ORCID Profile
0000-0002-8606-5889
Current Organisations
Murdoch Childrens Research Institute
,
Royal Children's Hospital Melbourne
,
University of Otago Christchurch
,
University of Melbourne
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Publications
ABCs of Natriuretic Peptides: Growth
Publisher: S. Karger AG
Date: 2007
DOI: 10.1159/000097558
Abstract: i Background: /i Although they are better known for their cardiovascular and antiproliferative effects, natriuretic peptides also have been found to produce skeletal overgrowth in transgenic rodents. This finding has unmasked a novel paracrine role in endochondral bone growth for this family of hormones. Genetic studies in which key components in the C-type natriuretic peptide (CNP) signaling pathway are disrupted or overexpressed and spontaneous mutations in the CNP receptor in humans indicate that CNP plays a crucial role in determining postnatal skeletal elongation. CNP appears to promote expansion within several areas of the growth plate, but its effects are most obvious in the hypertrophic zone. Since its actions are largely paracrine in nature, new approaches are needed to study CNP’s role in vivo. CNP itself degrades rapidly, but amino-terminal pro-CNP (NT pro-CNP) escapes rapid degradation and can be readily detected in plasma. i Methodology: /i Studies have been made of changes in CNP synthesis in humans and sheep by measuring NT pro-CNP levels. Plasma NT pro-CNP levels are markedly elevated in newborns, but fall progressively as growth velocity declines in both children and lambs. In keeping with these growth-related changes, CNP levels are inhibited by glucocorticoids and malnutrition in lambs and are stimulated by growth hormone and testosterone in adolescent boys. Further, levels fall abruptly in children receiving growth-suppressing chemotherapy regimens. i Conclusions: /i Plasma NT pro-CNP levels may be an indicator of CNP synthesis within skeletal tissues and provide a much needed biomarker of linear growth, with applications for diagnosis and management of growth disorders.
Cystatin C Based Equation Accurately Estimates Glomerular Filtration Rate in Children With Solid and Central Nervous System Tumours: Enough Evidence to Change Practice?
Publisher: Wiley
Date: 16-05-2016
DOI: 10.1002/PBC.26043
Abstract: Assessing the glomerular filtration rate (GFR) of paediatric patients receiving nephrotoxic chemotherapy is a vital element of clinical practice. Isotopically measured GFR is the gold standard in terms of accuracy but requires injection of tracer followed by several hours of blood tests. Estimation of GFR using creatinine is widely used but inaccurate, and there is increasing concern regarding its usage for paediatric oncology patients. Cystatin C (CysC) based equations are increasingly used in other paediatric specialities to estimate GFR, and their usefulness in paediatric oncology practice is becoming evident. We assessed the renal function of children with solid tumours and CNS tumours receiving nephrotoxic chemotherapy over a 1-year period using paired CysC and isotopic GFR. Fifty-six sets of measurements were reviewed with estimated GFR predicted using CysC-based and creatinine-based equations. The best performing equation was the 'new CKiD' equation, which estimated GFR within 30% of the measured GFR on 86% of occasions, outperforming the Schwartz equation. If estimated GFR using this equation was >100 ml/min/1.73 m(2) , all values of measured GFR were normal at >90 ml/min/1.73 m(2) , a category containing two-thirds of all measurements. The new CKiD equation predicts GFR in paediatric oncology patients with more accuracy than creatinine-based equations. When the estimated GFR is >100 ml/min/1.73 m(2) , isotopic GFR can be safely omitted.
Unravelling the genetics of vesicoureteric reflux: A common familial disorder
Publisher: Oxford University Press (OUP)
Date: 09-1996
DOI: 10.1093/HMG/5.SUPPLEMENT_1.1425
Abstract: Primary vesicoureteric reflux (VUR) is one of the more common genetic disorders. Little is yet known about the genetics of this potentially manageable childhood condition, which is characterised by regurgitation of urine from the bladder to the kidney. The VUR phenotype is associated with shortness of the submucosal segment of the ureter due to congenital lateral ectopia of the ureteric orifice. VUR is found in 30-50% of infants and young children with a urinary tract infection. A serious concern in families with an affected patient is that approximately one half of siblings or offspring will be affected, but up to a half of these affected siblings and offspring may be asymptomatic in childhood. If left untreated, these patients may present later in life with proteinuria, hypertension or renal failure. VUR is the commonest cause of end-stage renal failure in children, and an important cause in adults. As the kidney damage resulting from severe VUR is preventable, early detection is desirable. The techniques for clinical diagnosis are invasive and costly, reinforcing the importance of identification of a gene for VUR to facilitate genetic screening. Although family studies suggest a major dominant gene, the inheritance pattern is still a matter of debate. In rare instances, VUR occurs in association with other diseases, such as the coloboma-ureteric-renal syndrome, which is caused by a PAX2 gene mutation. In this review, we present evidence that this common disorder may be caused by mutations in the developmental pathway of which the PAX2 gene forms a part.
Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation
Publisher: Springer Science and Business Media LLC
Date: 09-12-1999
Abstract: Relaxation of IGF2 imprinting occurs in Wilms tumours and many other cancers, but the mechanism of loss of imprinting (LOI) remains unknown. To investigate the role of altered DNA methylation in LOI, we examined the pattern of methylation of the human insulin-IGF2 region in Wilms tumours and the normal kidney. The analysis included regions homologous to three 'differentially methylated regions' of the mouse Igf2 gene (dmrs 0, 1 and 2). In tumours displaying normal IGF2 imprinting, and in the normal kidney, maternal allele-specific DNA methylation was identified spanning exons 2 and 3. This region is homologous to dmr 0, a site of maternal-specific differential methylation in the mouse. In Wilms tumours with relaxed imprinting or 11p15.5 LOH this region was unmethylated. No other differential methylation was identified. In particular, two sites of paternal methylation in the mouse (dmrs 1 and 2), and all three imprinted IGF2 promoters were not methylated in the kidney or in Wilms tumours. We postulate that LOI in Wilms tumours is associated with loss of maternal allele-specific methylation from a region located upstream of the imprinted IGF2 promoters. This region may contain cis acting sequences that coordinately influence imprinting.
Low rates of recurrence and slow progression of pediatric pilocytic astrocytoma after gross-total resection: justification for reducing surveillance imaging.
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Date: 05-2016
Abstract: Pilocytic astrocytomas (PAs) are common brain tumors in children. Optimal management of PA is gross-total resection (GTR), after which event-free survival (EFS) is excellent. The tempo of recurrences, when they do occur, is relatively sparsely reported, and there is no agreed upon surveillance recommendation for patients in this category. It has been suggested that surveillance MRI is performed too frequently and could be safely reduced in both frequency and duration. The authors conducted a retrospective review of pediatric patients with PA who underwent GTR at a single institution over an 18-year period and who had documented recurrences. All patients under 18 years of age who had undergone GTR of a PA between 1996 and 2013 were included in the study. Clinical, radiological, and tumor characteristics were recorded. Sixty-seven patients met the criteria for GTR over the period studied. The 5-year EFS rate was 95% (95% CI 89%–100%) and overall survival was 100%. Recurrences showed a nonsignificant trend of occurring more commonly in patients with persistent nonenhancing FLAIR abnormalities after surgery, but there was no difference with regard to tumor location. All recurrences occurred before 3 years postresection, all were asymptomatic, and all patients were observed for at least one additional scan after the initial detection during routine surveillance MRI before further therapy was undertaken. EFS and overall survival are excellent after GTR in this population with PAs. Progression after recurrence occurs slowly and is asymptomatic. A less intensive schedule of MRI surveillance in this group of patients would result in time and cost savings, without compromising safety. The authors suggest a schedule of 6 MRI scans to be obtained postoperatively, at 3–6 months, then at 1, 2, 3.5, and 5 years.
A Clinical Decision Support System to Assist Pediatric Oncofertility: A Short Report
Publisher: Mary Ann Liebert Inc
Date: 08-2018
Abstract: Fertility preservation discussions with pediatric and adolescent cancer patients can be difficult for clinicians. This study describes the acceptability of a fertility clinician decision support system (CDSS). A cross-sectional study of clinicians at The Royal Children's Hospital, Melbourne. Participants were trained on CDSS purpose, contents, and use. A survey captured the perceived benefits and weaknesses of the CDSS. Thirty-nine clinicians participated. Over 90% felt the CDSS aims and format were clear, and understood the components. Over 80% felt it would enable adherence to clinical pathways, policy, and standards of care. The CDSS provided significant perceived benefits to oncofertility care.
