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The fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, multipotent progenitors or committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes indicating that the execution and maintenance of lymphoid lineage differentiation is impaired. We show that this subversion is recurrently associated with the dysregulation of repressive chromatin modifiers, notably the nucleosome remodelling and deacetylation complex, NuRD. In addition to mutations, we show differential expression or alternative splicing of NuRD members and other genes is able to reprogram the B lymphoid into a myeloid gene regulatory network. Lineage switching in MLL-AF4 leukaemia is therefore driven and maintained by defunct epigenetic regulation.Statement of SignificanceWe demonstrate diverse cellular origins of lineage switched relapse within MLL-AF4 pro-B acute leukaemia. Irrespective of the developmental origin of relapse, dysregulation of NuRD and/or other epigenetic machinery underpins fundamental lineage reprogramming with profound implications for the increasing use of epitope directed therapies in this high-risk leukaemia.

Summary Background Marked variation exists in the use of genomic data in tumour diagnosis, and optimal integration with conventional diagnostic technology remains uncertain despite several studies reporting improved diagnostic accuracy, selection for targeted treatments, and stratification for trials. Our aim was to assess the added value of molecular profiling in routine clinical practice and the impact on conventional and experimental treatments. Methods This population-based study assessed the diagnostic and clinical use of DNA methylation-based profiling in childhood CNS tumours using two large national cohorts in the UK. In the diagnostic cohort—which included routinely diagnosed CNS tumours between Sept 1, 2016, and Sept 1, 2018—we assessed how the methylation profile altered or refined diagnosis in routine clinical practice and estimated how this would affect standard patient management. For the archival cohort of diagnostically difficult cases, we established how many cases could be solved using modern standard pathology, how many could only be solved using the methylation profile, and how many remained unsolvable. Findings Of 484 patients younger than 20 years with CNS tumours, 306 had DNA methylation arrays requested by the neuropathologist and were included in the diagnostic cohort. Molecular profiling added a unique contribution to clinical diagnosis in 107 (35%; 95% CI 30–40) of 306 cases in routine diagnostic practice—providing additional molecular subtyping data in 99 cases, amended the final diagnosis in five cases, and making potentially significant predictions in three cases. We estimated that it could change conventional management in 11 (4%; 95% CI 2–6) of 306 patients. Among 195 historically difficult-to-diagnose tumours in the archival cohort, 99 (51%) could be diagnosed using standard methods, with the addition of methylation profiling solving a further 34 (17%) cases. The remaining 62 (32%) cases were unresolved despite specialist pathology and methylation profiling. Interpretation Together, these data provide estimates of the impact that could be expected from routine implementation of genomic profiling into clinical practice, and indicate limitations where additional techniques will be required. We conclude that DNA methylation arrays are a useful diagnostic adjunct for childhood CNS tumours. Funding The Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research.

Background Less than 5% of medulloblastoma (MB) patients survive following failure of contemporary radiation-based therapies. Understanding the molecular drivers of medulloblastoma relapse (rMB) will be essential to improve outcomes. Initial genome-wide investigations have suggested significant genetic divergence of the relapsed disease. Methods We undertook large-scale integrated characterization of the molecular features of rMB—molecular subgroup, novel subtypes, copy number variation (CNV), and driver gene mutation. 119 rMBs were assessed in comparison with their paired diagnostic samples (n = 107), alongside an independent reference cohort sampled at diagnosis (n = 282). rMB events were investigated for association with outcome post-relapse in clinically annotated patients (n = 54). Results Significant genetic evolution occurred over disease-course; 40% of putative rMB drivers emerged at relapse and differed significantly between molecular subgroups. Non-infant MBSHH displayed significantly more chromosomal CNVs at relapse (TP53 mutation-associated). Relapsed MBGroup4 demonstrated the greatest genetic divergence, enriched for targetable (eg, CDK amplifications) and novel (eg, USH2A mutations) events. Importantly, many hallmark features of MB were stable over time; novel subtypes (>90% of tumors) and established genetic drivers (eg, SHH/WNT/P53 mutations; 60% of rMB events) were maintained from diagnosis. Critically, acquired and maintained rMB events converged on targetable pathways which were significantly enriched at relapse (eg, DNA damage signaling) and specific events (eg, 3p loss) predicted survival post-relapse. Conclusions rMB is characterised by the emergence of novel events and pathways, in concert with selective maintenance of established genetic drivers. Together, these define the actionable genetic landscape of rMB and provide a basis for improved clinical management and development of stratified therapeutics, across disease-course.

Aims Application of advanced molecular pathology in rare tumours is hindered by low sample numbers, access to specialised expertise/technologies and tissue/assay QC and rapid reporting requirements. We assessed the feasibility of co‐ordinated real‐time centralised pathology review (CPR), encompassing molecular diagnostics and contemporary genomics (RNA‐seq/DNA methylation‐array). Methods This nationwide trial in medulloblastoma (, Application of advanced molecular pathology in rare tumours is hindered by low sample numbers, access to specialised expertise/technologies, and tissue/assay QC and rapid reporting requirements. We undertook a UK‐wide trial in medulloblastoma (

Background Occasions of self-discharge from health services before being seen by a health profession or against medical advice are often used by health systems as an indicator of quality care. People self-discharge because of factors such as dissatisfaction with care, poor communication, long waiting times, and feeling better in addition to external factors such as family and employment responsibilities. These factors, plus a lack of cultural safety, and interpersonal and institutional racism contribute to the disproportionately higher rates of Indigenous people self-discharging from hospital. This qualitative study aimed to increase understanding about the causative and contextual factors that culminate in people self-discharging and identify opportunities to improve the hospital experience for all. Methods Semi-structured interviews with five Aboriginal and/or Torres Strait Islander (hereafter, respectfully, Indigenous) people and six non-Indigenous people who had self-discharged from a major tertiary hospital in Brisbane, Australia, were audio-recorded, transcribed and thematically analysed. Results Study participants all respected hospitals’ vital role of caring for the sick, but the cumulative impact of unmet needs created a tipping point whereby they concluded that remaining in hospital would compromise their health and wellbeing. Five key categories of unmet needs were identified – the need for information; confidence in the quality of care; respectful treatment; basic comforts; and peace of mind. Although Indigenous and non-Indigenous participants had similar unmet needs, for the former, the deleterious impact of unmet needs was compounded by racist and discriminatory behaviours they experienced while in hospital. Conclusions Respectful, empathetic, person-centred care is likely to result in patients’ needs being met, improve the hospital experience and reduce the risk of people self-discharging. For Indigenous people, the ongoing legacy of white colonisation is embodied in everyday lived experiences of interpersonal and institutional racism. Racist and discriminatory behaviours experienced whilst hospitalised are thus rendered both more visible and more traumatic, and exacerbate the deleterious effect of unmet needs. Decreasing self-discharge events requires a shift of thinking away from perceiving this as the behaviour of a deviant individual, but rather as a quality improvement opportunity to ensure that all patients are cared for in a respectful and person-centred manner.

