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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

The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

Background: The timing and necessity of repeated blood cultures (BCs) in children with cancer and febrile neutropenia (FN) are unknown. We evaluated the diagnostic yield of BCs collected pre- and post-empiric FN antibiotics. Method(s): Data collected prospectively from the Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study were used. Diagnostic yield was calculated as the number of FN episodes with a true bloodstream infection (BSI) detected divided by the number of FN episodes that had a BC taken. Result(s): A BSI was identified in 13% of 858 FN episodes. The diagnostic yield of pre-antibiotic BCs was higher than of post-antibiotic cultures (12.3% vs 4.4%, P <. 001). Two-thirds of the post-antibiotic BSIs were associated with a new episode of fever or clinical instability, and only 2 new BSIs were identified after 48 hours of empiric antibiotics and persistent fever. A contaminated BC was identified more frequently in post-antibiotic cultures. Conclusion(s): In the absence of new fever or clinical instability, BCs beyond 48 hours of persistent fever have limited yield. Opportunity exists to optimize BC collection in this population and reduce the burden of unnecessary tests on patients, healthcare workers, and hospitals.Copyright © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

BACKGROUND: The impact febrile neutropenia (FN) has on the health-related quality of life (HRQoL) of children with cancer and their families is poorly understood. We sought to characterize the course of child and parent HRQoL during and following FN episodes. METHOD: Data on HRQoL were collected in the multisite Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study. Participants were enrolled between November 2016 to January 2018. The Child Health Utility (CHU9D) was used to assess HRQoL in children (N = 167 FN events) and the Assessment of Quality of Life (AQoL-8D) was used to assess HRQoL parents (N = 218 FN events) at three time points: 0-3 days, 7-days and 30-days following the onset of FN. Group-based trajectory modeling (GBTM) was used to characterize the course of HRQoL. FINDINGS: For children, three distinct groups were identified: persistently low HRQoL over the 30-day course of follow-up (chronic: N = 78/167; 47%), increasing HRQoL after the onset of FN to 30 days follow-up (recovering: N = 36/167; 22%), and persistently high HRQoL at all three timepoints (resilient: N = 53/167; 32%). Applying these definitions, parents were classified into two distinct groups: chronic (N = 107/218, 49%) and resilient (N = 111/218, 51%). The child being male, having solid cancer, the presence of financial stress, and relationship difficulties between the parent and child were significant predictors of chronic group membership for both parents and children. Children classified as high-risk FN were significantly more likely to belong to the recovery group. Being female, having blood cancers and the absence of financial or relationship difficulties were predictive of both parents and children being in the resilient group. INTERPRETATION: Approximately half the children and parents had chronically low HRQoL scores, which did not improve following resolution of the FN episode. The child's sex, cancer type, and presence of financial and relations

BACKGROUND:The timing and necessity of repeated blood cultures (BCs) in children with cancer and febrile neutropenia (FN) are unknown. We evaluated the diagnostic yield of BCs collected pre- and post-empiric FN antibiotics. METHODS:Data collected prospectively from the Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study were used. Diagnostic yield was calculated as the number of FN episodes with a true bloodstream infection (BSI) detected divided by the number of FN episodes that had a BC taken. RESULTS:A BSI was identified in 13% of 858 FN episodes. The diagnostic yield of pre-antibiotic BCs was higher than of post-antibiotic cultures (12.3% vs 4.4%, P < .001). Two-thirds of the post-antibiotic BSIs were associated with a new episode of fever or clinical instability, and only 2 new BSIs were identified after 48 hours of empiric antibiotics and persistent fever. A contaminated BC was identified more frequently in post-antibiotic cultures. CONCLUSIONS:In the absence of new fever or clinical instability, BCs beyond 48 hours of persistent fever have limited yield. Opportunity exists to optimize BC collection in this population and reduce the burden of unnecessary tests on patients, healthcare workers, and hospitals.

The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.

