Discovery of novel predisposing coding and noncoding variants in familial Hodgkin lymphoma.

Familial aggregation of Hodgkin lymphoma (HL) has been demonstrated in large population studies, pointing to genetic predisposition to this hematological malignancy. To understand the genetic variants associated with the development of HL, we performed whole genome sequencing on 234 individuals with and without HL from 36 pedigrees that had 2 or more first-degree relatives with HL. Our pedigree selection criteria also required at least 1 affected individual aged <21 years, with the median age at diagnosis of 21.98 years (3-55 years). Family-based segregation analysis was performed for the identification of coding and noncoding variants using linkage and filtering approaches. Using our tiered variant prioritization algorithm, we identified 44 HL-risk variants in 28 pedigrees, of which 33 are coding and 11 are noncoding. The top 4 recurrent risk variants are a coding variant in KDR (rs56302315), a 5' untranslated region variant in KLHDC8B (rs387906223), a noncoding variant in an intron of PAX5 (rs147081110), and another noncoding variant in an intron of GATA3 (rs3824666). A newly identified splice variant in KDR (c.3849-2A>C) was observed for 1 pedigree, and high-confidence stop-gain variants affecting IRF7 (p.W238∗) and EEF2KMT (p.K116∗) were also observed. Multiple truncating variants in POLR1E were found in 3 independent pedigrees as well. Whereas KDR and KLHDC8B have previously been reported, PAX5, GATA3, IRF7, EEF2KMT, and POLR1E represent novel observations. Although there may be environmental factors influencing lymphomagenesis, we observed segregation of candidate germline variants likely to predispose HL in most of the pedigrees studied.

Treatment of high-risk Hodgkin lymphoma with a modified Stanford V regimen in the AHOPCA: Substituting chemotherapy agents and hampered outcomes.

BACKGROUND/OBJECTIVES: High-risk Hodgkin lymphoma (HRHL) in children is curable with combined modality therapy. The Association of Pediatric Hematology-Oncology of Central America (AHOPCA) is a consortium of cancer centers from Central America. In 2004, AHOPCA implemented a guideline with a short course of chemotherapy (mStanfordV), strict diagnostics, and radiation guidelines, aimed at reducing abandonment and improving outcomes. METHODS: Newly diagnosed children less than 18 years of age with high-risk HL (Ann Arbor stages: IIB, IIIB, IV) from AHOPCA centers were staged with chest radiography and ultrasound or computed tomography. Therapy was a modified Stanford V (mStanfordV), substituting cyclophosphamide for mechlorethamine and involved field radiation. RESULTS: Of 219 patients with HRHL, 181 patients were eligible and evaluable; 146 (81%) were boys, 22% being less than 6 years; 43 were stage IIB, 84 IIIB, and 54 IV. Thirty-one (17%) abandoned therapy, 28 (15%) progressed, 30 (17%) relapsed, and eight (4%) died of toxicity. Radiation guidelines were not followed. Five-year abandonment-sensitive event-free survival and overall survival (AS-EFS, AS-OS ± SE) for the cohort were 46% ± 4% and 56% ± 4%; 5-year AS-OS for stages IIB, IIIB, and IV was 76% ± 7%, 59% ± 7%, and 35% ± 7% (p = .0006). CONCLUSION: Despite instituting a short treatment guideline, it did not improve the abandonment rate (17%) and did not achieve the reported outcomes of Stanford V. The cyclophosphamide dose used to replace merchlorethamine was inadequate. Despite strict guidelines, the radiation therapy application was inaccurate. Weekly chemotherapy may have adversely affected abandonment of therapy by increasing the burden of travel time. Based on these results, AHOPCA established a new abandonment strategy and a new guideline.

Development of EPAT: An assessment tool for pediatric hematology/oncology training programs.

PURPOSE: In the absence of a standardized tool to assess the quality of pediatric hematology/oncology training programs, the Education Program Assessment Tool (EPAT) was conceptualized as a user-friendly and adaptable tool to evaluate and identify areas of opportunity, pinpoint needed modifications, and monitor progress for training programs around the world. METHODS: The development of EPAT consisted of three main phases: operationalization, consensus, and piloting. After each phase, the tool was iteratively modified based on feedback to improve its relevance, usability, and clarity. RESULTS: The operationalization process led to the development of 10 domains with associated assessment questions. The two-step consensus phase included an internal consensus phase to validate the domains and a subsequent external consensus phase to refine the domains and overall function of the tool. EPAT domains for programmatic evaluation are hospital infrastructure, patient care, education infrastructure, program basics, clinical exposure, theory, research, evaluation, educational culture, and graduate impact. EPAT was piloted in five training programs in five countries, representing diverse medical training and patient care contexts for proper validation of the tool. Face validity was confirmed by a correlation between the perceived and calculated scores for each domain (r = 0.78, p < .0001). CONCLUSIONS: EPAT was developed following a systematic approach, ultimately leading to a relevant tool to evaluate the different core elements of pediatric hematology/oncology training programs across the world. With EPAT, programs will have a tool to quantitatively evaluate their training, allowing for benchmarking with centers at the local, regional, and international level.

Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia.

There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with wild-type ETV6 with potentially dominant-negative effects. Whole-transcriptome and whole-genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy-number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both acute myeloid leukemia and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by assay for transposase-accessible chromatin sequencing profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.

