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BACKGROUND: Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. METHODS: We combined immunohistochemistry (IHC) with RNA sequencing and whole-genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Furthermore, we explored transcriptional features of immune archetypes and T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions and assessed the common adult biomarkers such as neoantigen load and TMB. RESULTS: A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. CONCLUSIONS: Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME.

Introduction: The Australian Technical Advisory Group on Immunisation and New Zealand Ministry of Health recommend all children aged >= 5 years receive either of the two mRNA COVID-19 vaccines: Comirnaty (Pfizer), available in both Australia and New Zealand, or Spikevax (Moderna), available in Australia only. Both vaccines are efficacious and safe in the general population, including children. Children and adolescents undergoing treatment for cancer and immunosuppressive therapy for non-malignant haematological conditions are particularly vulnerable, with an increased risk of severe or fatal COVID-19. There remains a paucity of data regarding the immune response to COVID-19 vaccines in immunosuppressed paediatric populations, with data suggestive of reduced immunogenicity of the vaccine in immunocompromised adults. Recommendations: Considering the safety profile of mRNA COVID-19 vaccines and the increased risk of severe COVID-19 in immunocompromised children and adolescents, COVID-19 vaccination is strongly recommended for this at-risk population. We provide a number of recommendations regarding COVID-19 vaccination in this population where immunosuppressive, chemotherapeutic and/or targeted biological agents are used. These include the timing of vaccination in patients undergoing active treatment, management of specific situations where vaccination is contraindicated or recommended under special precautions, and additional vaccination recommendations for severely immunocompromised patients. Finally, we stress the importance of upcoming clinical trials to identify the safest and most efficacious vaccination regimen for this population. Changes in management as a result of this statement: This consensus statement provides recommendations for COVID-19 vaccination in children and adolescents aged >= 5 years with cancer and immunocompromising non-malignant haematological conditions, based on evidence, national and international guidelines and expert opinion. Endorsed by

Purpose: SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. Patients and Methods: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. Results: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort (P = .74) or when patients were stratified by clinical risk (P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medu

The present study evaluated the effectiveness of an intervention intended to improve academy players’ performance under pressure. Male academy soccer players (n = 82; mean age = 14.12 years, SD = 2.28) completed a baseline pressure task producing performance scores (A) for decision making and skill execution. By completing a pressure task, players received pressure training (PT) (Wood & Wilson, 2012). Players were then randomly allocated to an intervention group (n = 41; receiving PT, three cognitive behavior workshops, and reflective diaries) or comparison group (n = 41; receiving PT only). Sixty-eight players (n = 29; intervention group; n = 39; comparison group) repeated the PT task at a six-week follow up (B), and of these, 26 (n = 15; intervention group; n = 11; PT only) also completed a re-test PT task (A) at 12-week follow up. Due to attrition at follow up, chi-square analysis was conducted across experimental groups A-B only. Analysis indicated intervention players scored significantly higher in their decision-making (p = .028) with a significant main effect of age-group on decision-making (p = .003) and skill execution (p = .005). Four players (highest scoring and lowest scoring player within intervention and comparison groups) from each academy age-group (n = 16) took part in individual interviews to explore intervention effectiveness. Thematic analysis found that some players perceived no benefits of the condition they completed, others perceived benefits to confidence, meta-cognitive skills, and challenge appraisals. Methodological implications for future pressure training interventions are presented. Lay summary: This study offers partial support in the effectiveness of contextualized pressure program to enhance elite academy players’ ability to cope with performance pressure. Some players felt the intervention had no benefits, whilst others said there were benefits for confidence, ability to understand helpful emotions and thoughts when performing unde

