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.

Neuropsychological assessment of paediatric brain tumour survivors: Factors associated with assessment.

AIM: Paediatric brain tumour survivors are at increased risk of neurocognitive deficits that affect their education. The aim of this study was to assess the proportion of brain tumour survivors who historically received a neuropsychological assessment and examine the demographic and treatment-related variables associated with neuropsychological assessment. A further aim was to determine the number and treatment profile of brain tumour survivors who would benefit from neuropsychological assessment. METHODS: Data from the New Zealand Children's Cancer Registry including treatments received, was used to identify children treated for a brain tumour at Starship Children's Hospital between January 2009 and December 2015. Clinical records were examined for evidence of a neuropsychological assessment in the form of a written report. Logistic regression models were used to determine factors associated with receipt of an assessment. RESULTS: Of the 132 brain tumour survivors, 37 (28.0%) had evidence of a neuropsychological assessment in their clinical records. In adjusted analysis, children who were treated with all three of surgery, chemotherapy and radiotherapy (n = 38) were more likely to have had an assessment (odds ratio: 12.90; 95% confidence interval: 4.76-34.93) than children who had either no treatment, chemotherapy alone, surgery alone or chemotherapy and surgery (n = 73). Treatment with radiotherapy alone or with either chemotherapy or surgery (n = 21) was not significantly associated with receipt of assessment (odds ratio = 2.40; 95% confidence interval: 0.69-8.37). CONCLUSIONS: It is important to identify the number of children who might benefit from neuropsychological assessment to inform prioritisation within existing resource and plan for additional resource if required. With a focus on reducing late effects, it is imperative that neuropsychological assessment is an integral component of a paediatric brain tumour programme.

Tailoring Strength Training Prescriptions for People with Rheumatoid Arthritis: A Scoping Review.

Introduction: Prescribing strength training (ST) for people with rheumatoid arthritis (RA) is complicated by factors (barriers and facilitators) that affect participation. It is unclear whether guidelines include recommendations beyond prescription parameters (frequency, intensity, time, type, volume, and progression) and adequately incorporate participation factors tailored to people with RA. Objective: To summarize available recommendations to aid in the tailoring of ST prescriptions for people with RA. Methods: Medline, Embase, and CINAHL databases and gray literature were searched for guidelines, recommendations, and review articles containing ST prescription recommendations for RA. Article screening and data extraction were performed in duplicate by two reviewers. Results: Twenty-seven articles met the inclusion criteria. The recommendations address RA-specific ST participation factors including: knowledge gaps (of equipment, ST benefits, disease), memory problems, the management of joint deformity, comorbidity, the fluctuating nature of the disease and symptoms (pain, stiffness, flares), fear avoidance, motivation, need for referral to other professionals, and provision of RA-specific resources. Conclusion: This review summarizes recommendations for tailoring ST prescriptions for people with RA. Future research is required to understand how pain, symptom assessment, and unaddressed ST participation factors like sleep and medication side effects can be addressed to support ST participation amongst people with RA.

Implementation of DNA Methylation Array Profiling in Pediatric Central Nervous System Tumors: The AIM BRAIN Project: An Australian and New Zealand Children's Haematology/Oncology Group Study.

DNA methylation array profiling for classifying pediatric central nervous system (CNS) tumors is a valuable adjunct to histopathology. However, unbiased prospective and interlaboratory validation studies have been lacking. The AIM BRAIN diagnostic trial involving 11 pediatric cancer centers in Australia and New Zealand was designed to test the feasibility of routine clinical testing and ran in parallel with the Molecular Neuropathology 2.0 (MNP2.0) study at Deutsches Krebsforschungszentrum (German Cancer Research Center). CNS tumors from 269 pediatric patients were prospectively tested on Illumina EPIC arrays, including 104 cases co-enrolled on MNP2.0. Using MNP classifier versions 11b4 and 12.5, we report classifications with a probability score ≥0.90 in 176 of 265 (66.4%) and 213 of 269 (79.2%) cases, respectively. Significant diagnostic information was obtained in 130 of 176 (74%) for 11b4, and 12 of 174 (7%) classifications were discordant with histopathology. Cases prospectively co-enrolled on MNP2.0 gave concordant classifications (99%) and score thresholds (93%), demonstrating excellent test reproducibility and sensitivity. Overall, DNA methylation profiling is a robust single workflow technique with an acceptable diagnostic yield that is considerably enhanced by the extensive subgroup and copy number profile information generated by the platform. The platform has excellent test reproducibility and sensitivity and contributes significantly to CNS tumor diagnosis.

