The Australian New Zealand Consortium in Children, Adolescents, and Young Adults Oncofertility action plan.

International and national oncofertility networks, including the US-led Oncofertility Consortium, FertiProtekt, and the Danish Network, have played pivotal roles in advancing the discipline of oncofertility over the last decade. Many other countries lack a shared approach to pediatric oncofertility health service delivery. This study aims to describe baseline oncofertility practices at Australian New Zealand Children's Haematology/Oncology Group centers in 2019-2021, describe binational priorities for care, and propose a 5-year action plan for best practice to be implemented by the newly formed Australian New Zealand Consortium in Children, Adolescents, and Young Adults (CAYA) Oncofertility (ANZCO).

Feasibility of a prospective physiotherapy model of care during the intense treatment phase of childhood cancer (FITChild): A mixed methods design.

BACKGROUND: Children diagnosed with cancer often develop significant physical treatment-related side effects. This study evaluated the feasibility of a targeted, proactive, individualised physiotherapy intervention programme for children with a recent cancer diagnosis. PROCEDURE: This feasibility study was a single-group mixed methods study, consisting of pre- and post-intervention assessment, followed by a survey and interviews of parents. Participants were children and adolescents with a new cancer diagnosis. The physiotherapy model of care consisted of education, surveillance, standardised assessment, individually tailored exercise and a fitness tracker. RESULTS: All participants (n = 14) completed over 75% of the supervised exercise sessions. No safety or adverse events occurred. Over the 8-week intervention period, an average of 7.5 supervised sessions were completed per participant. The overall experience provided by the physiotherapist service was rated as excellent by 86% (n = 12) and very good by 14% (n = 2) of parents. All parents surveyed (n = 14) rated the level of support provided by the physiotherapy service as excellent, and all participants completed the standardised assessments pre- and post-exercise intervention. There was a significant improvement in 6MWD from 240 m (SD 193 m) compared to 355 m (SD 115 m) (p = .015), as well as improvements in the Physical Function domain (p = .013) and combined Psychosocial and Physical Function domains (p = .030). CONCLUSIONS: A prospective structured and targeted physiotherapy model of care appears feasible for use with children and families in the acute phase of cancer treatment. The regular screening was acceptable and may have helped build a strong rapport between the physiotherapist and the families.

Prospective longitudinal evaluation of treatment-related toxicity and health-related quality of life during the first year of treatment for pediatric acute lymphoblastic leukemia.

BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) therapy is accompanied by treatment-related toxicities (TRTs) and impaired quality of life. In Australia and New Zealand, children with ALL are treated with either Children's Oncology Group (COG) or international Berlin-Frankfurt-Munster (iBFM) Study Group-based therapy. We conducted a prospective registry study to document symptomatic TRTs (venous thrombosis, neurotoxicity, pancreatitis and bone toxicity), compare TRT outcomes to retrospective TRT data, and measure the impact of TRTs on children's general and cancer-related health-related quality of life (HRQoL) and parents' emotional well-being. METHODS: Parents of children with newly diagnosed ALL were invited to participate in the ASSET (Acute Lymphoblastic Leukaemia Subtypes and Side Effects from Treatment) study and a prospective, longitudinal HRQoL study. TRTs were reported prospectively and families completed questionnaires for general (Healthy Utility Index Mark 3) and cancer specific (Pediatric Quality of Life Inventory (PedsQL)-Cancer Module) health related quality of life as well the Emotion Thermometer to assess emotional well-being. RESULTS: Beginning in 2016, 260 pediatric patients with ALL were enrolled on the TRT registry with a median age at diagnosis of 59 months (range 1-213 months), 144 males (55.4%), majority with Pre-B cell immunophenotype, n = 226 (86.9%), 173 patients (66.5%) treated according to COG platform with relatively equal distribution across risk classification sub-groups. From 2018, 79 families participated in the HRQoL study through the first year of treatment. There were 74 TRT recorded, reflecting a 28.5% risk of developing a TRT. Individual TRT incidence was consistent with previous studies, being 7.7% for symptomatic VTE, 11.9% neurotoxicity, 5.4% bone toxicity and 5.0% pancreatitis. Children's HRQoL was significantly lower than population norms throughout the first year of treatment. An improvement in general HRQoL, measured by the HUI3, contrasted with the lack of improvement in cancer-related HRQoL measured by the PedsQL Cancer Module over the first 12 months. There were no persisting differences in the HRQoL impact of COG compared to iBFM therapy. CONCLUSIONS: It is feasible to prospectively monitor TRT incidence and longitudinal HRQoL impacts during ALL therapy. Early phases of ALL therapy, regardless of treatment platform, result in prolonged reductions in cancer-related HRQoL.

