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The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre-clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53-status-dependant manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53-status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre-clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease.

BACKGROUND The cost of socioeconomic inequality in health service use among Australian children with chronic health conditions is poorly understood. OBJECTIVES To quantify the cost of socioeconomic inequality in health service use among Australian children with chronic health conditions. METHODS Cohort study using a whole-of-population linked administrative data for all births in Queensland, Australia, between July 2015 and July 2018. Socioeconomic status was defined by an areas-based measure, grouping children into quintiles from most disadvantaged (Q1) to least disadvantaged (Q5) based on their postcode at birth. Study outcomes included health service utilisation (inpatient, emergency department, outpatient, general practitioner, specialist, pathology and diagnostic imaging services) and healthcare costs. RESULTS Of the 238,600 children included in the analysis, 10.4% had at least one chronic health condition. Children with chronic health conditions in Q1 had higher rates of inpatient (6.6, 95% confidence interval [CI] 6.4, 6.7), emergency department (7.2, 95% CI 7.0, 7.5) and outpatient (20.3, 95% CI 19.4, 21.3) service use compared to children with chronic health conditions in Q5. They also had lower rates of general practitioner (37.5, 95% CI 36.7, 38.4), specialist (8.9, 95% CI 8.5, 9.3), pathology (10.7, 95% CI 10.2, 11.3), and diagnostic imaging (4.3, 95% CI 4.2,4.5) service use. Children with any chronic health condition in Q1 incurred lower median out-of-pocket fees than children in Q5 ($0 vs $741, respectively), lower median Medicare funding ($2710, vs $3408, respectively), and higher median public hospital funding ($31, 052 vs $23, 017, respectively). CONCLUSIONS Children of most disadvantage are more likely to access public hospital provided services, which are accessible free of charge to patients. These children are less likely to access general practitioner, specialist, pathology and diagnostic imaging services; all of which are critical to the ongoing management of chronic health conditions, but often attract an out-of-pocket fee.

Background The development of high-throughput drug screening (HTS) using primary cultures provides a promising, clinically translatable approach to tailoring treatment strategies for patients with cancer. However, this has been challenging for solid tumors because of often limited amounts of tissue available. In most cases, in vitro expansion is required before HTS, which may lead to overgrowth and contamination by non-neoplastic cells. Methods In this study, hematoxylin and eosin staining and immunohistochemical staining were performed on 129 cytopathology cases from 95 patients. These cytopathology cases comprised cell block preparations derived from primary tumor specimens or patient-derived xenografts as part of a pediatric precision oncology trial. Cytopathology cases were compared with the morphology and immunohistochemical staining profile of the original tumor. Cases were reported as tumor cells present, equivocal, or tumor cells absent. The HTS results from cytopathologically validated cultures were incorporated into a multidisciplinary tumor board report issued to the treating clinician to guide clinical decision making. Results On cytopathologic examination, tumor cells were present in 77 of 129 cases (60%) and were absent in 38 of 129 cases (29%), whereas 14 of 129 cases (11%) were equivocal. Cultures that contained tumor cells resembled the tumors from which they were derived. Conclusions Cytopathologic examination of tumor cell block preparations is feasible and provides detailed morphologic characterization. Cytopathologic examination is essential for ensuring that samples submitted for HTS contain representative tumor cells and that in vitro drug sensitivity data are clinically translatable.

Disease relapse is the greatest cause of treatment failure in paediatric B-cell acute lymphoblastic leukaemia (B-ALL). Current risk stratifications fail to capture all patients at risk of relapse. Herein, we used a machine-learning approach to identify B-ALL blast-secreted factors that are associated with poor survival outcomes. Using this approach, we identified a two-gene expression signature (CKLF and IL1B) that allowed identification of high-risk patients at diagnosis. This two-gene expression signature enhances the predictive value of current at diagnosis or end-of-induction risk stratification suggesting the model can be applied continuously to help guide implementation of risk-adapted therapies.

Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO2 max testing is a more sensitive predictor of cardiac reserve in paediatric and adolescent and young adult oncology patients exposed to cardiac toxic therapies.

Objectives The Psychosocial Standards of Care (PSSC) in paediatric oncology prescribe the minimum standards for education support. It is unknown, however, if published education support programmes for children with cancer meet the PSSC standards for education support. Successful implementation of standards for education support is challenging but may be achieved with guidance. We aimed to (1) review education support programmes for childhood cancer patients and survivors against the PSSC standards and (2) provide practical recommendations for future research and implementation of education support programmes. Methods We searched PsycINFO, PubMed, CINAHL, EMBASE, and Educational Resources Information and Center databases. We reviewed the education support programmes using five evaluation criteria derived from the PSSC and summarised the structure of identified programmes. We examined the features and limitations of programmes that met all evaluation criteria. Results We identified 20 education support programmes in paediatric oncology, including peer programmes (n = 3), teacher programmes (n = 5), and school re-entry programmes (SRPs n = 12). We found that three SRPs met all evaluation criteria and that SRP components were timed according to the child's position on the cancer trajectory (e.g., diagnosis and treatment, school re-entry, and follow up throughout schooling). The supporting evidence of the programmes, however, is unclear due to the lack of adequately designed studies. Conclusions SRPs provide a promising structure for future education support programmes. We recommend strategies for developing and evaluating education support that adheres to the PSSC and adapts to international and local contexts.

Patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein overexpression have very poor prognosis. The cyclin-dependent kinase 7 (CDK7)/super-enhancer inhibitor THZ1 suppresses MYCN gene transcription, reduces neuroblastoma cell proliferation, but does not cause significant cell death. The protein kinase phosphatase 1 nuclear targeting subunit (PNUTS) has recently been shown to interact with c-Myc protein and suppresses c-Myc protein degradation. Here we screened the U.S. Food and Drug Administration-Approved Oncology Drugs Set V from the National Cancer Institute, and identified tyrosine kinase inhibitors (TKIs), including ponatinib and lapatinib, as the Approved Oncology Drugs exerting the best synergistic anticancer effects with THZ1 in MYCN-amplified neuroblastoma cells. Combination therapy with THZ1 and ponatinib or lapatinib synergistically induced neuroblastoma cell apoptosis, while having little effects in normal nonmalignant cells. Differential gene expression analysis identified PNUTS as one of the genes most synergistically reduced by the combination therapy. Reverse transcription polymerase chain reaction and immunoblot analyses confirmed that THZ1 and the TKIs synergistically downregulated PNUTS mRNA and protein expression and reduced N-Myc protein but not N-Myc mRNA expression. In addition, PNUTS knockdown resulted in decreased N-Myc protein but not mRNA expression and decreased MYCN-amplified neuroblastoma cell proliferation and survival. As CDK7 inhibitors are currently under clinical evaluation in patients, our data suggest the addition of the TKI ponatinib or lapatinib in CDK7 inhibitor clinical trials in patients.

Aim Approximately 20-30% of children/adolescents with cancer will not respond to standard therapies. These children are usually offered experimental treatment in the form of an early-phase clinical trial. We examined the perspectives of health-care professionals (HCPs) regarding obtaining informed consent for early-phase trials in paediatric oncology. Methods We collected survey data from 87 HCPs working in paediatric cancer centres across Australia and New Zealand. Results HCPs were, on average, 44 years old (range = 25-74), with 15.8 years' experience in paediatric oncology (range = 1-40). Few HCPs (17.4%) received training for early-phase trial consent; however, most were willing to attend training (77.9%). HCPs (61.6%) reported that they informed families about early-phase trials without any attempt to influence their decision. However, 23.3% of HCPs reported that they informed families that their child would benefit. HCPs' main obstacle in obtaining consent was their perception of parents' eagerness to 'try anything' (52.3%). HCPs perceived that many parents misunderstood key clinical trials concepts, with 25.2% of HCPs believing that not being given clear information influenced parents' decisions. Physicians were more likely than social workers/nurses to inform families that other children will benefit from enrolment in the study. Social workers/nurses appeared to rate the chance of benefits for the patient higher than physicians. Conclusions HCPs may experience difficulty conducting early-phase trial consultations and obtaining valid informed consent. Our study highlights the need for formal training for HCPs and additional patient education tools.