SACCSG HL-2018. Barriers and enablers of a harmonized treatment protocol for childhood and adolescent Hodgkin lymphoma in South Africa.

Introduction: Collaborative studies have contributed to improved survival of pediatric Hodgkin lymphoma in well-resourced settings, but few are documented in resource-constrained countries. The South Africa Children's Cancer Study Group initiated harmonization of management protocols in 2015. This article analyzes barriers and enablers of the process. Methods: Clinician-researchers at 11 state-funded pediatric oncology units completed preparatory questionnaires in June 2018. Parameters included infrastructure, access to therapeutic modalities and clinician numbers. A reassessment of 13 sites (two new pediatric oncology unit) in February 2021 ascertained changes in resources and identified challenges to full participation. Questions investigated the presence and quality of diagnostic radiology, availability of surgeons, cytology/pathology options and hematology laboratory facilities. Results: The response rate was 11/11 to survey 1 and 13/13 to survey 2. The anticipated pre-study barriers to participation of pediatric oncology units included time constraints and understaffing. PET-CT was unavailable to two centers. The majority of pediatric oncology units met the minimum criteria to participate. The interim survey confirmed chemotherapy and radiotherapy availability nearly 100% of the time. One site reported improved access to radiotherapy while another reported improved access to PET-CT. Barriers to participation included excessive times to obtain regulatory approvals, time constraints and lack of dedicated research staff. Enablers include the simple management algorithm and communication tools. Conclusion: This study demonstrates that multicenter collaboration and harmonization of management protocols are achievable in a middle-income setting. Minimal funding is required but full participation to run high-quality studies requires more financial investment. Focused funding and increased prioritization of research may address systemic barriers to full participation.

Regional collaboration for the development of national childhood cancer plans in Latin America and the Caribbean.

This article aims to describe the activities conducted by the National Childhood Cancer Plan Working Group to support the development of national childhood cancer plans in Latin America and the Caribbean in the period 2019-2022, and to present the stage of plan development. The Working Group activities were supported by the Pan American Health Organization and St. Jude Children's Research Hospital, which is the World Health Organization (WHO) Collaborating Centre for Childhood Cancer. Year after year, the workshops and activities developed with the Working Group mobilized key stakeholders: pediatric oncologists, representatives of the Ministry of Health, foundations supporting childhood cancer initiatives, and hospital administrators. As of February 2023, one regional framework is in place, approved by the Council of Ministries of Health of Central America and the Dominican Republic, nine countries are currently implementing national plans or laws that include childhood cancer, and ten countries are writing new plans. The WHO three-step framework helped to guide the Working Group activities. All plans were supported by a situational analysis, which highlighted the importance of having systematized data for evidence-based policies. To increase implementation success, an accompanying budget and timeline help to ensure the adequate implementation of the interventions. More than anything, committed stakeholders remain the most fundamental element to successfully write and approve a national childhood cancer plan. This is an opportunity to share these countries' experience so the strategy can be adapted to support other countries developing a childhood cancer plan and extended to other public health areas.

En este artículo se describen las actividades realizadas por el grupo de trabajo del plan nacional contra el cáncer infantil dirigidas a brindar apoyo para la formulación de planes nacionales contra el cáncer infantil en América Latina y el Caribe en el período 2019-2022, así como la presentación de la etapa de formulación de los planes. Las actividades del Grupo de Trabajo contaron con el apoyo de la Organización Panamericana de la Salud y el St. Jude Children's Research Hospital, que es el centro colaborador de la Organización Mundial de la Salud (OMS) contra el cáncer infantil. Año tras año, los talleres y actividades llevados a cabo con el grupo de trabajo han logrado convocar a las principales partes interesadas: especialistas en oncología pediátrica, representantes del Ministerio de Salud, fundaciones que apoyan iniciativas contra el cáncer infantil y gerentes de los hospitales. Desde febrero del 2023, existe un marco regional, aprobado por el Consejo de Ministerios de Salud de Centroamérica y República Dominicana; nueve países ya están aplicando planes o leyes nacionales en los que se incluye el cáncer infantil, y diez países están redactando nuevos planes. Para orientar las actividades del Grupo de Trabajo, se recurrió al marco en tres pasos de la OMS. Todos los planes se sustentaron en un análisis de situación lo que subraya la importancia de contar con datos sistematizados para que las políticas puedan estar basadas en evidencias. Asimismo, si se pretende aumentar el éxito de la aplicación, sería conveniente contar con un presupuesto y un cronograma que aseguren la aplicación adecuada de las intervenciones. Las partes interesadas implicadas siguen siendo, ante todo, el componente más trascendente en la redacción y aprobación exitosa de un plan nacional contra el cáncer infantil. Esta es una oportunidad para transmitir la experiencia de estos países, con el fin de que la estrategia pueda adaptarse para brindar apoyo a otros países que estén elaborando un plan contra el cáncer infantil y que puede hacerse extensiva a otros ámbitos de la salud pública.