The rapid emergence of SARS-CoV-2 mutants with new phenotypic properties is a critical challenge to the control of the ongoing pandemic. B.1.1.7 was monitored in the UK through routine testing and S-gene target failures (SGTF), comprising over 90% of cases by March 2021. Now, the reverse is occurring: SGTF cases are being replaced by an S-gene positive variant, which we associate with B.1.617.2. Evidence from the characteristics of S-gene positive cases demonstrates that, following importation, B.1.617.2 is transmitted locally, growing at a rate higher than B.1.1.7 and a doubling time between 5-14 days. S-gene positive cases should be prioritised for sequencing and aggressive control in any countries in which this variant is newly detected.One-Sentence SummaryThe B.1.617.2 variant of SARS-CoV-2 is replacing B.1.1.7 and emerging as the dominant variant in England, evidenced by sustained local transmission.

Purpose Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) persist as public health issues in developing countries and among disadvantaged communities in high-income countries, with rates in Aboriginal and Torres Strait Islander peoples in Australia among the highest recorded globally. A robust evidence base is critical to support policy recommendations for eliminating RHD, but available data are fragmented and incomplete. The End RHD in Australia: Study of Epidemiology (ERASE) Project aims to provide a comprehensive database of ARF and RHD cases in Australia as a basis for improved monitoring and to assess prevention and treatment strategies. The objective of this paper is to describe the process for case ascertainment and profile of the study cohort. Patients and methods The ERASE database has been built using linked administrative data from RHD registers, inpatient hospitalizations, and death registry data from 2001 to 2017 (mid-year). Additional linked datasets are available. The longitudinal nature of the data is harnessed to estimate onset and assess the progression of the disease. To accommodate systematic limitations in diagnostic coding for RHD, hospital-only identified RHD has been determined using a purposefully developed prediction model. Results Of 132,053 patients for whom data were received, 42,064 are considered true cases of ARF or RHD in the study period. The patient population under 60 years in the compiled dataset is more than double the number of patients identified in ARF/RHD registers (12,907 versus 5049). Non-registered patients were more likely to be older, non-Indigenous, and at a later disease stage. Conclusion The ERASE Project has created an unprecedented linked administrative database on ARF and RHD in Australia. These data provide a critical baseline for efforts to end ARF/RHD in Australia. The methodological work conducted to compile this database resulted in significant improvements in the robustness of epidemiological estimates and entails valuable lessons for ARF/RHD research globally.

Background: Prevention of avoidable preterm birth in Aboriginal and Torres Strait Islander (Indigenous) families is a major public health priority in Australia. Evidence about effective, scalable strategies to improve maternal and infant outcomes is urgently needed. In 2013, a multiagency partnership between two Aboriginal Community Controlled Health Organisations and a tertiary maternity hospital co-designed a new service aimed at reducing preterm birth: ‘Birthing in Our Community’. Methods: A prospective interventional cohort study compared outcomes for women with an Indigenous baby receiving care through a new service (n = 461) to women receiving standard care (n = 563), January 2013–December 2017. The primary outcome was preterm birth (

The role of general practitioners in cancer care has expanded in recent years. However, little is known about utilization of primary health care (PHC) services by patients with cancer, particularly among socio-economically disadvantaged groups. We describe utilization of PHC services by patients with cancer, and the nature of the care provided. The study focuses on a disadvantaged group in Australia, namely Indigenous Australians. A retrospective audit of clinical records in ten PHC services in Queensland, Australia. Demographic and clinical data of Indigenous Australians diagnosed with cancer during 2010–2016 were abstracted from patient’s medical records at the PHC services. The rates of cancer-related visits were calculated using person years at risk as a denominator. A total of 138 patients’ records were audited. During 12 months following the cancer diagnosis, patients visited the PHC service on average 5.95 times per year. Frequency of visits were relatively high in remote areas and among socioeconomic disadvantaged patients (IRR = 1.87, 95%CI 1.61–2.17; IRR = 1.79, 95%CI 1.45–2.21, respectively). Over 80% of visits were for seeking attention for symptoms, wound care, and emotional or social support. Patients who did not undergo surgery, had greater comorbidity, received chemotherapy and/or radiotherapy, and male gender had significantly greater rate of visits than their counterparts. The frequency of utilization of PHC services, especially by patients with comorbidities, and the range of reasons for attendance highlights the important role of PHC services in providing cancer care. The reliance on PHC services, particularly by patients in remote and disadvantaged communities, has important implications for appropriate resourcing and support for services in these locations.

Objectives Rheumatoid arthritis (RA) is a common autoimmune disease where methotrexate is widely used as first-line therapy. The combination of RA and methotrexate are associated with lymphoproliferative disorders. RA patients with Epstein-Barr virus (EBV) have impaired T-lymphocyte function, thus allowing an overgrowth of EBV-positive lymphoblastoid cells. We examined the association of EBV with lymphoproliferative disorders in immunosuppressed RA patients, particularly those treated with methotrexate. Methods We reported two cases of RA patient with long-term methotrexate treatment who subsequently developed EBV-positive lymphoproliferative disorder, followed by a review of the relevant literature. Results Compared with normal population, RA patients have a higher risk of lymphoma with diffused large B-cell lymphoma the most common subtype. Methotrexate withdrawal can lead to lymphoma regression. Other biological therapies, such as abatacept and tocilizumab, are not associated with increased EBV-positive lymphoma diagnosis in RA patients. Conclusion The association between EBV, lymphoma and methotrexate highlight the need to consider reducing or stopping methotrexate in patients that have had stable RA for many years. This article is protected by copyright. All rights reserved.