Protocol for SARS-CoV-2 post-vaccine surveillance study in Australian adults and children with cancer: an observational study of safety and serological and immunological response to SARS-CoV-2 vaccination (SerOzNET).

BACKGROUND: Cancer is associated with excess morbidity and mortality from coronavirus disease 2019 (COVID-19) following infection by the novel pandemic coronavirus SARS-CoV-2. Vaccinations against SARS-CoV-2 have been rapidly developed and proved highly effective in reducing the incidence of severe COVID-19 in clinical trials of healthy populations. However, patients with cancer were excluded from pivotal clinical trials. Early data suggest that vaccine response is less robust in patients with immunosuppressive conditions or treatments, while toxicity and acceptability of COVID-19 vaccines in the cancer population is unknown. Unanswered questions remain about the impact of various cancer characteristics (such as treatment modality and degree of immunosuppression) on serological response to and safety of COVID-19 vaccinations. Furthermore, as the virus and disease manifestations evolve, ongoing data is required to address the impact of new variants. METHODS: SerOzNET is a prospective observational study of adults and children with cancer undergoing routine SARS-CoV-2 vaccination in Australia. Peripheral blood will be collected and processed at five timepoints (one pre-vaccination and four post-vaccination) for analysis of serologic responses to vaccine and exploration of T-cell immune correlates. Cohorts include: solid organ cancer (SOC) or haematological malignancy (HM) patients currently receiving (1) chemotherapy, (2) immune checkpoint inhibitors (3) hormonal or targeted therapy; (4) patients who completed chemotherapy within 6-12 months of vaccination; (5) HM patients with conditions associated with hypogammaglobulinaemia or immunocompromise; (6) SOC or HM patients with allergy to PEG or polysorbate 80. Data from healthy controls already enrolled on several parallel studies with comparable time points will be used for comparison. For children, patients with current or prior cancer who have not received recent systemic therapy will act as controls. Standardised scales for quality-of-life assessment, patient-reported toxicity and vaccine hesitancy will be obtained. DISCUSSION: The SerOzNET study was commenced in June 2021 to prospectively study immune correlates of vaccination in specific cancer cohorts. The high proportion of the Australian population naïve to COVID-19 infection and vaccination at study commencement has allowed a unique window of opportunity to study vaccine-related immunity. Quality of life and patient-reported adverse events have not yet been reported in detail post-vaccination for cancer patients. Trial registration This trial is registered on the Australia New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621001004853. Submitted for registration 25 June 2021. Registered 30 July 2021 (Retrospectively registered). https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382281&isReview=true.

COVID-19 vaccination in children and adolescents aged 5 years and older undergoing treatment for cancer and non-malignant haematological conditions: Australian and New Zealand Children's Haematology/Oncology Group consensus statement.

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 Australian and New Zealand Children's Haematology/Oncology Group.

Paroxysmal Cold Hemoglobinuria: Diagnosis From the Blood Smear.

Phagocytosis of red cells by neutrophils, referred to as neutrophil erythrophagocytosis, on the blood smear as a helpful diagnostic sign of paroxysmal cold hemoglobinuria is underrecognized. We present a child with paroxysmal cold hemoglobinuria and prominent neutrophil erythrophagocytosis to highlight the importance of this finding in the diagnosis of paroxysmal cold hemoglobinuria.

Ganglion Cell Layer Thickness Variance Using SPECTRALIS Optical Coherence Tomography.

BACKGROUND: To determine the normal variance of the mean macular ganglion cell layer (GCL) volume among subjects without significant ocular pathology using SPECTRALIS optical coherence tomography (OCT). METHODS: Fifty subjects underwent a baseline scan using SPECTRALIS OCT followed by 2 more studies with (reg-ON) and without (reg-OFF) eye registration all taken at the same session. The mean GCL volume was measured using built-in SPECTRALIS software. Eyes with macular pathology were excluded. The reproducibility of the measurements of the GCL volume was evaluated with Bland-Altman plots and limits of agreement, intraclass correlation coefficient (ICC), and the coefficient of repeatability (CR). RESULTS: A total of 98 eyes met criteria for the analysis. The mean GCL volume difference was 0.0002 ± 0.029 and -0.0005 ± 0.035 mm 3 for scans 1 versus 2 (baseline vs reg-ON) and 3 (baseline vs reg-OFF), respectively. The ICCs were 0.985 and 0.977 for the baseline vs reg-ON and reg-OFF groups. The CR for baseline vs reg-ON was 0.056 while CR for baseline vs reg-OFF was 0.069. Ninety percent of eyes fell within 0.04 mm 3 of test-retest reliability. CONCLUSIONS: Our model found a predictable threshold of 0.07 mm 3 or less for SPECTRALIS OCT mean GCL volume variance, which did not significantly change with eye registration in eyes without macular pathology. Clinicians may also consider a threshold of 0.04 mm 3 when determining stable vs progressive changes in mean GCL volume using this device.

