002) were searched. In addition, conference abstracts, the reference lists of included studies, and other reviews were searched and experts in the field were contacted. SELECTION CRITERIA: Each identified study was assessed for possible inclusion by two independent reviewers based on the methods sections. The determinants for inclusion were that the trial include a psychological and/or educational prevention programme for young people aged 5 to 19 years-old, who did not meet DSM or ICD criteria for depression and/or did not fall into the clinical range on standardised, validated, and reliable rating scales of depression. DATA COLLECTION AND ANALYSIS: The methodological quality of the included trials was assessed by two independent reviewers according to a list of pre-determined criteria, which were based on quality ratings devised by Moncrieff and colleagues (Moncrieff 2001). Outcome data was extracted and entered into Revman 4.2. Means and standard deviations for continuous outcomes and number of events for dichotomous outcomes were extracted where available. For trials where the required data were not reported or could not be calculated, further details were requested from first authors. If no further details were provided, the trial was included in the review and described, but not included in the meta-analysis. Results were presented for each type of intervention: targeted or universal interventions; and educational or psychological interventions and if data were provided, by gender. Where possible data were combined in meta-analyses to give a treatment effect across all trials. Sensitivity analysis were conducted on studies rated as "adequate" or "high" quality, that is with a score over 22, based on the scale by Moncrieff et al (Moncrieff 2001). The presence of publication bias was assessed using funnel plots. MAIN RESULTS: Studies were divided into those that compared intervention with an active comparison or placebo (i.e. a control condition that resembles the intervention being investigated but which lacks the elements thought to be active in preventing depression) and those that used a "wait-list" or no intervention comparison group. Only two studies fell into the former category and neither showed effectiveness although one study was inadequately powered to show a difference and in the other the "placebo" contained active therapeutic elements, reducing the ability to demonstrate a difference from intervention. Psychological interventions were effective compared with non-intervention immediately after the programmes were delivered with a significant reduction in scores on depression rating scales for targeted (standardised mean difference (SMD) of -0.26 and a 95% confidence interval (CI) of -0.40 to -0.13 ) but not universal interventions (SMD -0.21, 95% CI -0.48, 0.06), with a significant effect maintained on pooling data (SMD -0.26, 95% CI -0.36, -0.15). While small effect sizes were reported, these were associated with a significant reduction in depressive episodes. The overall risk difference after intervention translates to "numbers needed to treat" (NNT) of 10. The most effective study is the targeted programme by Clarke (Clarke 2001) where the initial effect size of -0.46 is associated with an initial risk difference of -0.22 and NNT 5. There was no evidence of effectiveness for educational interventions. Reports of effectiveness for boys and girls were contradictory. The quality of many studies was poor, and only two studies made allocation concealment explicit. Sensitivity analysis of only high quality studies did not alter the results significantly. The only analysis in which there was significant statistical heterogeneity was the sub-group analysis by gender where there was variability in the response to different programmes for both girls and boys. For the most part funnel plots indicate findings are robust for short term effects with no publication bias evident. There are too few studies to comment on whether there is publication bias for studies reporting long-term (12-36 month) follow-up. REVIEWER'S CONCLUSIONS: Although there is insufficient evidence to warrant the introduction of depression prevention programmes currently, results to date indicate that further study would be worthwhile. There is a need to compare interventions with a placebo or some sort of active comparison so that study participants do not know whether they are in the intervention group or not, to investigate the impact of booster sessions to see if effectiveness immediately after intervention can be prolonged, ideally for a year or longer, and to consider practical implementation of prevention programmes when choosing target populations. Until now most studies have focussed on psychological interventions. The potential effectiveness of educational interventions has not been fully investigated. Given the gender differences in prevalence, and the change in these that occurs in adolescence with a disproportionate increase in prevalence rates for girls, it is likely that girls and boys will respond differently to interventions. Although differences have been reported in studies in this review the findings are contradictory and a more definitive delineation of gender specific responses to interventions would be helpful.