Autopsy case of microcephalic osteodysplastic primordial dwarfism type II
Publisher: Wiley
Date: 06-08-2002
DOI: 10.1002/AJMG.10716
Abstract: Microcephalic osteodysplastic primordial "dwarfism" (MOPD) is a group of disorders similar to Seckel syndrome. Three subtypes (types I-III) have been reported. We report here the first autopsy case of MOPD type II. The patient was a Japanese girl with typical clinical and radiological manifestations of MOPD type II. The manifestations included severe intrauterine and postnatal growth failure, microcephaly, a distinctive facial appearance, micromelia, brachytelephalangy, coxa vara, and V-shaped metaphyses of the distal femora. Other than small cerebral hemispheres, no neuropathological abnormalities were found. Chondro-osseous histology showed thinning of the growth plate, ballooned chondrocytes, reduced cellularity, lack of zonal and columnar formations, and poor formation of primary trabeculae. These findings suggest that impairment of chondrocytic formation and differentiation is the major pathogenesis of MOPD type II.
Banking on cord blood stem cells
Publisher: Springer Science and Business Media LLC
Date: 10-2008
DOI: 10.1038/NRC2418-C3
LG-15RISK ASSESSMENT IN PAEDIATRIC GLIOMA - TIME TO MOVE ON FROM THE BINARY CLASSIFICATION.
Publisher: Oxford University Press (OUP)
Date: 06-2016
Counterstaining improves visualization of the myenteric plexus in immunolabelled whole-mount preparations
Publisher: Springer Science and Business Media LLC
Date: 12-09-2006
DOI: 10.1007/S10895-006-0120-X
Abstract: Immunocytochemistry has emerged as a powerful research tool in neurobiology. One of the widely used methods is an indirect fluorescence technique that uses FITC- conjugated IgG to visualise protein expression within tissues, but a major drawback of this technique is the high background fluorescence due to non-specific antibody binding. Gut innervation is complex and best visualized in three-dimensions in whole mount preparations. We describe a simple and easy to use counterstaining procedure in conjunction with an indirect immunofluorescence technique in gut whole mount preparations that largely eliminates background fluorescence and creates a contrasting background against the bright antigen-antibody complexes. Furthermore, this technique allows the detailed qualitative and quantitative study of myenteric plexuses in whole-mount preparations.
Switched-on Sonic hedgehog: A gene whose activity extends beyond fetal development - To oncogenesis
Publisher: Wiley
Date: 23-05-2007
DOI: 10.1111/J.1440-1754.2007.01104.X
Abstract: Embryonic and fetal development is a highly complex process choreographed by several families of genes that regulate early development of the embryo. Disruption in the structure and/or function of developmental genes produces morphogenic errors of development. One such family is the Hedgehog (Hh) signalling pathway, which plays an important role in the embryonal development of both invertebrates and vertebrates, including normal development of the brain, eye, limbs, foregut and its derivatives. Disruption of the Sonic hedgehog expression during critical periods of development is associated with developmental disorders of the brain, namely, holoprosencephaly, and the VATER association. Inappropriate activation of the pathway in post-embryonic development has been demonstrated in several human malignancies, including those of the brain and skin, both in children and adults. Specific inhibition of Hh signalling in these tumours inhibits growth of a wide range of malignancies. This demonstrates a requirement for Hh signalling in these tumours. These observations suggest that a better understanding of the genetic control of morphogenesis can ultimately provide us with greater knowledge of how congenital structural abnormalities occur, as well as the processes that lead to several childhood and other tumours. There may be a closer relationship between embryogenesis and oncogenesis than previously realised.
Potential biomarkers for hepatoblastoma: Results from the SIOPEL-3 study
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.EJCA.2011.10.019
Abstract: Hepatoblastoma (HB) is a rare malignant liver tumour found in infants. Many heterogeneous histological tumour subtypes exist. Although survival rates have improved dramatically in recent years with the use of platinum-based chemotherapy, there still exists a subset of HB that does not respond to treatment. There are currently no tumour biomarkers in use and in this study we aim to evaluate potential biomarkers to aid identification of relapse cases that would otherwise be overlooked by current prognostication. This may identify patients that would benefit from more aggressive therapy and could improve overall survival rates. We used immunohistochemistry to analyse the expression of β-catenin, E-cadherin, Cyclin D1, Ki-67 and alpha-fetoprotein (AFP) protein in tumours from 91 patients prospectively enroled into the SIOPEL 3 clinical trial. The relationship between these biomarkers and clinicopathologic features and patient survival were statistically analysed. We identified one biomarker, Cyclin D1, which has a correlation with mixed epithelial/mesenchymal HB approaching significance (P = 0.07). Survival analysis using these markers has revealed two potential prognostic indicators Cyclin D1 and Ki-67 (P = 0.01, 0.01).
Small Numbers, Big Challenges: Adolescent and Young Adult Cancer Incidence and Survival in New Zealand.
Publisher: Mary Ann Liebert Inc
Date: 06-2017
Abstract: This study was undertaken to determine cancer survival and describe the unique spectrum of cancers diagnosed among New Zealand's adolescents and young adult (AYA) population. Registrations for 1606 15-24 year olds diagnosed with a new primary malignant tumor between 2000 and 2009 were obtained from the New Zealand Cancer Registry and classified according to AYA diagnostic group and subgroup, age, sex, and prioritized ethnicity. Age-standardized incidence rates (IRs) per million person years and 5-year relative survival ratios were calculated. Cancer incidence was 228.6 per million for adolescents aged 15-19 years and 325.7 per million for young adults aged 20-24 years. Overall IRs were consistent across all ethnic groups but there were unique ethnic differences by tumor group including a higher incidence of bone tumors, carcinoma of the gastrointestinal tract, and gonadal germ cell tumors among Maori, a higher incidence of leukemia among Pacific peoples, and a higher incidence of melanoma among non-Maori/non-Pacific peoples. Five-year relative survival for adolescents (75.1%) and AYA overall (80.6%) appeared poorer than had been achieved in other high-income countries. Maori (69.5%) and Pacific (71.3%) AYA had lower 5-year survival compared to non-Maori/non-Pacific peoples (84.2%). The survival disparities observed require further investigation to identify and address the causes of these inferior outcomes. The newly established AYA Cancer Network Aotearoa has been tasked with improving cancer survival and care and ensuring equality of access for New Zealand AYAs with cancer.
The threat of the COVID-19 pandemic on reversing global life-saving gains in the survival of childhood cancer: a call for collaborative action from SIOP, IPSO, PROS, WCC, CCI, St Jude Global, UICC and
Publisher: Ecancer Global Foundation
Date: 15-02-2021
Development of paediatric non-stage prognosticator guidelines for population-based cancer registries and updates to the 2014 Toronto Paediatric Cancer Stage Guidelines
Publisher: Elsevier BV
Date: 09-2020
C-type Natriuretic Peptide: A novel biomarker of steroid induced bone toxicity in children with acute lymphoblastic leukemia (ALL)
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.PEPTIDES.2012.04.017
Abstract: Impaired bone growth and mineralization, and osteonecrosis are significant and common long-term sequelae of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Here we have evaluated the relationship between linear bone growth during chemotherapy for ALL and bone derived C-type Natriuretic Peptide (CNP). CNP is known to be critical to normal endochondral bone growth in both rodents and humans, and plasma concentration of the amino terminal pro CNP (NTproCNP) is strongly correlated with concurrent height velocity in children. Plasma NTproCNP and CNP were measured by radio-immunoassay in 12 children aged 2-9 years during induction and maintenance chemotherapy for children with ALL. Height velocity was calculated from stadiometer readings at intervals of 3-12 months and related to plasma NTproCNP during each growth interval. Plasma NTproCNP was markedly suppressed in all subjects during induction chemotherapy. Brief periods of NTproCNP decline and rapid rebound during maintenance treatment coincided with the use of dexamethasone but not with other chemotherapeutics. Height velocity was markedly reduced during ALL induction but unaffected in maintenance phase, and these changes in growth were strongly correlated with plasma NTproCNP concentration. Plasma NTproCNP has potential use as a biomarker of glucocorticoid-induced bone toxicity.
