Assessing the appropriateness of the management of otitis media in Australia: A population-based sample survey.

AIM: Acute otitis media (AOM) is the most common infectious disease for which antibiotics are prescribed; its management is costly and has the potential to increase the antimicrobial resistance of this infection. This study measured the levels of adherence to the clinical practice guidelines (CPGs) of AOM and otitis media with effusion (OME) management in Australian children. METHODS: We searched for national and international CPGs relating to AOM and OME in children and created 37 indicators for assessment. We reviewed medical records for adherence to these indicators in 120 locations, across one inpatient and three ambulatory health-care settings. Our review sample was obtained from three Australian states that contain 60% of the nation's children. RESULTS: We reviewed the records of 1063 children with one or more assessments of CPG adherence for otitis media. Of 22 indicators with sufficient data, estimated adherence ranged from 7.4 to 99.1%. Overuse of treatment, particularly overprescribing of antibiotics, was more common than underuse. A frequent lack of adherence with recommended care was observed for children aged between 1 and 2 years with AOM. Adherence varied by health-care setting, with emergency departments and inpatient settings more adherent to CPGs than general practices. CONCLUSIONS: Our assessment of a number of indicators in the common settings in which otitis media is treated found that guideline adherence varied widely between individual indicators. Internationally agreed standards for diagnosis and treatment, coupled with clinician education on the existence and content of CPGs and clinical decision support, are needed to improve the management of children presenting with AOM and OME.

Quality of Health Care for Children in Australia, 2012-2013.

Importance: The quality of routine care for children is rarely assessed, and then usually in single settings or for single clinical conditions. Objective: To estimate the quality of health care for children in Australia in inpatient and ambulatory health care settings. Design, Setting, and Participants: Multistage stratified sample with medical record review to assess adherence with quality indicators extracted from clinical practice guidelines for 17 common, high-burden clinical conditions (noncommunicable [n = 5], mental health [n = 4], acute infection [n = 7], and injury [n = 1]), such as asthma, attention-deficit/hyperactivity disorder, tonsillitis, and head injury. For these 17 conditions, 479 quality indicators were identified, with the number varying by condition, ranging from 9 for eczema to 54 for head injury. Four hundred medical records were targeted for sampling for each of 15 conditions while 267 records were targeted for anxiety and 133 for depression. Within each selected medical record, all visits for the 17 targeted conditions were identified, and separate quality assessments made for each. Care was evaluated for 6689 children 15 years of age and younger who had 15 240 visits to emergency departments, for inpatient admissions, or to pediatricians and general practitioners in selected urban and rural locations in 3 Australian states. These visits generated 160 202 quality indicator assessments. Exposures: Quality indicators were identified through a systematic search of local and international guidelines. Individual indicators were extracted from guidelines and assessed using a 2-stage Delphi process. Main Outcomes and Measures: Quality of care for each clinical condition and overall. Results: Of 6689 children with surveyed medical records, 53.6% were aged 0 to 4 years and 55.5% were male. Adherence to quality of care indicators was estimated at 59.8% (95% CI, 57.5%-62.0%; n = 160 202) across the 17 conditions, ranging from a high of 88.8% (95% CI, 83.0%-93.1%; n = 2638) for autism to a low of 43.5% (95% CI, 36.8%-50.4%; n = 2354) for tonsillitis. The mean adherence by condition category was estimated as 60.5% (95% CI, 57.2%-63.8%; n = 41 265) for noncommunicable conditions (range, 52.8%-75.8%); 82.4% (95% CI, 79.0%-85.5%; n = 14 622) for mental health conditions (range, 71.5%-88.8%); 56.3% (95% CI, 53.2%-59.4%; n = 94 037) for acute infections (range, 43.5%-69.8%); and 78.3% (95% CI, 75.1%-81.2%; n = 10 278) for injury. Conclusions and Relevance: Among a sample of children receiving care in Australia in 2012-2013, the overall prevalence of adherence to quality of care indicators for important conditions was not high. For many of these conditions, the quality of care may be inadequate.

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

The outcomes and treatment burden of childhood acute myeloid leukaemia in Australia, 1997-2008: A report from the Australian Paediatric Cancer Registry.

