High-dose chemotherapy for Ewing sarcoma and Rhabdomyosarcoma: A systematic review by the Australia and New Zealand sarcoma association clinical practice guidelines working party.

INTRODUCTION: Patients with high-risk or metastatic Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) have a guarded prognosis. High-dose chemotherapy (HDT) with autologous stem cell transplant (ASCT) has been evaluated as a treatment option to improve outcomes. However, survival benefits remain unclear, and treatment is associated with severe toxicities. METHODS: A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether utilization of HDT/ASCT impacts the outcome of patients with ES and RMS compared to standard chemotherapy alone, as part of first line treatment or in the relapse setting. Medline, Embase and Cochrane Central were queried for publications from 1990 to October 2022 that evaluated event-free survival (EFS), overall survival (OS), and toxicities. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed. RESULTS: Of 1,172 unique studies screened, 41 studies were eligible for inclusion with 29 studies considering ES, 10 studies considering RMS and 2 studies considering both. In ES patients with high-risk localised disease who received HDT/ASCT after VIDE chemotherapy, consolidation with melphalan-based HDT/ASCT as first line therapy conveyed an EFS and OS benefit over standard chemotherapy consolidation. Efficacy of HDT/ASCT using a VDC/IE backbone, which is now standard care, has not been established. Survival benefits are not confirmed for ES patients with metastatic disease at initial diagnosis. For relapsed/refractory ES, four retrospective studies report improvement in outcomes with HDT/ASCT with the greatest evidence in patients who demonstrate a treatment response before HDT, and in patients under the age of 14. In RMS, there is no proven survival benefit of HDT/ASCT in primary localised, metastatic or relapsed disease. CONCLUSION: Prospective randomised trials are required to determine the utility of HDT/ASCT in ES and RMS. Selected patients with relapsed ES could be considered for HDT/ASCT.

Strengthening Public Health Through Primary Care and Public Health Collaboration: Innovative State Approaches.

OBJECTIVE: Partnerships are increasingly critical to achieve the mission of public health. We sought to understand the levers and tools that states use to better connect public health and primary care in efforts to strengthen public health. DESIGN: We reviewed literature focused on collaborative or integrative efforts between primary care and public health and examined strategies employed by 4 innovative states: North Carolina, Oregon, Rhode Island, and Washington. Using a purposive convenience sample, we conducted semistructured interviews with 17 state experts from January to March 2023. We asked leaders to describe their approaches to data sharing, communication, and systems change that could be adopted or adapted by other states interested in better connecting primary care and public health systems. We recorded and coded interviews. PARTICIPANTS: Seventeen state leaders from North Carolina, Oregon, Rhode Island, and Washington. MAIN OUTCOME MEASURES: Key experiences, strategies, policy levers, and lessons for integration or collaboration between primary care and public health sectors, both common and divergent, across the states. RESULTS: State activity can be categorized by 3 actions: (1) endeavors to support relationship building, both formal and informal; (2) efforts to employ coordinating bodies and champions to ensure all necessary actors are included in planning and communications with clear roles; and (3) approaches to identifying and elevating essential system elements and the change levers to support them. The integration is built primarily on the well-resourced medical care system rather than the public health system. CONCLUSION: States are engaged in creative approaches to collaboration between public health and primary care. Building blocks include backbone organizations, leadership training programs, payment reform spheres, interoperable data platforms, and intentional efforts to build relationships. Collaboration between primary care, public health, and community-based organizations is an opportunity to strengthen public health systems while staying focused on improving the public's health.

Gabapentin for Pain in Pediatric Palliative Care.