Epigenetic changes encompassing the IGF2/H19 locus associated with relaxation of IGF2 imprinting and silencing of H19 in Wilms tumor
Publisher: Proceedings of the National Academy of Sciences
Date: 14-03-1995
Abstract: In most tissues IGF2 is expressed from the paternal allele while H19 is expressed from the maternal allele. We have previously shown that in some Wilms tumors the maternal IGF2 imprint is relaxed such that the gene is expressed biallelically. We have now investigated this subset of tumors further and found that biallelic expression of IGF2 was associated with undetectable or very low levels of H19 expression. The relaxation of IGF2 imprinting in Wilms tumors also involved a concomitant reversal in the patterns of DNA methylation of the maternally inherited IGF2 and H19 alleles. Furthermore, the only specific methylation changes that occurred in tumors with relaxation of IGF2 imprinting were solely restricted to the maternal IGF2 and H19 alleles. These data suggest that there has been an acquisition of a paternal epigenotype in these tumors as the result of a pathologic disruption in the normal imprinting of the IGF2 and H19 genes.
MicroRNA expression patterns and signalling pathways in the development and progression of childhood solid tumours.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2017
Surgically Managed Ovarian Masses at the Royal Children’s Hospital, Melbourne –19 Year Experience
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.JPEDSURG.2019.05.005
Abstract: To describe the clinicopathological characteristics and management of surgically removed ovarian masses at the Royal Children's Hospital, Melbourne from 1993 to 2012. Medical records were reviewed retrospectively. Data regarding clinical findings, imaging and surgical management were evaluated. There were 266 ovarian masses found in 258 surgeries (eight had bilateral masses). Most were benign (246/266, 92.5%), 2.3% (6/266) were borderline, and 5.3% (14/266) were malignant. The most common presenting symptom was abdominal pain for benign masses (169/246, 68.7%), and a palpable mass for borderline and malignant masses (12/20, 60.0%). Sensitivity and specificity of ultrasound for detection of malignancy was 64.7% and 52.9% respectively. Ovarian torsion occurred in 22.1% (n=57), none with malignancy, with seven cases diagnosed under one year of age. Sensitivity and specificity of ultrasound for ovarian torsion was 22.0% and 91.9%, respectively. The proportion undergoing ovarian cystectomy rather than oophorectomy has increased from 56.3% during 1993-1997 to 93.8% during 2008-2012 (p<0.005). Ovarian torsion was managed with ovarian conservation in 82.6% of cases between 2008-2012. The majority of pediatric and adolescent ovarian masses were benign. Sensitivity of ultrasound was fair for detection of malignancy, and poor for ovarian torsion. Conservative surgeries are increasingly common. Level IV - case series with no comparison group TYPE OF STUDY: Retrospective Study.
Hepatoblastoma, cisplatin, and ototoxicity: Good news on deaf ears
Publisher: Wiley
Date: 07-10-2009
DOI: 10.1002/CNCR.24668
Sonic hedgehog, BMP4, and Hox genes in the development of anorectal malformations in Ethylenethiourea-exposed fetal rats
Publisher: Elsevier BV
Date: 12-2006
DOI: 10.1016/J.JPEDSURG.2006.08.035
Abstract: shh signaling pathway has been shown to be involved in the morphogenesis of many organ systems. In this study, we investigated the expression of shh and its targets, BMP4 and Hox genes, in the development of anorectal malformations in Ethylenethiourea (ETU)-exposed embryos. We used ETU murine model of the vertebral, anal, cardiac, tracheoesophageal, renal, and limb association. Ethylenethiourea 1% (125 mg/kg) was given to the pregnant females via gavage feeding on gestational day (gD) 10 and saline to control animals. Embryos were collected at gD12 to gD16 and gD21 hindguts were dissected and snap frozen. Highly purified RNA was isolated, and expression of shh, BMP4, Hoxa13, and Hoxd13 genes was confirmed with RT-PCR. Relative quantitative expression of shh and target genes at each time point was done with SYBR Green I qPCR. Normalized gene of interest expression was calculated by geNorm, and data analysis was done with 2-tail Student t test. shh, BMP4, Hoxa13, and Hoxd13 transcripts were detected in all s les, confirming that shh cascade is active during the process of hindgut development in fetal rats. Relative quantitation demonstrated that shh cascade expression shows time-dependent changes in the developing hindgut. This study shows that ETU disturbs the expression of shh signaling pathway during the development of hindgut. We provide evidence that shh plays a pivotal role in the hindgut morphogenesis, and its misexpression affect the expression of targets, BMP4 and Hox genes.
Living in the country and studying in the city. The art of passing exams and remaining sane
Publisher: Wiley
Date: 24-09-2008
DOI: 10.1111/J.1440-1754.2008.01382.X
Abstract: Doctors working in smaller centres have fewer resources available to help them pass the specialist examination components of their training. To describe the delivery of a teaching programme that helps paediatricians in training in both peripheral and regional centres in New Zealand (NZ) to successfully prepare for their specialist written examinations. The teaching programme was initially developed for paediatricians in training in Auckland and then developed into a national teaching resource. Real-time visual and auditory communication among the various teaching sites was established by the NZ Telepaediatric Service. The sessions were also available for subsequent review, initially as a DVD recording or via a Telepaediatric service videoconferencing unit and, since 2007, as a webcast. In association with the development of this teaching programme, the percentage pass rate for the paediatric specialist examinations has increased significantly for those exam candidates that access the teaching sessions remotely from other NZ centres (60% vs. 82%, chi(1)(2) = 4.28, P = 0.04). Between 80 and 90% of NZ candidates now pass the examination. In comparison, the pass rate for Australian candidates sitting the identical examination remains between 60 and 70%. Telepaediatrics has enabled interactive sessions to be conducted with students in peripheral and the other regional centres as well as those attending in person in Auckland. Its development has enabled examination pass rates in smaller centres to increase.
Mutation of PAX2 in two siblings with renal-coloboma syndrome
Publisher: Oxford University Press (OUP)
Date: 11-1995
Variations of Surveillance Practice for Patients with Bone Sarcoma: A Survey of Australian Sarcoma Clinicians
Publisher: Hindawi Limited
Date: 2017
DOI: 10.1155/2017/1837475
Abstract: Introduction . After treatment, bone sarcoma patients carry a high chance of relapse and late effects from multimodal therapy. We hypothesize that significant variation in surveillance practice exists between pediatric medical oncology (PO) and nonpediatric medical oncology (NP) sarcoma disciplines. Methods . Australian sarcoma clinicians were approached to do a web based survey that assessed radiologic surveillance (RS) strategies, late toxicity assessment, and posttreatment psychosocial interventions . Results . In total, 51 clinicians responded. No differences were identified in local disease RS. In metastatic disease response assessment, 100% of POs (23/23) and 93% of NPs (24/26) conducted CT chest. However, this was more likely to occur for NPs in the context of a CT chest/abdomen elvis (NP: 10/26 PO: 1/23 p = 0.006 ). POs were more likely to use CXR for RS ( p = 0.006 ). POs showed more prescriptive intensity in assessment of heart function ( p = 0.001 ), hearing ( p 0.001 ), and fertility ( p = 0.02 ). POs were more likely to deliver written information for health maintenance/treatment summary ( p = 0.04 ). The majority of respondents described enquiring about psychosocial aspects of health ( n = 33 /37, 89%), but a routine formal psychosocial screen was only used by 23% ( n = 6 /26). Conclusion . There is high variability in bone sarcoma surveillance between PO and NP clinicians. Efforts to harmonize approaches would allow early and late effects recognition/intervention and facilitate improved patient care/transition and research.
SIOP PODC Adapted treatment guidelines for low grade gliomas in low and middle income settings
Publisher: Wiley
Date: 12-2017
DOI: 10.1002/PBC.26737
Abstract: Effective treatment of children with low grade glioma (LGG) requires a functioning multi-disciplinary team with adequate neurosurgical, neuroradiological, pathological, radiotherapy and chemotherapy facilities and personnel. In addition, the treating centre should have the capacity to manage a variety of LGG and treatment-associated complications. These requirements have made it difficult for many centers in low and middle-income countries (LMIC) to offer effective treatment and follow up. This article provides management recommendations for children with LGG according to the level of facilities available.
Long-term visual outcome after chemotherapy for optic pathway glioma in children: Site and age are strongly predictive.