Childhood acute myeloid leukaemia (AML) requires intensive therapy and is associated with survival rates that are substantially inferior to many other childhood malignancies. We undertook a retrospective analysis of Australian Paediatric Cancer Registry data from 1997 to 2008 together with a single-centre audit during the same period assessing burden on service delivery at a tertiary children's hospital (Royal Children's Hospital, Brisbane). Although survival improved from 54.3% (1997-2002) to 69.2% (2003-2008), childhood AML caused a disproportionate number of childhood cancer deaths, accounting for 5.5% of all childhood cancer diagnoses yet 7.9% of all childhood cancer mortality. Furthermore, treatment was associated with significant toxicity requiring intensive use of local health resources. Novel therapeutic strategies aimed at improving survival and reducing toxicity are urgently required.

BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect.

The mechanisms of retinoid activity in tumors remain largely unknown. Here we establish that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, we defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. We also identified bone morphogenetic protein-2 (BMP-2) as a candidate mediator of retinoid activity. BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis. BMP-2 also induced p38 mitogen-activated protein kinase (MAPK), which is necessary for BMP-2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP-2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP-2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP-2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.

Home telemedicine for paediatric palliative care.

Children with life limiting conditions require intensive, complex management of the physical, psychosocial and spiritual issues that evolve for the child and their family as the focus of care moves from curative treatment to palliation. Optimal palliative care for children can be limited by the lack of health professionals with the necessary skills and experience to confidently and competently manage the care of both the child and the family. The University of Queensland's Centre for Online Health has been working closely with the Paediatric Palliative Care Service (PPCS) at the Royal Children's Hospital (RCH) in Brisbane, Australia, to investigate the potential of telemedicine for the delivery of specialist support in the home or local community. Research conducted in Queensland has shown how telemedicine can be effectively used to link the specialist paediatric palliative care team into the home of families caring for a child receiving palliative care, regardless of their physical distance from the RCH. This qualitative report describes two case studies, each illustrating the value of home telemedicine for families at this vulnerable and distressing time. This work should provide a useful insight for other specialty disciplines contemplating home telemedicine applications.

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants.

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.

Body composition, dietary intake and physical activity of young survivors of childhood cancer.

AIM: To describe the body composition, dietary intake and physical activity and of paediatric, adolescent and young adult childhood cancer survivors (CCS) and examine the factors that impact body composition after treatment. METHODS: This prospective cross-sectional study involved 74 subjects who were at least three years post treatment. Measurements included anthropometry, whole body potassium counting, air displacement plethysmography, and three day physical activity and diet diaries. RESULTS: The CCS had significantly reduced body cell mass index Z-scores compared to controls (p = 0.0001), with 59% considered undernourished. The CCS had a significantly higher percent fat (p = 0.002) than the controls, with 27% classified as obese. The intake of 60% of CCS met estimated energy requirements, but the CCS consumed high amount of energy from fat and low amount of energy from carbohydrates. A high percentage of CCS did not meet their dietary requirements for calcium (61%), magnesium (46%), folate (38%) and iodine (38%). The CCS group had a light active lifestyle with 64% spending more than 2 h daily on screen time. Receiving a bone marrow transplant (r = -0.27; p = 0.02) and physical activity level (r = 0.49; p = 0.0001) were significantly correlated with body cell mass index. CONCLUSIONS: This study demonstrates that increased fat mass and decreased body cell mass is a concern for CCS and that CCS have poor health behaviours including light active lifestyles, excessive screentime, high fat intake, and poor intake of essential nutrients. This study has highlighted that CCS are at risk of both obesity and undernutrition and that increasing body cell mass as well as decreasing fat mass should be a focus of energy balance interventions in survivorship. There is a need for parents and children undergoing treatment for cancer to be educated about diet quality and importance of daily physical activity to ensure healthy habits are established and maintained into survivorship.

Assessing the Quality of the Management of Tonsillitis among Australian Children: A Population-Based Sample Survey.

OBJECTIVE: The aims of this study were twofold: (1) to design and validate a set of clinical indicators of appropriate care for tonsillitis and (2) to measure the level of tonsillitis care that is in line with guideline recommendations in a sample of Australian children. STUDY DESIGN: A set of tonsillitis care indicators was developed from available national and international guidelines and validated in 4 stages. This research used the same design as the CareTrack Kids study, which was described in detail elsewhere. SETTING: Samples of patient records from general practices, emergency departments, and hospital admissions were assessed. SUBJECTS AND METHODS: Patient records of children aged 0 to 15 years were assessed for the presence of, and adherence to, the indicators for care delivered in 2012 and 2013. RESULTS: Eleven indicators were developed. The records of 821 children (mean age, 5.0 years; SD, 4.0) with tonsillitis were screened. The reviewers conducted 2354 eligible indicator assessments across 1127 visits. Adherence to 6 indicators could be assessed and ranged from 14.3% to 73.2% (interquartile range 31.5% to 72.2%). CONCLUSION: Our main findings are consistent with the international literature: the treatment of many children who present with confirmed or suspected tonsillitis is inconsistent with current guidelines. Future research should consider how the indicators could be applied in a structured and automated manner to increase the reliability and efficiency of record reviews and help raise clinicians' awareness of appropriate tonsillitis management.