Update on childhood rhabdomyosarcoma.

The overall survival of childhood rhabdomyosarcoma has improved dramatically over the past 10 years. Early diagnosis and appropriate referral to a specialised centre leading to an accurate and timely diagnosis reflects on overall outcome. Recent molecular studies have identified different biological subtypes resulting in the recognition of poorer subgroups and allowing more appropriate treatment to be administered. Clinical trials remain the cornerstone to further improve outcome, now carried out on an international basis.

Expression of the Hypermethylated in Cancer gene (HIC-1) is associated with good outcome in human breast cancer.

A new cancer gene, HIC-1 (Hypermethylated in Cancer) telomeric to p53 on chromosome 17p may be of clinical importance in sporadic breast cancer. Regional DNA hypermethylation of 17p13.3 resulting in suppression of gene expression has been shown to precede 17p structural changes in human carcinogenesis. In addition, loss of heterozygosity studies have suggested clinically significant involvement of a gene on 17p13.3 associated with poor prognosis in breast cancer. Using RT-PCR analysis, we demonstrate that the MCF7 (wild type p53) cell line expressed HIC-1 transcripts but the MDAMB231 (mutant p53) cell line did not, suggesting loss of HIC-1 expression and p53 malfunction may be synergistic events in sporadic breast cancer. HIC-1 expression was examined using RT-PCR on RNA extracted from 50 primary untreated, human breast cancers and was detected in only 7/50 (14%) cancers. All seven patients with HIC-1 expression were alive without disease recurrence after 8 years follow-up and 5/7 had detectable p53 wild type mRNA expression. This suggests that retained HIC-1 expression may offer a survival advantage. However the seven cancers had 17p13.3 loss of heterozygosity (LOH; four patients), a feature previously associated with poor prognosis, or were homozygous (three patients) suggesting there may be two genes at 17p13.3 involved in breast carcinogenesis. Using a demethylating drug 5-aza-2'-deoxycytidine (DeoxyC), HIC-1 expression was restored in the MDAMB231 cells, also suggesting restoration of HIC-1 function by reversing HIC-1 hypermethylation may offer a therapeutic avenue in breast cancer.

Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?

Rhabdomyosarcoma has 2 major histological subtypes, embryonal and alveolar. Alveolar histology is associated with the fusion genes PAX3-FKHR and PAX7-FKHR. Definition of alveolar has been complicated by changes in terminology and subjectivity. It is currently unclear whether adverse clinical behaviour is better predicted by the presence of these fusion genes or by alveolar histology. We have determined the presence of the PAX3/7-FKHR fusion genes in 91 primary rhabdomyosarcoma tumours using a combination of classical cytogenetics, FISH and RT-PCR, with a view to determining the clinical characteristics of tumours with and without the characteristic translocations. There were 37 patients with t(2;13)/PAX3-FKHR, 8 with t(1;13) PAX7-FKHR and 46 with neither translocation. One or other of the characteristic translocations was found in 31/38 (82%) of alveolar cases. Univariate survival analysis revealed the presence of the translocation t(2;13)/PAX3-FKHR to be an adverse prognostic factor. With the difficulties in morphological diagnosis of alveolar rhabdomyosarcoma on increasingly used small needle biopsy specimens, these data suggest that molecular analysis for PAX3-FKHR will be a clinically useful tool in treatment stratification in the future. This hypothesis requires testing in a prospective study. Variant t(1;13)/PAX7-FKHR appears biologically different, occurring in younger patients with more localised disease.

Ovarian adenocarcinoma in premenarchal girls.

Ovarian neoplasms are unusual in the paediatric age group; the majority of them are of germ cell origin. Malignant epithelial tumours of the ovary occur infrequently in adolescent girls. Ovarian carcinoma in particular is extremely rare before puberty. The authors describe 3 cases of adenocarcinoma of the ovary in premenarchal girls and highlight the unique characteristics of this tumour in this age group.