Borderline personality disorder (BPD) is associated with high risk of suicidality and high rates of health care utilization; however, the prevalence and characteristics of BPD among inpatients admitted for suicidality are unknown. In the present study of 72 adult psychiatric inpatients admitted for suicide risk, BPD was highly prevalent (n = 31; 43.1%), but 68% were misdiagnosed by admitting providers. Compared to patients without BPD, those with BPD were significantly younger, were prescribed more psychiatric medications, were more depressed, and had greater suicide ideation. Patients with BPD were also three times as likely to be readmitted to a psychiatric hospital at 30, 90, and 180 days postdischarge for an average of almost 9 days of inpatient care per patient for the first 180 days. In this sample, BPD was highly prevalent, underdiagnosed, and associated with frequent readmissions, findings that highlight the importance of improved recognition and access to specialized treatments.

IntroductionCardiovascular disease (CVD) represents a significant burden of disease for Aboriginal and Torres Strait Islander people, a population that continues to experience a lower life expectancy than other Australians. The aim of the Better Cardiac Care Data Linkage project is to describe patient care pathways and to identify disparities in care and health outcomes between Aboriginal and Torres Strait Islander people and other Queensland residents diagnosed with CVD in the state of Queensland.MethodsThis is a population-based retrospective cohort study using linked regional, state and national health and administrative data collections to describe disparities in CVD healthcare in primary and secondary prevention settings and during hospitalisation. The CVD cohort will be identified from the Queensland Hospital Admitted Patient Data Collection for admissions that occurred between 1 July 2010 and 31 June 2016 and will include relevant International Classification of Disease codes for ischaemic heart disease, congestive heart failure, stroke, acute rheumatic fever and rheumatic heart disease. Person-level data will be linked by Data Linkage Queensland and the Australian Institute of Health and Welfare (AIHW) in accordance with ethical and public health approvals to describe the patient journey prior to, during and post the hospital admission.AnalysisThis project will focus largely on descriptive epidemiological measures and multivariate analysis of clinical care standards and outcomes for Aboriginal and Torres Strait Islander people compared with other Queenslanders, including identification of risk factors for suboptimal care and change over time. Variation in care pathways and patient outcomes will be compared by Indigenous status, sex, age group, remoteness of residence, year of index hospitalisation and socioeconomic status. Cox models for time-to-event data and mixed models or generalised estimating equations for longitudinal data will be used to measure change over time where temporal effects exist.Ethics and disseminationEthical approval has been granted by Human Research Ethics Committees of the Prince Charles Hospital (HREC/15/QPCH/289) and the AIHW (EO2016-1-233). The Northern Territory Department of Health and Menzies School of Health Research have also provided reciprocal ethical approval of the project (HREC 2019–3490). The deidentified results will be summarised in a report and shared with investigators, advisory groups, Queensland Health and key stakeholders. Findings will be disseminated through workshops, conferences and will be published in peer-reviewed journals.

Exposure to air pollution in the form of fine particulate matter ( $\mathrm{PM}_{2.5}$ ) is known to cause diseases and cancers. Consequently, the public are increasingly seeking health warnings associated with levels of $\mathrm{PM}_{2.5}$ using mobile phone applications and websites. Often, these existing platforms provide one-size-fits-all guidance, not incorporating user specific personal preferences. ¶ This study demonstrates an innovative approach using Bayesian methods to support personalised decision making for air quality. We present a novel hierarchical spatio-temporal model for city air quality that includes buildings as barriers and captures covariate information. Detailed high resolution $\mathrm{PM}_{2.5}$ data from a single mobile air quality sensor is used to train the model, which is fit using R-INLA to facilitate computation at operational timescales. A method for eliciting multi-attribute utility for individual journeys within a city is then given, providing the user with Bayes-optimal journey decision support. As a proof-of-concept, the methodology is demonstrated using a set of journeys and air quality data collected in Brisbane city centre, Australia.

Aims\ud \ud Biomarker‐driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub‐classify iMB, and proffer strategies for personalized, risk‐adapted therapies.\ud \ud \ud \ud Methods\ud \ud We characterized the iMB molecular landscape, including second‐generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387).\ud \ud \ud \ud Results\ud \ud iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second‐generation subtypes II/III/IV. Subtype II strongly associated with large‐cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very‐high‐risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4) and subtype IV tumours were standard risk (80% OS) using upfront CSI‐based therapies; randomized‐controlled trials of upfront radiation‐sparing and/or second‐line radiotherapy should be considered. Seventy‐five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non‐DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH. iMBSHH harboured two distinct subtypes (iMBSHH‐I/II). Within the discriminated favourable‐risk iMBSHH DN/MBEN patient group, iMBSHH‐II had significantly better progression‐free survival than iMBSHH‐I, offering opportunities for risk‐adapted stratification of upfront therapies. Both iMBSHH‐I and iMBSHH‐II showed notable rescue rates (56% combined post‐relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development.\ud \ud \ud \ud Conclusions\ud \ud Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup‐dependent survival models highlight opportunities for biomarker‐directed therapies.

A Correction to this paper has been published: https://doi.org/10.1038/s42003-020-01502-2.