Background Serious chronic illness can have a detrimental effect on school attendance, participation and engagement, leaving affected students at risk of failing to meet their developmental potential. An improved understanding of factors that help to explain or mitigate this risk can help educators and health professionals deliver the most effective support. This meta-review critiqued the available evidence examining the link between six chronic illnesses (asthma, cancer, chronic kidney diseases, heart diseases, cystic fibrosis and gastrointestinal diseases) and children's and adolescents' school experiences and outcomes, as well as investigating the medical, school, psychosocial and sociodemographic factors that are linked to poorer or better school outcomes. Methods We searched CINAHL, Cochrane Database, EMBASE, ERIC, MEDLINE, ProQuest Theses and Dissertations, and PsycINFO (2000–2015). Systematic and narrative reviews, and meta-analyses, of original studies examining students' subjective school experiences and objective school outcomes were eligible. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria to critically appraise all systematic reviews. The Grading of Recommendations Assessment, Development, and Evaluation system guided our recommendations for practice and research. Results Eighteen reviews of 172 studies including more than 40 000 students were eligible. Therefore, we chose to conduct a meta-review to provide an overview of the literature on the relationship between chronic illness and school experiences and outcomes. We also explored the associated medical, school, psychosocial and sociodemographic factors affecting the relationship between illness and school experiences and outcomes. Conclusion Students with chronic illness demonstrate mixed school experiences and outcomes that are often worse than students without chronic illness. Modifiable factors, such as students' engagement with school, may be novel yet appropriate targets of educational support to ensure that these students reach their full schooling potential.

The MYCN gene is amplified and overexpressed in a large proportion of high stage neuroblastoma patients and has been identified as a key driver of tumorigenesis. However, the mechanism by which MYCN promotes tumor initiation is poorly understood. Here we conducted metabolic profiling of pre‐malignant sympathetic ganglia and tumors derived from the TH‐MYCN mouse model of neuroblastoma, compared to non‐malignant ganglia from wildtype littermates. We found that metabolites involved in the biosynthesis of glutathione, the most abundant cellular antioxidant, were the most significantly upregulated metabolic pathway at tumor initiation, and progressively increased to meet the demands of tumorigenesis. A corresponding increase in the expression of genes involved in ribosomal biogenesis suggested that MYCN‐driven transactivation of the protein biosynthetic machinery generated the necessary substrates to drive glutathione biosynthesis. Pre‐malignant sympathetic ganglia from TH‐MYCN mice had higher antioxidant capacity and required glutathione upregulation for cell survival, when compared to wildtype ganglia. Moreover, in vivo administration of inhibitors of glutathione biosynthesis significantly delayed tumorigenesis when administered prophylactically and potentiated the anticancer activity of cytotoxic chemotherapy against established tumors. Together these results identify enhanced glutathione biosynthesis as a selective metabolic adaptation required for initiation of MYCN‐driven neuroblastoma, and suggest that glutathione‐targeted agents may be used as a potential preventative strategy, or as an adjuvant to existing chemotherapies in established disease.

