Relationship between survivorship care plans and unmet information needs, quality of life, satisfaction with care, and propensity to engage with, and attend, follow-up care.

BACKGROUND: The impact of survivorship care plans (SCPs) on the proximal and distal outcomes of adult and childhood cancer survivors, and parent proxies, is unclear. This study aimed to determine the relationship between SCP receipt and these outcomes. METHODS: A cross-sectional survey of adult and childhood cancer survivors (and parent proxies for survivors aged younger than 16 years) across Australia and New Zealand was conducted. Multivariate regression models were fitted to measure the impact of SCP receipt on proximal (unmet information needs and propensity to engage with, and attend, cancer-related follow-up care) and distal outcomes (quality of life and satisfaction with cancer-related follow-up care) with control for cancer history and sociodemographic factors. RESULTS: Of 1123 respondents, 499 were adult cancer survivors and 624 were childhood cancer survivors (including 222 parent proxies). We found that SCP receipt was predictive of greater attendance at, and awareness of, cancer-related follow-up care (adult: odds ratio [OR], 2.46; 95% CI, 1.18-5.12; OR, 2.38; 95% CI, 1.07-5.29; child/parent: OR, 2.61; 95% CI, 1.63-4.17; OR, 1.63; 95% CI, 1.06-2.50; respectively). SCP receipt also predicted fewer unmet information needs related to "follow-up care required" and "possible late effects" (adult: OR, 0.44; 95% CI, 0.20-0.96; OR, 0.29; 95% CI, 0.13-0.64; child/parent: OR, 0.46; 95% CI, 0.30-0.72; OR, 0.57; 95% CI, 0.38-0.85; respectively). In terms of distal outcomes, SCP receipt predicted a better global quality of life for adult cancer survivors (ß, 0.08; 95% CI, -0.01-7.93), proxy-reported health-related quality of life (ß, 0.15; 95% CI, 0.44-7.12), and satisfaction with follow-up care for childhood cancer survivors (OR, 2.93; 95% CI, 1.64-5.23). CONCLUSIONS: Previous studies have shown little impact of SCPs on distal end points. Results suggest that SCPs may be beneficial to cancer survivors' proximal and distal outcomes.

Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification.

Group 4 tumours (MBGrp4) represent the majority of non-WNT/non-SHH medulloblastomas. Their clinical course is poorly predicted by current risk-factors. MBGrp4 molecular substructures have been identified (e.g. subgroups/cytogenetics/mutations), however their inter-relationships and potential to improve clinical sub-classification and risk-stratification remain undefined. We comprehensively characterised the paediatric MBGrp4 molecular landscape and determined its utility to improve clinical management. A clinically-annotated discovery cohort (n = 362 MBGrp4) was assembled from UK-CCLG institutions and SIOP-UKCCSG-PNET3, HIT-SIOP-PNET4 and PNET HR + 5 clinical trials. Molecular profiling was undertaken, integrating driver mutations, second-generation non-WNT/non-SHH subgroups (1-8) and whole-chromosome aberrations (WCAs). Survival models were derived for patients ≥ 3 years of age who received contemporary multi-modal therapies (n = 323). We first independently derived and validated a favourable-risk WCA group (WCA-FR) characterised by ≥ 2 features from chromosome 7 gain, 8 loss, and 11 loss. Remaining patients were high-risk (WCA-HR). Subgroups 6 and 7 were enriched for WCA-FR (p < 0·0001) and aneuploidy. Subgroup 8 was defined by predominantly balanced genomes with isolated isochromosome 17q (p < 0·0001). While no mutations were associated with outcome and overall mutational burden was low, WCA-HR harboured recurrent chromatin remodelling mutations (p = 0·007). Integration of methylation and WCA groups improved risk-stratification models and outperformed established prognostication schemes. Our MBGrp4 risk-stratification scheme defines: favourable-risk (non-metastatic disease and (i) subgroup 7 or (ii) WCA-FR (21% of patients, 5-year PFS 97%)), very-high-risk (metastatic disease with WCA-HR (36%, 5-year PFS 49%)) and high-risk (remaining patients; 43%, 5-year PFS 67%). These findings validated in an independent MBGrp4 cohort (n = 668). Importantly, our findings demonstrate that previously established disease-wide risk-features (i.e. LCA histology and MYC(N) amplification) have little prognostic relevance in MBGrp4 disease. Novel validated survival models, integrating clinical features, methylation and WCA groups, improve outcome prediction and re-define risk-status for ~ 80% of MBGrp4. Our MBGrp4 favourable-risk group has MBWNT-like excellent outcomes, thereby doubling the proportion of medulloblastoma patients who could benefit from therapy de-escalation approaches, aimed at reducing treatment induced late-effects while sustaining survival outcomes. Novel approaches are urgently required for the very-high-risk patients.

ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors.

Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.

A Primary Spinal Nongerminomatous Germ Cell Tumor With Multiple Intracranial Metastases in a Toddler.

Central nervous system germ cell tumors (CNS-GCTs) comprise 4% of all pediatric CNS tumors, with one third being nongerminomatous GCT (CNS-NG-GCT) type. The majority of these tumors arise in the intracranial compartment with 20% having drop metastases in the spine. We present a rare case of a 2-year-old boy with a primary intradural-extramedullary NG-GCT arising from the lumbosacral spine with a trifecta of unfavorable features, that is, young age, alpha-feto protein >1000 ng/mL, and disseminated disease within the cranium. Owing to his young age, he was treated with chemotherapy alone, avoiding radiation. His tumor marker (alpha-feto protein) declined from 8468 to 10 k-U/L over 8 weeks, and he remained in remission at the last follow-up. This atypical presentation of an intradural-extramedullary tumor with cranial dissemination in a childhood NG-GCT has yet to be described in the literature. Here we use this opportunity to highlight the treatment strategies and challenges in this unique clinical case.

Methylphenidate improves cognitive function and health-related quality of life in survivors of childhood brain tumours.

OBJECTIVES: The growing population of survivors of childhood brain tumors present the challenge of long-term quality of survival. The domains most affected by tumor and treatment are those implicated in development of typical intellectual functions: attention, working memory, and processing speed, with consequent effects upon function and quality of life. In this paper we present service evaluation data on the 12-month effect upon processing speed, visual and auditory attentional domains in 29 patients receiving methylphenidate aged 5-16 years (Mean=10.6). METHODS: Patients received immediate-release methylphenidate and were converted to modified-release as appropriate. Mean optimal dose of immediate-release methylphenidate was 0.34 mg/kg per dose (range 0.2-0.67). RESULTS: Patients showed a significant positive impact of methylphenidate on attention in all tests of selective visual attention from the Test of Everyday Attention for Children 2. A significant improvement was also shown on response time. Significant change was not found on psychometric measures of sustained auditory or visual attention, or selective auditory attention. Ratings of Health-Related Quality of Life showed a positive benefit of methylphenidate at 12 months. Side effects were minimal and not statistically significant. CONCLUSIONS: Survivors of childhood brain tumor with attentional and processing speed deficit show clinical benefit from methylphenidate.

Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma.

Relapse is the leading cause of death in patients with medulloblastoma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse. SIGNIFICANCE: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.

Medulloblastoma group 3 and 4 tumors comprise a clinically and biologically significant expression continuum reflecting human cerebellar development.

Medulloblastoma is currently subclassified into distinct DNA methylation subgroups/subtypes with particular clinico-molecular features. Using RNA sequencing (RNA-seq) in large, well-annotated cohorts of medulloblastoma, we show that transcriptionally group 3 and group 4 medulloblastomas exist as intermediates on a bipolar continuum between archetypal group 3 and group 4 entities. Continuum position is prognostic, reflecting a propensity for specific DNA copy-number changes, and specific switches in isoform/enhancer usage and RNA editing. Examining single-cell RNA-seq (scRNA-seq) profiles, we show that intratumoral transcriptional heterogeneity along the continuum is limited in a subtype-dependent manner. By integrating with a human scRNA-seq reference atlas, we show that this continuum is mirrored by an equivalent continuum of transcriptional cell types in early fetal cerebellar development. We identify distinct developmental niches for all four major subgroups and link each to a common developmental antecedent. Our findings show a transcriptional continuum arising from oncogenic disruption of highly specific fetal cerebellar cell types, linked to almost every aspect of group 3/group 4 molecular biology and clinico-pathology.