OBJECTIVE: Gabapentin is commonly used to treat pain in children receiving pediatric palliative care. This study describes the real-world use of gabapentin and the associated benefits and adverse effects/events (AEs). METHODS: A prospective, multicenter cohort of standardized data collection after a clinical decision was made to use gabapentin for managing neuropathic or nociplastic pain in children attended on by a pediatric palliative care service. It was conducted across 11 sites in seven countries including hospital, inpatient, and outpatient services. Clinical outcomes were graded using pain scales validated for age and cognitive ability and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) at baseline, 14 days, 28 days, six weeks and 12 weeks after initiation of gabapentin. Ad-hoc safety reporting continued throughout the study. RESULTS: Data were collected from 127 children with a median age of 4.7 years (IQR 0.1-17.9); 61% had a neurological disorder, 21% advanced cancer and the cohort had a high level of disability (Lansky/Karnofsky performance score 37.1). Gabapentin was prescribed at standard pediatric doses. On average, 76% of children had a reduction in pain and 42% experienced a potential AE. The mean pain score decreased from 6.0 (SD 2.6) at baseline to 3.3 (SD 2.4) at 14 days and 1.8 (SD 1.8) after 12-weeks of gabapentin therapy. Ten percent had increased pain at each time point. AEs did not increase when individual changes over time were accounted for except for somnolence (7%). Serious AEs attributable to gabapentin were possible or probable in 3% of children. CONCLUSIONS: Gabapentin prescribed at standard doses for advanced cancer and severe neurological injury in children under a pediatric palliative care service was associated with generally improved pain intensity at previously described levels of adverse effects.

A surgically optimized intraoperative poly(I:C)-releasing hydrogel prevents cancer recurrence.

Recurrences frequently occur following surgical removal of primary tumors. In many cancers, adjuvant therapies have limited efficacy. Surgery provides access to the tumor microenvironment, creating an opportunity for local therapy, in particular immunotherapy, which can induce local and systemic anti-cancer effects. Here, we develop a surgically optimized biodegradable hyaluronic acid-based hydrogel for sustained intraoperative delivery of Toll-like receptor 3 agonist poly(I:C) and demonstrate that it significantly reduces tumor recurrence after surgery in multiple mouse models. Mechanistically, poly(I:C) induces a transient interferon alpha (IFNα) response, reshaping the tumor/wound microenvironment by attracting inflammatory monocytes and depleting regulatory T cells. We demonstrate that a pre-existing IFN signature predicts response to the poly(I:C) hydrogel, which sensitizes tumors to immune checkpoint therapy. The safety, immunogenicity, and surgical feasibility are confirmed in a veterinary trial in canine soft tissue tumors. The surgically optimized poly(I:C)-loaded hydrogel provides a safe and effective approach to prevent cancer recurrence.

The benefit for radiotherapy at specialised sarcoma centres: A systematic review and clinical practice guidelines from the Australia and New Zealand Sarcoma Association.

Patients with sarcoma are best managed at specialised sarcoma centres as supported by published literature. Optimal management requires multidisciplinary team input to formulate the diagnosis and treatment sequencing taking into consideration multiple clinical and pathologic factors. This systematic review aimed to evaluate the impact on outcomes of radiotherapy at specialised sarcoma centres. A systematic review was conducted using the population, intervention, comparison and outcome model. A literature search was performed using Medline, Embase, Cochrane Central databases for publications from 1990 to February 2022 that evaluated the local control, survival and toxicity of radiotherapy at specialised sarcoma centres. A total of 21 studies were included (17 cancer registry studies, four retrospective comparative studies). Four studies reported the local recurrence endpoint when radiotherapy was part of limb conservation treatment and showed better conformity to clinical practice guidelines and an improved local recurrence free rate when radiotherapy treatment is supported through, but may not be necessarily delivered at a specialised sarcoma centres. Only one retrospective study analysed toxicity specifically and demonstrated that patients who received preoperative radiotherapy at community centres compared to radiotherapy at a specialised sarcoma centre were more likely to develop a major wound complication. Fourteen studies reported overall survival, and 12 of these showed significantly better 5-year overall survival for patients managed at specialised sarcoma centres, however the specific impact of radiotherapy delivered at sarcoma centres could not be determined. In conclusion, patients with sarcoma should be managed through specialised sarcoma centres for better oncological outcomes. Radiotherapy in specialised sarcoma centre is associated with a lower rate of wound complications and may contribute to improved oncological outcomes as part of the limb conservation treatment at a specialised sarcoma centre.

The COVID-19 Pandemic: Early Ripple Effects in Pediatric Palliative Care.

Palliative care, which aims to provide comprehensive, interdisciplinary, holistic care to children, adolescents and adults with life-threatening, and ultimately life-limiting conditions, is a discipline that has emerged as an integral component of healthcare systems throughout the world. Although the value of life-affirming palliative care (PC) has been shown across many domains, funding and acceptance of palliative care teams have been variable: some hospital systems have free-standing, dedicated interdisciplinary teams while, in many instances, palliative care services are provided "pro bono" by individuals with a special interest in the discipline, who provide PC in addition to other responsibilities. In this article, we hope to highlight some of the observations on the early effects of the COVID-19 pandemic on the provision of PC in children.