Este artigo visa a descrever as atividades realizadas pelo Grupo de Trabalho para Planos Nacionais de Combate ao Câncer infantil a fim de prestar apoio ao desenvolvimento de planos nacionais de combate ao câncer infantil na América Latina e no Caribe no período de 2019 a 2022 e apresentar a atual fase de desenvolvimento dos planos. As atividades do Grupo de Trabalho receberam apoio da Organização Pan-Americana da Saúde e do St. Jude Children's Research Hospital, o Centro Colaborador em Câncer infantil da Organização Mundial da Saúde (OMS). Ano após ano, as oficinas e atividades desenvolvidas com o Grupo de Trabalho mobilizaram as principais partes interessadas: oncologistas pediátricos, representantes dos ministérios da saúde, fundações que apoiam iniciativas de combate ao câncer infantil e administradores de hospitais. Até fevereiro de 2023, havia uma estrutura regional em vigor aprovada pelo Conselho de Ministros da Saúde da América Central e da República Dominicana, nove países estavam implementando planos ou leis nacionais que incluíam o câncer infantil e dez países estavam elaborando novos planos. A estrutura de três etapas da OMS ajudou a orientar as atividades do Grupo de Trabalho. Todos os planos estavam embasados em uma análise situacional, o que destacou a importância de dispor de dados sistematizados para políticas baseadas em evidências. Para aumentar o sucesso da implementação, um orçamento e um cronograma correspondentes ajudam a garantir a implementação adequada das intervenções. Acima de tudo, o compromisso das partes interessadas continua sendo o elemento mais fundamental para elaborar e aprovar com sucesso um plano nacional de combate ao câncer infantil. Esta é uma oportunidade de compartilhar a experiência desses países para que a estratégia possa ser adaptada a fim de apoiar outros países na elaboração de um plano de combate ao câncer infantil e possa ser estendida a outras áreas de saúde pública.

Partnering to implement the Global Initiative for Childhood Cancer in the Americas: prioritizing systems strengthening.

Working with PAHO/WHO to prioritize childhood cancer in the context of systems strengthening is central to St. Jude Children's Research Hospital (SJCRH)'s role as WHO Collaborating Centre for Childhood Cancer. This manuscript focuses on how SJCRH and PAHO/WHO have partnered to apply C5 (Country Collaboration for Childhood Cancer Control) to define and implement priority actions regionally, strengthening Ministry programs for childhood cancer, while implementing the Global Initiative for Childhood Cancer since 2018. Using C5, a tool developed by SJCRH, PAHO/WHO and SJCRH co-hosted regional/national workshops engaging authorities, clinicians and other stakeholders across 10 countries to map health systems needs and prioritize strategic activities (spanning Central America, Dominican Republic, Haiti, Brazil and Uruguay). SJCRH provided English/Spanish/Portuguese C5 versions/templates for analysis/prioritization exercises, and worked with PAHO/WHO and country teams to implement C5, analyze findings, and develop outputs. In an eight-country regional workshop, countries defined priorities within national/regional initiatives and ranked their value and political will, incorporating country-specific surveys and stakeholder dialogues. Each country prioritized one strategic activity for 2022-2023, exchanged insights via storytelling, and disseminated and applied results to inform country-specific and regional action plans. National workshops analyses have been incorporated into cancer control planning activities and collaborative work regionally. Implementation success factors include engaging actors beyond the clinic, enabling flexibility, and focusing on co-design with stakeholders. Joint implementation of C5 catalyzed prioritization and accelerated strategic activities to improve policies, capacity, and quality of care for children in the Americas, supporting Ministries to integrate childhood cancer interventions as part of systems strengthening.

La colaboración con la OPS/OMS para priorizar el cáncer infantil en el contexto del fortalecimiento de los sistemas es fundamental para la labor del St. Jude Children's Research Hospital (SJCRH) como centro colaborador de la OMS contra el cáncer infantil. Este artículo se centra en la alianza entre el SJCRH y la OPS/OMS en la aplicación de la herramienta C5 (colaboración nacional para el control del cáncer infantil) para definir y ejecutar medidas prioritarias a nivel regional, fortalecer los programas contra el cáncer infantil del ministerio y poner en marcha la Iniciativa Mundial contra el Cáncer Infantil desde el 2018. Con C5, una herramienta elaborada por el SJCRH, la OPS/OMS y este hospital organizaron conjuntamente talleres regionales y nacionales con autoridades, personal médico y otras partes interesadas en diez países para determinar cuáles son las necesidades de los sistemas de salud y priorizar las actividades estratégicas (en América Central, República Dominicana, Haití, Brasil y Uruguay). El SJCRH proporcionó versiones y plantillas de C5 en inglés, español y portugués para actividades de análisis y priorización y trabajó con la OPS/OMS y los equipos de país para ejecutar la herramienta C5, analizar los resultados y elaborar productos. En un taller regional de ocho países, se definieron las prioridades en las iniciativas regionales y nacionales, se clasificó su valor y la voluntad política y se incorporaron encuestas específicas para cada país y diálogos con las partes interesadas. Cada país priorizó una actividad estratégica para el período 2022-2023, intercambió ideas por medio de narrativas, y difundió y aplicó los resultados para fundamentar planes de acción tanto regionales como específicos para el país. Los análisis de los talleres nacionales se han incorporado a las actividades de planificación del control del cáncer y al trabajo colaborativo a nivel regional. Entre los factores de éxito de la ejecución se encuentra involucrar a los agentes más allá de lo clínico, permitir que haya flexibilidad y centrarse en un diseño elaborado en colaboración con las partes interesadas. La ejecución conjunta de la herramienta C5 catalizó la priorización y aceleró las actividades estratégicas para mejorar las políticas, la capacidad y la calidad de la atención infantil en la Región de las Américas y brindó apoyo a los ministerios para integrar las intervenciones contra el cáncer infantil en el fortalecimiento de los sistemas.