Behavioral and Emotional Functioning of Children and Adolescents at the End of Treatment for Acute Lymphoblastic Leukemia Compared to Healthy Peers.

This study describes the behavioral and emotional adjustment of 77 children and adolescents 3 months post-treatment for acute lymphoblastic leukemia (ALL), compared to 52 age and sex-matched healthy peers. Parents, teachers, and self-report ratings on the Behavioral Assessment System for Children, Second Edition (BASC-2) were utilized to measure psychological function. While overall mean scores were in the average range for both groups, parents and teachers rated patients higher on behavior symptoms, internalizing problems and adaptive skill difficulties. No significant differences between groups were observed on self-report, and inter-rater correlations were low to moderate. For the ALL group, maternal university completion was associated with elevations on parent report of behavioral problems, while no other factors predicted either parent or teacher report on other scales. Findings indicate that a subset of patients will require specialist psychosocial support to optimise their adjustment following treatment completion.

Parental adjustment following their child's completion of acute lymphoblastic leukemia treatment.

BACKGROUND: Few studies haveexamined parent and family adaptation in the early period following the end of childhood cancer treatment. We examined parent adjustment at the end of their child's treatment for acute lymphoblastic leukemia (ALL). METHODS: Parents of childhood cancer survivors (CCS), who were 3 months post-ALL treatment, and parents of typically developing children completed measures of psychological and family functioning. Parents of CCS also completed distress and posttraumatic stress symptom (PTSS) questionnaires related to their child's cancer experience. RESULTS: One hundred twenty-nine parents were recruited: 77 parents of CCS and 52 comparison parents. Overall mean psychological symptoms of depression, anxiety and stress, and family functioning were within normal limits for both groups. Parents of CCS endorsed higher scores for stress, depression, and family problems; however, mean scores for emotional distress were low for both groups, in particular the comparison group. Parents of CCS endorsed low rates of PTSS. Fifty-one percent of parents of CCS scored above the distress thermometer (DT-P) clinical cutoff (>4), with items elevated across all six DT-P domains. However, most parents did not indicate a wish to speak to a health professional about their symptoms. CONCLUSION: Specialist psychosocial intervention may be indicated for only a subset of parents at the end of treatment. As per psychosocial standards of care, effective screening at this timepoint is warranted. Further examination of appropriate timing of psychosocial information and support services that are tailored to parents' circumstances is needed. eHealth approaches may be appropriate.

The Australia and New Zealand Cardio-Oncology Registry: evaluation of chemotherapy-related cardiotoxicity in a national cohort of paediatric cancer patients.

Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO2 max testing is a more sensitive predictor of cardiac reserve in paediatric and adolescent and young adult oncology patients exposed to cardiac toxic therapies.

Health-related quality of life in paediatric patients up to five years post-treatment completion for acute lymphoblastic leukaemia: a systematic review.

PURPOSE: Despite survival rates greater than 90%, treatment for paediatric acute lymphoblastic leukaemia (ALL) remains challenging for families. The early post-treatment phase is an especially unique time of adjustment. The primary aim of this review was to identify and synthesise research on health-related quality of life (HRQoL) for patients up to five years post-treatment. The secondary aim was to identify if theorised risk/resistance model factors could explain any variance in reported HRQoL. METHODS: We conducted a systematic review using the PRISMA guidelines across five databases: Embase, Medline, Psychinfo, Pubmed, and Cochrane. Only studies examining HRQoL up to five years post-treatment were included. Studies were excluded if they covered periods greater than five years post-treatment or did not differentiate between patients with ALL and other cancers. After assessing the quality of each study sample size, patient characteristics, HRQoL outcomes and HRQoL correlates were extracted and summarised. RESULTS: A total of 14 studies representing 1254 paediatric patients, aged 2-18 years, were found. HRQoL findings were mixed, dependent on time since completion and comparison group. Patient HRQoL was mostly lower compared to normative data, whilst higher compared to healthy control groups, patients on treatment, and patients with other types of cancers. Lower HRQoL was also found to be associated with demographic (age and sex), family dysfunction, and treatment-related factors. CONCLUSIONS: Completing treatment signalled a significant improvement in HRQoL for patients compared to being on treatment. Overall, however, HRQoL was still significantly lower than the population during the early post-treatment period.

Satisfaction, disappointment and regret surrounding fertility preservation decisions in the paediatric and adolescent cancer population.

