Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors

BACKGROUND Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. OBJECTIVES This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. METHODS We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (\u3c= 250 mg/m(2)), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin \u3e250 mg/m(2) were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. RESULTS Thirty-one genes were differentially enriched for variants between case patients and control patients (p \u3c 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 x 10(-15)). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. CONCLUSIONS Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs

Inferior survival among Aboriginal children with cancer in Ontario

BACKGROUND: Pediatric cancer distribution and outcomes have not been examined in Canadian Aboriginal children. The objective of this study was to describe the distribution, event-free survival, and overall survival of Aboriginal children with malignancies who reside in Ontario compared with non-Aboriginal children.METHODS: This population-based study included 10,520 Ontario children (age

'A world of competing sorrows': A mixed methods analysis of media reports of children with cancer abandoning conventional treatment.

BACKGROUND:We aimed to provide health practitioners greater insight into the public perception of traditional and complementary medicine (T&CM) use. Our objectives were to identify news media reports of children abandoning conventional treatment for traditional and complementary medicine, analyze the thematic content of these news articles and estimate the tonality portrayed. METHODS:LexisNexis and Factiva were searched for terms related to cancer, children and T&CM. Inclusion criteria were children less than 18 years, in curative phase of treatment who attempted to abandon conventional therapy for any traditional and complementary medicine use. A secondary search was performed in LexisNexis, Factiva and Google News Archive with the names of children in identified cases. Qualitative analysis of news media reports was completed using a grounded theory approach. Quantitative analysis of article sentiment was performed using a linear support vector machine. RESULTS:Seventeen cases occurring between 2002 and 2016 were included. Five main themes were identified: treatment as torture, power imbalances, rights of parents, evidence versus beliefs and the rights of Indigenous Peoples. Sentiment analysis revealed an overall negative tone, as demonstrated by 73% of the articles. INTERPRETATION:A better understanding of factors that lead to abandonment of conventional therapy for traditional and complementary medicine as portrayed in the news media may help healthcare providers prevent the occurrence of these cases

Deficit-Based Indigenous Health Research and the Stereotyping of Indigenous People

Health research tends to be deficit-based by nature; as researchers we typically quantify or qualify absence of health markers or presence of illness. This can create a narrative with far reaching effects for communities already subject to stigmatization. In the context of Indigenous health research, a deficit-based discourse has the potential to contribute to stereotyping and marginalization of Indigenous Peoples in wider society. This is especially true when researchers fail to explore the roots of health deficits, namely colonization, Westernization, and intergenerational trauma, risking conflation of complex health challenges with inherent Indigenous characteristics. In this paper we explore the incompatibility of deficit-based research with principles from several ethical frameworks including the Tri-Council Policy Statement (TCPS2) Chapter 9, OCAP® (ownership, control, access, possession), Inuit Tapiriit Kanatami National Inuit Strategy on Research, and Canadian Coalition for Global Health Research (CCGHR) Principles for Global Health Research. Additionally we draw upon cases of deficit-based research and stereotyping in healthcare, in order to identify how this relates to epistemic injustice and explore alternative approaches

Deficit-Based Indigenous Health Research and the Stereotyping of Indigenous Peoples

Health research tends to be deficit-based by nature; as researchers we typically quantify or qualify absence of health markers or presence of illness. This can create a narrative with far reaching effects for communities already subject to stigmatization. In the context of Indigenous health research, a deficit-based discourse has the potential to contribute to stereotyping and marginalization of Indigenous Peoples in wider society. This is especially true when researchers fail to explore the roots of health deficits, namely colonization, Westernization, and intergenerational trauma, risking conflation of complex health challenges with inherent Indigenous characteristics. In this paper we explore the incompatibility of deficit-based research with principles from several ethical frameworks including the Tri-Council Policy Statement (TCPS2) Chapter 9, OCAP® (ownership, control, access, possession), Inuit Tapiriit Kanatami National Inuit Strategy on Research, and Canadian Coalition for Global Health Research (CCGHR) Principles for Global Health Research. Additionally we draw upon cases of deficit-based research and stereotyping in healthcare, in order to identify how this relates to epistemic injustice and explore alternative approaches.La recherche en santé a tendance à être basée sur les déficits ; en tant que chercheurs, généralement nous quantifions ou qualifions l’absence de marqueurs de santé ou la présence d’une maladie. Cela peut créer un récit ayant des effets d’une grande portée pour les communautés déjà victimes de stigmatisation. Dans le contexte de la recherche en santé autochtone, un discours basé sur les déficits peut contribuer aux stéréotypes et à la marginalisation des peuples autochtones dans une société élargie. C’est particulièrement vrai lorsque les chercheurs ne parviennent pas à explorer les racines des déficits de santé, à savoir la colonisation, l’occidentalisation et les traumatismes intergénérationnels, au risque de confondre des problèmes de santé complexes avec des caractéristiques autochtones inhérentes. Dans cet article, nous explorons l’incompatibilité de la recherche basée sur les déficits avec les principes de plusieurs cadres éthiques, y compris le chapitre 9 de l’Énoncé de politique des trois Conseils (EPTC2), les principes PCAP® (propriété, contrôle, accès, possession), la Stratégie nationale sur la recherche inuite Inuit Tapiriit Kanatami et les principes de la Coalition canadienne pour la recherche en santé mondiale (CCRSM). En outre, nous nous appuyons sur des cas de recherche basée sur les déficits et le stéréotypage dans le domaine des soins de santé, dans le but d’identifier leur lien avec l’injustice épistémique et d’explorer des approches alternatives