Publisher: Wiley
Date: 17-08-2015
DOI: 10.1002/CNCR.29649
Abstract: Optic pathway gliomas (OPGs) are commonly noted in pediatric oncology services. Radiotherapy is effective at controlling tumors, but has many undesirable late effects, especially in patients with neurofibromatosis. Chemotherapy is commonly used to preserve vision and delay or eliminate the need for radiotherapy. Despite visual threat being a common reason to initiate chemotherapy in patients with OPG, reports of visual outcome after chemotherapy are not common and reports of long-term visual outcome are even scarcer. In a single institution, all patients with OPG who had received chemotherapy or radiotherapy between 1996 and 2013 were identified from hospital databases. Visual, treatment, and radiological data were recorded. Categorized visual acuity was the primary outcome measure. Of 43 patients identified, visual data were available for 42 patients. Approximately 14% of patients experienced an improvement in visual acuity during therapy, 9% of patients experienced a deterioration, and the remainder were stable. At a mean follow-up of 78 months, 26% of patients were legally blind. Children aged 90% of children without these risk factors.
Beckwith- wiedemann syndrome, pancreatoblastoma, and the wnt signaling pathway [1] (multiple letters)
Publisher: Elsevier BV
Date: 04-2002
Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma – Results and treatment recommendations from the Childhood Liver Tumour Str
Publisher: Elsevier BV
Date: 08-2013
DOI: 10.1016/J.EJCA.2013.04.012
Abstract: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995-1998, 1998-2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan-Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice.
Toward the cure of all children with cancer through collaborative efforts: Pediatric oncology as a global challenge
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-09-2015
Abstract: Advances in the treatment of childhood cancers have resulted in part from the development of national and international collaborative initiatives that have defined biologic determinants and generated risk-adapted therapies that maximize cure while minimizing acute and long-term effects. Currently, more than 80% of children with cancer who are treated with modern multidisciplinary treatments in developed countries are cured however, of the approximately 160,000 children and adolescents who are diagnosed with cancer every year worldwide, 80% live in low- and middle-income countries (LMICs), where access to quality care is limited and chances of cure are low. In addition, the disease burden is not fully known because of the lack of population-based cancer registries in low-resource countries. Regional and ethnic variations in the incidence of the different childhood cancers suggest unique interactions between genetic and environmental factors that could provide opportunities for etiologic research. Regional collaborative initiatives have been developed in Central and South America and the Caribbean, Africa, the Middle East, Asia, and Oceania. These initiatives integrate regional capacity building, education of health care providers, implementation of intensity-graduated treatments, and establishment of research programs that are adjusted to local capacity and local needs. Together, the existing consortia and regional networks operating in LMICs have the potential to reach out to almost 60% of all children with cancer worldwide. In summary, childhood cancer burden has been shifted toward LMICs and, for that reason, global initiatives directed at pediatric cancer care and control are needed. Regional networks aiming to build capacity while incorporating research on epidemiology, health services, and outcomes should be supported.
Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss
Publisher: Massachusetts Medical Society
Date: 21-06-2018
T-cell acute lymphoblastic leukemia in association with Börjeson-Forssman-Lehmann syndrome due to a mutation in PHF6
Publisher: Wiley
Date: 05-05-2010
DOI: 10.1002/PBC.22574
Carboplatin Hypersensitivity Reactions in Pediatric Low Grade Glioma Are Protocol Specific and Desensitization Shows Poor Efficacy.
Publisher: Wiley
Date: 24-07-2015
DOI: 10.1002/PBC.25686
Abstract: The use of carboplatin for the treatment of pediatric low grade gliomas (PLGG) is often limited by the development of carboplatin hypersensitivity. Reported rates of carboplatin hypersensitivity reactions vary between 6% and 32% in these patients. Here we report the frequency of carboplatin hypersensitivity reactions depending on the treatment regimen used, and outcomes of carboplatin desensitization. The records of all patients in a single institution who were treated with carboplatin for PLGG were accessed and all patients receiving more than one dose of carboplatin are reported. Thirty four patients with PLGG were treated with carboplatin according to one of the two different regimens. Carboplatin hypersensitivity was documented in 47% of patients, but the frequency differed by treatment protocol. Those patients treated with 4-weekly single agent carboplatin had carboplatin allergy in 8% of cases whereas 68% of those treated with combined carboplatin and vincristine (every three weeks, according to the SIOP 2004 low grade glioma protocol) had carboplatin reactions (OR 23.6, P < 0.01). Desensitization was only successful in two out of 10 patients in whom it was attempted. Hypersensitivity reactions to carboplatin are more common in this cohort than previously reported and rates are protocol-dependent. Desensitization showed limited effectiveness in this cohort.
Mapping Pediatric Oncology Clinical Trial Collaborative Groups on the Global Stage
Publisher: American Society of Clinical Oncology (ASCO)
Date: 05-2022
DOI: 10.1200/GO.21.00266
Abstract: The global pediatric oncology clinical research landscape, particularly in Central and South America, Africa, and Asia, which bear the highest burden of global childhood cancer cases, is less characterized in the literature. Review of how existing pediatric cancer clinical trial groups internationally have been formed and how their research goals have been pursued is critical for building global collaborative research and data-sharing efforts, in line with the WHO Global Initiative for Childhood Cancer. A narrative literature review of collaborative groups performing pediatric cancer clinical research in each continent was conducted. An inventory of research groups was assembled and reviewed by current pediatric cancer regional and continental leaders. Each group was narratively described with identification of common structural and research themes among consortia. There is wide variability in the structure, history, and goals of pediatric cancer clinical trial collaborative groups internationally. Several continental regions have longstanding endogenously-formed clinical trial groups that have developed and published numerous adapted treatment regimens to improve outcomes, whereas other regions have consortia focused on developing foundational database registry infrastructure supported by large multinational organizations or twinning relationships. There cannot be a one-size-fits-all approach to increasing collaboration between international pediatric cancer clinical trial groups, as this requires a nuanced understanding of local stakeholders and resources necessary to form partnerships. Needs assessments, performed either by local consortia or in conjunction with international partners, have generated productive clinical trial infrastructure. To achieve the goals of the Global Initiative for Childhood Cancer, global partnerships must be sufficiently granular to account for the distinct needs of each collaborating group and should incorporate grassroots approaches, robust twinning relationships, and implementation science.
Single agent carboplatin for pediatric low-grade glioma: A retrospective analysis shows equivalent efficacy to multiagent chemotherapy.
Publisher: Wiley
Date: 13-08-2015
DOI: 10.1002/IJC.29711
Abstract: Pediatric low-grade gliomas (LGG) that are unresectable often require adjuvant chemotherapy such as carboplatin/vincristine. Small Phase II studies have suggested equivalent efficacy of single agent 4-weekly carboplatin. A single-institution retrospective review captured all patients aged 0 to 18 years diagnosed with LGG between 1996 and 2013 and treated with carboplatin monotherapy. The response and survival according to tumor site was compared to published results for multiagent chemotherapy. Of 268 children diagnosed with LGG diagnosed in this period, 117 received chemotherapy and 104 children received single agent carboplatin as first line chemotherapy. All patients received carboplatin at 560 mg/m(2), four-weekly for a median of 12 courses. The mean age at diagnosis was 5.8 years (range 3m-16y) and 32% had neurofibromatosis type 1. With a mean followup of 54 months, 86% of patients achieved stabilisation or better (SD/PR/CR). 3-year progression free survival (PFS) 66% (95% CI 57-76%), and 5-year PFS was 51% (95% CI 41-63%). 5-year overall survival was 97%. Multivariate analysis showed poorer PFS for those with chiasmatic/hypothalamic tumors. In this retrospective analysis single agent carboplatin shows comparable efficacy to historical multiagent chemotherapy for the treatment of patients with unresectable LGG. Equivalent outcomes are achieved with less chemotherapy, reduced side effects and fewer hospital visits. Further research is required to establish the place of this simplified regimen in the up-front treatment of unresectable LGG.