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. Despite advances in other cancer types, the morbidity and survival outcomes of patients with glioma have remained relatively stagnant. Recently, there has been recognition that MAPK dysregulation is almost universally present in paediatric and adult gliomas. These findings, accompanying broad molecular characterization of gliomas, has aided prognostication and offered opportunities for clinical trials testing targeted agents. The use of targeted therapies in this disease represents a paradigm shift, although the biochemical complexities has resulted in unexpected challenges in the development of effective BRAF inhibitors. Despite these challenges, there are promising data to support the use of BRAF inhibitors alone and in combination with MEK inhibitors for patients with both low-grade and high-grade glioma across age groups. Safety and efficacy data demonstrate that many of the toxicities of these targeted agents are tolerable while offering objective responses. Newer clinical trials will examine the use of these therapies in the upfront setting. Appropriate duration of therapy and durability of response remains unclear in the glioma patient cohort. Longitudinal efficacy and toxicity data are needed. Furthermore, access to these medications remains challenging outside of clinical trials in Australia and New Zealand. Compassionate access is limited, and advocacy for mechanism of action-based drug approval is ongoing.

A scoping review of interventions to improve strength training participation.

BACKGROUND: Low participation rates (1-31%) and unique barriers to strength training (e.g., specialized knowledge, equipment, perceived complexity) suggest effective strength training interventions may differ from effective aerobic or general physical activity interventions. The purpose of this scoping review was to examine interventions used to improve strength training participation through mapping theory, intervention characteristics, prescription parameters, and behaviour change techniques. METHODS: Recommendations by Levac et al. (2010) and PRISMA-ScR were followed in the conduct and reporting of this review, respectively. Patients and exercise professionals participated in developing the research question and data extraction form, interpreting the findings, and drafting the manuscript. Medline, Embase, PsycINFO, CINAHL, SPORTDiscus, and PubMed databases (inception-December 2020) were searched. The inclusion criteria were (a) original peer-reviewed articles and grey literature, (b) intervention study design, and (c) behavioural interventions targeted towards improving strength training participation. Two reviewers performed data screening, extraction, and coding. The interventions were coded using the Behaviour Change Technique Taxonomy version 1. Data were synthesized using descriptive and frequency reporting. RESULTS: Twenty-seven unique interventions met the inclusion criteria. Social cognitive theory (n = 9), the transtheoretical model (n = 4), and self-determination theory (n = 2) were the only behaviour change theories used. Almost all the interventions were delivered face-to-face (n = 25), with the majority delivered by an exercise specialist (n = 23) in community or home settings (n = 24), with high variability in exercise prescription parameters. Instructions on how to perform the behaviour, behavioural practice, graded tasks, goal setting, adding objects to the environment (e.g., providing equipment), and using a credible source (e.g., exercise specialist delivery) comprised the most common behaviour change techniques. CONCLUSIONS: Our results highlight gaps in theory, intervention delivery, exercise prescription parameters, and behaviour change techniques for future interventions to examine and improve our understanding of how to most effectively influence strength training participation.

Development and testing of the rheumatoid arthritis quality of care survey.