Summary Background Disease relapse occurs in around 30% of children with medulloblastoma, and is almost universally fatal. We aimed to establish whether the clinical and molecular characteristics of the disease at diagnosis are associated with the nature of relapse and subsequent disease course, and whether these associations could inform clinical management. Methods In this multicentre cohort study we comprehensively surveyed the clinical features of medulloblastoma relapse (time to relapse, pattern of relapse, time from relapse to death, and overall outcome) in centrally reviewed patients who relapsed following standard upfront therapies, from 16 UK Children's Cancer and Leukaemia Group institutions and four collaborating centres. We compared these relapse-associated features with clinical and molecular features at diagnosis, including established and recently described molecular features, prognostic factors, and treatment at diagnosis and relapse. Findings 247 patients (175 [71%] boys and 72 [29%] girls) with medulloblastoma relapse (median year of diagnosis 2000 [IQR 1995–2006]) were included in this study. 17 patients were later excluded from further analyses because they did not meet the age and treatment criteria for inclusion. Patients who received upfront craniospinal irradiation (irradiated group; 178 [72%] patients) had a more prolonged time to relapse compared with patients who did not receive upfront craniospinal irradiation (non-irradiated group; 52 [21%] patients; p

Medulloblastoma (MB), the most common brain pediatric tumor, is a pathology composed of four molecular subgroups. Despite a multimodal treatment, 30% of the patients eventually relapse, with the fatal appearance of metastases within 5 years. The major actors of metastatic dissemination are the lymphatic vessel growth factor, VEGFC, and its receptors/co-receptors. Here, we show that VEGFC is inversely correlated to cell aggressiveness. Indeed, VEGFC decreases MB cell proliferation and migration, and their ability to form pseudo-vessel in vitro. Irradiation resistant-cells, which present high levels of VEGFC, lose the ability to migrate and to form vessel-like structures. Thus, irradiation reduces MB cell aggressiveness via a VEGFC-dependent process. Cells intrinsically or ectopically overexpressing VEGFC and irradiation-resistant cells form smaller experimental tumors in nude mice. Opposite to the common dogma, our results give strong arguments in favor of VEGFC as a negative regulator of MB growth., Manon Penco-Campillo, Yannick Comoglio et al. show that VEGFC decreases the proliferation and migration of medulloblastoma cells, as well as their ability to form pseudo vessels. Cells expressing high levels of VEGFC also form smaller tumors when subcutaneously injected into the flank of nude mice, thus highlighting a negative regulatory role for VEGFC on tumor growth.

Immune-therapy is an attractive alternative therapeutic approach for targeting central nervous system (CNS) tumors and the constituency of the Tumor Immune Microenvironment (TIME) likely to predict patient response. Here, we describe the TIME of >6000 primarily pediatric CNS tumors using a deconvolution approach (methylCIBERSORT). We produce and validate a custom reference signature defining 11 non-cancer cell types to estimate relative proportions of infiltration in a panCNS tumor cohort spanning 80 subtypes. We group patients into three broad immune clusters associated with CNS tumor types/subtypes. In cohorts of medulloblastomas (n = 2325), malignant rhabdoid tumors (n = 229) and pediatric high-grade gliomas (n = 401), we show significant associations with molecular subgroups/subtypes, mutations, and prognosis. We further identify tumor-specific immune clusters with phenotypic characteristics relevant to immunotherapy response (i.e. Cytolytic score, PDL1 expression). Our analysis provides an indication of the potential future therapeutic and prognostic possibilities of immuno-methylomic profiling in pediatric CNS tumor patients that may ultimately inform approach to immune-therapy., Here, using methylCIBERSORT, the authors characterize the tumour-immune microenvironment of paediatric central nervous system (CNS) tumours and its association with tumour type and prognosis. These findings suggest that immuno-methylomic profiling may inform immunotherapy approaches in paediatric patients with CNS tumour.

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months(1,2). We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs.(3,4)), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT(5,6), B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3. BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.

Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancer-propagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr-deficient tumours and CPCs grown in vitro, showed elevated activation of the TGFβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr-deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor (AHRR) exhibited a significantly worse prognosis compared to AHRRlow tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity.

Poor communication is an important factor contributing to health disparity. This study sought to investigate clinicians’ perspectives about communicating with Aboriginal and Torres Strait Islander patients with pain. This multi-site and mixed-methods study involved clinicians from three pain management services in Queensland, Australia. Clinicians completed a survey and participated in focus groups. Clinicians rated the importance of communication training, their knowledge, ability, and confidence in communicating with Aboriginal and Torres Strait Islander patients using a 5-point Likert scale. Rating scores were combined into low (scores 1–2); moderate (score 3) and high (scores 4–5). Informed by an interpretive description methodology, thematic analysis of focus group data was used to identify the communication needs and training preferences of clinicians. Overall (N = 64), 88% of clinicians rated the importance of communication training when supporting Aboriginal and Torres Strait Islander patients as “high”. In contrast, far fewer clinicians rated as “high” their knowledge (28%), ability (25%) and confidence (28%) in effectively communicating with Aboriginal and Torres Strait Islander patients. Thematic analysis identified three areas of need: knowledge of Aboriginal and Torres Strait Islander cultures, health beliefs, and understanding cross-cultural cues. Communication skills can be learned and training, in the form of a tailored intervention to support quality engagement with Aboriginal and Torres Strait Islander patients, should combine cultural and communication aspects with biomedical knowledge.

Disease relapse occurs in ~30% of children with medulloblastoma, and is fatal in the majority. We sought to establish whether clinico-molecular characteristics at diagnosis are associated with the nature of relapse, subsequent disease-course, and whether these associations could inform clinical management. We surveyed the clinical features of medulloblastoma relapse (time-to-relapse, pattern-of-relapse, time-to-death and overall outcome) in 247 centrally-reviewed patients who relapsed following standard-upfront-therapies. We related these to clinico-molecular features at diagnosis, prognostic factors, and first-line/relapse treatment. Patients who received upfront craniospinal irradiation (CSI-treated) displayed prolonged time-to-relapse compared to CSI naïve patients (p

