Paediatrics (RCH) - Research Publications
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ItemMapping Pediatric Oncology Clinical Trial Collaborative Groups on the Global Stage(LIPPINCOTT WILLIAMS & WILKINS, 2022)PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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ItemSIOP PODC Adapted treatment guidelines for low grade gliomas in low and middle income settings(WILEY, 2017-12)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.
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ItemNo Preview AvailableHGG-20. DIAGNOSTIC AND BIOLOGICAL ROLE OF METHYLATION PATTERNS IN REPLICATION REPAIR DEFICIENT HIGH GRADE GLIOMAS(Oxford University Press (OUP), 2020-12-04)Abstract Replication repair deficiency (RRD) is an important driving mechanism of pediatric high grade glioma (pHGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although pHGG present specific patterns of DNA methylation corresponding to driving oncogenic processes, methylation patterns have not been well studied in RRD tumors. We analyzed 52 RRD pHGG using either 450k or 850k methylation arrays. These arrays were compared with 234 PHGG driven by other genetic or epigenetic mechanisms and 10 additional pHGG samples known to be hypermutant. RRD pHGG displayed a methylation pattern corresponding to specific secondary mutations such as IDH1 and H3K27M. Strikingly, RRD pHGG lacking these known secondary mutations largely clustered together with a poorly described group previously labelled Wild type-C. Most of the hypermutant tumors clustered in a similar location suggesting undiagnosed RRD may be a driving force for tumors clustering in this location. Analysis of methylation patterns revealed that RRD pHGG displayed a unique CpG Island Demethylator Phenotype in contrast to the Methylator Phenotype described in other cancers. This effect was most concentrated at gene promotors. Prominent demethylation was observed in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism and cellular organization. These data suggest that methylation profiles may provide diagnostic information for the detection of RRD pHGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide novel impact of hypermutation and RRD on the cancer epigenome.
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ItemNo Preview AvailableCOVD-04. CHARACTERISTICS OF SARS-COV-2 IN 64 CHILDREN WITH CNS TUMORS: A REPORT FROM THE SIOP/ST. JUDE CHILDREN’S RESEARCH HOSPITAL (SJCRH) GLOBAL COVID-19 CHILDHOOD CANCER REGISTRY(Oxford University Press (OUP), 2020-12-04)Abstract BACKGROUND The GCCCR is a collaboration between SIOP and SJCRH to describe the natural history of SARS-CoV-2 in children with cancer across the world. METHODS The GCCCR is a deidentified registry of patients <19 years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30-days and 60-days post infection. RESULTS As of August 10th 2020, the GCCCR included 730 cases from 35 countries, including 64 children with CNS tumors (8.8%) from 17 countries. The most frequent diagnoses were embryonal tumors (31.2%) and low-grade glioma (17.2%). Thirty-nine (60.9%) children were asymptomatic from infection, while 19 (29.7%) patients required hospital admission and 2 (6.3%) transferred to the intensive care unit. There was a significant association between infection severity and ANC <500 (p=0.04). At the time of infection, 44 (68.8%) patients were undergoing cancer-directed therapy. Thirty-two cases have follow-up data. No modification in cancer-directed therapy occurred in 11 (34.4%) patients, while chemotherapy was modified in 6 (18.8%), radiotherapy delayed in 2 (6.3%), and surgery postponed in 1 (3.1%). No patients died from SARS-CoV-2 infection, although 2 died from non-COVID-19 related causes. CONCLUSION The frequency and severity of COVID infection among children with CNS tumors appears to be proportionally lower compared to other children with cancer. Although this is the largest cohort of patients reported to date, additional insight is needed, including the effects of treatment modifications on outcomes.
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ItemRARE-15. EARLY PSEUDOPROGRESSION POST-RADIATION IN PAEDIATRIC HIGH-GRADE GLIOMA PATIENTS WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY: TWO CASE REPORTS FROM A SINGLE CENTRE(Oxford University Press (OUP), 2020-12-04)Abstract BACKGROUND Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition syndrome caused by biallelic mutations in the mismatch repair pathway, and high-grade glioma (HGG) constitute the most prevalent brain tumours. Pseudoprogression alludes to radiological changes that mimic tumour progression, but are in fact due to other causes such as therapy related inflammation. It can occur as early as three months post treatment. To our knowledge, its characteristics in CMMRD patients has not been reported. METHODS We retrospectively identified seven patients with CMMRD and history of HGG at The Royal Children’s Hospital, Melbourne from 2005 to 2019. Our objective was to review the characteristics of pseudoprogression in this cohort. RESULTS Out of the seven patients, two with constitutional loss of PMS2 demonstrated evidence of pseudoprogression. Patient 1 presented at 16 years old with a cerebellar anaplastic astrocytoma. She developed clinical and radiological progression within two weeks of starting radiotherapy, persisting up to four months after completion. However, six months post radiation she improved without intervention and the tumour remains stable five years post therapy. Patient 2 presented at 17 years old with a midbrain anaplastic astrocytoma, and showed signs of progression four weeks after completion of radiotherapy. She was then treated with Bevacizumab, an anti-VEGFA antibody with remarkable response. She subsequently received Nivolumab, a checkpoint inhibitor with ongoing stable disease for four months. CONCLUSION Our findings showed that pseudoprogression can occur early in the treatment course in CMMRD patients. Identification of this entity is important for appropriate clinical management.
