Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.

Incidence and survival for childhood cancer by endorsed non-stage prognostic indicators in Australia.

BACKGROUND: An international expert panel recently recommended 15 'non-stage prognostic indicators' (NSPIs) across eight childhood cancers, classified as essential or additional, for collection in population-based cancer registries. We aimed to describe the incidence distribution and survival of each of these NSPIs. PROCEDURES: Cases were extracted from the Australian Childhood Cancer Registry. The study cohort (n = 4187) comprised all children aged under 15 years diagnosed with an eligible cancer between 2010 and 2018, with follow-up until 31 December 2020. NSPI data were collected directly from each patient's medical records. Differences in 5-year relative survival were assessed using multivariable flexible parametric models, adjusted for sex and age group at diagnosis. RESULTS: The availability of data varied, exceeding 85% for all essential NSPIs apart from histologic subtype for Wilms tumours (69%) and lineage for acute lymphoblastic leukaemia (78%). Information on additional NSPIs tended to be recorded less often, particularly cytogenetic subtype for non-alveolar rhabdomyosarcoma (28%) and astrocytoma (4%). Eight NSPIs exhibited a significant difference in survival, with the largest disparity occurring among children with astrocytoma according to tumour grade (5-year relative survival of 18% for grade IV disease compared with 99% for grade I disease; p < .001). CONCLUSIONS: Our findings demonstrate that most of the recommended NSPIs can be retrieved from medical records in Australia in recent years, allowing the capability of assessing survival within patient subgroups of clinical interest. Reporting of NSPI data has the capability to inform local and global understanding of population-level disparities in childhood cancer survival.

Management of patients with diffuse intrinsic pontine glioma in Australia and New Zealand: Australian and New Zealand Children's Haematology/Oncology Group position statement.

INTRODUCTION: The main mission of the Australian and New Zealand Children's Haematology and Oncology Group (ANZCHOG) is to develop and facilitate local access to the world's leading evidence-based clinical trials for all paediatric cancers, including brain tumours, as soon as practically possible. Diffuse intrinsic pontine gliomas (DIPGs) - a subset of a larger group of tumours now termed diffuse midline glioma, H3K27-altered (DMG) - are paediatric brain cancers with less than 10% survival at two years. In the absence of any proven curative therapies, significant recent advancements have been made in pre-clinical and clinical research, leading many to seek integration of novel therapies early into standard practice. Despite these innovative therapeutic approaches, DIPG remains an incurable disease for which novel surgical, imaging, diagnostic, radiation and systemic therapy approaches are needed. MAIN RECOMMENDATIONS: All patients with DIPG should be discussed in multidisciplinary neuro-oncology meetings (including pathologists, neuroradiologists, radiation oncologists, neurosurgeons, medical oncologists) at diagnosis and at relapse or progression. Radiation therapy to the involved field remains the local and international standard of care treatment. Proton therapy does not yield a superior survival outcome compared with photon therapy and patients should undergo radiation therapy with the available modality (photon or proton) at their treatment centre. Patients may receive concurrent chemotherapy or radiation-sensitising agents as part of a clinical trial. Biopsy should be offered to facilitate consideration of experimental therapies and eligibility for clinical trial participation. After radiation therapy, each patient should be managed individually with either observation or considered for enrolment on a clinical trial, if eligible, after full discussion with the family. Re-irradiation can be considered for progressive disease. CHANGES IN MANAGEMENT AS A RESULT OF THE GUIDELINE: Every child diagnosed with DIPG should be offered enrolment on a clinical trial where available. Access to investigational drugs without biological rationale outside the clinical trial setting is not supported. In case of potentially actionable target identification with molecular profiling and absence of a suitable clinical trial, rational targeted therapies can be considered through compassionate access programs.

Grandparents' Experiences of Childhood Cancer: A Qualitative Study.