PURPOSE: With over 80% of paediatric and adolescent cancer patients surviving into adulthood, quality-of-life issues such as future fertility are increasingly important. However, little is known about regret around decisions to pursue or forgo fertility preservation (FP). We investigated the risk of decision regret in families involved in making a FP decision and explored contributive factors. METHODS: Parents and patients ≥ 15 years were invited to participate. Participants completed a 10-item survey, including a validated Decision Regret Scale. Scores ≥ 30 indicated high regret. Free-text response items allowed participants to provide reasons for satisfaction or regret. RESULTS: A total of 108 parents and 30 patients participated. Most (81.4%) reported low regret (mean score 13.7). On multivariate analysis, predictors of low regret included having a FP procedure and a fertility discussion pre-treatment. Most participants believed that FP offers hope for future fertility. Some reported dissatisfaction with the process of decision-making. CONCLUSION: Overall levels of regret in the study population were low, with factors associated with quality, timely discussion and belief in the success of FP technology being predictors of low regret. However, dissatisfaction with the decision-making process itself revealed that refinements to the programme are required to meet families' needs.

The relationship between cognitive and neuroimaging outcomes in children treated for acute lymphoblastic leukemia with chemotherapy only: A systematic review.

Cognitive late-effects have been identified in patients treated with chemotherapy-only protocols for childhood acute lymphoblastic leukemia (ALL), yet the underlying neuropathology is not well understood. This review synthesized recent findings from eight articles investigating the relationship between neurocognitive and neuroimaging outcomes for patients treated for ALL with chemotherapy-only protocols. Reported cognitive domains, imaging methods, and neuroanatomy examined were variable. Despite this, 62.5% (n = 5) of the reviewed studies found a significant relationship between cognitive and imaging outcomes. Greater understanding of the effects of treatment on neuroanatomy and cognitive outcomes is critical for proactively managing ALL cognitive late-effects. Research directions are suggested.

Initial Experience With Gallium-68 DOTA-Octreotate PET/CT and Peptide Receptor Radionuclide Therapy for Pediatric Patients With Refractory Metastatic Neuroblastoma.

RATIONALE: Pediatric patients with refractory neuroblastoma have limited therapeutic options. Neuroblastoma may express somatostatin receptors (SSTRs) allowing imaging with 68Ga-DOTA-Octreotate (GaTATE) positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT). We reviewed our experience with this theranostic combination. MATERIALS AND METHODS: GaTATE studies (8 patients; 2 to 9 years old) were reviewed and compared with 123I-MIBG or posttreatment 131I-MIBG studies. Immunohistochemistry (IHC) for SSTR subtype 2 was performed in 5 patients. Four patients received PRRT. RESULTS: GaTATE PET showed additional disease in 38% (3/8 patients), and upstaged 1 patient by detecting marrow involvement. IHC detected SSTR 2 in all patients assessed. Six patients were deemed suitable for PRRT on imaging. Four patients received 17 cycles of palliative PRRT (10 111In-DOTATATE; 5 177Lu-DOTATATE; 1 combined 111In and 177Lu-DOTATATE; 1 combined 177Lu and 90Y-DOTATATE) with no significant toxicity attributed to PRRT. All had objective responses. Two survivors are now 40 and 56 months from PRRT commencement. CONCLUSIONS: GaTATE PET was positive in a high proportion of patients with refractory neuroblastoma, correlating with SSTR 2 on IHC, with additional disease identified compared with MIBG imaging. PRRT seems safe, feasible, with responses observed in patients with progression despite multimodality treatment. These data support ongoing clinical trials in such patients.

Breastfeeding and nutrition to 2 years of age and risk of childhood acute lymphoblastic leukemia and brain tumors.

Acute lymphoblastic leukemia (ALL) and childhood brain tumors (CBT) are 2 of the most common forms of childhood cancer, but little is known of their etiology. In 2 nationwide case-control studies we investigated whether breastfeeding, age of food introduction, or early diet are associated with the risk of these cancers. Cases aged 0-14 years were identified from Australian pediatric oncology units between 2003 and 2007 (ALL) and 2005 and 2010 (CBT) and population-based controls through nationwide random-digit dialing. Mothers completed questionnaires giving details of infant feeding up to the age of 2 yr. Data from 322 ALL cases, 679 ALL controls, 299 CBT cases, and 733 CBT controls were analysed using unconditional logistic regression. Breastfeeding was associated with a reduced risk of ALL [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.32, 0.84), regardless of duration. Introduction of artificial formula within 14 days of birth was positively associated with ALL (OR = 1.57, 95% CI: 1.03, 2.37), as was exclusive formula feeding to 6 mo (OR = 1.81, 95% CI: 1.07, 3.05). No associations were seen between breastfeeding or formula use and risk of CBT. Our results suggest that breastfeeding and delayed introduction of artificial formula may reduce the risk of ALL but not CBT.

Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group.

Medulloblastoma is curable in approximately 70% of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization's classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children's Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.