Retinoids are an important component of neuroblastoma therapy at the stage of minimal residual disease, yet 40–50% of patients treated with 13-cis-retinoic acid (13-cis-RA) still relapse, indicating the need for more effective retinoid therapy. Vorinostat, or Suberoylanilide hydroxamic acid (SAHA), is a potent inhibitor of histone deacetylase (HDAC) classes I & II and has antitumor activity in vitro and in vivo. Fenretinide (4-HPR) is a synthetic retinoid which acts on cancer cells through both nuclear retinoid receptor and non-receptor mechanisms. In this study, we found that the combination of 4-HPR + SAHA exhibited potent cytotoxic effects on neuroblastoma cells, much more effective than 13-cis-RA + SAHA. The 4-HPR + SAHA combination induced caspase-dependent apoptosis through activation of caspase 3, reduced colony formation and cell migration in vitro, and tumorigenicity in vivo. The 4-HPR and SAHA combination significantly increased mRNA expression of thymosin-beta-4 (Tβ4) and decreased mRNA expression of retinoic acid receptor α (RARα). Importantly, the up-regulation of Tβ4 and down-regulation of RARα were both necessary for the 4-HPR + SAHA cytotoxic effect on neuroblastoma cells. Moreover, Tβ4 knockdown in neuroblastoma cells increased cell migration and blocked the effect of 4-HPR + SAHA on cell migration and focal adhesion formation. In primary human neuroblastoma tumor tissues, low expression of Tβ4 was associated with metastatic disease and predicted poor patient prognosis. Our findings demonstrate that Tβ4 is a novel therapeutic target in neuroblastoma, and that 4-HPR + SAHA is a potential therapy for the disease.

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment-related mortality of 8%. Leukaemia-free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre-HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre-HSCT (LFS 41%, OS 64%, P 0·0001) or post-HSCT (LFS 35%, OS 55%, P 0·0001). Patients with B-other ALL had more relapses (CIR 50%, LFS 41%) than T-ALL and the main precursor-B subtypes including BCR-ABL1, KMT2A (MLL), ETV6-RUNX1 (TEL-AML1) and hyperdiploidy50. A Cox multivariate regression model for LFS retained both B-other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post-HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post-HSCT therapy.

Retinoid therapy is used for chemo-prevention in immuno-suppressed patients at high risk of developing skin cancer. The retinoid signalling molecule, tripartite motif protein 16 (TRIM16), is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid-sensitive neuroblastoma. We sought to determine the role of TRIM16 in skin squamous cell carcinoma (SCC) pathogenesis. We have shown that TRIM16 expression was markedly reduced during the histological progression from normal skin to actinic keratosis and SCC. SCC cell lines exhibited lower cytoplasmic and nuclear TRIM16 expression compared with primary human keratinocyte (PHK) cells due to reduced TRIM16 protein stability. Overexpressed TRIM16 translocated to the nucleus, inducing growth arrest and cell differentiation. In SCC cells, TRIM16 bound to and down regulated nuclear E2F1, this is required for cell replication. Retinoid treatment increased nuclear TRIM16 expression in retinoid-sensitive PHK cells, but not in retinoid-resistant SCC cells. Overexpression of TRIM16 reduced SCC cell migration, which required the C-terminal RET finger protein (RFP)-like domain of TRIM16. The mesenchymal intermediate filament protein, vimentin, was directly bound and down-regulated by TRIM16 and was required for TRIM16-reduced cell migration. Taken together, our data suggest that loss of TRIM16 expression plays an important role in the development of cutaneous SCC and is a determinant of retinoid sensitivity. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Neuroblastoma is the most common solid tumor in children less than 5 years of age. The early onset of neuroblastoma suggests that genes involved in fetal development and pregnancy may have a putative role in the etiology of neuroblastoma. The human leukocyte antigen subtype G (HLA-G) molecule plays an important role in immune response regulation and appears to regulate immune tolerance during early pregnancy as well as tumor immunosurveillance. Elevated levels of soluble HLA-G (sHLA-G) have been detected in a number of malignancies including serum samples from neuroblastoma and have been reported to be predictive of tumor relapse in neuroblastoma. In light of previous investigations suggesting that single nucleotide polymorphisms in the HLA-G gene may impact on protein expression levels and isoform production, we examined the influence of HLA-G polymorphisms on the susceptibility and clinical outcome of neuroblastoma in 163 neuroblastoma patients and 404 healthy controls. The distribution of HLA-G polymorphisms, alleles, or allelic groups did not differ between children diagnosed with neuroblastoma and healthy controls. Our analyses did not detect an association between common HLA-G polymorphisms and clinical outcome in patients treated for neuroblastoma.