BACKGROUND: The timing and necessity of repeated blood cultures (BCs) in children with cancer and febrile neutropenia (FN) are unknown. We evaluated the diagnostic yield of BCs collected pre- and post-empiric FN antibiotics. METHOD(S): Data collected prospectively from the Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study were used. Diagnostic yield was calculated as the number of FN episodes with a true bloodstream infection (BSI) detected divided by the number of FN episodes that had a BC taken. RESULT(S): A BSI was identified in 13% of 858 FN episodes. The diagnostic yield of pre-antibiotic BCs was higher than of post-antibiotic cultures (12.3% vs 4.4%, P < .001). Two-thirds of the post-antibiotic BSIs were associated with a new episode of fever or clinical instability, and only 2 new BSIs were identified after 48 hours of empiric antibiotics and persistent fever. A contaminated BC was identified more frequently in post-antibiotic cultures. CONCLUSION(S): In the absence of new fever or clinical instability, BCs beyond 48 hours of persistent fever have limited yield. Opportunity exists to optimize BC collection in this population and reduce the burden of unnecessary tests on patients, healthcare workers, and hospitals.Copyright © The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Influenza vaccination is recommended for children following allogeneic haematopoietic stem cell transplant (HSCT), however there is limited evidence regarding its benefit. A prospective multicentre study was conducted to evaluate the immunogenicity of the inactivated influenza vaccine in children who have undergone HSCT compared with healthy age-matched controls. Participants were vaccinated between 2013 and 2016 according to Australian guidelines. Influenza-specific hemagglutinin inhibition antibody titres were performed prior to each vaccination and 4 weeks following the final vaccination. A nasopharyngeal aspirate for influenza was performed on participants that developed influenza-like illness. There were 86 children recruited; 43 who had undergone HSCT and 43 controls. For the HSCT group, seroprotection and seroconversion rates were 81.4% and 60.5% for H3N2, 41.9% and 32.6% for H1N1, and 44.2% and 39.5% for B strain respectively. There was a significant geometric mean fold increase to the H3N2 (GMFI 5.80, 95% CI 3.68-9.14, p < 0.001) and B (GMFI 3.44, 95% CI 2.36-5.00, p = 0.048) strains. Serological response was superior in age-matched controls to all vaccine strains. There were no serious adverse events following vaccination. For children who underwent HSCT, incidence of laboratory-proven influenza infection was 2.3%. Overall, this study provides evidence to support annual inactivated influenza vaccine administration to children following HSCT.

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Influenza vaccination is recommended for children following allogeneic haematopoietic stem cell transplant (HSCT), however there is limited evidence regarding its benefit. A prospective multicentre study was conducted to evaluate the immunogenicity of the inactivated influenza vaccine in children who have undergone HSCT compared with healthy age-matched controls. Participants were vaccinated between 2013 and 2016 according to Australian guidelines. Influenza-specific hemagglutinin inhibition antibody titres were performed prior to each vaccination and 4 weeks following the final vaccination. A nasopharyngeal aspirate for influenza was performed on participants that developed influenza-like illness. There were 86 children recruited; 43 who had undergone HSCT and 43 controls. For the HSCT group, seroprotection and seroconversion rates were 81.4% and 60.5% for H3N2, 41.9% and 32.6% for H1N1, and 44.2% and 39.5% for B strain respectively. There was a significant geometric mean fold increase to the H3N2 (GMFI 5.80, 95% CI 3.68–9.14, p < 0.001) and B (GMFI 3.44, 95% CI 2.36–5.00, p = 0.048) strains. Serological response was superior in age-matched controls to all vaccine strains. There were no serious adverse events following vaccination. For children who underwent HSCT, incidence of laboratory-proven influenza infection was 2.3%. Overall, this study provides evidence to support annual inactivated influenza vaccine administration to children following HSCT.

Background: Primary care physicians (PCPs) are well placed to provide holistic care to survivors of childhood cancer and may relieve growing pressures on specialist-led follow-up. We evaluated PCPs' role and confidence in providing follow-up care to survivors of childhood cancer. Subjects, Materials, and Methods: In Stage 1, survivors and parents (of young survivors) from 11 Australian and New Zealand hospitals completed interviews about their PCPs' role in their follow-up. Participants nominated their PCP for an interview for Stage 2. In Stage 2, PCPs completed interviews about their confidence and preparedness in delivering childhood cancer survivorship care. Results: Stage 1: One hundred twenty survivors (36% male, mean age: 25.6 years) and parents of young survivors (58% male survivors, survivors' mean age: 12.7 years) completed interviews. Few survivors (23%) and parents (10%) visited their PCP for cancer-related care and reported similar reasons for not seeking PCP-led follow-up including low confidence in PCPs (48%), low perceived PCP cancer knowledge (38%), and difficulty finding good/regular PCPs (31%). Participants indicated feeling "disconnected" from their PCP during their cancer treatment phase. Stage 2: Fifty-one PCPs (57% male, mean years practicing: 28.3) completed interviews. Fifty percent of PCPs reported feeling confident providing care to childhood cancer survivors. PCPs had high unmet information needs relating to survivors' late effects risks (94%) and preferred a highly prescriptive approach to improve their confidence delivering survivorship care. Conclusion: Improved communication and greater PCP involvement during treatment/early survivorship may help overcome survivors' and parents' low confidence in PCPs. PCPs are willing but require clear guidance from tertiary providers. Implications for Practice: Childhood cancer survivors and their parents have low confidence in primary care physicians' ability to manage their survivorship care. Encou