"I Feel Happy Again": Methylphenidate Supports Health-Related Quality of Life in Survivors of Pediatric Brain Tumor.

BACKGROUND: The deleterious impact upon the cognitive development of survivors of pediatric brain tumors (PBT) is well documented. Impairment in cognitive function is associated with reduced health-related quality of life (HRQoL), such that survivors of PBT report difficulties in multiple distinct domains and an overall reduced quality of life. Studies of the use of methylphenidate in survivors of PBT to alleviate impairment in cognitive functions have shown some success. The current study aimed to explore the impact upon HRQoL in survivors of PBT of a trial of psychostimulant medication. METHOD: Data were collected from 12 pediatric neuro-oncology patients aged 7-17 years receiving methylphenidate treatment. HRQoL was measured using the PEDS QL quality of life self-report measure and a semi-structured questionnaire-based interview. RESULTS: Analyses of data demonstrates benefit to five domains associated with HRQoL: social, emotional, academic, physical, and cognition. CONCLUSION: Survivors of PBT reported favorable views as to the subjective benefit of methylphenidate on post-treatment impairment of HRQoL. This medication may offer the potential for restoration of a sense of 'normality' of function following cancer treatment in this clinical population.

Single-cell DNA sequencing identifies risk-associated clonal complexity and evolutionary trajectories in childhood medulloblastoma development.

We reconstructed the natural history and temporal evolution of the most common childhood brain malignancy, medulloblastoma, by single-cell whole-genome sequencing (sc-WGS) of tumours representing its major molecular sub-classes and clinical risk groups. Favourable-risk disease sub-types assessed (MBWNT and infant desmoplastic/nodular MBSHH) typically comprised a single clone with no evidence of further evolution. In contrast, highest risk sub-classes (MYC-amplified MBGroup3 and TP53-mutated MBSHH) were most clonally diverse and displayed gradual evolutionary trajectories. Clinically adopted biomarkers (e.g. chromosome 6/17 aberrations; CTNNB1/TP53 mutations) were typically early-clonal/initiating events, exploitable as targets for early-disease detection; in analyses of spatially distinct tumour regions, a single biopsy was sufficient to assess their status. Importantly, sc-WGS revealed novel events which arise later and/or sub-clonally and more commonly display spatial diversity; their clinical significance and role in disease evolution post-diagnosis now require establishment. These findings reveal diverse modes of tumour initiation and evolution in the major medulloblastoma sub-classes, with pathogenic relevance and clinical potential.

Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse.

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.

Findings From a Provider-Led, Mindfulness-Based, Internet-Streamed Yoga Video Addressing the Psychological Outcomes of Breast Cancer Survivors.

The aim of this study was to explore the psychological outcomes of a mindfulness-based Internet-streamed yoga video in breast cancer survivors. A one-group, repeated-measures, purposive sample using a directed qualitative descriptive and convergent mixed-methods approach was used. Participants were recruited from breast oncology practices across 2 settings in the northeastern United States in April 2019. Education about the video was provided, and the link to the video was sent to participants. Demographic information, Knowing Participation in Change Short Form (KPCSF), Short Warwick-Edinburgh Mental Well-being Scale (WEMWBS), and the Generalized Anxiety Distress Scale (GAD-7) were obtained at baseline and at 2 and 4 weeks. A semistructured interview was conducted at 4 weeks. Thirty-five women (mean age = 56 years) participated. A one-group, repeated-measures analysis of variance indicated statistically significant changes occurred in all measures between week 0 and week 4: decreased GAD (t = -2.97, P = .004), improved WEMWBS (t = 2.52, P = .008), and increased KPC (t = 2.99, P = .004). Qualitative findings suggest the overall experience of the video was positive and the women would recommend its use to others. Improvements in all psychological measures were achieved with video use. Findings indicate an improvement in psychological measures and support the theory of Knowing Participation in Change. This work further contributes to accessible, flexible interventions available through the Internet and/or mobile applications aimed at improving breast cancer survivorship.

Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment.