Risk assessment in paediatric glioma-Time to move on from the binary classification.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.CRITREVONC.2017.01.012
Abstract: Paediatric glioma encompasses a wide range of entities with highly variable prognoses. Gliomas are grouped by histopathological features into high- and low-grade glioma but this classification until recently has not taken into account many emerging risk factors in this disease. A comprehensive risk classification has not been published for paediatric glioma despite many risk factors being established in this disease. A comprehensive literature review was carried out identifying risk factors for paediatric low-grade and high-grade glioma. The most consistently described risk factors in high-grade glioma included midline location and extent of surgical resection. For patients with progressive unresectable low-grade glioma, age under 1, neurofibromatosis type I status and location were the most consistently prognostic. Molecular classification shows promise in accurately reassigning diagnosis for some gliomas. Risk profiling in paediatric glioma will require a focused multinational effort but will result in a more accurate and nuanced assessment of prognosis.
Banking on cord blood stem cells
Publisher: Springer Science and Business Media LLC
Date: 12-06-2008
DOI: 10.1038/NRC2418
Abstract: Umbilical cord blood gifted to non-profit public cord blood banks is now routinely used as an alternative source of haematopoietic stem cells for allogeneic transplantation for children and adults with cancer, bone marrow failure syndromes, haemoglobinopathies and many genetic metabolic disorders. Because of the success and outcomes of public cord banking, many companies now provide private cord banking services. However, in the absence of any published transplant evidence to support autologous and non-directed family banking, commercial cord banks currently offer a superfluous service.
TUMOUR BIOLOGY
Publisher: Oxford University Press (OUP)
Date: 06-2014
Fertility Preservation in Children and Adolescents With Cancer: Pilot of a Decision Aid for Parents of Children and Adolescents With Cancer (Preprint)
Publisher: JMIR Publications Inc.
Date: 21-03-2018
Abstract: uture infertility is a significant concern for survivors of childhood and adolescent cancer. Children and adolescents may have the opportunity to undergo fertility preservation (FP) procedures (which preserve gonadal tissue or gametes for future use) prior to the cancer treatment. However, the decision is very complex, as it is often made by parents as proxy decision makers at the time of cancer diagnosis, and is time-sensitive (needing to occur before the cancer treatment begins). Furthermore, FP procedures in children and adolescents are experimental and cannot guarantee future fertility. An uninformed decision may result in future decision regret. his study aimed to assess the acceptability, usability, and feasibility of a Web-based FP decision aid (DA) in parents of children and adolescents with cancer and clinicians. Fertility knowledge and decision regret were compared in families who reviewed the DA compared with those who did not. he Web-based DA was developed according to the International Patient Decision Aid Standards. A cross-sectional study of parents of patients with cancer, who discussed fertility, and clinicians at a tertiary children’s hospital was undertaken. The acceptability, usability, and feasibility of the DA were assessed using a pre-post survey design. Measures included the validated Decision Regret Scale, a purpose-designed fertility-related knowledge scale, questions regarding satisfaction with the DA, and open-ended responses for additional feedback. Furthermore, clinicians involved in FP were also invited to review the DA. e enrolled 34 parents and 11 clinicians in this study. Participants who reviewed the DA (15 parents and 11 clinicians) expressed satisfaction with its content and functionality. Parents reported an improved understanding of cancer treatments, infertility, and FP procedures and did not report greater decision regret after DA review. Most parents (13/15, 86%) would recommend the DA to other parents. All clinicians had a consensus that this was a valid and relevant information source for all involved in fertility care. t is an international standard of care to discuss the impact of cancer treatment on fertility before cancer treatment. This is the first fertility DA for parents of children and adolescents with cancer and is found to be relevant and acceptable by parents and clinicians. This DA has the potential to help support parents to make informed fertility-related decisions for their children and adolescents. However, future research is needed to assess the impact of the DA on prospective decision making.
The Global COVID‐19 Observatory and Resource Center for Childhood Cancer: A response for the pediatric oncology community by SIOP and St. Jude Global
Publisher: Wiley
Date: 24-02-2021
DOI: 10.1002/PBC.28962
Abstract: The COVID‐19 pandemic quickly led to an abundance of publications and recommendations, despite a paucity of information on how COVID‐19 affects children with cancer. This created a dire need for a trusted resource with curated information and a space for the pediatric oncology community to share experiences. The Global COVID‐19 Observatory and Resource Center for Childhood Cancer was developed, launched, and maintained by the International Society of Pediatric Oncology and St. Jude Children's Research Hospital. The three components (Resource Library, Global Registry, and Collaboration Space) complement each other, establishing a mechanism to generate and transfer knowledge rapidly throughout the community.
Abstracts from the Thirteenth International Symposium on Pediatric Neuro-Oncology
Publisher: Oxford University Press (OUP)
Date: 06-2008
Osteosarcoma in a Child Below 2 Years of Age
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2018
Early advice on managing children with cancer during the COVID‐19 pandemic and a call for sharing experiences
Publisher: Wiley
Date: 24-04-2020
DOI: 10.1002/PBC.28327
Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale
Publisher: American Society of Clinical Oncology (ASCO)
Date: 07-2012
Abstract: The platinum chemotherapy agents cisplatin and carboplatin are widely used in the treatment of adult and pediatric cancers. Cisplatin causes hearing loss in at least 60% of pediatric patients. Reducing cisplatin and high-dose carboplatin ototoxicity without reducing efficacy is important. This review summarizes recommendations made at the 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston, October 21-24, 2010, reflecting input from international basic scientists, pediatric oncologists, otolaryngologists, oncology nurses, audiologists, and neurosurgeons to develop and advance research and clinical trials for otoprotection. Platinum initially impairs hearing in the high frequencies and progresses to lower frequencies with increasing cumulative dose. Genes involved in drug transport, metabolism, and DNA repair regulate platinum toxicities. Otoprotection can be achieved by acting on several these pathways and generally involves antioxidant thiol agents. Otoprotection is a strategy being explored to decrease hearing loss while maintaining dose intensity or allowing dose escalation, but it has the potential to interfere with tumoricidal effects. Route of administration and optimal timing relative to platinum therapy are critical issues. In addition, international standards for grading and comparing ototoxicity are essential to the success of prospective pediatric trials aimed at reducing platinum-induced hearing loss. Collaborative prospective basic and clinical trial research is needed to reduce the incidence of irreversible platinum-induced hearing loss, and optimize cancer control. Wide use of the new internationally agreed-on SIOP Boston ototoxicity scale in current and future otoprotection trials should help facilitate this goal.
The COVID‐19 pandemic: A rapid global response for children with cancer from SIOP, COG, SIOP‐E, SIOP‐PODC, IPSO, PROS, CCI, and St Jude Global
Publisher: Wiley
Date: 13-05-2020
DOI: 10.1002/PBC.28409
Abstract: The COVID‐19 pandemic is one of the most serious global challenges to delivering affordable and equitable treatment to children with cancer we have witnessed in the last few decades. This Special Report aims to summarize general principles for continuing multidisciplinary care during the SARS‐CoV‐2 (COVID‐19) pandemic. With contributions from the leadership of the International Society for Pediatric Oncology (SIOP), Children's Oncology Group (COG), St Jude Global program, and Childhood Cancer International, we have sought to provide a framework for healthcare teams caring for children with cancer during the pandemic. We anticipate the burden will fall particularly heavily on children, their families, and cancer services in low‐ and middle‐income countries. Therefore, we have brought together the relevant clinical leads from SIOP Europe, COG, and SIOP‐PODC (Pediatric Oncology in Developing Countries) to focus on the six most curable cancers that are part of the WHO Global Initiative in Childhood Cancer. We provide some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures taken to contain it (e.g., extreme social distancing), and how to prepare for the anticipated recovery period.
Mast cells dysregulate apoptotic and cell cycle genes in mucosal squamous cell carcinoma
Publisher: Springer Science and Business Media LLC
Date: 12-2006
Abstract: Mucosal squamous cell carcinoma of the head and neck is a disease of high mortality and morbidity. Interactions between the squamous cell carcinoma and the host's local immunity, and how the latter contributes to the biological behavior of the tumor are unclear. In vivo studies have demonstrated sequential mast cell infiltration and degranulation during squamous cell carcinogenesis. The degree of mast cell activation correlates closely with distinct phases of hyperkeratosis, dysplasia, carcinoma in-situ and invasive carcinoma. However, the role of mast cells in carcinogenesis is unclear. This study explores the effects of mast cells on the proliferation and gene expression profile of mucosal squamous cell carcinoma using human mast cell line (HMC-1) and human glossal squamous cell carcinoma cell line (SCC25). HMC-1 and SCC25 were co-cultured in a two-compartment chamber, separated by a polycarbonate membrane. HMC-1 was stimulated to degranulate with calcium ionophore A23187. The experiments were done in quadruplicate. Negative controls were established where SCC25 were cultured alone without HMC-1. At 12, 24, 48 and 72 hours, proliferation and viability of SCC25 were assessed with MTT colorimetric assay. cDNA microarray was employed to study differential gene expression between co-cultured and control SCC25. HMC-1/SCC25 co-culture resulted in suppression of growth rate for SCC-25 (34% compared with 110% for the control by 72 hours, p 0.001), and dysregulation of genes TRAIL, BIRC4, CDK6, Cyclin G2 and CDC6 in SCC25. We show that mast cells have a direct inhibitory effect on the proliferation of mucosal squamous cell carcinoma in vitro by dysregulating key genes in apoptosis and cell cycle control.