Objective: To describe wellbeing and nutrition-related side effects in a group of paediatric oncology patients undergoing chemotherapy, and to examine associations with nutritional status, disease and treatment-related factors. Methods: Cross-sectional survey of patients attending the Sydney (n = 41) or John Hunter Children’s Hospitals (n = 13). Wellbeing was assessed using the Multi-attribute Health Status Classification Scheme (MHSCS) and the Play Performance Scale (PPS). Disease and treatment details were obtained through patient and parent interviews and audit of medical records. Nutritional status was assessed using anthropometric and biochemical measurements. Results: Twenty-four per cent and 33% scored maximum points on the MHSCS and PPS, respectively. Advanced stage of solid tumour or lymphoma was associated with worse MHSCS scores, P = 0.008. Longer time on treatment correlated negatively with PPS scores (r = −0.35; P = 0.030). The most frequent side effects were nausea, decreased appetite, vomiting and changes in taste. While 67% experienced five or more side effects concurrently, the number increased with length of time on treatment (r = 0.38; P = 0.006). Of the 23 patients experiencing five or more side effects, only two had been seen by a dietitian in the previous two months. Conclusion: Nutrition-related side effects are common in children undergoing chemotherapy, with the number of side effects not decreasing over time. While wellbeing scores were generally satisfactory, those with advanced stage of solid tumour or lymphoma, or with longer time on treatment, reported lower scores. We recommend that all paediatric oncology patients are referred for dietetic review, even those in the later stages of treatment, in order to optimise nutritional status and wellbeing.

Nuclear retinoid receptors mediate retinoid effects through tissue-specific, ligand-receptor interactions and subsequent transcriptional regulation of secondary target genes. Retinoic acid receptor beta (RARbeta) is itself a retinoid target gene with a retinoic acid response element (betaRARE) in the 5' untranslated region of the RARbeta2 gene. Altered transcriptional regulation of RARbeta may play a role in human carcinogenesis and the retinoid-responsiveness of malignant cells. Here we used retinoid X receptor-specific antibodies in electrophoretic mobility shift assays to show that the retinoid X receptor beta (RXRbeta) protein was recruited to the betaRARE, after retinoid treatment of retinoid-sensitive neuroblastoma (NB), lung and breast cancer cell lines, but not retinoid-resistant lung and breast cancer cell lines. RXRbeta selectively enhanced retinoid-induced transcriptional activation of the betaRARE. Stable overexpression of RXRalpha and RXRbeta in NB cells resulted in marked growth inhibition and cell death, which increased after retinoid treatment. However, only proteins from the RXRbeta transfectants exhibited specific RXRbeta binding to the betaRARE in vitro and in vivo, enhanced histone acetylation and increased endogenous RARbeta expression. These data indicate that recruitment of RXRbeta to the betaRARE, and consequent induction of endogenous RARbeta expression, is an important component in the retinoid anticancer signal. RXRalpha may also participate in the retinoid signal, but through mechanisms that do not involve RARbeta.

Children with acute lymphoblastic leukemia (ALL) undergo intense anticancer treatment. We systematically reviewed 22 studies evaluating 2,073 ALL patients' health-related quality of life (HRQL) and its clinical/demographic correlates during treatment. Overall HRQL was significantly reduced on treatment. Despite HRQL improvements over time, longitudinal studies reported a proportion of children continued to experience reduced HRQL after treatment completion. We found inconsistent associations between clinical/demographic factors and HRQL outcomes. Tentative evidence emerged for worse HRQL being associated with intensive phases of chemotherapy, corticosteroid therapy, experiencing greater toxicity, older age, and female sex. Longitudinal studies are needed to identify children at-risk of reduced HRQL.