A child's cancer diagnosis has a significant impact on the lives of grandparents. Grandparents experience the stress of worrying about both their adult children and their grandchildren. Our study aimed to explore the lived experience of grandparents of children diagnosed with cancer. A qualitative design involving semi-structured interviews was used and data were analyzed using reflexive thematic analysis. Twenty grandparents aged 41 to 77 years were interviewed. Six themes were identified: (a) Diagnosis: changing everything; (b) Aspects of treatment: A different world; (c) Sandwich generation; (d) Family: Worrying about everyone; (e) Balancing work; and (f) It's like suddenly a door opens. Our study demonstrates the life-changing impact of having a grandchild diagnosed with cancer. It expands on existing knowledge and shows that, due to an aging population and demographic changes, some grandparents must juggle the demands of caring for aging family members and working while supporting adult children and grandchildren.

Children's Oncology Group's 2023 blueprint for research: Central nervous system tumors.

Tumors of the central nervous system (CNS) are a leading cause of morbidity and mortality in the pediatric population. Molecular characterization in the last decade has redefined CNS tumor diagnoses and risk stratification; confirmed the unique biology of pediatric tumors as distinct entities from tumors that occur in adulthood; and led to the first novel targeted therapies receiving Food and Drug Administration (FDA) approval for children with CNS tumors. There remain significant challenges to overcome: children with unresectable low-grade glioma may require multiple prolonged courses of therapy affecting quality of life; children with high-grade glioma have a dismal long-term prognosis; children with medulloblastoma may suffer significant short- and long-term morbidity from multimodal cytotoxic therapy, and approaches to improve survival in ependymoma remain elusive. The Children's Oncology Group (COG) is uniquely positioned to conduct the next generation of practice-changing clinical trials through rapid prospective molecular characterization and therapy evaluation in well-defined clinical and molecular groups.

Imaging of pediatric brain tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee/ASPNR White Paper.

Tumors of the central nervous system are the most common solid malignancies in children and the most common cause of pediatric cancer-related mortality. Imaging plays a central role in diagnosis, staging, treatment planning, and response assessment of pediatric brain tumors. However, the substantial variability in brain tumor imaging protocols across institutions leads to variability in patient risk stratification and treatment decisions, and complicates comparisons of clinical trial results. This White Paper provides consensus-based imaging recommendations for evaluating pediatric patients with primary brain tumors. The proposed brain magnetic resonance imaging protocol recommendations balance advancements in imaging techniques with the practicality of deployment across most imaging centers.

Intravascular Tumor Extension and Pulmonary Tumor Embolism in Children With Solid Malignancies: Is There a Role for Inferior Vena Cava Filters?

Intravascular tumor extension is an uncommon complication of solid malignancies that, when present in the inferior vena cava (IVC), can result in fatal pulmonary tumor embolism. Currently, neoadjuvant chemotherapy and surgery are the mainstays of treatment; however, there are no consensus guidelines for management. We describe three cases of pediatric solid malignancies with associated IVC extension and pulmonary tumor embolism. We hypothesize that there is scope for IVC filter placement in such cases to mitigate the risk of fatal pulmonary tumor embolism.

Fathers' Experiences of Childhood Cancer: A Phenomenological Qualitative Study.

Research has shown differences in how fathers and mothers respond to a child's cancer diagnosis. Previous studies have highlighted that sociocultural norm shape fathers' experiences of their child's cancer diagnosis. Our phenomenological qualitative study aimed to examine the lived experiences of fathers whose children have been diagnosed with cancer and explore the impact of sociocultural gender roles. Fathers whose children were currently receiving treatment or had completed treatment in the previous 15 months were recruited from across Australia. Twenty-one fathers were interviewed. Five themes were identified: (a) Your world falls apart: Diagnosis and treatment; (b) Care for the child: Just the way it is; (c) Keeping strong: Finding ways to cope; (d) Employment: Practical and emotional support at work; and (e) Guilt, relief, and grief: Facing death. This study demonstrates the profound impact of a child's diagnosis on fathers and demonstrates that societal-cultural norms influence fathers' experience of childhood cancer.

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.

Parents' Experiences of Childhood Cancer During the COVID-19 Pandemic: An Australian Perspective.