Epidermal growth factor receptor: a novel biomarker for aggressive head and neck cutaneous squamous cell carcinoma
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.HUMPATH.2007.07.004
Abstract: There is currently no prognostic tool that reliably predicts the risk of metastasis in cutaneous squamous cell carcinoma, most of which occur in the head and neck region. Epidermal growth factor receptor has received much interest in recent years with the advent of epidermal growth factor receptor-targeted molecular therapy in clinical oncology. We investigate the role of epidermal growth factor receptor as a biomarker for head and neck cutaneous squamous cell carcinoma. Using immunohistochemistry and fluorescence in situ hybridization, we assessed the epidermal growth factor receptor protein expression and gene copy in 3 groups of head and neck cutaneous squamous cell carcinoma: primary lesions not associated with metastasis (P), primary lesions associated with subsequent metastasis (PM), and metastatic nodal disease (M). Epidermal growth factor receptor overexpression was detected in 36% and 79% of P and PM cases, respectively. Epidermal growth factor receptor overexpression was significantly associated with PM (P = .03) and was found to be an independent prognostic factor for metastasis on multivariate analysis (P = .05). However, epidermal growth factor receptor overexpression was only maintained in 47% of cases in the M group. None of the 27 cases that overexpressed the epidermal growth factor receptor protein showed gene lification: the results were uninterpretable in 2, and polysomy and balanced disomy were detected in 5 and 20 cases, respectively. These observations may have important prognostic and therapeutic implications for head and neck cutaneous squamous cell carcinoma.
Erratum: A cross comparison of technologies for the detection of microRNAs in clinical FFPE samples of hepatoblastoma patients
Publisher: Springer Science and Business Media LLC
Date: 02-09-2015
DOI: 10.1038/SREP13505
Abstract: Although formalin fixed paraffin embedded (FFPE) tissue is a major biological source in cancer research, it is challenging to work with due to macromolecular fragmentation and nucleic acid crosslinking. Therefore, it is important to characterise the quality of data that can be obtained from FFPE s les. We have compared three independent platforms (next generation sequencing, microarray and NanoString) for profiling microRNAs (miRNAs) using clinical FFPE s les from hepatoblastoma (HB) patients. The number of detected miRNAs ranged from 228 to 345 (median=294) using the next generation sequencing platform, whereas 79 to 125 (median=112) miRNAs were identified using microarrays in three HB s les, including technical replicates. NanoString identified 299 to 372 miRNAs in two s les. Between the platforms, we observed high reproducibility and significant levels of shared detection. However, for commonly detected miRNAs, a strong correlation between platforms was not observed. Analysis of 10 additional HB s les with NanoString identified significantly overlapping miRNA expression profiles, and an alternative pattern was identified in a poorly differentiated HB with an aggressive phenotype. This investigation serves as a roadmap for future studies investigating miRNA expression in clinical FFPE s les, and as a guideline for the selection of an appropriate platform.
PD-1 blockade using pembrolizumab in adolescent and young adult patients with advanced bone and soft tissue sarcoma
Publisher: Wiley
Date: 13-12-2020
DOI: 10.1002/CNR2.1327
Sonic hedgehog expression in the development of hindgut in ETU-exposed fetal rats
Publisher: Springer Science and Business Media LLC
Date: 21-12-2006
DOI: 10.1007/S00383-005-1575-6
Abstract: Sonic hedgehog (Shh) has been shown to be involved in the morphogenesis of many organ systems including the notochord, floor plate and limbs, as well as in the development of the left-right axis in vertebrates. Recent evidence suggests the Shh cascade plays a crucial role in the development of the foregut and hindgut. We have previously shown that prenatal exposure of fetal rats to ethylenethiourea (ETU) induces hindgut malformations and other abnormalities of the VACTERL association. The aim of this study was to determine the pattern of expression of Shh and its downstream genes during hindgut development in ETU-exposed embryos with anorectal malformations (ARMs). Pregnant Sprague-Dawley rats were mated together overnight and a positive vaginal plug was marked as gD0. On gD10, 1% ETU (125 mg/kg) was given to the experimental group and controls received the same volume of saline. Embryos were collected from both groups at gD12-16. The developing hindgut of each embryo was dissected under magnification and snap frozen. Highly purified RNA was isolated from each hindgut and first strand cDNA was prepared with appropriate negative controls. Reverse transcriptase (RT) polymerase chain reaction (PCR) was done to determine the transcripts of Shh in each s le and quantitative real-time PCR was carried out to show relative quantitative expression of Shh at each time point. Shh was detected in all s les confirming that Shh is active during the process of hindgut development in fetal rats. Relative quantitation demonstrated that Shh expression shows time-dependent changes in the developing hindgut of ETU-exposed rat embryos, and when results were compared with control s les, there was significant decrease in expression on gD14 and 15, when the cloaca normally separates into the rectum and urethra occurs in the rat fetus. The misregulated expression of Shh in the hindgut of ETU-exposed rat embryos suggests that ETU may interfere with Shh signalling. Downregulation at the time of cloacal separation into rectum and urethra indicates that Shh plays a crucial role in the development of hindgut.
A cross comparison of technologies for the detection of microRNAs in clinical FFPE samples of hepatoblastoma patients
Publisher: Springer Science and Business Media LLC
Date: 03-06-2015
DOI: 10.1038/SREP10438
Abstract: Although formalin fixed paraffin embedded (FFPE) tissue is a major biological source in cancer research, it is challenging to work with due to macromolecular fragmentation and nucleic acid crosslinking. Therefore, it is important to characterise the quality of data that can be obtained from FFPE s les. We have compared three independent platforms (next generation sequencing, microarray and NanoString) for profiling microRNAs (miRNAs) using clinical FFPE s les from hepatoblastoma (HB) patients. The number of detected miRNAs ranged from 228 to 345 (median=294) using the next generation sequencing platform, whereas 79 to 125 (median=112) miRNAs were identified using microarrays in three HB s les, including technical replicates. NanoString identified 299 to 372 miRNAs in two s les. Between the platforms, we observed high reproducibility and significant levels of shared detection. However, for commonly detected miRNAs, a strong correlation between platforms was not observed. Analysis of 10 additional HB s les with NanoString identified significantly overlapping miRNA expression profiles and an alternative pattern was identified in a poorly differentiated HB with an aggressive phenotype. This investigation serves as a roadmap for future studies investigating miRNA expression in clinical FFPE s les and as a guideline for the selection of an appropriate platform.
HGF/c-Met related activation of β-catenin in hepatoblastoma
Publisher: Springer Science and Business Media LLC
Date: 12-10-2011
ANZCCSG BabyBrain99; intensified systemic chemotherapy, second look surgery and involved field radiation in young children with central nervous system malignancy
Publisher: Wiley
Date: 04-02-2011
DOI: 10.1002/PBC.22942
Abstract: ANZCCSG BabyBrain99 is a trial of intensive systemic chemotherapy with dual stem cell supported treatment, second look surgery and involved field radiation for children less than four years of age with malignant central nervous system tumours. Following primary resection, treatment included two courses of cisplatin and oral etoposide, a third course of mobilising chemotherapy (vincristine, etoposide, cyclophosphamide) with stem cell harvest, followed by intensive stem cell supported chemotherapy with high dose cyclophosphamide, etoposide and vincristine. Children were evaluated for second resection before proceeding to a second stem cell supported consolidation therapy consisting of melphalan and carboplatin. Patients then received involved field radiation therapy. Thirty three children with a range of diagnoses were enrolled. Nine percent of children had metastatic disease at diagnosis. Eighteen children completed treatment including irradiation. At the end of induction the event free survival was 70% (54-86). Forty eight percent of children had a complete response, 18% had stable disease and 3% had a partial response. Five year overall survival was 40% (22-56) and event free survival was 33% (17-50). Children in whom a complete resection were achieved had a significantly superior outcome compared to those children without a complete resection, 5 year EFS 60% (45-75), as compared to 22% (13-30), P-value <0.05. BabyBrain99 confirms that intensive stem cell supported chemotherapy can be safely administered to infants with CNS tumours however overall prognosis remains poor. Importantly, the study reinforces a complete surgical resection as an important favourable prognostic indicator. Pediatr Blood Cancer 2011 :1055-1061. © 2011 Wiley-Liss, Inc.