A colaboração com a OPAS/OMS para priorizar o câncer infantil no contexto do fortalecimento dos sistemas é fundamental para o papel do St. Jude Children's Research Hospital (SJCRH) como Centro Colaborador da OMS para o Câncer Infantil. Este artigo mostra como o SJCRH e a OPAS/OMS se associaram para aplicar a ferramenta C5 (Colaboração Nacional para Controle do Câncer Infantil), com o propósito de definir e implementar ações prioritárias regionalmente, fortalecendo programas ministeriais para o câncer na infância, durante a implementação da Iniciativa Global para o Câncer Infantil desde 2018. Com auxílio da C5, uma ferramenta desenvolvida pelo SJCRH, a OPAS/OMS e o SJCRH organizaram conjuntamente oficinas regionais/nacionais com a participação de autoridades, profissionais de saúde e outras partes interessadas em 10 países, com a finalidade de mapear as necessidades dos sistemas de saúde e priorizar atividades estratégicas (abrangendo América Central, República Dominicana, Haiti, Brasil e Uruguai). O SJCRH forneceu versões/modelos da C5 em inglês, espanhol e português para exercícios de análise/priorização e colaborou com a OPAS/OMS e as equipes dos países para implementar a C5, analisar resultados e desenvolver produtos. Em uma oficina regional com oito países, foram definidas as prioridades das iniciativas nacionais/regionais e classificados seu valor e vontade política, incorporando levantamentos nacionais e diálogos entre as partes interessadas. Cada país priorizou uma atividade estratégica para 2022-2023, trocou conhecimentos por meio da narração de histórias e disseminou e aplicou os resultados para informar planos de ação nacionais e regionais. As análises das oficinas nacionais foram incorporadas às atividades de planejamento para controle do câncer e ao trabalho conjunto no âmbito regional. Entre os fatores de êxito da implementação estão o engajamento de agentes de fora do segmento da saúde, a oferta de flexibilidade e a ênfase no planejamento conjunto com as partes interessadas. A implementação conjunta da C5 catalisou a priorização e acelerou atividades estratégicas para aprimorar as políticas, a capacidade e a qualidade da atenção às crianças nas Américas, apoiando os ministérios na integração das intervenções contra o câncer infantil como parte do fortalecimento dos sistemas.

Advances in the Global Initiative for Childhood Cancer: implementation in Latin America and the Caribbean.

This report describes the status of childhood cancer control initiatives in Latin America and the Caribbean (LAC). Progress between 2017 and 2023 is measured using the outcome indicators from the Pan American Health Organization (PAHO) childhood cancer logic model aligned with the World Health Organization Global Initiative for Childhood Cancer (GICC). This report also describes the advances, barriers, and facilitators for the implementation of the GICC at the Regional level. Methods used in this report encompassed a comprehensive approach, incorporating a literature review, interviews, surveys, and a Delphi study developed by the technical team of the PAHO Non-Communicable Diseases and Mental Health Department and by the GICC LAC working group. Since 2017, there has been a substantial increase in the number of countries that have included childhood cancer in their national regulations. Currently, 21 LAC countries are involved in the GICC implementation, activities, and dialogues. However, the objectives for 2030 will only be achieved if Member States overcome the barriers to accelerating the pace of initiative implementation. There is an urgent need to increase the efforts in childhood cancer control in LAC, especially regarding the prioritization of timely detection, essential diagnostics, access to cancer treatment, palliative care, and close follow-up of children and adolescents with cancer.

En este artículo se describe la situación de las iniciativas para el control del cáncer infantil en América Latina y el Caribe. Para medir los progresos entre el 2017 y el 2023, se utilizan los indicadores de resultados del modelo lógico del cáncer infantil de la Organización Panamericana de la Salud (OPS) que es coherente con la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud. También se describen los avances, los obstáculos y los elementos que han facilitado la aplicación de esa iniciativa en la Región Los métodos utilizados en este trabajo incluyeron un enfoque integral que incorporó una revisión bibliográfica, entrevistas, encuestas y un estudio de tipo Delfos llevado a cabo por el equipo técnico del Departamento de Enfermedades No Transmisibles y Salud Mental de la OPS y por el grupo de trabajo de América Latina y el Caribe de la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud.Desde el 2017 ha habido un incremento considerable en el número de países que incorporan el cáncer infantil en sus regulaciones nacionales. En la actualidad, 21 países de América Latina y el Caribe participan en la puesta en práctica, las actividades y las deliberaciones de la Iniciativa Mundial contra el Cáncer Infantil de la Organización Mundial de la Salud. No obstante, los objetivos para el 2030 solo podrán alcanzarse si los Estados Miembros son capaces de superar los obstáculos que dificultan la aceleración del ritmo de aplicación de esta iniciativa. Existe una necesidad urgente de aumentar las actividades dirigidas al control del cáncer infantil en América Latina y el Caribe, en especial en lo que respecta a priorizar la detección temprana, los medios de diagnóstico esenciales, el acceso a los tratamientos oncológicos, los cuidados paliativos y el seguimiento estricto de la población infantil y adolescente con cáncer.