Cancer-related fatigue in childhood cancer survivors : a systematic scoping review on contributors of fatigue and how they are targeted by non-pharmacological interventions

Objectives We aimed to identify contributors to cancer-related fatigue (CRF), explore non-pharmacological interventions addressing CRF, and highlight which contributors were targeted by these interventions in childhood cancer survivors. Methods We performed a search in various databases and used the PRISMA-ScR checklist. Findings were synthesized in various different tables and figures in accordance with our objectives. Results We included 49 articles in this systematic scoping review. We identified 59 significant contributors. Depression and physical activity level were some of the most studied significant contributors. Ten interventional studies were identified (e.g., yoga, physical activity intervention) that addressed 6 contributors (e.g., physical activity level). Discussion This review is the first to describe and relate contributors and non-pharmacological interventions targeting CRF in childhood cancer survivors. Important clinical implications could be derived from the variety of factors explaining CRF and how it is currently addressed

Exercise interventions for patients with pediatric cancer during inpatient acute care: A systematic review of literature

Physical inactivity has been shown to exacerbate negative side effects experienced by pediatric patients undergoing cancer therapy. Exercise interventions are being created in response. This review summarizes current exercise intervention data in the inpatient pediatric oncology setting. Two independent reviewers collected literature from three databases, and analyzed data following the PRISMA statement for systematic reviews and meta-analyses. Ten studies were included, representing 204 patients. Good adherence, positive trends in health status, and no adverse events were noted. Common strategies included individual, supervised, combination training with adaptability to meet fluctuating patient abilities. We recommend that general physical activity programming be offered to pediatric oncology inpatients

Global Use of Traditional and Complementary Medicine in Childhood Cancer: A Systematic Review

Purpose: Traditional and complementary medicine (T&CM) strategies are commonly used in pediatric oncology. Patterns may vary based on country income. We systematically reviewed published studies describing T&CM use among pediatric oncology patients in low-income countries (LIC/LMIC), middle-income countries (UMIC), and high-income countries (HIC). Objectives included describing estimated prevalence of use, reasons for use, perceived effectiveness, modalities used, rates of disclosure, and reporting of delayed or abandoned treatment. Methods: MEDLINE, EMBASE, Global Health, CINAHL, PsycINFO, Allied and Complementary Medicine Database, Cochrane Database of Systematic Reviews, and ProceedingsFirst were searched. Inclusion criteria were primary studies involving children younger than the age of 18 years, undergoing active treatment of cancer, and any T&CM use. Exclusion criteria included no pediatric oncology–specific outcomes and studies involving only children off active treatment. Data were extracted by two reviewers using a systematic data extraction form determined a priori. Results: Sixty-five studies published between 1977 and 2015 were included, representing 61 unique data sets and 7,219 children from 34 countries. The prevalence of T&CM use ranged from 6% to 100%. Median rates of use were significantly different in LIC/LMIC (66.7% ± 19%), UMIC (60% ± 26%), and HIC (47.2% ± 20%; P = .02). Rates of disclosure differed significantly by country income, with higher median rates in HIC. Seven studies reported on treatment abandonment or delays. Conclusion: The use of T&CM in pediatric oncology is common worldwide, with higher median prevalence of use reported in LIC/LMIC. Further research is warranted to examine the impact on treatment abandonment and delay

Evolución de los niños tratados por leucemia linfoblástica aguda recidivante en América Central