BACKGROUND: Management of a cleft of the lip and/or palate (CL/P) involves a multidisciplinary team approach lasting from birth to potentially postskeletal maturity. This condition is complex, with both medical and psychosocial implications that may place individuals with a cleft at higher risk of developing psychosocial problems. METHODOLOGY: A self-administered questionnaire was completed by a sample from the Western Australian cleft population comprising 3 age groups: child (n = 100), adolescent (n = 101), and adult (n = 158). RESULTS: Public speaking, being photographed, special relationships, and participation in school were identified as the areas most impacted by having a cleft. Hearing and speech were reported to have a higher importance than facial and dental appearance. Participants rated support given to them by their parents as the most important, with high ratings for treatment providers. For teasing, the impact of cleft was significantly higher among participants with cleft lip and palate for both the adolescent and adult age groups. There was little significant difference by gender across the variables, which suggests that males are just as likely to require support as females. CONCLUSION: The impact of a cleft across multiple psychosocial domains needs to be recognized and addressed as part of craniofacial team care across age groups., Nicholls, Wendy Selvey, Linda A Harper, Craig Persson, Martin Robinson, Suzanne eng Cleft Palate Craniofac J. 2018 Jan 1:1055665618769660. doi: 10.1177/1055665618769660.

BACKGROUND: Living with a cleft condition involves many years of multidisciplinary therapy, treatment, and surgical intervention. This complex process may have both physical and psychosocial long-term impacts. There is limited evidence of the psychosocial impact of cleft on individuals in Australia. AIM: To obtain an understanding of the adult patient perception of having a cleft and explore the impact of the condition on their lives. DESIGN: Qualitative methodologies at one case study site in Western Australia. Population of Interest: Adults with a cleft lip and/or palate (CL/P) who had received treatment at Princess Margaret Hospital, the only treatment center for cleft in Western Australia. METHODOLOGY: Individual in-depth semi-structured qualitative interviews were conducted and recorded and transcribed for analysis. RESULTS: Fifteen adults with a CL/P. Two main themes were identified: lived experience (with 3 subthemes: normality, support networks, and impacts in later life) and advice to others. The majority of participants reported social rejection and isolation, which occurred mostly at school and in some instances at home, but did not often last into adulthood. The greatest protective factor was the support of family and friends, which if missing during their childhood, was desired and appreciated in adulthood. CONCLUSION: Adults with CL/P may require psychosocial support from their cleft team including referral to clinicians in adult services. There is also the need for earlier psychological interventions and social programs to support those with appearance-related social difficulties., Nicholls, Wendy Persson, Martin Robinson, Suzanne Selvey, Linda eng Cleft Palate Craniofac J. 2018 Jan 1:1055665618770184. doi: 10.1177/1055665618770184.

BACKGROUND: While several studies have examined the treatment of adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL), studies of acute myeloid leukemia (AML) are rare. Using national data for Australia, we describe (i) the number and type of treatment centers caring for AYAs, (ii) induction/first-line treatments, and (iii) survival outcomes. PROCEDURE: National population-based study assessing treatment of 15- to 24-year-olds diagnosed with ALL or AML between 2007 and 2012. Treatment details were abstracted from hospital medical records. Treatment centers were classified as pediatric or adult (adult AYA-focused or other adult; and by AYA volume [high/low]). Cox proportional hazard regression analyses examined associations between treatment and overall, event-free, and relapse-free survival outcomes. RESULTS: Forty-seven hospitals delivered induction therapy to 351 patients (181 ALL and 170 AML), with 74 (21%) treated at pediatric centers; 70% of hospitals treated less than two AYA leukemia patients per year. Regardless of treatment center, 82% of ALL patients were on pediatric protocols. For AML, pediatric protocols were not used in adult centers, with adult centers using a non-COG 7+3-type induction protocol (51%, where COG is Cooperative Oncology Group) or an ICE-type protocol (39%, where ICE is idarubicin, cytarabine, etoposide). Exploratory analyses suggested that for both ALL and AML, AYAs selected for adult protocols have worse overall, event-free, and relapse-free survival outcomes. CONCLUSIONS: Pediatric protocols were commonly used for ALL patients regardless of where they are treated, indicating rapid assimilation of recent evidence by Australian hematologists. For AML, pediatric protocols were only used at pediatric centers. Further investigation is warranted to determine the optimal treatment approach for AYA AML patients.

