Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial.

Background: Due to their anatomical locations, optic pathway gliomas (OPGs) can rarely be cured by resection. Given the importance of preserving visual function, we analyzed radiological and visual acuity (VA) outcomes for the type II RAF inhibitor tovorafenib in the OPG subgroup of the phase 2 FIREFLY-1 trial.

Methods: FIREFLY-1 investigated the efficacy (arm 1, n=77), safety, and tolerability (arms 1/2) of tovorafenib (420 mg/m2 once weekly; 600 mg maximum) in patients with BRAF-altered relapsed/refractory pediatric low-grade glioma (pLGG).

Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma: A Phase 2 Randomized Clinical Trial.

Importance: The combination of ifosfamide and etoposide (IE) is commonly used to treat relapsed or refractory osteosarcoma; however, second-line treatment recommendations vary across guidelines.

Objective: To evaluate whether the addition of lenvatinib to IE (LEN-IE) improves outcomes in children and young adults with relapsed or refractory osteosarcoma.

Design, Setting, And Participants: The OLIE phase II, open-label, randomized clinical trial was conducted globally across Europe, Asia and the Pacific, and North America.

A Phase 1 Study of Intravenous EGFR-ErbituxEDVsMIT in Children with Solid or CNS Tumours Expressing Epidermal Growth Factor Receptor.

Background: Recurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV.

Quantitative ctDNA Detection in Hepatoblastoma: Implications for Precision Medicine.

Hepatoblastoma is characterized by driver mutations in , making it an attractive biomarker for a liquid biopsy approach utilizing circulating tumor DNA (ctDNA). This prospective observational study sought to ascertain the feasibility of ctDNA detection in patients with hepatoblastoma and explore its associations with established clinical indicators and biomarkers, including serum Alpha-fetoprotein (AFP). We obtained 38 plasma samples and 17 tumor samples from 20 patients with hepatoblastoma.

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma.

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG.

BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience.

The mitogen-activated protein kinase (MAPK) pathway signaling pathway is one of the most commonly mutated pathways in human cancers. In particular, BRAF alterations result in constitutive activation of the rapidly accelerating fibrosarcoma-extracellular signal-regulated kinase-MAPK significant pathway, leading to cellular proliferation, survival, and dedifferentiation. The role of BRAF mutations in oncogenesis and tumorigenesis has spurred the development of targeted agents, which have been successful in treating many adult cancers.

A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer.

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.

In vitro and in vivo drug screens of tumor cells identify novel therapies for high-risk child cancer.

Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found.

"We Have All This Knowledge to Give, So Use Us as a Resource": Partnering with Adolescent and Young Adult Cancer Survivors to Determine Consumer-Led Research Priorities.

Involvement of adolescent and young adult (AYAs) cancer survivors as consumers in research is increasingly encouraged, yet few studies have identified the feasibility and acceptability of methods used to involve them. We aimed to identify: (1) How feasible and acceptable is a consumer-driven, workshop-based research priority-setting approach? And (2) what research priorities do Australian AYA consumers endorse? AYA cancer survivors diagnosed 15-30 years old and currently younger than 35 years were invited to participate. The AYAs completed a pre-workshop survey to rank their top three priorities from the United Kingdom-based James Lind Alliance list, participated in a 90-minute focus group, and completed a post-workshop evaluation survey.

Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and Genotyping via Cell-Free Circulating Tumor DNA Profiling.

Background: amplification (MNA), segmental chromosomal aberrations (SCA) and activating mutations are biomarkers for risk-group stratification and for targeted therapeutics for neuroblastoma, both of which are currently assessed on tissue biopsy. Increase in demand for tumor genetic testing for neuroblastoma diagnosis is posing a challenge to current practice, as the small size of the core needle biopsies obtained are required for multiple molecular tests. We evaluated the utility of detecting these biomarkers in the circulation.

Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03).

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.

Metabolic response as assessed by F-fluorodeoxyglucose positron emission tomography-computed tomography does not predict outcome in patients with intermediate- or high-risk rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

Background: Strategies to optimize management in rhabdomyosarcoma (RMS) include risk stratification to assign therapy aiming to minimize treatment morbidity yet improve outcomes. This analysis evaluated the relationship between complete metabolic response (CMR) as assessed by F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET) imaging and event-free survival (EFS) in intermediate-risk (IR) and high-risk (HR) RMS patients.