OBJECTIVES: The Rheumatoid Arthritis (RA) Quality of Care Survey (RAQCS) was developed to measure care quality according to a previously developed national RA quality improvement framework. METHODS: The development of the RAQCS occurred over 3 phases. First, the survey was developed by a team of healthcare providers, researchers, and two patient partners based on the existing national quality framework's 21 performance measures (PMs) and strategic objectives. Second, cognitive debriefing interviews were conducted with individuals living with RA to identify survey clarity, appropriateness of survey questions, and response options. Third, the survey was revised and distributed to participants recruited from Rheum4U (rheumatology longitudinal cohort). Results were tabulated and compared with a chart audit of participant medical records. RESULTS: Fifty-three participants completed the RAQCS. High performance (i.e., ≥70% meeting PM) was observed for 13 of 20 PMs. Lower performance was seen for the remaining PMs, which included documentation of body mass index (BMI) and smoking status, discussion of physical activity goals, comorbidity management including risk assessments for cardiovascular health and fragility fractures and disease activity assessment. There was high agreement (≥70%) between the RAQCS and chart review for 9 of 20 PMs. CONCLUSIONS: High agreement was observed between the RAQCS and chart review for selected PMs. The RAQCS may also be a valuable tool for quality improvement for measures where data are not usually available through other sources. Further testing of the RAQCS is needed to ascertain its reliability and validity as a patient self-reported tool to measure RA care quality.

Characteristics of children ≤36 months of age with DIPG: A report from the international DIPG registry.

BACKGROUND: Children ≤36 months with diffuse intrinsic pontine glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. METHODS: Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. RESULTS: Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (P = .018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. CONCLUSIONS: Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

Strategies for developing and implementing a rheumatoid arthritis healthcare quality framework: a thematic analysis of perspectives from arthritis stakeholders.

OBJECTIVES: To obtain stakeholder perspectives to inform the development and implementation of a rheumatoid arthritis (RA) healthcare quality measurement framework. DESIGN: Qualitative study using thematic analysis of focus groups and interviews. SETTING: Arthritis stakeholders from across Canada including healthcare providers, persons living with RA, clinic managers and policy leaders were recruited for the focus groups and interviews. PARTICIPANTS: Fifty-four stakeholders from nine provinces. INTERVENTIONS: Qualitative researchers led each focus group/interview using a semistructured guide; the digitally recorded data were transcribed verbatim. Two teams of two coders independently analysed the transcripts using thematic analysis. RESULTS: Perspectives on the use of different types of measurement frameworks in healthcare were obtained. In particular, stakeholders advocated for the use of existing healthcare frameworks over frameworks developed in the business world and adapted for healthcare. Persons living with RA were less familiar with specific measurement frameworks, however, they had used existing online public forums for rating their experience and quality of healthcare provided. They viewed a standardised framework as potentially useful for assisting with monitoring the care provided to them individually. Nine guiding principles for framework development and 13 measurement themes were identified. Perceived barriers identified included access to data and concerns about how measures in the framework were developed and used. Effective approaches to framework implementation included having sound knowledge translation strategies and involving stakeholders throughout the measurement development and reporting process. Clinical models of care and health policies conducive to outcome measurement were highlighted as drivers of successful measurement initiatives. CONCLUSION: These important perspectives will be used to inform a healthcare quality measurement framework for RA.

Development of a Patient-centered Quality Measurement Framework for Measuring, Monitoring, and Optimizing Rheumatoid Arthritis Care in Canada.