Clinical indicators for common paediatric conditions: Processes, provenance and products of the CareTrack Kids study.

BACKGROUND: In order to determine the extent to which care delivered to children is appropriate (in line with evidence-based care and/or clinical practice guidelines (CPGs)) in Australia, we developed a set of clinical indicators for 21 common paediatric medical conditions for use across a range of primary, secondary and tertiary healthcare practice facilities. METHODS: Clinical indicators were extracted from recommendations found through systematic searches of national and international guidelines, and formatted with explicit criteria for inclusion, exclusion, time frame and setting. Experts reviewed the indicators using a multi-round modified Delphi process and collaborative online wiki to develop consensus on what constituted appropriate care. RESULTS: From 121 clinical practice guidelines, 1098 recommendations were used to draft 451 proposed appropriateness indicators. In total, 61 experts (n = 24 internal reviewers, n = 37 external reviewers) reviewed these indicators over 40 weeks. A final set of 234 indicators resulted, from which 597 indicator items were derived suitable for medical record audit. Most indicator items were geared towards capturing information about under-use in healthcare (n = 551, 92%) across emergency department (n = 457, 77%), hospital (n = 450, 75%) and general practice (n = 434, 73%) healthcare facilities, and based on consensus level recommendations (n = 451, 76%). The main reason for rejecting indicators was 'feasibility' (likely to be able to be used for determining compliance with 'appropriate care' from medical record audit). CONCLUSION: A set of indicators was developed for the appropriateness of care for 21 paediatric conditions. We describe the processes (methods), provenance (origins and evolution of indicators) and products (indicator characteristics) of creating clinical indicators within the context of Australian healthcare settings. Developing consensus on clinical appropriateness indicators using a Delphi approach and collaborative online wiki has methodological utility. The final indicator set can be used by clinicians and organisations to measure and reflect on their own practice.

Investigating the cost-effectiveness of videotelephone based support for newly diagnosed paediatric oncology patients and their families: design of a randomised controlled trial.

BACKGROUND: Providing ongoing family centred support is an integral part of childhood cancer care. For families living in regional and remote areas, opportunities to receive specialist support are limited by the availability of health care professionals and accessibility, which is often reduced due to distance, time, cost and transport. The primary aim of this work is to investigate the cost-effectiveness of videotelephony to support regional and remote families returning home for the first time with a child newly diagnosed with cancer METHODS/DESIGN: We will recruit 162 paediatric oncology patients and their families to a single centre randomised controlled trial. Patients from regional and remote areas, classified by Accessibility/Remoteness Index of Australia (ARIA+) greater than 0.2, will be randomised to a videotelephone support intervention or a usual support control group. Metropolitan families (ARIA+ < or = 0.2) will be recruited as an additional usual support control group. Families allocated to the videotelephone support intervention will have access to usual support plus education, communication, counselling and monitoring with specialist multidisciplinary team members via a videotelephone service for a 12-week period following first discharge home. Families in the usual support control group will receive standard care i.e., specialist multidisciplinary team members provide support either face-to-face during inpatient stays, outpatient clinic visits or home visits, or via telephone for families who live far away from the hospital. The primary outcome measure is parental health related quality of life as measured using the Medical Outcome Survey (MOS) Short Form SF-12 measured at baseline, 4 weeks, 8 weeks and 12 weeks. The secondary outcome measures are: parental informational and emotional support; parental perceived stress, parent reported patient quality of life and parent reported sibling quality of life, parental satisfaction with care, cost of providing improved support, health care utilisation and financial burden for families. DISCUSSION: This investigation will establish the feasibility, acceptability and cost-effectiveness of using videotelephony to improve the clinical and psychosocial support provided to regional and remote paediatric oncology patients and their families.

Peripherally InSerted CEntral catheter dressing and securement in patients with cancer: the PISCES trial. Protocol for a 2x2 factorial, superiority randomised controlled trial.