INTRODUCTION: COVID-19 has had far-reaching impacts including changes in work, travel, social structures, education, and healthcare. OBJECTIVE: This study aimed to explore the experiences of parents of children receiving treatment for cancer during the COVID-19 pandemic. METHODS: Parents whose children were currently in treatment for childhood cancer or had completed treatment in the previous 12 months, participated in semi-structured interviews, face-to-face or via teleconferencing. Thematic analysis was used to analyze the data. RESULTS: The sample consisted of 34 participants (17 fathers and 17 mothers) from all states across Australia. Median age 37.5 years (range 29-51, years, SD = 6.3). Five main themes were identified: "Welcome to the Club"; "Remote Work and Study"; "Silver Linings"; "The Loneliest Experience" with three sub-themes "Immediate Family"; "Friends"; and "Overseas Family" and "Lack of Support" with two sub-themes: "Community Support" and "Organized Support." CONCLUSION: These findings revealed contrasting experiences of the impact of the COVID-19 pandemic. For parents whose children were neutropenic, the pandemic provided benefits in increased community understanding of infection control. Parents also reflected that the movement to remote work made it easier to earn an income. In contrast, some parents observed that restrictions on visitors and family intensified feelings of isolation. Parents also described how the COVID-19 reduced access to support services. These findings contribute to an understanding of the multifaceted impacts of the COVID-19 pandemic on families of children with cancer.

'Torn in two': Experiences of Mothers Who Are Pregnant when Their Child Is Diagnosed With Cancer.

Mothers of children diagnosed with cancer have been shown to experience high rates of psychological distress and poor physical health. Pregnancy further increases the healthcare needs of mothers due to the marked physiological changes and psychological adaptations. Our study aimed to explore the experiences of mothers who were pregnant and/or had a baby while their older child was receiving treatment for cancer. Our study employed a qualitative description methodology using semi-structured interviews. Participants were recruited from across Australia via notices on social media sites and the distribution of flyers. The sample comprised 13 mothers who were pregnant and/or had a baby and had a child diagnosed with cancer who was under 17 years old. Thematic analysis was used to analyse the data from which six themes were identified: (1) an impossible balancing act, (2) mother's health and well-being, (3) creating certainty: birthing plans, (4) a bit of sunshine and a time to rest, (5) challenges of caring for the baby and (6) an unenviable position: doing my best versus feeling guilty. Our study demonstrates the additional challenges faced by mothers who are pregnant while their child is receiving cancer treatment. There is a need for a comprehensive and coordinated program that provides pregnant mothers with practical and psychological support. The implementation of such a program has the potential to improve health outcomes for all family members, particularly the mother and their newborn.

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

Incidence and survival for childhood central nervous system tumours in Australia, 1983-2016.

PURPOSE: To investigate incidence and survival of childhood tumours of the central nervous system (CNS) by histological subtype, tumour behaviour and tumour grade. METHODS: National, population-based data on all children under 15 years old diagnosed with a CNS tumour between 1983 and 2016 were sourced from the Australian Childhood Cancer Registry. Incidence rate trends were calculated using Joinpoint regression. Relative survival was calculated using the cohort method, with changes in survival over time by cancer type and tumour grade assessed by multivariable flexible parametric survival modelling. RESULTS: The study cohort included 4914 patients, with astrocytoma (n = 2181, 44%) and embryonal tumours (n = 931, 19%) the most common diagnostic subgroups. Almost half (n = 2181, 44%) of all tumours were classified as high grade (III or IV). Incidence rates increased by 29% between 1983 and 2016, with high grade tumours rising by an annual average of + 1.1% (95% CI = + 0.7%, + 1.5%, p < 0.001). 5-year survival for all patients combined was 72% (95% CI = 71-74%), ranging from 50% (46-54%) for those with other gliomas to 81% (79-83%) for astrocytoma (p < 0.001). Survival improved over time for grade II and III ependymomas but not for patients with astrocytoma irrespective of grade. CONCLUSION: Improvements in diagnostic technology leading to more precise tumour classification are likely to explain some of the differences in incidence rate trends by histological type and grade. While improvements in survival over time were noted for some tumours, outcomes remained poor among patients with high-grade astrocytoma.

Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Challenges in the Management of Childhood Intracranial Germ Cell Tumors in Middle-Income Countries: A 20-Year Retrospective Review From a Single Tertiary Center in Malaysia.

BACKGROUND: A higher incidence of pediatric intracranial germ cell tumors (iGCTs) in Asian countries compared with Western countries has been reported. In Malaysia, the literature regarding pediatric iGCTs have been nonexistent. The aim of this study was to review the management, survival, and long-term outcomes of pediatric iGCTs at a single tertiary center in Malaysia. PATIENTS AND METHODS: We retrospectively reviewed data from patients below 18 years of age with iGCTs treated at the University Malaya Medical Center (UMMC) from 1998 to 2017. RESULTS: Thirty-four patients were identified, with a median follow-up of 3.54 years. Sixteen (47%) patients had pure germinoma tumors (PGs), and the remaining patients had nongerminomatous germ cell tumors (NGGCTs). The median age was 12 years, with a male:female ratio of 4.7:1. Abnormal vision, headache with vomiting, and diabetes insipidus were the commonest presenting symptoms. Twenty-eight patients received initial surgical interventions, 24 were treated with chemotherapy, and 28 received radiotherapy. Eight patients experienced relapses. The 5- and 10-year event-free survival rates were similar at 61.1%±12.6% and 42.9%±12.1% for PG and NGGCT, respectively. The 5- and 10-year overall survival rates were the same at 75.5%±10.8% and 53.3%±12.3% for PG and NGGCT, respectively. Four patients died of treatment-related toxicity. Most of the survivors experienced good quality of life with satisfactory neurologic status. CONCLUSIONS: The survival rate of childhood iGCTs in UMMC was inferior to that reported in developed countries. Late diagnosis, poor adherence to treatment, and treatment-related complications were the contributing factors. Although these results highlight a single institution experience, they most likely reflect similar treatment patterns, outcomes, and challenges in other centers in Malaysia.

Conduct of neuro-oncology multidisciplinary team meetings and closing the "gaps" in the clinical management of childhood central nervous system tumors in a middle-income country.

PURPOSE: Multidisciplinary team meetings (MDTMs) are essential in the clinical management of pediatric central nervous system (CNS) tumors. Evaluations of the impact of MDTMs on childhood CNS tumors and clinicians' perspectives on their effectiveness are scarce. METHODS: We retrospectively reviewed the clinical data of pediatric patients (aged <18 years) with CNS tumors diagnosed and treated in the Pediatric Hematology-Oncology Division at the University Malaya Medical Center from 2008 to 2019. We also conducted a web-based survey of the core members of the multidisciplinary team to evaluate the impact of the MDTMs. RESULTS: During the pre-MDTM era (2008-2012), 29 CNS tumors were diagnosed and treated, and during the MDTM era (2014-2019), 49 CNS tumors were diagnosed and treated. The interval for histologic diagnosis was significantly shorter during the MDTM era (p=0.04), but the interval from diagnosis to chemotherapy or radiotherapy and the 5-year overall survival of the 78 patients did not improve (62.1% ± 9.0% vs. 68.8% ± 9.1%; p=0.184). However, the 5-year overall survival of patients with medulloblastoma or rare tumors significantly improved in the MDTM era (p=0.01). Key factors that contributed to delayed treatment and poor outcomes were postoperative complications, the facility's lack of infrastructure, poor parental education about early treatment, cultural beliefs in alternative medicine, and infection during chemotherapy. Eighteen clinicians responded to the survey; they felt that the MDTMs were beneficial in decision-making and enhanced the continuity of coordinated care. CONCLUSION: MDTMs significantly reduced the diagnostic interval and improved the overall outcomes. However, delayed treatment remains a major challenge that requires further attention.

Correction to: International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma.

There are two errors and one omission in the original article. Author Gottardo's correct name is Nicholas G. Gottardo, author Hulleman's correct affiliation is no. 3 (VUMC, Amsterdam), and the Acknowledgements should include the following sentence: "We would like to thank Dr Angel Montero Carcaboso (Hospital Sant Joan de Deu, Barcelona, Spain) for generously supplying the HSJD-DIPG007 cells."

"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.