OBJECTIVE: The aim of this study was to develop a patient-centered quality measurement framework to address a predefined vision statement and 7 strategic objectives for rheumatoid arthritis (RA) care that was developed in prior qualitative work with arthritis stakeholders. METHODS: One hundred forty-seven RA-related performance measures (PMs) were identified from a systematic review. A candidate list of 26 PMs meeting predefined criteria and addressing the strategic objectives previously defined was then assessed during a 3-round (R) modified Delphi. Seventeen panelists with expertise in RA, quality measurement, and/or lived experience with RA rated each PM on a 1-9 scale based on the items of importance, feasibility, and priority for inclusion in the framework during R1 and R3, with a moderated discussion in R2. PMs with median scores ≥ 7 on all 3 items without disagreement were included in the final set, which then underwent public comment. RESULTS: Twenty-one measures were included in the final framework (15 PMs from the Delphi and 6 published system-level measures on access to care and treatment). The measures included 4 addressing early access to care and timely diagnosis, 12 evidence-based care for RA and related comorbidities, 1 addressing patient participation as an informed partner in care, and 4 on patient outcomes. CONCLUSION: The proposed framework builds upon existing measures capturing early access to care and treatment in RA and adds important PMs to promote high-quality RA care and outcome measurement. In the next phase, the authors will test the framework in clinical practice in addition to addressing certain areas where no suitable PMs were identified.

Priorities for High-quality Care in Rheumatoid Arthritis: Results of Patient, Health Professional, and Policy Maker Perspectives.

OBJECTIVE: To elucidate the essential elements of high-quality rheumatoid arthritis (RA) care in order to develop a vision statement and a set of strategic objectives for a national RA quality framework. METHODS: Focus groups and interviews were conducted by experienced qualitative researchers using a semistructured interview or focus group guide with healthcare professionals, patients, clinic managers, healthcare leaders, and policy makers to obtain their perspectives on elements essential to RA care. Purposive sampling provided representation of stakeholder types and regions. Recorded data was transcribed verbatim. Two teams of 2 coders independently analyzed the deidentified transcripts using thematic analysis. Strategic objectives and the vision statement were drafted based on the overarching themes from the qualitative analysis and finalized by a working group. RESULTS: A total of 54 stakeholders from 9 Canadian provinces participated in the project (3 focus groups and 19 interviews). Seven strategic objectives were derived from the qualitative analysis representing the following themes: (1) early access and timeliness of care; (2) evidence-informed, high-quality care for the ongoing management of RA and comorbidities; (3) availability of patient self-management tools and educational materials for shared decision making; (4) multidisciplinary care; (5) patient outcomes; (6) patient experience and satisfaction with care; and (7) equity, the last of which emerged as an overarching theme. The ultimate vision obtained was "ensuring patient-centered, high-quality care for people living with rheumatoid arthritis." CONCLUSION: The 7 strategic objectives that were identified highlight priorities for RA quality of care to be used in developing the National RA Quality Measurement Framework.

Implementation and Evaluation of Audit and Feedback for Monitoring Treat-to-Target (T2T) Strategies in Rheumatoid Arthritis Using Performance Measures.

INTRODUCTION: In collaboration with the Alberta Medical Association's Physician Learning Program we developed individualized physician reports and held a group feedback session on rheumatoid arthritis (RA) performance measures (PM) to facilitate treat-to-target (T2T) strategies and evaluated physician experiences with this process. METHODS: 5 PMs addressing T2T concepts from an established Canadian quality framework were operationalized for physician practice reports at 2 university-affiliated rheumatology clinics. Rheum4U, a quality improvement and research platform, was the data source. The audit results were reviewed in a facilitated group feedback session. Rheumatologists provided experiential feedback on the process through survey and/or an interview. Transcripts from interviews were analyzed using a 6-step thematic analysis. RESULTS: 11 of 12 eligible rheumatologists consented to receive practice reports and provided feedback through surveys (n = 5) and interviews (n = 6). The practice reports from Rheum4U (n = 448 patients) revealed high rates of yearly follow-up (> 85%, PM1) and 100% performance on documentation of disease activity at ≥ 50% of visits (PM2). Only 34% of patients were seen within 3 months if not in remission (PM3) with 62% (2017) and 69% (2018) of those with active RA achieving a LDA state within 6 months (PM4). Approximately 70% of patients were in remission at any time point (PM5). All survey respondents agreed or strongly agreed comparison to peers was valuable and helped them reflect on their practice. Several strategies for improvement were identified, including but not limited to, leveraging of electronic records for future audit and feedback reports, providing additional granularity of results, additional stratification of results, and using high-performing peers as the comparator rather than the group mean. CONCLUSIONS: Audit and feedback was perceived by clinicians as a useful strategy for evaluating T2T efforts in RA. Future work will focus on longitudinal evaluation of the clinical impact of this quality improvement initiative.