Este relatório descreve a situação das iniciativas de controle do câncer infantil na Região da América Latina e do Caribe (ALC). O progresso alcançado entre 2017 e 2023 foi medido usando os indicadores de resultados intermediários do modelo lógico de câncer infantil da Organização Pan-Americana da Saúde (OPAS), em linha com a Iniciativa Global para o Câncer Infantil (GICC) da Organização Mundial da Saúde. O relatório também descreve os avanços, as barreiras e os facilitadores para a implementação da iniciativa em nível regional. Os métodos utilizados neste relatório aplicaram uma abordagem abrangente que incluiu revisão da literatura, entrevistas, levantamentos e um estudo Delphi desenvolvido pela equipe técnica do Departamento de Doenças Não Transmissíveis e Saúde Mental da OPAS e pelo grupo de trabalho da GICC para a ALC.Desde 2017, houve um aumento significativo no número de países que passaram a incluir o câncer infantil em regulamentações nacionais. Atualmente, 21 países da América Latina e do Caribe estão envolvidos na implementação da GICC, bem como em atividades e diálogos relacionados. No entanto, os objetivos para 2030 só serão alcançados se os Estados Membros superarem as barreiras ao aceleramento do ritmo de implementação da iniciativa. Existe uma necessidade urgente de intensificar os esforços de controle do câncer infantil na ALC, especialmente no tocante à priorização da detecção em tempo hábil, diagnósticos essenciais, acesso a tratamentos oncológicos, cuidados paliativos e acompanhamento cuidadoso de crianças e adolescentes com câncer.

Collaboration for success: the Global Initiative for Childhood Cancer in Latin America.

The Global Initiative for Childhood Cancer (GICC) aims to increase the cure rate for children with cancer globally by improving healthcare access and quality. The Pan American Health Organization (PAHO), St. Jude Children's Research Hospital (St. Jude), and collaborators have joined efforts to improve outcomes of children with cancer in Latin America and the Caribbean (LAC) using the CureAll framework. In this article, we describe the process of developing regional resources aimed at accelerating the GICC implementation in LAC. In March 2021, PAHO formed regional working groups to develop core projects aligned with CureAll pillars and enablers. Seven working groups emerged from regional dialogues: early detection, nursing, psychosocial, nutrition, supportive care, treatment abandonment, and palliative care. PAHO arranged regular online meetings under the mentorship and support of St. Jude regional/transversal programs and international mentors. Between April and December 2021, 202 multidisciplinary experts attended 43 online meetings to promote the dialogue between stakeholders to improve childhood cancer outcomes. Fourteen technical outputs were produced: four regional snapshots, four technical documents, two virtual courses, one set of epidemiological country profiles, one educational content series for parents/caregivers, and two communication campaigns. The ongoing dialogue and commitment of PAHO, St. Jude, LAC working committees, and international collaborators are essential foundations to successfully accelerate GICC implementation. This is achievable through the development of materials of regional and global relevance. Further research and evaluation are needed to determine the impact of these strategies and resources on childhood cancer outcomes in LAC and other regions.

La Iniciativa Mundial contra el Cáncer Infantil tiene como objetivo aumentar a nivel mundial la tasa de curación del cáncer infantil mediante la mejora del acceso a la atención de salud y de su calidad. La Organización Panamericana de la Salud (OPS), el St. Jude Children's Research Hospital y los colaboradores han aunado esfuerzos para mejorar los resultados en la población infantil con cáncer en América Latina y el Caribe valiéndose del marco CureAll. En este artículo describimos el proceso de elaboración de recursos regionales destinados a acelerar la aplicación de la Iniciativa Mundial en América Latina y el Caribe.En marzo del 2021, la OPS formó grupos de trabajo regionales para elaborar proyectos básicos que estuvieran en consonancia con los pilares y los elementos facilitadores del CureAll. De los diálogos regionales surgieron siete grupos de trabajo: detección temprana, enfermería, aspectos psicosociales, nutrición, tratamientos de apoyo, abandono del tratamiento y cuidados paliativos. La OPS organizó con regularidad reuniones virtuales en las que se contó con la tutoría y el apoyo de programas regionales o transversales del St. Jude Children's Research Hospital y de mentores internacionales.Entre abril y diciembre del 2021 hubo 43 reuniones virtuales a las que asistieron 202 expertos multidisciplinarios, con el objetivo de promover el diálogo entre las partes interesadas para mejorar los resultados en materia de cáncer infantil. Se elaboraron catorce productos técnicos: cuatro panoramas regionales, cuatro documentos técnicos, dos cursos virtuales, un conjunto de perfiles epidemiológicos de países, una serie con contenidos educativos para padres y cuidadores y dos campañas de comunicación.El diálogo y el compromiso constantes de la OPS, el St. Jude Children's Research Hospital, los comités de trabajo de América Latina y el Caribe y los colaboradores internacionales son las bases fundamentales para conseguir que se acelere la aplicación de la Iniciativa Mundial. Esto se puede lograr mediante la elaboración de materiales que resulten pertinentes a nivel regional y mundial. Son necesarias más investigaciones y evaluaciones para determinar el impacto que tienen estas estrategias y recursos en los resultados que se obtienen en el cáncer infantil en América Latina y el Caribe y en otras subregiones.