Group 3 medulloblastoma (MBGroup3) is a highly aggressive tumour characterised by MYC amplification and elevated expression (17% of MBGroup3). MYC amplification in MBGroup3 confers a dismal prognosis using standard therapies, and there is an urgent unmet need for novel therapeutic approaches. The identification and targeting of MYC’s biological dependencies thus represents a promising strategy to treat MYC-MBGroup3 tumours. Three independent isogenic MYC-regulable MBGroup3 human cell-based models, in which elevated MYC expression can be directly down-regulated by doxycycline-inducible shRNAs, were developed and used initially to establish MYC-dependent growth of each model. Our novel models were then used to investigate MYC-dependent drug sensitivity, by characterising responses to a panel of candidate cancer therapeutics and small molecule inhibitors, including a high-throughput compound screen of >500 established/clinically-relevant small molecule inhibitors. This approach identified several specific, consistently observed, druggable MYC-dependencies (e.g. cell cycle regulators, DNA-damage response controllers, mitotic control machinery) with potential for the development of treatments against MYC-MBGroup3 tumours. PLK1, CHK1 and AURK were identified as prime candidate targets with consistent MYC-dependent response profiles. Subsequent validation of each candidate, by genetic and pharmacological target inhibition, confirmed their MYC-dependent effects, associated with downregulation of MYC and established target-dependent pharmacodynamic biomarkers/pathways. Results were consistent across all of our MBGroup3 models. In summary, our novel models reveal druggable MYC-associated dependencies as a feature of MBGroup3. Our findings support the development of PLK1, CHK1 and AURK inhibition as therapeutic approaches against MYC-dependent MBGroup3. Future work is now essential to validate our findings in vivo, to support the design of future clinical trials.

Malignant Rhabdoid Tumors (MRTs) are a textbook model of epigenetic dysregulation within cancer. The biallelic inactivation of a single gene SMARCB1 in >95% of MRTs is sufficient to provoke a lethal pediatric cancer. SMARCB1 encodes a core subunit of the SWI/SNF complex and inactivation results in genome-wide deregulation of gene expression/pathways. SMARCB1 loss was previously shown to impair SWI/SNF enhancer targeting at TSS-distal enhancers and a model proposed whereby mutant residual SWI/SNF complexes preferentially binds to super-enhancers over typical-enhancers; thereby inappropriately maintaining progenitor lineage processes and blocking differentiation. This model deemphasizes the action of mutant SWI/SNF complexes upon cell cycle/oncogenic processes. We performed a consensus analysis on a cohort of novel and published ChIP-seq profiles (n=6 +/- SMARCB1 models) to define consensus SMARCB1-dependent epigenetic changes. We further used parallel RNA-seq, methylation and whole-genome CRISPR screen data to emphasize the significance of specific regulatory processes from the perspective of likely biological effects and functional essentiality. We bioinformatically identified consensus super and typical-enhancers from H3K27ac peaks, multiple datasets enabled high confidence regions to be called. SMARCB1 loss did not significantly impact SWI/SNF occupancy of super-enhancers, permutation test revealed significant (p Citation Format: Emma L. Lishman-Walker, Martina A. Finetti, James P. Hacking, Matthew Selby, Yura Grabovska, Stephen Crosier, Simon Bailey, Steven C. Clifford, Daniel Williamson. Interrogation of regulatory and expression changes in Malignant Rhabdoid Tumours to identify new therapeutic approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2120.

Introduction Medulloblastoma (MB) is the most common malignant brain tumour in children. The most frequent molecular subgroup, Group 4 (MBGrp4) accounts for ~35/40% of cases, however it has the least understood underlying biology. Clinical outcomes are heterogeneous in MBGrp4 and are not accounted for by established clinico-pathological risk factors. There is now a requirement for a comprehensive study of MBGrp4, considering established clinico-pathological features and novel molecular biomarkers to enhance risk-stratification and identify novel therapeutic targets. Methods A clinically-annotated, retrospective MBGrp4 discovery cohort (n = 420) was generated from UK CCLG institutions, collaborating European centres and SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 clinical trials. Contemporary, multi-omics profiling was performed. Focal and arm level copy number aberrations (CNAs) were determined from molecular inversion probe (MIP) or DNA methylation array which additionally provided next generation non-WNT/non-SHH (Grp3/Grp4) subtype classifications. Targeted next-generation DNA sequencing was performed to overlay the mutational landscape. Survival modelling was carried out with patients >3 years old who received craniospinal irradiation. Results MBGrp4 subtypes were assigned to 88% of tumours with available data. Subtype VIII was strongly associated with i17q (p Conclusion Comprehensive genetic and epigenetic profiling in this large retrospective cohort has improved our understanding of the molecular and clinical heterogeneity within MBGrp4. Incorporation of molecular biomarkers improved risk-stratification for MBGrp4.

Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

The purpose of this study was to explore Indigenous Australian cancer survivors’ perspectives of follow-up cancer care and management.. This is a qualitative study employing individual interviews with 21 Indigenous cancer survivors (13 females, 8 males) recruited from a rural primary health service and large tertiary hospital in Brisbane, Queensland. Yarning methods were used to conduct semi-structured interviews. Yarning is a culturally appropriate, informal conversational process emphasising the importance of storytelling. Findings describe a range of ways in which follow-up cancer care is experienced with four major categories elucidated, namely: links to tertiary health services, links to primary health services, communication between tertiary and primary health services, and lost in transition. Both positive and negative experiences were described; however, the importance of timely and informative discharge information, continuity of care, good communication between tertiary and primary health services, and strong therapeutic relationships were salient issues raised by participants. These findings highlight the importance of establishing strong therapeutic relationships between patients and tertiary and primary health professionals. Also important for survivorship is provision of discharge summaries or care plans at discharge for survivors and general practitioners as well as access to a range of allied health services. Alternative means for follow-up could be investigated for regional and rural survivors to facilitate convenient and cost-effective follow-up care. Finally, provision of responsive and flexible follow-up care to cater for the diverse range of needs and preferences of cancer survivors is required. A patient navigator available across the cancer continuum could go some way to addressing this.

Malignant Rhabdoid Tumours (MRT) are the quintessential example of an epigenetic cancer. Mutation of a single gene, SMARCB1 or more rarely SMARCA4, is capable of causing one of the most aggressive and lethal cancers of early childhood and infancy. SMARCB1 encodes a core subunit of the SWI/SNF complex and its mutation evokes genome-wide downstream effects which may be counteracted therapeutically. Here we review and discuss the use of translational genomics in the study of MRT biology and the ways in which this has impacted clinical practice or may do so in the future. First, the diagnosis and definition of MRT and the transition from a histopathological to a molecular definition. Second, epigenetic and transcriptomic subgroups within MRT, their defining features and potential prognostic or therapeutic significance. Third, functional genomic studies of MRT by mouse modelling and forced re-expression of SMARCB1 in MRT cells. Fourth, studies of underlying epigenetic mechanisms (e.g. EZH2, HDACs) or deregulated kinases (e.g. PDGFR, FGFR1) and the potential therapeutic opportunities these provide. Finally, we discuss likely future directions and proffer opinion on how future translational genomics should be integrated into future biological/clinical studies to select and evaluate the best anti-MRT therapeutic agents.