"It Is a Whole Different Life from the Life I Used to Live": Assessing Parents' Support Needs in Paediatric Palliative Care.

AIMS: This feasibility study aimed to systematically identify and address the support needs of parents of children with life-limiting illnesses and to assess whether the systematic approach was acceptable and relevant to parents. METHODS: The CSNAT (Paediatric) intervention consisted of two assessment visits with the paediatric palliative care team, 2-8 weeks apart, comprising conversations about sources for support in a tertiary children hospital in Western Australia (2018-2019). Audio-recorded telephone interviews were conducted with parents, and inductive thematic analysis was undertaken. RESULTS: All 28 parents who were involved in the intervention agreed to be interviewed. Five themes summarised their experience: caregiving challenges, perceived gaps and feelings of isolation; the usefulness and practicality of the systematic assessment; emotional responses to self-reflection; feelings of validation and empowerment; and received supports responsive to their needs. CONCLUSIONS: Parents appreciated the value of this systematic approach in engaging them in conversations about their needs and solutions to address them. While clinical service support was affirmed by parents, they were left wanting in other areas of practical, psychosocial, and emotional support. Palliative care services need to build stronger partnerships with supportive community networks through compassionate communities volunteer models of care to address the non-clinical needs of these families.

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.

Palliative care and COVID-19 in the Australian context: a review of patients with COVID-19 referred to palliative care.

Objective Palliative care has played a key role in the response to the coronavirus disease 2019 (COVID-19) pandemic in Australia. This review of consecutive patients with COVID-19 referred to the palliative care consultancy service of a tertiary health service in Melbourne describes the palliative care experience with COVID-19 in Australia. Methods The experiences of 55 patients (median age 86 years; interquartile range (IQR) 81-90 years; 55% male; median Charlson comorbidity score 6 (IQR 5-8); 85% with Australia-modified Karnofsky Performance Status ≤50; 67% from residential aged care facilities) were reviewed to collect relevant data points. Results Most patients were referred for end-of-life care with symptoms including dyspnoea (80%) and agitation/delirium (60%). Continuous subcutaneous infusions were commenced in 71% of patients, with the most frequent medications being opioids and benzodiazepines in relatively small doses; 81% required ≤20 mg subcutaneous morphine equivalent and 64% required ≤10 mg subcutaneous midazolam over 24 h. Fifty patients (91%) died in hospital and the median time from palliative care referral to death was 3 days (IQR 1-5 days). Five patients were discharged back to residential aged care facilities. Overall, 80% of referrals were from the aged care team. Conclusion Our patients had similar demographics, symptoms, medication needs and outcomes to patients in similar settings overseas. We found the symptom management of patients with COVID-19 to be generally straightforward. However, the psychosocial needs of patients were predominant and contributed to complexity. This study highlights the need for well-integrated relationships between the palliative care consultancy service and the diverse range of key treating teams involved in the delivery of pandemic health care. What is known about the topic? Palliative care has played a key role in the response to the COVID-19 pandemic in Australia. There is limited research describing the Australian palliative care experience with the COVID-19 pandemic. What does this paper add? Patients with COVID-19 referred to a hospital-based palliative care consultancy service in Australia had similar demographic characteristics, symptoms, medication needs and outcomes to patients with COVID-19 referred to other palliative care services in the UK and the US. There were significant psychosocial issues affecting patients, families and staff in the context of the pandemic. What are the implications for practitioners? This study highlights the need for well-functioning working relationships between the palliative care consultancy service and other hospital teams that can be leveraged at a time of crisis, such as a pandemic, to provide optimal palliative care to patients.

Treatment and Outcomes for Central Nervous System Tumors in Australian Adolescents and Young Adults: A Population-Based National Study.