A Iniciativa Global para o Câncer Infantil tem como objetivo aumentar a taxa de cura de crianças com câncer no mundo todo, melhorando o acesso a cuidados e a qualidade da assistência médica. A Organização Pan-Americana da Saúde (OPAS), o St. Jude Children's Research Hospital (St. Jude) e colaboradores uniram esforços para melhorar o desfecho de crianças com câncer na América Latina e no Caribe (ALC) no âmbito do marco CureAll. Neste artigo, descrevemos o processo de desenvolvimento de recursos regionais com o objetivo de acelerar a implementação da Iniciativa na ALC.Em março de 2021, a OPAS formou grupos de trabalho regionais para desenvolver projetos centrais alinhados com os pilares e facilitadores do CureAll. A partir das reuniões de diálogo regionais, foram criados sete grupos de trabalho: detecção precoce, enfermagem, atenção psicossocial, nutrição, cuidados de suporte, abandono do tratamento e cuidados paliativos. A OPAS organizou reuniões virtuais regulares sob a orientação e o apoio dos programas regionais e transversais do St. Jude e de mentores internacionais.Entre abril e dezembro de 2021, 202 especialistas multidisciplinares participaram de 43 reuniões virtuais para promover o diálogo entre as partes interessadas a fim de melhorar os desfechos do câncer infantil. Foram produzidos 14 materiais técnicos: quatro panoramas regionais, quatro documentos técnicos, dois cursos virtuais, um conjunto de perfis epidemiológicos nacionais, uma série de conteúdo educacional para pais e cuidadores e duas campanhas de comunicação.O diálogo e o compromisso contínuos da OPAS, do St. Jude, dos comitês de trabalho da ALC e dos colaboradores internacionais são bases essenciais para acelerar com sucesso a implementação da Iniciativa Global para o Câncer Infantil. Isso é possível por meio do desenvolvimento de materiais de relevância regional e mundial. São necessárias mais pesquisas e avaliações para determinar o impacto dessas estratégias e recursos nos resultados do câncer infantil na ALC e em outras regiões.

Equity in national cancer control plans in the region of the Americas.

Many social determinants that are outside an individual's control affect their exposure to cancer risk factors and access to high-quality care. There is increasing recognition that national cancer control plans are fundamental tools to address cancer burden and promote equitable care. To investigate how policies in the WHO region of the Americas promote equity in cancer care, we evaluated 46 cancer-related health plans covering 34 countries. We analysed and coded the text of the documents according to 40 indicators and three dimensions (context, equity, and governance). Our results suggest that equity is not sufficiently integrated in national cancer control plans in the region. 17 documents defined inequity as a problem mainly related to difficulties in the access to care. Although 25 countries had designed equitable interventions, none had dedicated a budget for their implementation. Countries still need to translate their expressed concern with equity in health into funded, targeted interventions that accompany patients throughout the entire cancer care continuum.

Primary hypothyroidism in childhood cancer survivors: Prevalence, risk factors, and long-term consequences.

BACKGROUND: Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes. METHODS: This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored. RESULTS: The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age < 5 years (OR, 1.05; 95% CI, 1.01-1.09). Primary hypothyroidism was associated with frailty (OR, 1.54; 95% CI, 1.05-2.26), dyslipidemia (OR, 1.52; 95% CI, 1.14-2.04), impaired physical QOL (OR, 1.66; 95% CI, 1.12-2.48), and having health care insurance (OR, 1.51; 95% CI, 1.07-2.12). CONCLUSIONS: Primary hypothyroidism is common in survivors and is associated with unfavorable physical health and QOL outcomes. The impact of thyroid hormone replacement practices on these outcomes should be investigated further.

Comprehensive analysis of dose intensity of acute lymphoblastic leukemia chemotherapy.

Chemotherapy dosages are often compromised, but most reports lack data on dosages that are actually delivered. In two consecutive acute lymphoblastic leukemia trials that differed in their asparaginase formulation, native E. coli L-asparaginase in St. Jude Total 15 (T15, n=365) and pegaspargase in Total 16 (T16, n=524), we tallied the dose intensities for all drugs on the low-risk or standard-risk arms, analyzing 504,039 dosing records. The median dose intensity for each drug ranged from 61-100%. Dose intensities for several drugs were more than 10% higher on T15 than on T16: cyclophosphamide (P<0.0001 for the standard- risk arm), cytarabine (P<0.0001 for the standard-risk arm), and mercaptopurine (P<0.0001 for the low-risk arm and P<0.0001 for the standardrisk arm). We attributed the lower dosages on T16 to the higher asparaginase dosages on T16 than on T15 (P<0.0001 for both the low-risk and standard-risk arms), with higher dose-intensity for mercaptopurine in those with anti-asparaginase antibodies than in those without (P=5.62x10-3 for T15 standard risk and P=1.43x10-4 for T16 standard risk). Neutrophil count did not differ between protocols for low-risk patients (P=0.18) and was actually lower for standard-risk patients on T16 than on T15 (P<0.0001) despite lower dosages of most drugs on T16. Patients with low asparaginase dose intensity had higher methotrexate dose intensity with no impact on prognosis. The only dose intensity measure predicting a higher risk of relapse on both studies was higher mercaptopurine dose intensity, but this did not reach statistical significance (P=0.03 T15; P=0.07 T16). In these intensive multiagent trials, higher dosages of asparaginase compromised the dosing of other drugs for acute lymphoblastic leukemia, particularly mercaptopurine, but lower chemotherapy dose intensity was not associated with relapse.

