15 research outputs found
Re-imagining the data collection and analysis research process by proposing a rapid qualitative data collection and analytic roadmap applied to the dynamic context of precision medicine
Our implementation science study focuses on implementing a new way of practice and offers methodological specificity about how to rapidly investigate an individually tailored precision medicine intervention. A qualitative study advancing a new methodology for speedily identifying barriers and enablers to implementation in the context of childhood cancer. Data were collected through rapid ethnography, coded using the Consolidated Framework for Implementation Research, and analysed by Sentiment Analysis. Thirty-eight data collection events occurred during 14 multidisciplinary tumour board meetings, 14 curation meetings, and 10 informal conversations. Sentiment Analysis distilled Consolidated Framework for Implementation Research codes to reveal key barriers and enablers to implementation. A traffic light labelling system has been used to present levels of positivity and negativity (green for strong enablers and red for strong barriers), highlighting levels of concern regarding implementation. Within the intervention design characteristics, âAdaptabilityâ was the strongest enabler and âDesign quality and safetyâ the strongest barrier. Among the contextual factors: âNetworks and communicationâ were the strongest enabler, and âAvailable resourcesâ were the strongest barrier. Overall, there was a higher percentage of negative sentiment towards intervention design characteristics and contextual factors than positive sentiment, while more concerns were raised about intervention design factors than contextual factors. This study offers a rapid qualitative data collection and analytic methodological roadmap for establishing barriers and enablers to a paediatric precision medicine intervention
The rise of rapid implementation: a worked example of solving an existing problem with a new method by combining concept analysis with a systematic integrative review
Background The concept of rapid implementation has emerged in the literature recently, but without a precise definition. Further exploration is required to distinguish the conceptâs unique meanings and significance from the perspective of implementation science. The study clarifies the concept of rapid implementation and identifies its attributes, antecedents, and consequences. We present a theoretical definition of rapid implementation to clarify its unique meaning and characteristics. Methods Rodgers evolutionary concept analysis method, combined with a systematic integrative review, were used to clarify the concept of rapid implementation. A comprehensive search of four databases, including EMBASE, MEDLINE, SCOPUS, and WEB OF SCIENCE was conducted, as well as relevant journals and reference lists of retrieved studies. After searching databases, 2442 papers were identified from 1963 to 2019; 24 articles were found to fit the inclusion criteria to capture data on rapid implementation from across healthcare settings in four countries. Data analysis was carried out using descriptive thematic analysis. Results The results locate the introduction of rapid implementation, informed by implementation science. Guidance for further conceptualisation to bridge the gap between research and practice and redefine rigour, adapting methods used (current approaches, procedures and frameworks), and challenging clinical trial design (efficacy-effectiveness-implementation pipeline) is provided. Conclusions It is possible that we are on the cusp of a paradigm shift within implementation brought about by the need for faster results into practice and policy. Researchers can benefit from a deeper understanding of the rapid implementation concept to guide future implementation of rapid actionable results in clinical practice
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Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.
Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer
Consequences Matter : Compassion in Conservation Means Caring for Individuals, Populations and Species
Funding This research received no external funding. Acknowledgments The manuscript benefitted from significant input from Dan Brockington, J.B. Callicott, Peter Coals, Tim Hodgetts, David Macdonald and Jeremy Wilson. Conflicts of Interest The authors declare no conflict of interest.Peer reviewedPublisher PD
âBalancing Expectations with Actual Realitiesâ: Conversations with Clinicians and Scientists in the First Year of a High-Risk Childhood Cancer Precision Medicine Trial
Precision medicine is changing cancer care and placing new demands on oncology professionals. Precision medicine trials for high-risk childhood cancer exemplify these complexities. We assessed clinicians’ (<i>n</i> = 39) and scientists’ (<i>n</i><i> </i>= 15) experiences in the first year of the PRecISion Medicine for Children with Cancer (PRISM) trial for children and adolescents with high-risk cancers, through an in-depth semi-structured interview. We thematically analysed participants’ responses regarding their professional challenges, and measured oncologists’ knowledge of genetics and confidence with somatic and germline molecular test results. Both groups described positive early experiences with PRISM but were cognisant of managing parents’ expectations. Key challenges for clinicians included understanding and communicating genomic results, balancing biopsy risks, and drug access. Most oncologists rated ‘good’ knowledge of genetics, but a minority were ‘very confident’ in interpreting (25%), explaining (34.4%) and making treatment recommendations (18.8%) based on somatic genetic test results. Challenges for scientists included greater emotional impact of their work and balancing translational outputs with academic productivity. Continued tracking of these challenges across the course of the trial, while assessing the perspectives of a wider range of stakeholders, is critical to drive the ongoing development of a workforce equipped to manage the demands of paediatric precision medicine
A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer
Abstract Background Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers. Methods We combined immunohistochemistry (IHC) with RNA sequencing and whole-genome sequencing across a diverse spectrum of high-risk paediatric cancers to develop an alternative, expression-based signature associated with CD8+ T-cell infiltration of the TIME. Furthermore, we explored transcriptional features of immune archetypes and T-cell receptor sequencing diversity, assessed the relationship between CD8+ and CD4+ abundance by IHC and deconvolution predictions and assessed the common adult biomarkers such as neoantigen load and TMB. Results A novel 15-gene immune signature, Immune Paediatric Signature Score (IPASS), was identified. Using this signature, we estimate up to 31% of high-risk cancers harbour infiltrating T-cells. In addition, we showed that PD-L1 protein expression is poorly correlated with PD-L1 RNA expression and TMB and neoantigen load are not predictive of T-cell infiltration in paediatrics. Furthermore, deconvolution algorithms are only weakly correlated with IHC measurements of T-cells. Conclusions Our data provides new insights into the variable immune-suppressive mechanisms dampening responses in paediatric solid cancers. Effective immune-based interventions in high-risk paediatric cancer will require individualised analysis of the TIME
Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer
The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.</p