INTRODUCTION: Around 30% of peripherally inserted central catheters (PICCs) fail from vascular, infectious or mechanical complications. Patients with cancer are at highest risk, and this increases morbidity, mortality and costs. Effective PICC dressing and securement may prevent PICC failure; however, no large randomised controlled trial (RCT) has compared alternative approaches. We designed this RCT to assess the clinical and cost-effectiveness of dressing and securements to prevent PICC failure. METHODS AND ANALYSIS: Pragmatic, multicentre, 2×2 factorial, superiority RCT of (1) dressings (chlorhexidine gluconate disc (CHG) vs no disc) and (2) securements (integrated securement dressing (ISD) vs securement device (SED)). A qualitative evaluation using a knowledge translation framework is included. Recruitment of 1240 patients will occur over 3 years with allocation concealment until randomisation by a centralised service. For the dressing hypothesis, we hypothesise CHG discs will reduce catheter-associated bloodstream infection (CABSI) compared with no CHG disc. For the securement hypothesis, we hypothesise that ISD will reduce composite PICC failure (infection (CABSI/local infection), occlusion, dislodgement or thrombosis), compared with SED. SECONDARY OUTCOMES: types of PICC failure; safety; costs; dressing/securement failure; dwell time; microbial colonisation; reversible PICC complications and consumer acceptability. Relative incidence rates of CABSI and PICC failure/100 devices and/1000 PICC days (with 95% CIs) will summarise treatment impact. Kaplan-Meier survival curves (and log rank Mantel-Haenszel test) will compare outcomes over time. Secondary end points will be compared between groups using parametric/non-parametric techniques; p values <0.05 will be considered to be statistically significant. ETHICS AND DISSEMINATION: Ethical approval from Queensland Health (HREC/15/QRCH/241) and Griffith University (Ref. No. 2016/063). Results will be published. TRIAL REGISTRATION: Trial registration number is: ACTRN12616000315415.

A statistical method for predicting splice variants between two groups of samples using GeneChip expression array data.

BACKGROUND: Alternative splicing of pre-messenger RNA results in RNA variants with combinations of selected exons. It is one of the essential biological functions and regulatory components in higher eukaryotic cells. Some of these variants are detectable with the Affymetrix GeneChip that uses multiple oligonucleotide probes (i.e. probe set), since the target sequences for the multiple probes are adjacent within each gene. Hybridization intensity from a probe correlates with abundance of the corresponding transcript. Although the multiple-probe feature in the current GeneChip was designed to assess expression values of individual genes, it also measures transcriptional abundance for a sub-region of a gene sequence. This additional capacity motivated us to develop a method to predict alternative splicing, taking advance of extensive repositories of GeneChip gene expression array data. RESULTS: We developed a two-step approach to predict alternative splicing from GeneChip data. First, we clustered the probes from a probe set into pseudo-exons based on similarity of probe intensities and physical adjacency. A pseudo-exon is defined as a sequence in the gene within which multiple probes have comparable probe intensity values. Second, for each pseudo-exon, we assessed the statistical significance of the difference in probe intensity between two groups of samples. Differentially expressed pseudo-exons are predicted to be alternatively spliced. We applied our method to empirical data generated from GeneChip Hu6800 arrays, which include 7129 probe sets and twenty probes per probe set. The dataset consists of sixty-nine medulloblastoma (27 metastatic and 42 non-metastatic) samples and four cerebellum samples as normal controls. We predicted that 577 genes would be alternatively spliced when we compared normal cerebellum samples to medulloblastomas, and predicted that thirteen genes would be alternatively spliced when we compared metastatic medulloblastomas to non-metastatic ones. We checked the consistency of some of our findings with information in UCSC Human Genome Browser. CONCLUSION: The two-step approach described in this paper is capable of predicting some alternative splicing from multiple oligonucleotide-based gene expression array data with GeneChip technology. Our method employs the extensive repositories of gene expression array data available and generates alternative splicing hypotheses, which can be further validated by experimental studies.

The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas.