Durable remission for four pediatric patients with high-risk relapsed classical Hodgkin lymphoma treated with brentuximab vedotin plus gemcitabine but without autologous stem cell transplantation: A report from the Children's Oncology Group.

Patients with therapy-refractory or high-risk relapsed classical Hodgkin lymphoma are typically treated with the high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) to consolidate the response to salvage therapy. The combination of brentuximab vedotin with gemcitabine has recently been shown to be an effective and safe salvage regimen. While the majority of patients with complete responses to this regimen ultimately underwent HDC/ASCT consolidation, four subjects, reported herein, achieved durable complete remissions lasting more than 4 years after the study treatment but without ASCT consolidation. Further investigation of treatment strategies incorporating targeted agents may allow omission of HDC/ASCT for select patients.

Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies.

BACKGROUND: A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children and adolescents with relapsed or refractory hematologic malignancies. METHODS: Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m2 /d) in combination with clofarabine (40 mg/m2 ), etoposide (100 mg/m2 ), and dexamethasone (8 mg/m2 ) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5. RESULTS: Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m2 /d, 6 were treated at the dose level of 40 mg/m2 /d, and 4 were treated at the dose level of 60 mg/m2 /d. The dose-limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m2 /d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease-negative complete remission without platelet recovery in a patient with early T-cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event-free survival rate was 40.6% (95% confidence interval [CI], 17.5%-63.7%) at 1 year and 33.9% (95% CI, 11.9%-55.9%) at 3 years. CONCLUSIONS: Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509). LAY SUMMARY: Improvements to the existing chemotherapy regimen are still needed for patients who relapse after targeted therapies and immunotherapies and for those who are not eligible for or have no access to such therapies. A regimen combining cyclophosphamide, clofarabine, and etoposide has been used in relapsed and refractory pediatric patients with hematologic malignancies. This study shows that substituting bendamustine for cyclophosphamide in combination with clofarabine and etoposide is safe and effective.

A sustainable model for pediatric oncology nursing education and capacity building in Latin American hospitals: Evolution and impact of a nurse educator network.

Through an "educate-the-educator" twinning model, pediatric oncology nurse educator roles and programs have been established at hospitals in Latin America since 2008. However, with increasing demand for nurse educator programs in the region, a twinning approach was no longer sustainable. Thus, a "nurse educator network" approach was established to scale adaptable, standardized multisite education and quality initiatives. The development, expansion, and impact of a sustainable network approach for pediatric oncology nursing capacity building in Latin America is described. The educator network approach serves as a potential model for other geographical regions. Coronavirus disease 2019 (COVID-19) impact and adaptations are addressed.

The management of Hodgkin lymphoma in adolescents and young adults: burden of disease or burden of choice?

Adolescents and young adults (AYAs) comprise the largest age group affected by Hodgkin lymphoma (HL). Despite excellent overall survival of AYA patients with HL due to advances in treatment regimens, therapy-associated late effects continue to be a concern in HL survivors, especially for younger patients who have decades of life remaining. Since the first clinical trial for HL with chemotherapy in 1964, subsequent protocols have attempted to reduce chemotherapy-induced toxicities and yet maintain high overall survival rates. Today, new analytic methods applied to data from survivorship cohorts, such as the recently described cumulative burden of disease metric, can be used to inform changes for future protocols. Although pediatric and adult trial consortia have followed this process, the AYA population, an age cohort split between pediatric and adult health care services, faces many barriers to care and is the least likely to be enrolled in clinical trials. AYA patients with HL theoretically have a choice to be treated in pediatric or adult protocols when presented with these options. Recent efforts by the National Clinical Trials Network, the Children's Oncology Group, and others have been made to ensure that the burden of choice for the AYA population is not greater than the burden of disease.

The association of mediastinal mass in the formation of thrombi in pediatric patients with non-lymphoblastic lymphomas.