Background. Outcomes for relapsed childhood acute lymphoblastic leukemia (ALL) have not been documented in resource-limited settings. This study examined survival after relapse for children with ALL in Central America. Methods. A retrospective cohort study was performed and included children with first relapse of ALL in Guatemala, Honduras, or El Salvador between 1990 and 2011. Predictors of subsequent eventfree survival (EFS) and overall survival (OS) were examined. Results. There were 755 children identified with relapsed disease. The median time from diagnosis to relapse was 1.7 years (interquartile range, 0.8-3.1 years). Most relapses occurred during (53.9%) or following (24.9%) maintenance chemotherapy, and the majority occurred in the bone marrow (63.1%). Following the initial relapse, subsequent 3-year EFS (± standard error) and OS were 22.0% ± 1.7%, and 28.2% ± 1.9%, respectively. In multivariable analysis, worse post relapse survival was associated with age ± 10 years, white blood cell count ± 50 ± 109/L, and positive central nervous system status at the original ALL diagnosis, relapse that was not isolated central nervous system or testicular, and relapse < 36 months following diagnosis. Site and time to relapse were used to identify a favorable risk group whose 3-year EFS and OS were 50.0% ± 8.9% and 68.0% ± 8.1%, respectively. Conclusions. Prognosis after relapsed ALL in Central America is poor, but a substantial number of those with favorable risk features have prolonged survival, despite lack of access to stem cell transplantation. Stratification by risk factors can guide therapeutic decision-making.Fondo. Los resultados de la leucemia linfoblástica aguda (LLA) infantil en recaída no se han documentado en entornos de recursos limitados. Este estudio examinó la supervivencia después de la recaída en niños con LLA en América Central. Métodos. Se realizó un estudio de cohorte retrospectivo e incluyó niños con primera recaída de LLA en Guatemala, Honduras o El Salvador entre 1990 y 2011. Se examinaron los predictores de supervivencia libre de eventos (SSC) y supervivencia general (SG) subsiguientes. Resultados. Hubo 755 niños identificados con enfermedad recidivante. La mediana de tiempo desde el diagnóstico hasta la recaída fue de 1,7 años (rango intercuartílico, 0,8-3,1 años). La mayoría de las recaídas ocurrieron durante (53,9 %) o después (24,9 %) de la quimioterapia de mantenimiento, y la mayoría ocurrió en la médula ósea (63,1 %). Después de la recaída inicial, la SSC (± error estándar) y la SG posteriores a los 3 años fueron de 22,0 % ± 1,7 % y 28,2 % ± 1,9 %, respectivamente. En el análisis multivariable, la peor supervivencia posterior a la recaída se asoció con la edad ± 10 años, el recuento de glóbulos blancos ± 50 ± 109/l y el estado positivo del sistema nervioso central en el diagnóstico original de LLA, recaída que no fue del sistema nervioso central aislada o testicular, y recaída < 36 meses después del diagnóstico. El sitio y el tiempo hasta la recaída se usaron para identificar un grupo de riesgo favorable cuya SSC y SG a 3 años fueron 50,0 % ± 8,9 % y 68,0 % ± 8,1 %, respectivamente. Conclusiones. El pronóstico después de la LLA recidivante en América Central es malo, pero un número considerable de personas con características de riesgo favorables tienen una supervivencia prolongada, a pesar de la falta de acceso al trasplante de células madre. La estratificación por factores de riesgo puede orientar la toma de decisiones terapéuticas

Contribution of Fatigue to Cognitive Dysfunction in Childhood Acute Lymphoblastic Leukemia Survivors

Late effects such as neurocognitive issues and fatigue have been reported in childhood acute lymphoblastic leukemia (cALL) survivors. Yet, their association is often poorly understood. In this study, we wished to (1) describe neurocognitive difficulties and fatigue in a well-characterized cohort of long-term cALL survivors and (2) explore the risk of having neurocognitive deficits as a function of fatigue. Childhood ALL survivors (N = 285) from three Canadian treatment centers completed the DIVERGT battery of cognitive tests and the PedsQL Multidimensional Fatigue Scale. We performed logistic regressions to assess the risk of a survivor to show cognitive deficits (d = 0.35). The risk for cognitive deficits increased independently with levels of fatigue in the domains of cognitive speed and flexibility, working memory, and verbal fluency. For every 10-point increase on general or sleep/rest fatigue on the 0-100 scale, there was a median +23–35% risk of showing a deficit among the 7 tasks significantly associated with fatigue. Fatigue may constitute a complementary target when searching to mitigate cognitive issues in this population.</p