Relapsed medulloblastoma (rMB) accounts for a considerable, and disproportionate amount of childhood cancer deaths. Recent advances have gone someway to characterising disease biology at relapse including second malignancies that often cannot be distinguished from relapse on imaging alone. Furthermore, there are now multiple international early-phase trials exploring drug-target matches across a range of high-risk/relapsed paediatric tumours. Despite these advances, treatment at relapse in pre-irradiated patients is typically non-curative and focuses on providing life-prolonging and symptom-modifying care that is tailored to the needs and wishes of the individual and their family. Here, we describe the current understanding of prognostic factors at disease relapse such as principal molecular group, adverse molecular biology, and timing of relapse. We provide an overview of the clinical diagnostic process including signs and symptoms, staging investigations, and molecular pathology, followed by a summary of treatment modalities and considerations. Finally, we summarise future directions to progress understanding of treatment resistance and the biological mechanisms underpinning early therapy-refractory and relapsed disease. These initiatives include development of comprehensive and collaborative molecular profiling approaches at relapse, liquid biopsies such as cerebrospinal fluid (CSF) as a biomarker of minimal residual disease (MRD), modelling strategies, and the use of primary tumour material for real-time drug screening approaches.

Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study.

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<0·0001). In the non-irradiated group, craniospinal irradiation at relapse (hazard ratio [HR] 0·27, 95% CI 0·11-0·68) and desmoplastic/nodular histology (0·23, 0·07-0·77) were associated with prolonged time to death after relapse, MYC amplification was associated with a reduced overall survival (23·52, 4·85-114·05), and re-resection at relapse was associated with longer overall survival (0·17, 0·05-0·57). In the irradiated group, patients with MBGroup3 tumours relapsed significantly more quickly than did patients with MBGroup4 tumours (median 1·34 [0·99-1·89] years vs 2·04 [1·39-3·42 years; p=0·0043). Distant disease was prevalent in patients with MBGroup3 (23 [92%] of 25 patients) and MBGroup4 (56 [90%] of 62 patients) tumour relapses. Patients with distantly-relapsed MBGroup3 and MBGroup4 displayed both nodular and diffuse patterns of disease whereas isolated nodular relapses were rare in distantly-relapsed MBSHH (1 [8%] of 12 distantly-relapsed MBSHH were nodular alone compared with 26 [34%] of 77 distantly-relapsed MBGroup3 and MBGroup4). In MBGroup3 and MBGroup4, nodular disease was associated with a prolonged survival after relapse (HR 0·42, 0·21-0·81). Investigation of second-generation MBGroup3 and MBGroup4 molecular subtypes refined our understanding of heterogeneous relapse characteristics. Subtype VIII had prolonged time to relapse and subtype II had a rapid time from relapse to death. Subtypes II, III, and VIII developed a significantly higher incidence of distant disease at relapse whereas subtypes V and VII did not (equivalent rates to diagnosis). INTERPRETATION: This study suggests that the nature and outcome of medulloblastoma relapse are biology and therapy-dependent, providing translational opportunities for improved disease management through biology-directed disease surveillance, post-relapse prognostication, and risk-stratified selection of second-line treatment strategies. FUNDING: Cancer Research UK, Action Medical Research, The Tom Grahame Trust, The JGW Patterson Foundation, Star for Harris, The Institute of Child Health - Newcastle University - Institute of Child Health High-Risk Childhood Brain Tumour Network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK).

Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity.

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.

Survivorship Care Plans in Cancer: A Meta-Analysis and Systematic Review of Care Plan Outcomes.