To develop a genetically faithful model of medulloblastoma with increased tumor incidence compared with the current best model we activated the Sonic Hedgehog (Shh) pathway by transgenically expressing a constitutively active form of Smoothened in mouse cerebellar granule neuron precursors (ND2:SmoA1 mice). This resulted in early cerebellar granule cell hyper-proliferation and a 48% incidence of medulloblastoma formation. Gene expression studies showed an increase in the known Shh targets Gli1 and Nmyc that correlated with increasing hyperplasia and tumor formation. Notch2 and the Notch target gene, HES5, were also significantly elevated in Smoothened-induced tumors showing that Shh pathway activation is sufficient to induce Notch pathway signaling. In human medulloblastomas reverse transcription-PCR for Shh and Notch targets revealed activation of both of these pathways in most tumors when compared with normal cerebellum. Notch pathway inhibition with soluble Delta ligand or gamma secretase inhibitors resulted in a marked reduction of viable cell numbers in medulloblastoma cell lines and primary tumor cultures. Treatment of mice with D283 medulloblastoma xenografts with a gamma secretase inhibitor resulted in decreased proliferation and increased apoptosis, confirming that Notch signaling contributes to human medulloblastoma proliferation and survival. Medulloblastomas in ND2:SmoA1 mice and humans have concomitant increase in Shh and Notch pathway activities, both of which contribute to tumor survival.

Central venous Access device SeCurement And Dressing Effectiveness (CASCADE) in paediatrics: protocol for pilot randomised controlled trials.

INTRODUCTION: Paediatric central venous access devices (CVADs) are associated with a 25% incidence of failure. Securement and dressing are strategies used to reduce failure and complication; however, innovative technologies have not been evaluated for their effectiveness across device types. The primary aim of this research is to evaluate the feasibility of launching a full-scale randomised controlled efficacy trial across three CVAD types regarding CVAD securement and dressing, using predefined feasibility criteria. METHODS AND ANALYSIS: Three feasibility randomised, controlled trials are to be undertaken at the Royal Children's Hospital and the Lady Cilento Children's Hospital, Brisbane, Australia. CVAD securement and dressing interventions under examination compare current practice with sutureless securement devices, integrated securement dressings and tissue adhesive. In total, 328 paediatric patients requiring a peripherally inserted central catheter (n=100); non-tunnelled CVAD (n=180) and tunnelled CVAD (n=48) to be inserted will be recruited and randomly allocated to CVAD securement and dressing products. Primary outcomes will be study feasibility measured by eligibility, recruitment, retention, attrition, missing data, parent/staff satisfaction and effect size. CVAD failure and complication (catheter-associated bloodstream infection, local infection, venous thrombosis, occlusion, dislodgement and breakage) will be compared between groups. ETHICS AND DISSEMINATION: Ethical approval to conduct the research has been obtained. All dissemination will be undertaken using the CONSORT Statement recommendations. Additionally, the results will be sent to the relevant organisations which lead CVAD focused clinical practice guidelines development. TRIAL REGISTRATION NUMBERS: ACTRN12614001327673; ACTRN12615000977572; ACTRN12614000280606.

p38 MAP kinase: a convergence point in cancer therapy.

Recent studies show that activation of p38 mitogen-activated protein kinase (MAPK) results in cancer cell apoptosis initiated by retinoids, cisplatin and other chemotherapeutic agents. The observation that divergent therapies act through a common signal transduction pathway raises the possibility of developing new anti-cancer agents that lack the side-effects caused by events upstream of p38 MAPK. Here, we review p38-MAPK-mediated tumor cell apoptosis and implications for cancer therapeutics.

Body composition of children with cancer during treatment and in survivorship.

BACKGROUND: Malnutrition as assessed with the use of body-composition measurements is a poorly understood short- and long-term complication of childhood cancer. OBJECTIVES: We aimed to evaluate the body composition of 2 childhood cancer cohorts as follows: 1) children currently undergoing cancer treatment and 2) childhood cancer survivors. We also aimed to compare the prevalence of obesity and undernutrition between the cancer groups and investigate the impact of cancer type on body composition. DESIGN: Eighty-two children during the treatment of cancer and 53 childhood cancer survivors were involved in the study. Height, weight, body cell mass, percentage of fat, fat mass index, and fat-free mass index were assessed. Subjects were compared with age- and sex-matched healthy controls. RESULTS: The on-treatment group had a higher percentage of fat (P = 0.0001) and fat mass index (P = 0.0001) and a significantly lower body cell mass index (P = 0.0001) and fat-free mass index (P = 0.003) than did matched controls. The survivor group had a significantly higher percentage of fat (P = 0.03) and fat mass index (P = 0.04) and significantly lower body cell mass index (P = 0.0001) than did matched controls. The prevalence of undernutrition was high in both groups with 48% (95% CI: 36%, 60%) of the on-treatment group and 53% (95% CI: 40%, 66%) of the survivors considered undernourished. According to the percentage of fat cutoffs, significantly more on-treatment patients were obese (55%; 95% CI: 40%, 60%) than were survivors (26%; 95% CI: 14%, 38%) (P = 0.005). There were no statistically significant differences in body composition between cancer types in either the on-treatment or the survivor group. CONCLUSIONS: Overnutrition and undernutrition are major concerns in the short and long term for children with cancer. Children treated for cancer have increased fat mass and decreased body cell mass, which are evident during treatment and in survivorship. This trial was registered at http://www.ANZCTR.org.au as ACTRN12614001279617 and ACTRN12614001269628.

Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells.

Neurocognitive deficits are serious sequelae that follow cranial irradiation used to treat patients with medulloblastoma and other brain neoplasms. Cranial irradiation causes apoptosis in the subgranular zone of the hippocampus leading to cognitive deficits. Valproic acid (VPA) treatment protected hippocampal neurons from radiation-induced damage in both cell culture and animal models. Radioprotection was observed in VPA-treated neuronal cells compared to cells treated with radiation alone. This protection is specific to normal neuronal cells and did not extend to cancer cells. In fact, VPA acted as a radiosensitizer in brain cancer cells. VPA treatment induced cell cycle arrest in cancer cells but not in normal neuronal cells. The level of anti-apoptotic protein Bcl-2 was increased and the pro-apoptotic protein Bax was reduced in VPA treated normal cells. VPA inhibited the activities of histone deacetylase (HDAC) and glycogen synthase kinase-3ß (GSK3ß), the latter of which is only inhibited in normal cells. The combination of VPA and radiation was most effective in inhibiting tumor growth in heterotopic brain tumor models. An intracranial orthotopic glioma tumor model was used to evaluate tumor growth by using dynamic contrast-enhanced magnetic resonance (DCE MRI) and mouse survival following treatment with VPA and radiation. VPA, in combination with radiation, significantly delayed tumor growth and improved mouse survival. Overall, VPA protects normal hippocampal neurons and not cancer cells from radiation-induced cytotoxicity both in vitro and in vivo. VPA treatment has the potential for attenuating neurocognitive deficits associated with cranial irradiation while enhancing the efficiency of glioma radiotherapy.

Targeting survivin with YM155 (Sepantronium Bromide): a novel therapeutic strategy for paediatric acute myeloid leukaemia.

Despite aggressive chemotherapy, approximately one-third of children with acute myeloid leukaemia (AML) relapse. More effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein with key roles in regulating cell division, proliferation and apoptosis. Furthermore, high expression of Survivin has been associated with poor clinical outcome in AML. The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in paediatric AML. YM155 potently inhibited cell viability in a diverse panel of AML cell lines. All paediatric cell lines were particularly sensitive, with a median IC50 of 0.038 µM. Cell cycle analyses demonstrated concentration-dependent increases in a sub-G1 population with YM155 treatment, suggestive of apoptosis that was subsequently confirmed by an increase in annexin-V positivity. YM155-mediated apoptosis was confirmed across a panel of 8 diagnostic bone marrow samples from children with AML. Consistent with the proposed mechanism of action, YM155 treatment was associated with down-regulation of survivin mRNA and protein expression and induction of DNA damage. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation.

Conditional survival estimates for childhood cancer in Australia, 2002-2011: A population-based study.

BACKGROUND: Conditional survival estimates take into account the time that a patient has remained alive following diagnosis to provide a realistic perspective on the probability of longer term survival. Such estimates are scarce for childhood cancer, particularly by age at diagnosis or stage of cancer. METHODS: De-identified population-based data were obtained from the Australian Paediatric Cancer Registry for children aged 0-14 years diagnosed with cancer between 1983 and 2010. Mortality status was followed up to the end of 2011. The hybrid period method was used to calculate relative survival estimates for those who were at risk during the period 2002-2011. Conditional survival stratified by diagnostic group or subgroup, age and stage at diagnosis was then obtained from the ratio of the relative survival estimates at different time points. RESULTS: A total of 13,537 children were eligible for inclusion. Five-year survival for all childhood cancers combined improved from 82% at diagnosis (95% confidence interval=81-83%) to 89% (88-90%) conditional on surviving one year, and 97% (97-98%) conditional on surviving five years after diagnosis. Conditional survival reached 95% within five years of diagnosis for nearly all types of cancer, regardless of a child's age or stage at diagnosis. CONCLUSION: Most children diagnosed with cancer who are alive five years after diagnosis can anticipate similar survival to children in the general population. This information may help alleviate some of the distress associated with childhood cancer, particularly for those with an initially poor prognosis.