Background The recently characterised p53 homologue, p73, has been mapped to chromosome 1p36, a region often found deleted in neuroblastoma. Although p73 has been implicated as a candidate tumour suppressor for neuroblastoma, mutations in the gene appear to be rare, thus suggesting other mechanisms for its aberrant behaviour. Procedure We analysed p73 gene expression in a panel of primary neuroblastoma tumours and cell lines, as well as other tumours of childhood, using a reverse transcriptase-polymerase chain reaction assay. Results Although low-level p73 expression was detected in 44/45 primary neuroblastoma tumours, no association with prognostic markers could be discerned. In no case was the level of p73 expression in the primary tumours as high as that observed in p73-expressing neuroblastoma cell lines. Expression of the p73 gene was also detected in 24/34 other childhood tumours. Conclusion Collectively, the data raise doubts over the role of this gene as a tumour suppressor in neuroblastoma. Med. Pediatr. Oncol. 36:48–51, 2001. © 2001 Wiley-Liss, Inc.

BACKGROUND We have recently shown that high-level expression of the multidrug resistance-associated protein (MRP) gene is a powerful independent predictor of poor outcome in neuroblastoma. The clinical implication of these findings is that MRP modulators may prove therapeutically useful. PROCEDURE We therefore investigated the ability of difloxacin, a quinolone antimicrobial antibiotic, to increase drug cytotoxicity in unselected cultured human neuroblastoma cells. Drug cytotoxicity was determined using a microtiter assay in neuroblastoma cells expressing low (SH-EP), intermediate (NBL-S), or high [BE(2)-C] levels of MRP. RESULTS Difloxacin (50 microg/ml) increased sensitivity to the MRP substrates, vincristine, doxorubicin, daunorubicin, and potassium antimony tartrate to an extent directly proportional to their level of MRP expression. No change in the response to cisplatin, which is not a substrate for MRP, was observed in any of the cell lines. CONCLUSIONS The data demonstrate that difloxacin can reverse drug resistance in unselected human neuroblastoma cells and is therefore a potential candidate for future clinical trials.

We present three cases of pleuropulmonary blastoma (PPB) in Australian children. Each had a family history of childhood tumors which collectively included PPB, infant lung cyst, cystic nephroma, medullo-epithelioma and a Sertoli–Leydig ovarian tumor. Two of the patients also had additional malignancies: a concurrent bladder rhabdomyosarcoma and a post therapy non-PPB malignant lung tumor. In two cases, the family histories were elicited years after the PPB diagnosis. Archived pathology material allowed revision of pathologic diagnoses from decades earlier. These cases illustrate the importance of detailed inquiry into family medical history and the pleiotropy of the PPB-related familial cancer predisposition syndrome, which appears to result from heterozygous DICER1 mutations. Pediatr Blood Cancer. 2010;55:1417–1419. © 2010 Wiley-Liss, Inc.

A number of prospective studies have indicated the clinical utility of measuring minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia (ALL) and have highlighted the need for improved methodology for quantification of residual disease. We describe a novel real-time polymerase chain reaction (PCR) strategy for MRD analysis based on the exonuclease activity of Taq polymerase to cleave a fluorescently labelled probe. Using a consensus probe designed to the framework 2 region of the IgH gene, together with leukaemia-specific primers, the utility of this technique for simultaneous detection and quantification of MRD was demonstrated in samples from six ALL patients. This technique provides a rapid quantitative assay for determining MRD levels which lends itself to the routine monitoring of minimal residual leukaemia.