Prevention of cisplatin-induced ototoxicity in children and adolescents with cancer: a clinical practice guideline
Publisher: Elsevier BV
Date: 02-2020
Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study
Publisher: Elsevier BV
Date: 08-2013
Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.
Publisher: Springer Science and Business Media LLC
Date: 08-09-2020
Evidence of broad-based family support for the use of archival childhood tumour samples in future research.
Publisher: BMJ
Date: 10-05-2016
DOI: 10.1136/MEDETHICS-2015-103141
Abstract: This study aimed to determine the ability to successfully contact past paediatric patients and their families to request participation in research, to assess familial views on the use of previously collected archival clinical s les for research purposes, and to highlight the ethical and practical issues in obtaining this type of retrospective consent. To assess familial views on the use of such s les for research, we contacted a cohort of families with children previously diagnosed with a brain tumour to ask for consent to an epigenetic/genetic study. Examining participants' responses allowed us to gauge their opinions on the use of such tissue for research, and whether they would like to receive genetic information uncovered during research. We were able to successfully contact 107 out of 178 families and found a significant positive correlation between year of diagnosis and ability to make contact. Of those families contactable that returned a consent form (75/107), 74 agreed to the use of their/their child's archival tissue in future research, and 70 of 74 requested notification should a gene change of potential clinical relevance be found. There were no differences in opinion between parents of living or deceased children or the patients themselves. This study highlights the importance of time since diagnosis on the ability to make contact with previous patients and their families. When contactable, our data highlight the altruistic views of families towards the use of archival clinical s les for research purposes, irrespective of the outcome of their child's illness.
Erratum: Mutation of the gene in a family with optic nerve colobomas, renal anomolies and vesicoureteral reflux (Nature Genetics (1995) 9 (358- 364))
Publisher: Springer Science and Business Media LLC
Date: 05-1996
DOI: 10.1038/NG0596-129C
Pediatric Pleomorphic Xanthoastrocytoma Treated with Surgical Resection Alone: Clinicopathologic Features
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2016
Multi-platform microRNA profiling of hepatoblastoma patients using formalin fixed paraffin embedded archival samples
Publisher: Oxford University Press (OUP)
Date: 25-11-2015
Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux
Publisher: Springer Science and Business Media LLC
Date: 04-1995
DOI: 10.1038/NG0495-358
Abstract: Paired box (PAX) genes play a critical role in human development and disease. The PAX2 gene is expressed in primitive cells of the kidney, ureter, eye, ear and central nervous system. We have conducted a mutational analysis of PAX2 in a family with optic nerve colobomas, renal hypoplasia, mild proteinuria and vesicoureteral reflux. We report a single nucleotide deletion in exon five, causing a frame-shift of the PAX2 coding region in the octapeptide domain. The phenotype resulting from the PAX2 mutation in this family was very similar to abnormalities that have been reported in Krd mutant mice. These data suggest that PAX2 is required for normal kidney and eye development.
Unkonventionelle Therapien bei Krebserkrankungen im Kindesalter: Richtlinien zur Abgrenzung unbedenklicher von schädlichen Behandlungsmethoden: Ein Bericht der SIOP-Arbeitsgruppe für Psychosoziale Fra
Publisher: Georg Thieme Verlag KG
Date: 03-2004
Abstract: This is the 11th official document of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology, instituted in 1991. There is a tendency for some physicians to make blanket statements against the use of non-proven, nonconventional therapies, even when these therapies are not harmful. There is an equal and opposite tendency on the part of many parents to do all that they possibly can for their children, including using any non-conventional therapy they feel might do some good. The health care team must open a healthy dialogue with parents that will lead to a clear distinction between those complementary therapies that are harmful and those that are not, indeed, might even be helpful psychologically if not therapeutically.
Methylation profiling of paediatric pilocytic astrocytoma reveals variants specifically associated with tumour location and predictive of recurrence
Publisher: Wiley
Date: 06-07-2018
Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03)
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2021
DOI: 10.1200/JCO.20.01372
Abstract: SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS 60%). These results establish a new risk stratification for future medulloblastoma trials.
NEURO/MEDICAL ONCOLOGY
Publisher: Oxford University Press (OUP)
Date: 11-2013
Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency
Publisher: American Society of Clinical Oncology (ASCO)
Date: 07-2016
Abstract: Recurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition. We performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab. All malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), similar to other cancers that responded favorably to immune checkpoint inhibitors. bMMRD GBM had a significantly higher mutational load than sporadic pediatric and adult gliomas and all other brain tumors (P .001). bMMRD GBM harbored mean neoantigen loads seven to 16 times higher than those in immunoresponsive melanomas, lung cancers, or microsatellite-unstable GI cancers (P .001). On the basis of these preclinical data, we treated two bMMRD siblings with recurrent multifocal GBM with the anti–programmed death-1 inhibitor nivolumab, which resulted in clinically significant responses and a profound radiologic response. This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.
HGG-20. DNA METHYLATION ANALYSIS OF HIGH-GRADE GLIOMA IN PATIENTS WITH MISMATCH REPAIR DEFICIENCIES.
Publisher: Oxford University Press (OUP)
Date: 06-2018
Pancreatoblastoma is associated with chromosome 11p loss of heterozygosity and IGF2 overexpression
Publisher: Wiley
Date: 19-05-2002
DOI: 10.1002/MPO.10050
Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation.
Publisher: Springer Science and Business Media LLC
Date: 19-03-2016
DOI: 10.1007/S11060-016-2109-X
Abstract: Disseminated glioneuronal tumors of childhood are rare. We present a retrospective IRB-approved review of the clinical course and frequency of BRAF mutations in disseminated glioneuronal tumors at two institutions. Defining features of our cohort include diffuse leptomeningeal-spread, often with a discrete spinal cord nodule and oligodendroglioma-like histologic features. Patients were identified through a pathology database search of all cases with disseminated low-grade neoplasms with an oligodendroglioma-like component. De-identified clinical information was collected by chart review and all imaging was reviewed. We retrieved the results of targeted genomic analyses for alterations in BRAF. Ten patients (aged 2-14 years) were identified from the Dana-Farber/Boston Children's Hospital and the Royal Children's Hospital, Melbourne pathology databases. Nine patients received chemotherapy. Eight patients are alive, although three have had episodes of progressive disease. We identified genomic alterations affecting the MAPK pathway in six patients. One patient had a germline RAF1 mutation and a clinical diagnosis of cardio-facio-cutaneous syndrome. BRAF duplications were identified in four and BRAF V600E mutation was identified in one. These data support the presence of targetable genomic alterations in this disease.
The contribution of the sonic hedgehog cascade in the development of the enteric nervous system in fetal rats with anorectal malformations
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.JPEDSURG.2007.08.036
Abstract: This study was designed to determine the expression of Sonic hedgehog (Shh) and its downstream genes during development of the enteric nervous system (ENS) in ethylenethiourea (ETU)-exposed fetal rats with anorectal malformations (ARMs). Anorectal malformations were induced by 1% ETU (125 mg/kg) given on gestational day 10, and the litter was harvested at term. The fetal anorectum and rectosigmoid region, including any communication with the urinary tract, were collected for gene expression studies and immunofluorescence study of the ENS. Gene expression of Shh cascade was performed using reverse transcription and real-time polymerase chain reaction (PCR). The myenteric plexuses of the ENS in normal and ARM rats were visualized with fluorescent antibodies. Reverse transcription-PCR confirmed expression of Shh and its target genes in all parts of the ARMs. Quantitative PCR demonstrated that levels of expression of the genes of the Shh cascade were low in the ARMs. The immunoreactivity of neuromarkers was markedly reduced in high ARMs and slightly reduced in low ARMs. This study demonstrates reduced expression of Shh and its target genes in ARMs in ETU-exposed fetal rats. Neurons in the myenteric plexus were decreased in high and low types of ARMs. Our results support a role for the Shh cascade during development of the ENS during hindgut development.