Methods: FDG-PET imaging characteristics, including assessment of CMR and maximum standard uptake values (SUVmax) of the primary tumor, were evaluated by central review.

Exploration of CTNNB1 ctDNA as a putative biomarker for hepatoblastoma.

Driver mutations in the CTNNB1 gene (encoding β-catenin) are a hallmark of sporadic hepatoblastoma (HBL). Our results show that CTNNB1 circulating tumour DNA (ctDNA) is readily detected in patients diagnosed with localised HBL, with serial sampling along the course of therapy and follow up providing a sensitive mechanism to monitor tumour dynamics and response to treatment. This exciting potential for CTNNB1 ctDNA to serve as a biomarker for treatment response in HBL holds clinical value, and requires assessment in a larger cohort of mixed tumour stages and recurrent disease.

Chimeric Antigen Receptor-modified T cells targeting EphA2 for the immunotherapy of paediatric bone tumours.

Chimeric Antigen Receptor (CAR) T-cell therapy, as an approved treatment option for patients with B cell malignancies, demonstrates that genetic modification of autologous immune cells is an effective anti-cancer regimen. Erythropoietin-producing Hepatocellular receptor tyrosine kinase class A2 (EphA2) is a tumour associated antigen expressed on a range of sarcomas, including paediatric osteosarcoma (OS) and Ewing sarcoma (ES). We tested human EphA2 directed CAR T cells for their capacity to target and kill human OS and ES tumour cells using in vitro and in vivo assays, demonstrating that EphA2 CAR T cells have potent anti-tumour efficacy in vitro and can eliminate established OS and ES tumours in vivo in a dose and delivery route dependent manner.

Accelerating development of high-risk neuroblastoma patient-derived xenograft models for preclinical testing and personalised therapy.

Background: Predictive preclinical models play an important role in the assessment of new treatment strategies and as avatar models for personalised medicine; however, reliable and timely model generation is challenging. We investigated the feasibility of establishing patient-derived xenograft (PDX) models of high-risk neuroblastoma from a range of tumour-bearing patient materials and assessed approaches to improve engraftment efficiency.

Methods: PDX model development was attempted in NSG mice by using tumour materials from 12 patients, including primary and metastatic solid tumour samples, bone marrow, pleural fluid and residual cells from cytogenetic analysis.

Long-term morbidity of respiratory viral infections during chemotherapy in children with leukaemia.

Background: Respiratory viruses are a common cause of infection in immunosuppressed children undergoing cancer therapy. Pulmonary sequelae have been documented following respiratory viral infections (RVIs) in hematopoietic stem cell transplant (HSCT) recipients; however potential late effects in children undergoing nonmyeloablative chemotherapy have not been investigated.

Aim: To evaluate the long-term pulmonary morbidity of respiratory viral infections during chemotherapy in children with acute lymphoblastic leukemia (ALL).

Pre-irradiation intensive induction and marrow-ablative consolidation chemotherapy in young children with newly diagnosed high-grade brainstem gliomas: report of the "head-start" I and II clinical trials.

Background: The dismal outcome in children with high-grade brainstem gliomas (BSG) accentuates the need for effective therapeutic strategies. We investigated the role of intensive, including marrow-ablative, chemotherapy regimens in the treatment of young children with newly-diagnosed high-grade BSG.

Methods: Between 1991-and-2002, 15 eligible children less than 10 years of age with a diagnosis of high-grade BSG were treated on "Head-Start" I and II protocols (HSI and HSII).

Emergency Ross Procedure for Pediatric Aortic Valve Myxofibrosarcoma.

Primary cardiac tumors in children are uncommon and rarely demand surgical intervention. We report a malignant tumor arising from the aortic root in a 5-year-old boy presenting with left ventricular outflow tract obstruction and tumor embolism, its surgical management using the Ross procedure, and the unique histopathological aspects of the tumor.

Psychosocial Assessment Using Telehealth in Adolescents and Young Adults With Cancer: A Partially Randomized Patient Preference Pilot Study.

Background: Adolescent and young adults with cancer are at increased risk of psychosocial difficulties relative to their healthy peers. Current models of inpatient face-to-face psychosocial care might limit the capacity for clinicians to provide timely and personalized assessment and intervention for this group. Telehealth offers a promising alternative toward increasing access to the provision of evidence-based psychosocial assessment and treatment for adolescent and young adults with cancer.