Background Although the association between N-myc gene amplification and poor clinical outcome in neuroblastoma is well established, the mechanism by which amplification influences prognosis is not well defined. Procedure We used a human N-myc transgenic mouse model to investigate the role of N-myc in neuroblastoma, including its relationship to the multidrug-resistance-associated protein (MRP) gene. We developed a rapid real-time PCR method to distinguish homozygous and hemizygous N-myc mice that is comparable to Southern analysis. Results A highly significant correlation (P < 0.0001) between N-myc and MRP expression was demonstrated in murine tumors. Amplification of the transgene was observed in the majority of tumors, highlighting the clinical relevance of this model. However, no correlation between N-myc expression and transgene dosage or tumor latency was observed. Conclusions The data suggest that increased N-myc dosage contributes to increased tumor incidence and decreased latency by mechanisms independent of N-myc expression. Med. Pediatr. Oncol. 35:585–589, 2000. © 2000 Wiley-Liss, Inc.

High-dose methotrexate (HDMTX), adriamycin (ADR), and cisplatinum (CDDP) are effective agents in the treatment of osteogenic sarcoma (OS). Individual patient doses are determined by prior successful clinical trials but may be reduced due to ongoing toxicities. It is unknown whether individualized dose reductions of these drugs influence disease outcome. We retrospectively studied 27 consecutively enrolled children treated with HDMTX, ADR, and CDDP as adjuvant chemotherapy for OS, for correlations between disease outcome and several characteristics of drug, dosing: the cumulative MTX, CDDP, and ADR doses administered and the mean MTX blood levels for each patient. With a median follow-up of 59 months, the actuarial overall and disease-free survival rates were 70% and 59%, respectively. Factors which favorably influenced prognosis on univariate analysis were a cumulative ADR dose of >300 mg/m2 (P = 0.0002) and a cumulative MTX dose > 114 gm/m2 (P = 0.0048). By multivariate analysis only the cumulative ADR dose >300 mg/m2 retained prognostic value. We conclude that adjuvant chemotherapy dosages may need to be adjusted for therapeutic efficacy in addition to adjustments made for toxicity. The effect of different cumulative HDMTX and ADR dosages on prognosis in osteosarcoma patients needs to be evaluated in a prospective trial. Med. Pediatr. Oncol. 28:179–182 © 1997 Wiley-Liss, Inc.

OBJECTIVE: To determine the survival for children with malignant disease diagnosed in the period 1964-1987 and treated in a single paediatric oncology unit. DESIGN: Records of patients treated by the Department of Haematology and Oncology at the Prince of Wales Children's Hospital were reviewed to determine the survival of children with cancer according to decade of diagnosis and diagnostic group. PATIENTS: Patients were eligible for the study if referred for treatment at or soon after diagnosis of malignancy. One thousand patients were treated during the study period. There were 363 with acute lymphoblastic leukaemia (ALL), 126 with tumours of the central nervous system (CNS), 86 with acute non-lymphoblastic leukaemia (ANLL), 81 with lymphoma, 79 with neural crest tumours, 69 with renal tumours, 66 with bone sarcomas, 53 with soft tissue sarcomas, and 77 with various other diagnoses. Age range was one day to 20.75 years. INTERVENTIONS: Treatment included surgery, radiotherapy and chemotherapy in a variety of protocols. RESULTS: Ten-year survival for the 1960s, 1970s and 1980s was 15%, 51% and 64% respectively (P < 0.001), excluding tumours of the CNS. From 1985 onwards, actual survival at five years has been 79%. Survival from Wilms' tumour and Hodgkin's disease remained high throughout the study period, and significant improvement in survival occurred with ALL, non-Hodgkin's lymphoma (NHL) and osteogenic sarcoma. Survival remained poor with neuroblastoma and ANLL. CONCLUSIONS: Significant improvement in outcomes for childhood malignancy has been achieved over the last three decades, with five-year survival currently at 79% (excluding tumours of the CNS). Some diagnostic groups have had only small improvements in outcome and require new strategies.