A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation.

A phase I study of nolatrexed, administered as a continuous 5 day intravenous infusion every 28 days, has been undertaken for children with advanced malignancy. 16 patients were treated at 3 dose levels; 420, 640 and 768 mg/m(2)24 h(-1). 8 patients were evaluable for toxicity. In the 6 patients treated at 768 mg/m(2)24 h(-1), dose-limiting oral mucositis and myelosuppression were observed. Plasma nolatrexed concentrations and systemic exposure, measured in 14 patients, were dose related, with mean AUC values of 36 mg(-1)ml(-1)min(-1), 50 mg ml(-1)min(-1)and 80 mg ml(-1)min(-1)at the 3 dose levels studied. Whereas no toxicity was encountered if the nolatrexed AUC was <45 mg ml(-1)min(-1), Grade 3 or 4 toxicity was observed with AUC values of >60 mg ml(-1)min(-1). Elevated plasma deoxyuridine levels, measured as a surrogate marker of thymidylate synthase inhibition, were seen at all of the dose levels studied. One patient with a spinal primitive neuroectodermal tumour had stable disease for 11 cycles of therapy, and in two patients with acute lymphoblastic leukaemia a short-lived 50% reduction in peripheral lymphoblast counts was observed. Nolatrexed can be safely administered to children with cancer, and there is evidence of therapeutic activity as well as antiproliferative toxicity. Phase II studies of nolatrexed in children at the maximum tolerated dose of 640 mg/m(2)24 h(-1)are warranted.

Localized paediatric orbital rhabdomyosarcoma: influence of imaging on treatment.

AIM: Orbital rhabdomyosarcoma is the most common primary malignant orbital tumour in children and has a good prognosis. The purpose of this paper was to review the imaging and consequent treatment of patients with localized orbital rhabdomyosarcoma from around the U.K. MATERIALS AND METHODS: Patients were identified through the U.K. Children's Cancer Study Group (UKCCSG) database. Investigations and therapy were dictated by the Malignant Mesenchymal Tumour '89 (MMT89) protocol. Imaging and radiological reports of 16 patients from 12 centres were reviewed. The number of patients receiving radiotherapy, timing of radiotherapy, and adherence to treatment protocols were assessed. RESULTS: Local radiologists' reports and imaging techniques varied between sequential examinations and centres. The imaging was adequate for management. No reports quoted measurements of the tumours. Treatment protocols were not always followed rigidly with regard to a residual mass at day 80 post-diagnosis. However, the protocol was not explicit for all outcomes. Fifteen out of 16 patients eventually received radiotherapy. CONCLUSION: There is no standardization of imaging between centres. The presence or absence of a post-therapeutic residue should be stated in the radiology report. Further investigation is needed to differentiate between fibrosis and recurrent tumour. Radiotherapy for residual mass at day 80 is probably more important than standardizing radiological technique.

Agriculture sector resource and environmental policy analysis: an economic and biophysical approach.

Agricultural pollution of the environment is jointly determined by economic decisions driving land use, production practices, and stochastic biophysical processes associated with agricultural production, land and climate characteristics. It follows that environmental and economic statistics, traditionally collected independently of each other, offer little insight into non-point pollutant loadings. We argue that effective policy development would be facilitated by integrating environmental and economic data gathering, combined with simulation modelling linking economic and biophysical components. Integrated data collection links economics, land use, production methods and environmental loadings. An integrated economic/biophysical modelling framework facilitates policy analysis because monetary incentives to reduce pollution can be evaluated in the context of market costs and returns that influence land use and production activity. This allows prediction of environmental and economic outcomes from alternative policies to solve environmental problems. We highlight steps taken to merge economic and biophysical modelling for policy analysis within the Economic Research Service of the United States Department of Agriculture. An example analysis of a policy to reduce agricultural nitrogen pollution is presented, with the economic and environmental results illustrating the value of linked economic and biophysical analysis.