ObjectivesOne of the outcomes of a medication review service is to identify and manage medication-related problems (MRPs). The most serious MRPs may result in hospitalisation, which could be preventable if appropriate processes of care were adopted. The aim of this study was to update and adapt a previously published set of clinical indicators for use in assessing the effectiveness of a medication review service tailored to meet the needs of Indigenous, please note that the use of the term ‘Indigenous’ in this manuscript includes all Aboriginal and Torres Strait Islander people and acknowledges their rich traditions and heterogenous cultures, people, who experience some of the worst health outcomes of all Australians.DesignA modified Delphi technique was used to: (i) identify additional indicators for consideration, (ii) assess whether the original indicators were relevant in the context of Indigenous health and (iii) reach consensus on a final set of indicators. Three rounds of rating were used via an anonymous online survey, with 70% agreement required for indicator inclusion.SettingThe indicators were designed for use in Indigenous primary care in Australia.ParticipantsThirteen panellists participated including medical specialists, general practice doctors, pharmacists and epidemiologists experienced in working with Indigenous patients.ResultsPanellists rated 101 indicators (45 from the original set and 57 newly identified). Of these, 41 were accepted unchanged, seven were rejected and the remainder were either modified before acceptance or merged with other indicators. A final set of 81 indicators was agreed.ConclusionsThis study provides a set of clinical indicators to be used as a primary outcome measure for medication review services for Indigenous people in Australia and as a prompt for pharmacists and doctors conducting medication reviews.Trial registration numberThe trial registration for the Indigenous Medication Review Service feasibility study is ACTRN12618000188235.

SummaryThe translocation MLL-AF4 defines a high-risk subtype of acute leukaemia which, uniquely amongst MLL translocations, is almost exclusively associated with a pro-B lymphoid phenotype. However, the ability to switch lineage at relapse allowed interrogation of the cellular origin and lineage determinants of this leukaemia. The origin of MLL-AF4 lymphoid leukaemia was commonly within a multipotent precursor population. In contrast, relapse as MLL-AF4 AML occurs from either a multipotent progenitor or a committed pro-B leukaemic clone. Lineage switching results from the dysregulation of chromatin modifiers, including the nucleosome remodelling and deacetylation complex, NuRD, completely extinguishing the B lymphoid gene regulatory network, instead establishing a myeloid epigenotype. We propose that, in contrast to mixed phenotype acute leukaemias, lineage switch in MLL-AF4 leukemia is driven and maintained by a reorganised epigenome.

Background: Cancer care involves many different healthcare providers. Delayed or inaccurate communication between specialists and general practitioners (GP) may negatively affect care. Aim: To describe the pattern and variation of communication between primary healthcare (PHC) services and hospitals and specialists in relation to the patient's cancer care. Methods: A retrospective audit of clinical records of Indigenous Australians diagnosed with cancer during 2010–2016 identified through 10 PHC services in Queensland is described. Poisson regression was used to model the dichotomous outcome availability of hospital discharge summary versus not. Results: A total of 138 patient records was audited; 115 of those patients visited the PHC service for cancer-related care after cancer diagnosis; 40.0% visited the service before a discharge summary was available, and 36.5% of the patients had no discharge summary in their medical notes. While most discharge summaries noted important information about the patient's cancer, 42.4% lacked details regarding the discharge medications regimen. Conclusions: Deficits in communication and information transfer between specialists and GP may adversely affect patient care. Indigenous Australians are a relatively disadvantaged group that experience poor health outcomes and relatively poor access to care. The low proportion of discharge summaries noting discharge medication regimen is of concern among Indigenous Australians with cancer who have high comorbidity burden and low health literacy. Our findings provide an insight into some of the factors associated with quality of cancer care, and may provide guidance for focus areas for further research and improvement efforts.

BACKGROUND:Disparity in outcomes between Indigenous and non-Indigenous people after cancer diagnosis is multifactorial, including lower cancer screening participation, later diagnosis, reduced access and uptake of cancer treatment, higher rate of comorbidities, and barriers accessing the health system. Little is known about cancer survivorship experiences. OBJECTIVE:The aim of this study was to explore Indigenous Australian cancer survivor's perspectives of cancer survivorship. METHODS:Indigenous people who completed cancer treatment 6 months to 5 years before fieldwork were recruited from a tertiary hospital and remote primary health service for this qualitative study. Data collection was guided by yarning methods, a culturally appropriate method emphasizing storytelling. Data were interpreted using a social constructionist framework. RESULTS:Thirteen women and 6 men were interviewed. Participants' past experiences contributed to their specific identity as survivors. Participants described factors affecting a positive transition from cancer patient to cancer survivor and the importance of ongoing family support in helping to manage survivorship. Finally, participants described a range of community support they received and provided to others and how this improved their cancer survivorship. CONCLUSION:Although a range of experiences are presented, this study provides evidence that the survivorship perspectives of Indigenous cancer survivors may be, in part, shared by non-Indigenous cancer survivors. IMPLICATIONS FOR PRACTICE:Acknowledging Indigenous cancer survivors' past experiences and how these influence their overall well-being is important for providing patient-centered and culturally appropriate care. Nurses and other healthcare professionals may use this knowledge to foster a range of coping strategies to assist Indigenous cancer survivors to live well.