OBJECTIVES: To determine if patients with cleft lip and/or palate (CL/P) from a Western Australian (WA) cohort were more dissatisfied with their body esteem than a normative non-cleft cohort, and identify demographic variables that may have significant associations with body esteem. DESIGN: Questionnaire study using the Body-Esteem Scale (BES) and Cleft Research Questionnaire (CRQ). PARTICIPANTS: Self-selected participants from a Western Australian CL/P population across 3 age groups (n=359). MAIN OUTCOME MEASURES: The BES is comprised of 3 factors: BE-Appearance, BE-Weight and BE-Attribution. Study mean BES factor scores were compared to normative non-cleft scores. Regression analysis was used to determine significant associations within each age group between BES factor scores and CRQ variables of: gender, self-reported body weight category, cleft type and importance of facial appearance rating. RESULTS: Study mean BE-Attribution scores were significantly lower than the normative scores and significantly lower than the mean BE-Appearance and BE-Weight factor scores within the same age groups of this study. Having a cleft type of lip and palate, being overweight, and placing a high importance on facial appearance had significant negative associations with BES scores. Maintaining a normal body weight and placing a lower level of importance on facial appearance had significant positive associations. Gender had no significant associations. CONCLUSION: In this study, the attribution aspect of body esteem had a greater negative impact on patients than their appearance and body weight. This has important implications for clinical treatment and support of patients., Nicholls, Wendy Harper, Craig Selvey, Linda A Robinson, Suzanne Hartig, Gerald Persson, Martin eng Cleft Palate Craniofac J. 2018 Apr;55(4):487-498. doi: 10.1177/1055665617730362. Epub 2017 Dec 14.

BACKGROUND: People with a cleft of the lip and/or palate (CL/P) differ from their peers due to their facial appearance, hearing and speech difficulties, and the significant time spent attending appointments and recovering from surgical interventions. These differences may impact life outcomes including occupation, income, education, relationships, psychosocial health issues, and lifestyle choices. METHODOLOGY: A self-administered questionnaire was posted to 338 former and current patients of the Cleft Lip and Palate Unit of Princess Margaret Hospital (PMH), Perth, Western Australia. RESULTS: Completed questionnaires were returned by 158 former and current patients. In comparison to the Australian Bureau of Statistics, study participants attained equivalent highest education levels, full-time annual income levels, occupational categories, employment rates, and home ownership levels. They did not marry later and demonstrated positive health-related lifestyle behaviors. However independent living was significantly delayed, and the number of romantic relationships, marriages, and children was lower, with separation/divorce rates also being lower. A key finding was that 78% of participants self-reported that they experienced at least 1 psychosocial health issue and more than half experienced anxiety and/or depression. CONCLUSION: When comparing the sociological outcomes for the study participants, the psychosocial outcomes were the areas of most concern. Further investigation is required to determine the causes for the high self-reported rates of anxiety and/or depression found in this study., Nicholls, Wendy Harper, Craig Robinson, Suzanne Persson, Martin Selvey, Linda eng Cleft Palate Craniofac J. 2018 Nov;55(10):1419-1429. doi: 10.1177/1055665618768540. Epub 2018 Apr 5.

BACKGROUND: People with a cleft of the lip and/or palate (CL/P) differ from their peers due to their facial appearance, hearing and speech difficulties, and the significant time spent attending appointments and recovering from surgical interventions. These differences may impact life outcomes including occupation, income, education, relationships, psychosocial health issues, and lifestyle choices.METHODOLOGY: A self-administered questionnaire was posted to 338 former and current patients of the Cleft Lip and Palate Unit of Princess Margaret Hospital (PMH), Perth, Western Australia.RESULTS: Completed questionnaires were returned by 158 former and current patients. In comparison to the Australian Bureau of Statistics, study participants attained equivalent highest education levels, full-time annual income levels, occupational categories, employment rates, and home ownership levels. They did not marry later and demonstrated positive health-related lifestyle behaviors. However independent living was significantly delayed, and the number of romantic relationships, marriages, and children was lower, with separation/divorce rates also being lower. A key finding was that 78% of participants self-reported that they experienced at least 1 psychosocial health issue and more than half experienced anxiety and/or depression.CONCLUSION: When comparing the sociological outcomes for the study participants, the psychosocial outcomes were the areas of most concern. Further investigation is required to determine the causes for the high self-reported rates of anxiety and/or depression found in this study.