Report of a bi-allelic truncating germline mutation in TP53.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2019
DOI: 10.1007/S10689-018-0087-1
Abstract: The TP53 gene is fundamental to genomic integrity, cell cycle regulation, and apoptosis it is the most commonly mutated gene in human cancer. Heterozygous germline mutations cause the autosomal dominant cancer predisposition syndrome, Li-Fraumeni Syndrome. Homozygous germline TP53 mutations in humans are rare. We report an infant from a consanguineous family who presented with synchronous malignancies. Remarkably, he carries a homozygous germline TP53 mutation (NM_000546.4:c.52delA), predicted to cause protein truncation. The family history is consistent with Li-Fraumeni syndrome.
HER2 Polysomy in aggressive head and neck cutaneous squamous cell carcinoma
Publisher: Elsevier BV
Date: 06-2009
HG-53HYPERMUTATION AND NEOANTIGEN FORMATION PREDICT RESPONSE TO IMMUNE CHECKPOINT INHIBITION IN CHILDHOOD BIALLELIC MISMATCH REPAIR DEFICIENT GLIOBLASTOMA.
Publisher: Oxford University Press (OUP)
Date: 06-2016
Clinical presentation and endoscopic features of primary gastric Burkitt lymphoma in childhood, presenting as a protein-losing enteropathy: A case report
Publisher: Springer Science and Business Media LLC
Date: 2009
Fertility Preservation in Children and Adolescents With Cancer: Pilot of a Decision Aid for Parents of Children and Adolescents With Cancer
Publisher: JMIR Publications Inc.
Date: 28-11-2018
DOI: 10.2196/10463
Analysis of paediatric tumour types associated with hemihyperplasia in childhood
Publisher: Wiley
Date: 12-1994
DOI: 10.1111/J.1440-1754.1994.TB00724.X
Abstract: In order to further explore the relationship between hemihyperplasia in children and the occurrence of embryonal tumours of childhood, the records at St Jude Children's Research Hospital were examined for patients who presented with a malignant tumour and hemihyperplasia. Of 27 evaluable patients, 19 had Wilm's tumour and one had massive bilateral nephroblastomatosis. The tumours were more likely to occur on the side affected by hemihyperplasia than to be found contralaterally. All but five of these patients developed the tumours before the age of six. Twenty-two of the 27 patients developed tumours associated with allelic loss on chromosome band 11p15, suggesting that the locus associated with hemihyperplasia may be also located at chromosome band 11p15.
Reply to Comment on: Carboplatin Hypersensitivity Reactions in Pediatric Low Grade Glioma Are Protocol Specific and Desensitization Shows Poor Efficacy.
Publisher: Wiley
Date: 23-09-2015
DOI: 10.1002/PBC.25747
Outcome of young children with high‐grade glioma treated with irradiation‐avoiding intensive chemotherapy regimens: Final report of the Head Start II and III trials
Publisher: Wiley
Date: 22-06-2016
DOI: 10.1002/PBC.26118
Wilms Tumor Associated with the 9q22.3 Microdeletion Syndrome: 2 New Case Reports and a Review of the Literature
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2019
Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group
Publisher: Springer Science and Business Media LLC
Date: 22-11-2013
Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.CANCERGEN.2015.11.005
Abstract: Fanconi anaemia (FA) caused by biallelic mutation in FANCD1/BRCA2 is rare but carries a high risk of early onset cancer. Medulloblastoma is well described in this cohort but reports of other brain tumours are uncommon. The molecular profile of tumours from FA patients is not well reported. A glioblastoma multiforme (GBM) from a 3-year-old patient with FA and confirmed biallelic BRCA2 mutations was submitted for methylation analysis. This revealed strong clustering with the K27 mutation subgroup and copy number analysis showed gains of chromosomes 1q, 4q, part of 7q, part of 8q and 17q with resultant lifications of MDM4, CDK6, MET, MYC and PPM1D (WIP1). We also describe for the first time the germline mutation in BRCA2 c.8057T > C resulting in p.Leu2686Pro in our patient with confirmed FA. Biallelic BRCA2 mutations have predisposed to an aggressive and universally fatal subtype of childhood GBM in our patient. Copy number alterations and multiple oncogenic lifications may be secondary to inherent chromosomal instability and this raises the question of what role BRCA2 may play in the development of GBM in children without FA.
SIOP PODC–adapted treatment guidelines for craniopharyngioma in low‐ and middle‐income settings
Publisher: Wiley
Date: 13-08-2020
DOI: 10.1002/PBC.28493
Abstract: Pediatric craniopharyngioma is a rare tumor with excellent survival but significant long‐term morbidities due to the loco‐regional tumor growth or secondary to its treatment. Visual impairment, panhypopituitarism, hypothalamic damage, and behavioral changes are among the main challenges. This tumor should be managed under the care of a multidisciplinary team to determine the optimum treatment within the available resources. This is particularly important for low middle‐income countries where resources are variable. This report provides risk‐stratified management guidelines for children diagnosed with craniopharyngioma in a resource‐limited setting.
Non-Conventional Therapies in Childhood Cancer: Guidelines for Distinguishing Non-Harmful from Harmful Therapies: A Report of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology
Publisher: Wiley
Date: 2004
DOI: 10.1002/PBC.10418
Abstract: This is the 11th official document of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology, instituted in 1991. There is a tendency for some physicians to make blanket statements against the use of non-proven, non-conventional therapies, even when these therapies are not harmful. There is an equal and opposite tendency on the part of many parents to do all that they possibly can for their children, including using any non-conventional therapy they feel might do some good. The health care team must open a healthy dialogue with parents that will lead to a clear distinction between those complementary therapies that are harmful and those that are not, indeed, might even be helpful psychologically if not therapeutically.
Understanding decisions to participate in genomic medicine in children's cancer care: A comparison of what influences parents, health care providers, and the general community
Publisher: Wiley
Date: 05-06-2021
DOI: 10.1002/PBC.29101
Abstract: The emerging role of genomically guided precision medicine in pediatric cancer care presents significant clinical, practical, and ethical challenges. We investigated the factors that influence decision‐making in genomic medicine from the perspective of different stakeholders in the context of difficult‐to‐treat childhood cancer. Health care providers (HCPs), parents of childhood cancer survivors, and general community members completed an online discrete choice experiment survey. Respondents considered whether to recommend (HCPs) or choose (parents/community) a genomically guided approach to pediatric cancer treatment. Respondents completed eight choice questions varying by survival benefit, prognosis, likelihood of finding a target, quality of life (QoL), HCP arent preference, need for biopsy, cost, and who pays. Data were analyzed using a probability regression model, with findings expressed as relative importance, stated importance, and marginal willingness to pay (mWTP). One hundred twenty‐six HCPs, 130 parents, and 531 community members participated. The probability of recommending/choosing genomically guided treatment increased significantly with better prognosis, survival benefit, improvements in QoL, and decision‐making partner support. It decreased with increasing costs and if parents paid for treatment. HCPs were more responsive to all factors but were most influenced by survival outcomes, and parents and community members by QoL. In contrast to these forced choice preference results, HCPs stated they were most influenced by QoL and community members by survival. Our findings support the primacy of QoL in genomic decision‐making, with some differences across stakeholders in the other factors influencing decision‐making. These findings emphasize the need for high‐quality information giving and communication to support genomic medicine choices.
Pilocytic astrocytomas have telomere-associated promyelocytic leukemia bodies without alternatively lengthened telomeres
Publisher: Elsevier BV
Date: 12-2010
LG-22METHYLATION PROFILING OF PAEDIATRIC PILOCYTIC ASTROCYTOMA REVEALS DIFFERENCES ASSOCIATED WITH TUMOUR LOCATION AND BEHAVIOUR.
Publisher: Oxford University Press (OUP)
Date: 06-2016
LMI-01DEVELOPMENT OF CLINICAL GUIDELINES FOR THE TREATMENT OF LOW GRADE GLIOMAS IN LOWER AND LOWER MIDDLE INCOME COUNTRIES – A SIOP PODC INITIATIVE
Publisher: Oxford University Press (OUP)
Date: 06-2016
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