SHH medulloblastoma patients have a variable prognosis. Infants (

TP53 pathway alterations are well-described events in medulloblastoma (MB) and are predictive of poor clinical outcome. Alterations are rare at diagnosis in Group3 (Gr3) and Group4, but enriched in Sonic Hedgehog and WNT subgroups. However, TP53 mutations are observed in all subgroups at relapse. Radiation therapy, along with surgery and chemotherapy, represents the standard of care treatment for MB. Loss of p53 function correlates with increased resistance to radiation in several cancers conferring poor survival for patients. In this study, we exposed the MYCN-driven/Trp53kiki (with tamoxifen-inducible p53 activation) Gr3 MB GEMM to a clinically relevant fractionated radiation therapy (RT) regime, to assess the role of p53 in Gr3 radio-resistance and relapse. Mice exhibiting tumour progression (bioluminescence (BLI) signal >109 photons/second) were randomized to treatment groups. A small animal radiation research platform was used to deliver CT-guided cranio-spinal irradiation (CSI) and a cranial boost (CB). Mice were followed for survival and tumour burden tracked using BLI. Bodyweight was monitored to evaluate treatment tolerability. Full dose radiation therapy (54Gy CB, 36Gy CSI, α/β=10) or dose modulation (12Gy CB, 8Gy CSI) was performed. The results showed comparable primary tumour regression in response to RT in p53 inactive and active backgrounds, followed by imminent relapse or prolonged remission respectively. No significant acute toxicity was observed. Temporary activation of p53 during RT improved tumour-free survival and decreased the incidence of relapse. In conclusion, we developed a new model which will help improve understanding of the radiobiology of high-risk MB and future preclinical trials.

Medulloblastomas harbor clinically-significant intra-tumoral heterogeneity for key biomarkers (e.g. MYC/MYCN, β-catenin). Recent studies have characterized transcriptional heterogeneity at the single-cell level, however the underlying genomic copy number and mutational architecture remains to be resolved. We therefore sought to establish the intra-tumoural genomic heterogeneity of medulloblastoma at single-cell resolution. Copy number patterns were dissected by whole-genome sequencing in 1024 single cells isolated from multiple distinct tumour regions within 16 snap-frozen medulloblastomas, representing the major molecular subgroups (WNT, SHH, Group3, Group4) and genotypes (i.e. MYC amplification, TP53 mutation). Common copy number driver and subclonal events were identified, providing clear evidence of copy number evolution in medulloblastoma development. Moreover, subclonal whole-arm and focal copy number alterations covering important genomic loci (e.g. on chr10 of SHH patients) were detected in single tumour cells, yet undetectable at the bulk-tumor level. Spatial copy number heterogeneity was also common, with differences between clonal and subclonal events detected in distinct regions of individual tumours. Mutational analysis of the cells allowed dissection of spatial and clonal heterogeneity patterns for key medulloblastoma mutations (e.g. CTNNB1, TP53, SMARCA4, PTCH1) within our cohort. Integrated copy number and mutational analysis is underway to establish their inter-relationships and relative contributions to clonal evolution during tumourigenesis. In summary, single-cell analysis has enabled the resolution of common mutational and copy number drivers, alongside sub-clonal events and distinct patterns of clonal and spatial evolution, in medulloblastoma development. We anticipate these findings will provide a critical foundation for future improved biomarker selection, and the development of targeted therapies.

Medulloblastoma relapse (rMB) occurs in 30–40% of patients and is almost universally fatal. Understanding the genomic landscape of rMB, and its relationship to disease characteristics at diagnosis, will be essential to underpin the development of improved therapeutic strategies, delivered at both diagnosis and relapse. Utilising NGS and Illumina DNA methylation arrays, we interrogated the molecular landscape of >100 rMBs, alongside matched diagnostic samples (n>80), encompassing molecular subgroup, novel subtypes, copy number (CNV) and mutational variants. Molecular subgroup and novel subtypes were stable over disease-course. The majority of genomic aberrations were also maintained (total arm-level CNVs at relapse, 60% maintained/40% acquired; deleterious/driver mutations, 75% maintained/25% acquired). Importantly, however, the landscape of alterations differed markedly at relapse, through both selective maintenance and acquisition of specific gene and pathway aberrations. For instance, we observed significant enrichment of subgroup-specific events at relapse, including focal CDK6/CDK14 amplifications (4/26 (15%) of MBGroup4) and CDKN2A/CDKN2B deletions (3/48 (6%) of MBSHH). In contrast, mutations in DNA damage response pathways were commonly enriched across all molecular subgroups, most significantly in MBSHH (~40% of rMBSHH; TP53, 9/36 (25%); ATM, 5/36 (14%)). Driver events in rMB are characterised by both selective maintenance and acquisition across disease-course, and together combine to define its actionable genetic landscape. Evaluation of their clinical and biological significance will be essential to establish their potential (i) as biomarkers to direct disease management and (ii) as a basis for therapeutic strategies targeted against medulloblastoma relapse.

The purpose of the present study is to explore the role of the general practitioners, family physicians and primary care physicians (GP) in the provision of follow-up cancer care. PubMed, MEDLINE and CINAHL were systematically searched for primary research focussing on the role of the GP from the perspective of GPs and patients. Data were extracted using a standardised form and synthesised using a qualitative descriptive approach. The initial search generated 6487 articles: 25 quantitative and 33 qualitative articles were included. Articles focused on patients’ and GPs’ perspectives of the GP role in follow-up cancer care. Some studies reported on the current role of the GP, barriers and enablers to GP involvement from the perspective of the GP and suggestions for future GP roles. Variations in guidelines and practice of follow-up cancer care in the primary health care sector exist. However, GPs and patients across the included studies supported a greater GP role in follow-up cancer care. This included greater support for care coordination, screening, diagnosis and management of physical and psychological effects of cancer and its treatment, symptom and pain relief, health promotion, palliative care and continuing normal general health care provision. While there are variations in guidelines and practice of follow-up cancer care in the primary health care sector, GPs and patients across the reviewed studies supported a greater role by the GP. Greater GP role in cancer care could improve the quality of patient care for cancer survivors. Better communication between the tertiary sector and GP across the cancer phases would enable clear delineation of roles.