Purpose: While central nervous system (CNS) tumors account for only 10% of adolescent and young adult (AYA) cancers, they are the leading cause of cancer death in this age group. Using national data for Australia, we describe the presentation, treatment, and survival for AYAs diagnosed with CNS tumors. Methods: A population-based study of 15-24 year-olds diagnosed with CNS tumors (low- and high-grade glioma [LGG, HGG], medulloblastoma [MB], primitive neuroectodermal tumors [PNET], ependymoma [EP]) or other (e.g., low-grade neuronal tumor) between 2007 and 2012. Clinical details were extracted from hospital medical records for each patient. Treatment centers were classified as pediatric or adult services. Results: Two hundred seventy-five patients (129 LGG, 77 HGG, 23 MB, 10 PNET, 19 EP, 17 other) were identified, with 17% treated at pediatric hospitals. Symptoms (headache [53%], nausea [31%]) were present for a median of 3 weeks before consulting a health professional. Of LGG patients, 15% had radiotherapy (RT) and 12% chemotherapy (CT). Of HGG patients, 81% had RT and 75% CT. All MB and PNET were managed with surgery, and 74% of MB and 80% of PNET had both RT and CT. Treatment did not differ by treatment center type. Five-year survival for LGG and EP was over 80%, but was 42% for HGG and 20% for PNET. Conclusions: This national, population-based study indicates similar treatment for AYA patients with CNS tumors between pediatric and adult services. Poor outcomes for HGG and PNET patients highlight the need for clinical trials of novel approaches for these tumors.

Diagnostic Yield of Initial and Consecutive Blood Cultures in Children With Cancer and Febrile Neutropenia.

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 profile and support needs of parents in paediatric palliative care: comparing cancer and non-cancer groups.

BACKGROUND: Parents of children with life-limiting illnesses experience considerable burden and distress, yet few interventions have targeted their well-being. OBJECTIVES: Evaluate the use and feasibility of the Paediatric Carer Support Needs Assessment Tool (pCSNAT) in assessing and addressing parents' needs caring for cancer and non-cancer conditions. Carer well-being outcomes were also tested. METHODS: A non-randomised prospective intervention pilot study. Twenty-eight parents (out of 42 approached) and 5 health professionals working in paediatric palliative care services in Western Australia (2018-2019) completed the pilot study. RESULTS: Two-thirds of eligible parents completed the study. The highest support needs included having time for yourself; practical help in the home; knowing what to expect in the future; financial, legal or work issues; and knowing who to contact if you are concerned. Almost all needs were considerably more pronounced for the non-cancer group. The pCSNAT seemed feasible and outcomes demonstrated a tendency to improve. CONCLUSION: Using the pCSNAT provided a concise and comprehensive 'one stop shop' for health professionals to evaluate difficulties encountered by parents. The disadvantages reported by the non-cancer group warrant increased attention. Paediatric palliative care should adopt routine assessment of parents' support needs to anticipate early and tailored supports including partnerships with the community.

Neurodisability with Severe Restriction of Mobility Is Associated with Reduced Serum Creatinine Values.

INTRODUCTION: We investigated whether reduced mobility is associated with a reduction in serum creatinine in otherwise well children with neurodisability. MATERIALS AND METHODS: This was a record based retrospective study and creatinine levels of children in groups with Gross Motor Function Classification System (GMFCS) category 1, 2, or 3 (group I); GMFCS 4 or 5 (group II); and age matched controls (group III) were compared. RESULTS: Creatinine values were significantly different (p=0.002) between patients with neurodisability (mean 32.0 (SD 9.3), n=88) compared to patients without (mean 36.5 SD (9.8), n=88). There was no significant difference in creatinine levels (p=0.684) between group I (mean 35.6 (9.1), n=23) and group III (mean 36.5 (9.8), n=88). A significantly lower creatinine level (p<0.001) was found in group II (mean 30.7 (9.1), n=65) compared to group III and group I compared to group II (p=0.034). Creatinine levels were with a mean (SD) of 25.7 (4.1) micromol/l significantly lower in patients with GMFCS 4 or 5 who died (n=4) compared to survivors (31.1 (3.6)), (p=0.04, n=61). CONCLUSIONS: Children with neurodisability with severe mobility restriction had a significantly lower serum creatinine compared to controls with less severe or no neurodisability. Death in severe neurodisability may be associated with lower creatinine levels.

Management of Sarcoma in Adolescents and Young Adults: An Australian Population-Based Study.