BACKGROUND: The Institute of Medicine recommends that survivorship care plans (SCPs) be included in cancer survivorship care. Our meta-analysis compares patient-reported outcomes between SCP and no SCP (control) conditions for cancer survivors. Our systematic review examines the feasibility of implementing SCPs from survivors' and health care professionals' perspectives and the impact of SCPs on health care professionals' knowledge and survivorship care provision. METHODS: We searched seven online databases (inception to April 22, 2018) for articles assessing SCP feasibility and health care professional outcomes. Randomized controlled trials comparing patient-reported outcomes for SCP recipients versus controls were eligible for the meta-analysis. We performed random-effects meta-analyses using pooled standardized mean differences for each patient-reported outcome. RESULTS: Eight articles were eligible for the meta-analysis (n = 1,286 survivors) and 50 for the systematic review (n = 18,949 survivors; n = 3,739 health care professionals). There were no significant differences between SCP recipients and controls at 6 months postintervention on self-reported cancer and survivorship knowledge, physical functioning, satisfaction with information provision, or self-efficacy or at 12 months on anxiety, cancer-specific distress, depression, or satisfaction with follow-up care. SCPs appear to be acceptable and potentially improve survivors' adherence to medical recommendations and health care professionals' knowledge of survivorship care and late effects. CONCLUSION: SCPs appear feasible but do not improve survivors' patient-reported outcomes. Research should ascertain whether this is due to SCP ineffectiveness, implementation issues, or inappropriate research design of comparative effectiveness studies. IMPLICATIONS FOR PRACTICE: Several organizations recommend that cancer survivors receive a survivorship care plan (SCP) after their cancer treatment; however, the impact of SCPs on cancer survivors and health care professionals is unclear. This systematic review suggests that although SCPs appear to be feasible and may improve health care professionals' knowledge of late effects and survivorship care, there is no evidence that SCPs affect cancer survivors' patient-reported outcomes. In order to justify the ongoing implementation of SCPs, additional research should evaluate SCP implementation and the research design of comparative effectiveness studies. Discussion may also be needed regarding the possibility that SCPs are fundamentally ineffective.

DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study.

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.

Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes.

In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and 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 1501 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 the 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 clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological 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. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which 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.

Implications of Ankyloglossia on Breastfeeding.

OBJECTIVE: The purpose of this integrative review was to synthesize the literature on the relationship between infant breastfeeding and ankyloglossia. DATA SOURCES: The search terms tongue-tie or ankyloglossia and breastfeeding were used via CINAHL, Ovid MEDLINE, Health Reference Academic, and PsycINFO. Primary research articles and clinical reviews were considered in the search parameters. STUDY SELECTION: Searches yielded 201 articles written in English and published between 1999 and 2018. After screening, 50 full-text articles were assessed for eligibility, 43 of which were omitted for irrelevance. Three qualitative and four quantitative studies remained for inclusion in the review. DATA EXTRACTION: Studies were reviewed for information on the relationship between ankyloglossia and breastfeeding. Studies examining results of ankyloglossia treatment were omitted. Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. DATA SYNTHESIS: Analysis revealed a varied degree of difficulties with breastfeeding when the infant has ankyloglossia. Prevalence is uncertain due to lack of universal screening guidelines, and infrequent use of screening tools. No studies were found that examined psychological ramifications of feeding difficulties with ankyloglossia. There are no validated screening tools for ankyloglossia. CONCLUSION: More research is necessary on effects of breastfeeding difficulties of infants with ankyloglossia on the mother-infant relationship. A reliable screening tool needs to be developed and validated. Education for nurses to assess infants with ankyloglossia in a systematic fashion should be explored. Investigation of psychological sequelae, including maternal stress, postpartum depression, and mother-infant bonding is an important next step in the research of infants with ankyloglossia.

Predictors of objectively measured physical activity in 12-month-old infants: A study of linked birth cohort data with electronic health records.

BACKGROUND: Physical activity (PA) levels are associated with long-term health, and levels of PA when young are predictive of adult activity levels. OBJECTIVES: This study examines factors associated with PA levels in 12-month infants. METHOD: One hundred forty-one mother-infant pairs were recruited via a longitudinal birth cohort study (April 2010 to March 2013). The PA level was collected using accelerometers and linked to postnatal notes and electronic medical records via the Secure Anonymised Information Linkage databank. Univariable and multivariable linear regressions were used to examine the factors associated with PA levels. RESULTS: Using univariable analysis, higher PA was associated with the following (P value less than 0.05): being male, larger infant size, healthy maternal blood pressure levels, full-term gestation period, higher consumption of vegetables (infant), lower consumption of juice (infant), low consumption of adult crisps (infant), longer breastfeeding duration, and more movement during sleep (infant) but fewer night wakings. Combined into a multivariable regression model (R2  = 0.654), all factors remained significant, showing lower PA levels were associated with female gender, smaller infant, preterm birth, higher maternal blood pressure, low vegetable consumption, high crisp consumption, and less night movement. CONCLUSION: The PA levels of infants were strongly associated with both gestational and postnatal environmental factors. Healthy behaviours appear to cluster, and a healthy diet was associated with a more active infant. Boys were substantially more active than girls, even at age 12 months. These findings can help inform interventions to promote healthier lives for infants and to understand the determinants of their PA levels.