s: AACR Special Conference on the Advances in Pediatric Cancer Research; September 17-20, 2019; Montreal, QC, Canada In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1,501 medulloblastomas with DNA methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class definition confidence and reproducibility. While lowest-complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (Types I-VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinicopathologic features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events among subtypes and identified highly disparate survival outcomes, further supporting their biologic and clinical relevance. Collectively, this study provides continued support for consensus groups 3 and 4, while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Further, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) that may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families. Citation Format: Tanvi Sharma, Edward C. Schwalbe, Daniel W. Williamson, Martin Sill, Volker Hovestadt, Martin Mynarek, Stefan Rutkowski, Giles W. Robinson, Amar Gajjar, Florence Cavalli, Vijay Ramaswamy, Michael D. Taylor, Janet C. Lindsey, Rebecca M. Hill, Natalie Jager, Andrey Korshunov, Debbie Hicks, Simon Bailey, Marcel Kool, Lukas Chavez, Paul A. Northcott, Stefan M. Pfister, Steven C. Clifford. Second-generation molecular subgrouping of medulloblastoma: An international meta-analysis of Group 3 and Group 4 subtypes [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B73.

© 2018 The Author(s). Background: With persisting maternal and infant health disparities, new models of maternity care are needed to meet the needs of Aboriginal and Torres Strait Islander people in Australia. To date, there is limited evidence of successful and sustainable programs. Birthing on Country is a term used to describe an emerging evidence-based and community-led model of maternity care for Indigenous families; its impact requires evaluation. Methods: Mixed-methods prospective birth cohort study comparing different models of care for women having Aboriginal and Torres Strait Islander babies at two major maternity hospitals in urban South East Queensland (2015-2019). Includes women's surveys (approximately 20 weeks gestation, 36 weeks gestation, two and six months postnatal) and infant assessments (six months postnatal), clinical outcomes and cost comparison, and qualitative interviews with women and staff. Discussion: This study aims to evaluate the feasibility, acceptability, sustainability, clinical and cost-effectiveness of a Birthing on Country model of care for Aboriginal and Torres Strait Islander families in an urban setting. If successful, findings will inform implementation of the model with similar communities. Trial registration: Australian New Zealand Clinical Trial Registry # ACTRN12618001365257. Registered 14 August 2018 (retrospectively registered).

Malignant Rhabdoid Tumours (MRT) are rare, highly aggressive childhood malignancies characterised by biallelic inactivation of gene SMARCB1. MRT may occur anywhere, most frequently in the brain (Atypical Teratoid/Rhabdoid Tumor, ATRT), kidneys and soft tissues. The aetiology of MRT regarding cell of origin and how this relates to tumour location and molecular subtype is largely unknown. Although biallelic loss of SMARCB1 is minimally sufficient to initiate tumourigenesis, we postulate that this is exquisitely dependent upon mutation in a particular type of cell of origin most likely an early pluripotent cell. We performed a meta-analysis cross-referencing expression profiles from primary MRT (n= 119), and functional models in which SMARCB1 was re-expressed (n=5 lines) with expression profiles from multiple candidate stem cell types including epithelial, embryonic, neural, mesenchymal and neural crest (n= 446) suggesting three putative candidate cell populations within the family of neural crest (NC), neural progenitor and mesenchymal stem cells. The extent of transcriptional overlap clearly reflects differences in tumor location and molecular subgroup. We developed a lentiviral CRISPR-CAS9 system to efficiently model SMARCB1 mutation in primary candidate cells of origin ex vivo. Unlike most cells tested, early neural crest cells (O9-1) tolerated SMARCB1 mutation and conferred proliferative advantage resembling human MRT molecularly and immunophenotypically. Our findings suggest NC as a potential cell of origin for MRT. We describe a system for ranking putative cells of origin and a practical means for testing SMARCB1 mutation ex vivo. Furthermore, we show evidence that subtypes within MRT have different cells of origin.

Understanding the specific molecular pathology of infant medulloblastoma (iMB) is urgently required to inform contemporary treatments, risk-stratification and clinical trials. Comprehensive analysis incorporating central clinical/ pathological review and molecular subgroup, copy number aberration and mutational status was performed in 204 iMBs (0-5yrs). iMB represented a three-subgroup disease with MB(SHH) (n=61, 40%) and MB(Grp3) (n=62, 42%) predominant. iMB(Grp3) was strongly associated with LCA (23%) and MYC amplification (19%). Presence of either feature defined a very high-risk group (10yr OS, 23%), with common rapid progression on therapy. Remaining MB(Grp3) tumours could be further stratified by chr11 status into standard (with chr11 loss, 10yr OS 84%) and high (without chr11 loss, 10yr OS, 65%) risk groups. iMB(SHH) and DN/MBEN pathology were strongly associated (75%); p

An international consensus study reported in 2012 that medulloblastoma comprises four molecular subgroups (WNT, SHH, Grp3, Grp4), each associated with distinct genomic features and clinical behaviours. Independently, recent work by three groups, using either DNA-methylation microarrays or combined DNA-methylation and expression-microarrays has defined varying intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes within subgroups. However, due to differences in patient cohorts and analytical methods, estimates of subtype number and their precise definition differed, especially within Grp3/Grp4. This study aims to establish consensus on the number and definition of Grp3/Grp4 medulloblastoma subtypes. By combining published cohorts with novel cases, we assembled a cohort of 1,506 Grp3/4 samples with methylation data, including 852 with matched DNA-methylation and transcriptome data. We analysed these cohorts using the techniques previously employed in the recent subgrouping studies (i.e. NMF, t-SNE/DBSCAN, SNF), additionally adding objective subgroup definition and robustness measures by multiple resampling of the datasets. Regardless of technique, increasing cohort size did not increase the number of identified Grp3/Grp4 subtypes beyond a maximum of eight. Through mapping of subtype calls across different analytical methods, we identified many areas of agreement between the published studies (e.g. ‘subtype VIII’ is equivalent to ‘Grp4_HighRisk’, etc.), and are working to understand remaining inconsistencies before presenting a final consensus which current data indicates is broadly consistent with the previously published subtypes I-VIII. After establishing a consensus on Grp3/4 medulloblastoma subtypes, we will identify their molecular determinants, describe their clinico-pathological correlates, and explore their translational potential and clinical relevance.

Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.