BACKGROUND: Children diagnosed with cancer are at a significantly higher risk of developing a thrombotic event (TE) compared with the general population. The rarity of these events makes it difficult to discern the specific risk factors; however, age, sex, presence of central venous lines, inherited thrombophilia, and mediastinal mass may play a role. The primary aim of this study is to identify prognostic characteristics of children diagnosed with non-lymphoblastic lymphomas associated with a greater risk of developing a TE early on in their disease, with an increased focus on mediastinal mass characteristics. METHODS: Retrospective chart review of pediatric patients diagnosed with non-lymphoblastic lymphoma between 2004 and 2014 at St. Jude Children's Research Hospital. RESULTS: TE occurred in 8.5% (n = 28/330) of individuals at a median of 21 days from the diagnosis of a non-lymphoblastic lymphoma, with 60% of TEs occurring within 30 days of diagnosis. Of the variables evaluated, only presence of a peripherally inserted central catheter (odds ratio [OR]: 3.14 [95% CI: 1.24-7.98; P = 0.02]) and degree of superior vena cava (SVC) compression of > 25% increased the odds of developing a TE (OR: 2.2 [95% CI: 1.01-4.93; P = 0.048]). CONCLUSION: Pediatric patients with non-lymphoblastic lymphoma are at increased risk of developing TEs. In contrast to previous studies, the presence of a mediastinal mass alone was not associated with a higher risk of TE, but individuals with a mediastinal mass with 25% or greater degree of SVC compression were more likely to develop a TE. This finding highlights a high-risk group of children who may benefit from prophylactic anticoagulation.

Liver involvement in pediatric Hodgkin lymphoma: A systematic review by an international collaboration on Staging Evaluation and Response Criteria Harmonization (SEARCH) for Children, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL).

Hepatic involvement in Hodgkin lymphoma (HL) is uncommon (∼5% of patients) but always implies stage IV disease. Accurate staging is mandatory for making the appropriate risk assignment and treatment decisions. The Staging Evaluation and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) international working group conducted a systematic literature review of liver involvement in HL patients with the aim to propose a universally acceptable definition for liver involvement in pediatric HL. Thirty-three articles describing 6985 pediatric and adult HL patients were reviewed, of which 539 (7.7%) mentioned liver involvement. The literature did not provide a uniform definition of hepatic involvement and we propose consensus criteria derived from the EuroNet and Children's Oncology Group protocols, where liver involvement is defined as any hepatic lesion on computed tomography scan that correlates with 18 F-FDG uptake greater than background liver. A clear definition of liver lesions is necessary to consistently identify liver involvement and compare its impact on outcomes among protocols worldwide.

Definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma: A report from the International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH).

BACKGROUND: The International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH) seeks to provide a universally acceptable definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma. PROCEDURE: A comprehensive literature search was performed using PubMed and Google Scholar with the search terms "Hodgkin lymphoma," "osseous lesions," "bony involvement," and "pediatric." Publications reviewed included case reports, retrospective analyses, and literature reviews. Each was evaluated for study design, number of participants, median age and age range at diagnosis, percentage of pediatric patients, criteria of interest definition, diagnostic tools, study objectives, and level of evidence. The final definition was based on the available data and consensus of the SEARCH working group. RESULTS: Twenty-five papers specifically addressing cortical bone involvement in Hodgkin lymphoma met the inclusion criteria. Eighteen papers were case reports with literature reviews; the remainder were observational cohort studies. Of these, 14 included pediatric patients (aged 0-21 years). The criteria for cortical bone involvement were not clearly defined in any paper, often varied within a study, and were inconsistent between publications. CONCLUSIONS: The SEARCH group for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL) proposes the following criteria as defining cortical bone involvement: any cortical bone biopsy-proven lesion; a positive bony window lesion on computer tomography (CT), with an FDG-PET positive correlate in a patient with biopsy-proven Hodgkin lymphoma, if there is no other typical skeletal pathology; auspicious skeletal lesions on FDG-PET or magnetic resonance imaging should be confirmed by CT or Tc-99m scan to distinguish cortical lesions from bone marrow involvement. Nodal masses that extend into bone with bony destruction are considered extranodal extension or "E" lesions and do not represent metastatic or stage IV disease.

Whole-joint magnetic resonance imaging to assess osteonecrosis in pediatric patients with acute lymphoblastic lymphoma.

BACKGROUND: Osteonecrosis is a debilitating complication in children and adolescents with acute lymphoblastic leukemia or acute lymphoblastic lymphoma (LLy). An objective screening test to identify patients at risk for symptomatic, extensive joint involvement will help manage osteonecrosis. METHODS: We performed a prospective, longitudinal pilot study with whole-joint magnetic resonance imaging (MRI) of shoulders, elbows, hips, knees, ankles, and hindfeet to evaluate the incidence and timing of osteonecrosis involving multiple joints in 15 patients with LLy aged 9-21 years at diagnosis. RESULTS: Osteonecrosis affecting ≥30% of the epiphysis occurred in eight of 15 patients, with a high prevalence in hips (12 of 26 examined [46%]) and knees (10 of 26 [38%]) post reinduction I and in shoulders (seven of 20 [35%]) post reinduction II. Most osteonecrotic hips and knees with ≥30% epiphyseal involvement became symptomatic and/or underwent surgery (100% and 82%, respectively). All eight patients with ≥30% epiphyseal involvement had multijoint involvement. Seven of these patients had hip or knee osteonecrosis by the end of remission induction, and only these patients developed osteonecrosis that became symptomatic and/or underwent surgery in their hips, knees, shoulders, ankles, and/or feet; all of these joints were associated with epiphyseal abnormalities on post reinduction I imaging. CONCLUSIONS: MRI screening in adolescent patients with LLy revealed osteonecrosis in multiple joints. Initial screening with hip and knee MRI at the end of induction may identify susceptible patients who could benefit from referrals to subspecialties, more extensive follow-up imaging of other joints, and early medical and surgical interventions.