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1.
Genome Med ; 15(1): 20, 2023 04 03.
Article in English | MEDLINE | ID: mdl-37013636

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.


Subject(s)
B7-H1 Antigen , Neoplasms , Adult , Humans , Child , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Neoplasms/genetics , CD8-Positive T-Lymphocytes/metabolism , Biomarkers, Tumor/genetics , Tumor Microenvironment/genetics , Mutation
2.
Qual Health Res ; 32(12): 1865-1880, 2022 10.
Article in English | MEDLINE | ID: mdl-36066496

ABSTRACT

We report a novel approach of amalgamating implementation outcomes of acceptability and fidelity alongside context as a new way of qualitatively evaluating implementation outcomes and context of a precision medicine intervention. A rapid qualitative online proforma was co-designed with stakeholders and sent to a purposive sample of healthcare professionals involved in an early-phase clinical trial intervention. Data were analysed using Framework Analysis. A total of 24 out of 68 proformas were returned. Although some participants raised concerns about drug medication access issues, the main intervention was well accepted and understood across professional groups. Comprehension was enhanced through exposure to specialist multidisciplinary meeting arrangements. In conclusion, a rapid data collection tool and framework are now available to assess readily measurable, qualitative indicators of acceptability, fidelity of receipt and contextual fit within the dynamic precision medicine context.


Subject(s)
Neoplasms , Precision Medicine , Australia , Child , Health Personnel , Humans , Neoplasms/therapy , Research Design
3.
EMBO Mol Med ; 14(4): e14608, 2022 04 07.
Article in English | MEDLINE | ID: mdl-34927798

ABSTRACT

Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high-risk pediatric cancer patients.


Subject(s)
Antineoplastic Agents , Neoplasms , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Child , Disease Models, Animal , Genomics/methods , Humans , Neoplasms/pathology , Precision Medicine/methods , Xenograft Model Antitumor Assays
4.
Cancer Cytopathol ; 129(10): 805-818, 2021 10.
Article in English | MEDLINE | ID: mdl-34043284

ABSTRACT

BACKGROUND: The development of high-throughput drug screening (HTS) using primary cultures provides a promising, clinically translatable approach to tailoring treatment strategies for patients with cancer. However, this has been challenging for solid tumors because of often limited amounts of tissue available. In most cases, in vitro expansion is required before HTS, which may lead to overgrowth and contamination by non-neoplastic cells. METHODS: In this study, hematoxylin and eosin staining and immunohistochemical staining were performed on 129 cytopathology cases from 95 patients. These cytopathology cases comprised cell block preparations derived from primary tumor specimens or patient-derived xenografts as part of a pediatric precision oncology trial. Cytopathology cases were compared with the morphology and immunohistochemical staining profile of the original tumor. Cases were reported as tumor cells present, equivocal, or tumor cells absent. The HTS results from cytopathologically validated cultures were incorporated into a multidisciplinary tumor board report issued to the treating clinician to guide clinical decision making. RESULTS: On cytopathologic examination, tumor cells were present in 77 of 129 cases (60%) and were absent in 38 of 129 cases (29%), whereas 14 of 129 cases (11%) were equivocal. Cultures that contained tumor cells resembled the tumors from which they were derived. CONCLUSIONS: Cytopathologic examination of tumor cell block preparations is feasible and provides detailed morphologic characterization. Cytopathologic examination is essential for ensuring that samples submitted for HTS contain representative tumor cells and that in vitro drug sensitivity data are clinically translatable.


Subject(s)
Neoplasms , Humans , Immunohistochemistry , Medical Oncology , Neoplasms/drug therapy , Neoplasms/pathology , Pathology , Precision Medicine
5.
Nat Med ; 26(11): 1742-1753, 2020 11.
Article in English | MEDLINE | ID: mdl-33020650

ABSTRACT

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.


Subject(s)
Epigenome/genetics , Neoplasm Proteins/genetics , Neoplasms/genetics , Transcriptome/genetics , Adolescent , Child , Child, Preschool , DNA Methylation/genetics , Female , Humans , Infant , Male , Mutation/genetics , Neoplasms/classification , Neoplasms/pathology , Pediatrics , Precision Medicine , Risk Factors , Exome Sequencing , Whole Genome Sequencing
6.
Br J Cancer ; 123(7): 1101-1113, 2020 09.
Article in English | MEDLINE | ID: mdl-32684628

ABSTRACT

BACKGROUND: Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify therapies to prevent and/or treat ALK inhibitor resistance. METHODS: Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts. RESULTS: Xenografts were validated by confirmation of RANBP2-ALK rearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft. CONCLUSIONS: CD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive, ALK-rearranged malignancies.


Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Anaplastic Lymphoma Kinase/genetics , Gene Rearrangement , Ki-1 Antigen/antagonists & inhibitors , Molecular Chaperones/genetics , Myofibroblasts/pathology , Nuclear Pore Complex Proteins/genetics , Sarcoma/drug therapy , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Aged, 80 and over , Animals , Brentuximab Vedotin/therapeutic use , Drug Resistance, Neoplasm , Humans , Inflammation , Male , Mice , Sarcoma/genetics , Xenograft Model Antitumor Assays
7.
BMC Health Serv Res ; 20(1): 449, 2020 May 21.
Article in English | MEDLINE | ID: mdl-32438909

ABSTRACT

BACKGROUND: The concept of rapid implementation has emerged in the literature recently, but without a precise definition. Further exploration is required to distinguish the concept's 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.


Subject(s)
Delivery of Health Care/organization & administration , Implementation Science , Concept Formation , Humans , Problem Solving , Systematic Reviews as Topic
8.
Pharmacogenet Genomics ; 21(12): 808-19, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21946896

ABSTRACT

OBJECTIVE: A SNP in the NQO1 gene has been implicated in the response of patients with breast cancer to anthracycline containing regimens. NQO1, and its homologue NQO2, share many substrates yet retain distinct functional differences, with NQO2 being a more permissive molecule for electron accepting substrates. We aimed to determine whether functional NQO2 variants are associated with altered response to adjuvant doxorubicin and cyclophosphamide therapy, with or without tamoxifen, in the treatment of breast cancer. METHODS: Genomic DNA samples from 227 women with early breast cancer were genotyped for NQO1 and NQO2 polymorphisms. All participants were treated with an AC adjuvant therapy regimen. The functional implications of NQO2 polymorphisms were validated in in-vitro ectopic expression models. RESULTS: The NQO1 SNP (rs1800566) was associated with a poorer outcome and a lower likelihood of having a treatment delay. Patients who had ER and PR negative disease and were wild type for both the NQO1 and an NQO2 SNP (rs1143684) had 100% 5-year overall survival compared with 88% for carriers of one minor allele and 70% for carriers of two or more minor alleles (P=0.018, log rank). Carriers of minor alleles of a triallelic NQO2 promoter polymorphism were more likely to be withdrawn from tamoxifen therapy prematurely due to intolerance (P=0.009, log rank). MCF-7 cells were sensitized to growth inhibition by doxorubicin and 4OH tamoxifen, but not cyclophosphamide, by ectopic expression of NQO2. CONCLUSION: This study suggests that both NQO1 and NQO2 modulate the efficacy of AC therapy and that NQO2 is associated with tamoxifen toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , NAD(P)H Dehydrogenase (Quinone)/genetics , Quinone Reductases/genetics , Alleles , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Genotype , Humans , Polymorphism, Genetic , Tamoxifen/administration & dosage
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