Exploring older adults' perceptions of a patient-centered education manual for hip fracture recovery: "everything in one place".

PURPOSE: To describe older adults' perspectives on a new patient education manual for the recovery process after hip fracture. MATERIALS AND METHODS: The Fracture Recovery for Seniors at Home (FReSH) Start manual is an evidence-based manual for older adults with fall-related hip fracture. The manual aims to support the transition from hospital to home by facilitating self-management of the recovery process. We enrolled 31 community-dwelling older adults with previous fall-related hip fracture and one family member. We collected data using a telephone-based questionnaire with eight five-point Likert items and four semi-structured open-ended questions to explore participants' perceptions on the structure, content, and illustration of the manual. The questionnaire also asked participants to rate the overall utility (out of 10 points) and length of the manual. We used content analysis to describe main themes from responses to the open-ended interview questions. RESULTS: Participants' ratings for structure, content, and illustrations ranged from 4 to 5 (agree to highly agree), and the median usefulness rating was 9 (10th percentile: 7, 90th percentile: 10). Main themes from the content analysis included: ease of use and presentation; health literacy; illustration utility; health care team delivery; general impression, information support from hospital to home; emotional and decision-making support; and the novelty of the manual. CONCLUSION: The FReSH Start manual was perceived as comprehensive in content and acceptable for use with older adults post-fall-related hip fracture. Participants expressed a need for delivery and explanation of the manual by a health care team member.

Subsequent neoplasms in survivors of childhood central nervous system tumors: risk after modern multimodal therapy.

BACKGROUND: Multimodal therapy has improved survival for some childhood CNS tumors. However, whether risk for subsequent neoplasms (SNs) also increases is unknown. We report the cumulative incidence of, and risk factors for, SNs after a childhood primary CNS tumor and determine whether treatment that combines radiation therapy (RT) with chemotherapy increases risk for SNs. METHODS: Analyses included 2779 patients with a primary CNS tumor treated at St Jude Children's Research Hospital between 1985 and 2012. Cumulative incidence and standardized incidence ratios (SIRs) were estimated for SNs confirmed by pathology report. Cumulative incidence among the 237 five-year medulloblastoma survivors treated with multimodal therapy (RT + chemotherapy) was compared with a historical cohort of 139 five-year survivors treated with RT but no chemotherapy in the Childhood Cancer Survivor Study. RESULTS: Eighty-one survivors had 97 SNs. The cumulative incidence of first SN was 3.0% (95% CI: 2.3%-3.9%) at 10 years, and 6.0% (95% CI: 4.6%-7.7%) at 20 years from diagnosis. Risks were highest for subsequent glioma, all grades (SIR = 57.2; 95% CI: 36.2-85.8) and acute myeloid leukemia (SIR = 31.8; 95% CI: 10.2-74.1). Compared with RT alone, RT + chemotherapy did not increase risk for SNs (hazard ratio: 0.64; 95% CI: 0.38-1.06). Among five-year survivors of medulloblastoma treated with multimodal therapy, cumulative incidence of SN was 12.0% (95% CI: 6.4%-19.5%) at 20 years, no different than survivors treated with RT alone (11.3%, P = .44). CONCLUSION: The cumulative incidence of SNs continues to increase with time from treatment with no obvious plateau, but the risk does not appear to be higher after exposure to multimodal therapy compared with RT alone. Continued follow-up of survivors as they age is essential.