Objective: Surgery for paediatric cancer presents many stresses on patients and families. The authors aimed to understand the long-term impact of childhood cancer surgery on survivors and parents. Methods: The study recruited participants from 11 Australia/New Zealand hospitals for telephone interviews. The authors used descriptive statistics to analyse participants’ quantitative distress ratings and conducted thematic analysis of shared surgical experiences and needs. Results: Of 32 participants (n = 17 survivors, n = 15 parents), survivors’ mean age at surgery was 6.9 (SD = 5.17) and parents’ children were 2.1 years old (SD = 1.41) at time of surgery. Survivors had surgery on average 15.2 years ago (SD = 6.72) and parents’ children 11.5 years ago (SD = 3.94). Parents and survivors rated surgery as highly distressing. Pre-operatively, survivors recalled experiencing fear and pain mainly associated with pre-operative procedures. Post-operatively, survivors reported immobility and some lasting behavioural disturbances. Parents described pre- and intra-operative anxiety and stress and some lasting post-operative psychological disturbances. Experiences appeared to improve with clear/consistent communication from hospital staff, proximity to hospital, and with support for parents and children post-operatively. Conclusions: Surgical treatment for childhood cancer can have a lasting impact for survivors and parents. Better information provision may improve families’ surgical experience whilst reducing anxiety, distress and physical discomfort.

CORRESPONDENCE To the Editor: Autologous stem cell transplant (SCT) is an upfront therapeutic modality for children with malignancies such as high-risk neuroblastoma and atypical teratoid rhabdoid tumour and a salvage option for children with lymphoma and a variety of solid tumours. The administration of highdose myeloablative chemotherapy during conditioning increases vulnerability to infection. Influenza infection can result in significant complications, in particular progression to pneumonia, in patients who have undergone autologous SCT [1, 2]. Influenza vaccination is recommended to prevent infection in children following autologous SCT [3], however, there is limited evidence regarding its benefit in this population [4]. Due to the paucity of data, we performed a prospective multicentre study to evaluate the immunogenicity of the seasonal inactivated influenza vaccine in children who have undergone autologous SCT compared with healthy matched controls.

Purpose: Survivors of pediatric cancer are prone to late effects which require ongoing medical care. Young adult survivors often transition from specialist pediatric care to adult-oriented or community-based healthcare. This study aims to describe the attitudes and experiences of survivors and their parents towards transition barriers and enablers. Methods: Long-term survivors and parents (of survivors < 16 years) were recruited from 11 hospitals in Australia and New Zealand to participate in a semi-structured telephone interview regarding their transition experiences. Transcribed interviews were coded and content analysis was used to number participants within themes. Results: Thirty-three participants were interviewed, of which 18 were survivors (mean age 26 years, SD = 6.3; mean time since treatment completion 13.3 years, SD = 6.1) and 15 were parents (mean survivor age 15 years, SD = 1.9; mean time since treatment completion 8.4 years, SD = 2.8). Participants described their transition attitudes as positive (55%), neutral (15%), or negative (30%). Key barriers to transition included dependence on pediatric healthcare providers, less confidence in primary care physicians (PCPs), inadequate communication, and cognitive difficulty. Enablers included confidence in and proximity to physicians, good communication, information, independence, and age. Conclusions: Many survivors face barriers to their transition out of pediatric care. Early introduction to transition, greater collaboration between healthcare professionals, and better information provision to survivors may improve the transition process. Future research of survivors’ experience of barriers/enablers to transition is needed. Development of interventions, such as those that address self-management skills, is required to facilitate transition and encourage long-term engagement.

Aim: Childhood cancer survivors remain at risk of developing life-altering and/or life-threatening health conditions following the completion of curative treatment. However, no uniform model of care for childhood cancer survivors exists in Australia and New Zealand (ANZ). This study reports on current childhood cancer survivorship care in ANZ, highlighting the challenges childhood cancer survivor long-term follow-up (LTFU) clinics face. Methods: We conducted semistructured, telephone interviews with the pediatric medical director and clinical nurse consultant from all 11 LTFU clinics at tertiary referral pediatric oncology units across ANZ (n = 19; 100% response rate). Data were analyzed using NVivo10. Results: Participants unanimously identified limited options for transitioning older survivors out of pediatrics and inadequate funding as central challenges to the provision of best-practice LTFU care. There is duplication of resource development between clinics (e.g. survivorship care plan templates and clinic systems). Although participants recognized an overly prescriptive model of LTFU care as potentially unfeasible, the majority endorsed a national, or even bi-national, model of care that could be tailored to meet the needs of their local environment. Conclusion: The lack of an accepted model of optimal childhood cancer survivorship care across ANZ prevents the synergistic development of survivorship guidelines, survivorship care plans, transition pathways, information technology solutions, funding streams and late effects data consortiums. Sufficient resources to facilitate growth may be difficult to secure if approached by individual centers rather than via a national, cooperative effort. Improved solutions are urgently needed for transitioning survivors to appropriate care beyond the pediatric age.