Background: While overall survival (OS) for cancer in adolescents and young adults (AYA) has improved, there has been little change in AYA survival for several types of sarcomas. Using national data for Australia we describe (1) the treatment centers caring for AYA sarcoma, (2) treatments provided, and (3) survival outcomes. Procedure: National population-based study assessing treatment of 15-24 year-olds diagnosed with soft tissue sarcoma (STS), bone sarcoma (BS), and Ewing family tumors (ET) between 2007 and 2012. Treatment details were abstracted from hospital medical records. Treatment centers were classified as pediatric or adult specialist AYA/sarcoma center, or other adult. Cox proportional hazard regression analyses examined associations between type of treatment center and OS. Results: Sixty-one hospitals delivered treatment to 318 patients (135 STS; 91 BS, 92 ET), with 9%, 22%, and 17% of STS, BS, and ET, respectively, treated at pediatric and 62%, 59%, and 71% at adult specialist hospitals. Of 18-24 year-olds, 82% of BS, 90% of ET, and 73% of rhabdomyosarcomas at adult specialist centers were on a trial or standard protocol, compared with 42%, 89%, and 100%, respectively, at nonspecialist adult hospitals. After adjusting for disease and patient characteristics, survival was not associated with treatment center type for any disease type. However, ET survival was poorer for patients not receiving a standard chemotherapy protocol. Conclusions: Around 10% of AYA sarcoma patients attending adult hospitals were not on a standard protocol. Poorer survival for ET patients not on a standard protocol highlights the importance of ensuring all patients receive optimal care.

Clinical trial participation by adolescents and young adults with cancer: A continued cause for concern?

International data indicate that rates of clinical trial enrolment for Adolescents and Young Adults (AYAs) with cancer are markedly lower than for any other age group. This paper reviews the recent literature reporting international trends in clinical trial enrolment since 2010. Subsequently, we present the first population-based, national assessment of clinical trial enrolment for AYAs with cancer in Australia. Reported rates of trial enrolment from Australia, Canada, the United States, and the United Kingdom were variable, though consistently low, ranging between 2% and 29%. Trial enrolment was higher for younger AYAs (typically 15-19 years) and those attending pediatric hospitals, and this was replicated in the recent Australian data. The findings highlight a lack of substantial improvement in AYA clinical trial enrolment and in particular, a need for improved opportunities to access trials for patients treated at adult centers.

Factors influencing the provision of fertility counseling and impact on quality of life in adolescents and young adults with cancer.

PURPOSE: This study investigated the impact of fertility-related discussions on Adolescent and Young Adult (AYA) cancer patients' quality of life (QoL) and the factors influencing provision of these discussions. METHODS: Recruitment was conducted through population-based state cancer registries. Eligible AYAs were 15-24 years at diagnosis, 3-24 months postdiagnosis, with any cancer (except early stage melanoma). As part of a larger survey, AYAs were asked about their experiences of fertility-related discussions and QoL (FACT-G). RESULTS: Of the 207 AYAs returning surveys (29% response rate) 88% reported a discussion about infertility risks, 75% reported a discussion about preservation options and 59% were offered a referral to a fertility specialist. Patients attending health services with an AYA focus were more likely than those attending other types of centers to report discussions of fertility preservation (FP) options (85% versus 67%) and referrals (75% versus 49%). Social well-being was positively related to discussions about preservation options and being provided fertility risk information in a sensitive, supportive manner. CONCLUSIONS: Providing a sensitive and proactive discussion about fertility-related risks may benefit AYAs' well-being. Services with an AYA focus are fulfilling their mandate of ensuring optimal fertility-related care for AYA cancer patients.

"Pre-emptive strike"-the case for early treatment of hepatic sinusoidal obstruction syndrome with defibrotide.

The initial signs of hepatic sinusoidal obstruction syndrome (HSOS) can be challenging to recognize in children, especially outside the hematopoietic stem cell transplantation setting. To assist clinicians to promptly identify HSOS, the European Society for Blood and Marrow Transplantation has proposed pediatric HSOS diagnostic criteria which emphasize unexplained consumptive and transfusion-refractory thrombocytopenia. To highlight the importance of these "bellwether" early signs of HSOS and the efficacy of pre-emptive treatment with defibrotide, we describe the case of a child with a right 11th rib primitive neuroectodermal tumor who developed HSOS following focal radiotherapy and actinomycin-D treatment.