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ItemPATH-09. SJMB12 CLINICAL TRIAL: DISCREPANCY BETWEEN LOCAL AND CENTRAL PATHOLOGY IN ASSESSING ANAPLASTIC MEDULLOBLASTOMA – REPORT FROM A SINGLE SITE EXPERIENCE(Oxford University Press (OUP), 2020-12-04)Abstract INTRODUCTION SJMB12 is a phase 2 clinical trial led by the St. Jude Children’s Research Hospital (St. Jude) that enrolls patients with medulloblastoma based on their biological subgroup. The large cell/anaplastic (LCA) histologic variant has been identified as an important independent risk factor associated with poor outcome. However, the histologic criteria for LCA is subjective, making the distinction between anaplastic and non-anaplastic medulloblastoma difficult in some cases. METHODS Pathological central review was performed at St. Jude. For all patients enrolled in the study to date, concordance was assessed between the initial and central review diagnosis and histologic variant calls made at the Royal Children’s Hospital Melbourne (RCH) and at St. Jude, respectively. RESULTS Since the SJMB12 clinical trial opened locally in 2014, 34 patients were enrolled, and 31 were eligible for this retrospective study. A total of 12 (39%) cases with discordance were identified. The most frequent disagreement was between the designation of LCA (10 cases, 32%). In five cases the tumour was not designated as LCA variant locally. In five cases the initial designation of LCA was refuted centrally. Overall, this led to a change of treatment stratum for four patients (13%). CONCLUSION A high discordance rate exists between neuropathologists in the designation of LCA variant. Differences in interpretation of the subjective histologic criteria and inconsistencies in the material submitted for central review contributed to the discordance. Incorporation of more objective histologic criteria and implementation of unbiased diagnostic tools may improve the generalisability of future risk stratification.
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ItemLINC-10. SIOP PODC ADAPTED TREATMENT GUIDELINES FOR CRANIOPHARYNGIOMA IN LOW- AND MIDDLE-INCOME SETTINGS(Oxford University Press (OUP), 2020-12-04)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 amongst 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 (LMICs) where resources are variable. We provide a risk-stratified management guideline for children diagnosed with craniopharyngioma in a resource limited setting based on the service levels describing the facilities and personnel required for management as previously specified by the Pediatric Oncology in Developing Countries (PODC) committee of The International Society of Pediatric Oncology (SIOP). A multi-disciplinary group of neurosurgeons, radiation and pediatric oncologists, radiologists, pediatric endocrinologists and an ophthalmologist with experience in managing children with craniopharyngioma in LMIC setting was formed and carried online meetings to form a consensus guideline. The clinical characteristics (including the visual and endocrine presentations), suggestive radiological features as well as potential treatment options including surgery, radiotherapy and intra-cystic therapies were discussed in depth and in relation to available resources. In addition, hormonal management, pre- and post-operative PICU care and expected future complications related to craniopharyngioma and to follow up these children were discussed and documented in the guideline. We believe this guideline is a useful reference for health care providers in LMIC.
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ItemEPEN-36. THE TREATMENT OUTCOME OF PAEDIATRIC SUPRATENTORIAL C11ORF95-RELA FUSED EPENDYMOMA: A COMBINED REPORT FROM E-HIT SERIES AND AUSTRALIAN NEW ZEALAND CHILDREN’S HAEMATOLOGY/ONCOLOGY GROUP(Oxford University Press (OUP), 2020-12-04)Abstract AIM Advances in molecular classification of paediatric ependymoma have been pivotal in improving risk stratification and understanding of this disease. C11orf95-RELA fused supratentorial ependymoma (ST-EPN) have been reported to have a poor outcome, with 10-year overall survival (OS) of 49% and progression free survival (PFS) of 19%. A cohort of patients from multiple international institutions with molecularly confirmed C11orf95-RELA fused ST-EPN were reviewed to assess their disease behaviour. METHOD: We reviewed patients with molecularly determined C11orf95-RELA supratentorial ependymoma diagnosed between 1999 – 2019. Demographic information, extent of surgical resection, use of radiotherapy and/or chemotherapy, disease recurrence, treatment at recurrence and clinical outcome data was collected. PFS and OS of all patients were estimated using Kaplan-Meier method. RESULTS A total of 76 ST-EPN patients with C11orf95-RELA fusion were identified (median age: 7 years3 months, range: 5 months – 18 years7 months). 58 patients (76.3%) had complete surgical resection. 70 patients(92.1%) received radiotherapy. 55 patients(72.3%) received chemotherapy. The 10-year OS of C11orf95-RELA fused ST-EPN was 72.4% and PFS was 63.8%. In contrast, ST-EPN at a single institution with unconfirmed molecular status had an OS of 61.1% and PFS of 34.9%. CONCLUSION Detailed molecular analysis identified distinct subgroups of patients with ST-EPN. Patients from this cohort with C11orf95-RELA methylation profiles had a significantly higher OS compared to previous reports and those with unconfirmed fusion status, emphasising the critical importance of complete molecular profiling to assist in treatment decision making. Complete molecular analysis in future prospective cohorts is essential for accurate risk stratification and treatment selection.
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ItemNo Preview AvailableThe Global COVID-19 Observatory and Resource Center for Childhood Cancer: A response for the pediatric oncology community by SIOP and St. Jude Global(WILEY, 2021-05)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.