Objective This mixed-method study assessed 1) survivors’ and parents’ information needs; and 2) associations between unmet information needs and clinical and socio-demographic characteristics. Methods Stage 1: CCS and parents of CCS, >5years post-diagnosis completed a questionnaire on information needs, overall health and perceived risk. Predictors for unmet information needs were assessed by multivariable regression. Stage 2: participants were interviewed in-depth on these topics. Results Questionnaires were completed by 485 participants comprising 322 survivors (mean age: 26.7years, SD = 7.9; time since diagnosis: 19.7years, SD = 8.8) and 163 parents (child age: 12.9years, SD = 2.4; time since diagnosis: 9.7years, SD = 2.3), and complemented by 70 interviews. Survivors reported unmet information needs about late effects (57.5%) and parents for fertility issues (62.5%). Survivors had more unmet needs for medical information whereas parents had significantly more regarding sexual issues and lifestyle. Being a parent (p = 0.001), dissatisfaction with follow-up care (p = 0.003), lower overall health (p = 0.014), higher perceived risk of late effects (p < 0.001), and greater anxiety/depression (p < 0.001) were significantly associated with more unmet needs. Conclusion Unmet information needs were common for survivors and parents of CCS. Practice implications Future efforts towards tailoring information on potential late effects, healthy lifestyles and follow-up care may help to address unmet information needs.

There is a need for new approaches to supplement the existing methods of taking research from bench to bedside and from bedside to practice. Community-based participatory research (CBPR) is an emerging model of research that enhances ongoing clinical research by involving key stakeholders, including community members and patients. A practice-based research network (PBRN) is a group of primary care practices devoted principally not only to the primary care of patients, but also with a mission to investigate questions related to community-based practice and to improve the quality of primary care. Traditionally, PBRN research has not included patients or community members, while CBPR has excluded health providers as key stakeholders. Typical overlap topics of PBRN and CBPR research are health-care disparities, prevention, chronic disease management and mental health. The inclusion of CBPR within a PBRN has been identified as an important next step with the potential to significantly enhance the research process. This review focuses on bringing together the ideals of CBPR and PBRNs in order to tackle intractable problems such as disparities in health-care access and outcomes and translate these results into practice. Specifically, the CBPR PBRN approach can: (1) guide the research process so that studies more closely match the needs of all stakeholders (including providers, patients and community members); (2) assist in the development of the research protocol and identification of research methodologies so that the study is more amenable to participants; (3) facilitate recruitment of research participants; (4) enrich the data collection and analysis; and (5) allow rapid translation of results from the study back into clinical practice and the community. Once these mechanisms have been clearly elucidated, their widespread adoption will positively impact overall health at both a local and national level.

Population-based evidence on second cancer risk following autologous haematopoietic SCT (HCT) is lacking. We quantified second cancer risk for a national, population-based cohort of adult Australians receiving autologous HCT for cancer and notified to the Australasian Bone Marrow Transplant Recipient Registry 1992-2007 (n=7765). Cancer diagnoses and deaths were ascertained by linkage with the Australian Cancer Database and National Death Index. Standardized incidence ratios (SIRs) were calculated and Cox regression models were used to estimate within-cohort risk factors treating death as a competing risk. During a median 2.5 years follow-up, second cancer risk was modestly increased compared with the general population (SIR 1.4, 95% confidence interval 1.2-1.6); significantly elevated risk was also observed for AML/myelodysplastic syndrome (SIR=20.6), melanoma (SIR=2.6) and non-Hodgkin lymphoma (SIR=3.3). Recipients at elevated risk of any second cancer included males, and those transplanted at a younger age, in an earlier HCT era, or for lymphoma or testicular cancer. Male sex, older age (>45 years) and history of relapse after HCT predicted melanoma risk. Transplantation for Hodgkin lymphoma and older age were associated with lung cancer risk. Second malignancies are an important late effect and these results inform and emphasize the need for cancer surveillance in autologous HCT survivors. © 2014 Macmillan Publishers Limited.