Roadmap to Liquid Biopsy Biobanking from Pediatric Cancers–Challenges and Opportunities

Kahana-Edwin, Smadar; Cain, Lucy E; Karpelowsky, Jonathan

doi:10.1089/bio.2020.0117

Cited by 12 publications

(12 citation statements)

References 28 publications

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“…In terms of diagnostic strategies, minimally invasive diagnostic tools with a broadened spectrum should be developed integrating different biometric data ( 46 ). Moreover, with the same approach, it would be helpful to identify early disease markers, both for diagnosis and disease relapse.…”

Section: Discussionmentioning

confidence: 99%

Gaps and Opportunities of Artificial Intelligence Applications for Pediatric Oncology in European Research: A Systematic Review of Reviews and a Bibliometric Analysis

et al. 2022

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The application of artificial intelligence (AI) systems is emerging in many fields in recent years, due to the increased computing power available at lower cost. Although its applications in various branches of medicine, such as pediatric oncology, are many and promising, its use is still in an embryonic stage. The aim of this paper is to provide an overview of the state of the art regarding the AI application in pediatric oncology, through a systematic review of systematic reviews, and to analyze current trends in Europe, through a bibliometric analysis of publications written by European authors. Among 330 records found, 25 were included in the systematic review. All papers have been published since 2017, demonstrating only recent attention to this field. The total number of studies included in the selected reviews was 674, with a third including an author with a European affiliation. In bibliometric analysis, 304 out of the 978 records found were included. Similarly, the number of publications began to dramatically increase from 2017. Most explored AI applications regard the use of diagnostic images, particularly radiomics, as well as the group of neoplasms most involved are the central nervous system tumors. No evidence was found regarding the use of AI for process mining, clinical pathway modeling, or computer interpreted guidelines to improve the healthcare process. No robust evidence is yet available in any of the domains investigated by systematic reviews. However, the scientific production in Europe is significant and consistent with the topics covered in systematic reviews at the global level. The use of AI in pediatric oncology is developing rapidly with promising results, but numerous gaps and challenges persist to validate its utilization in clinical practice. An important limitation is the need for large datasets for training algorithms, calling for international collaborative studies.

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Section: Discussionmentioning

confidence: 99%

Gaps and Opportunities of Artificial Intelligence Applications for Pediatric Oncology in European Research: A Systematic Review of Reviews and a Bibliometric Analysis

et al. 2022

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“…The age and weight of children are limitations that should be considered when collecting large volumes of blood for informative ctDNA data analysis. This is further confounded by the volume of sample, that is, clinically feasible to collect in children ( Kahana-Edwin et al, 2021a ). Detection and quantification of ctDNA therefore require highly optimal and sensitive methods which should be tailored for individual cancer types ( Yi et al, 2017 ).…”

Section: Challenges Of Circulating Tumor Dna Analysis In Childhood Ca...mentioning

confidence: 99%

“…Current ctDNA assays have been used for the detection of somatic mutations such as EGFR ( Jensen et al, 2021 ), however these somatic mutations have relatively lower frequencies in childhood cancer due to less exposure to mutagens including smoking and ionizing radiation. Also, liquid biopsy sampling for adult cancers is generally 5–20 ml of blood and in children, this amount is considerably lower, depending on age and weight ( Kahana-Edwin et al, 2021a ). It is probable that the sensitivity of ctDNA detection would be impacted by restrictions in pediatric sampling due to low levels of tumor burden in plasma.…”

Section: Introductionmentioning

confidence: 99%

Circulating Tumor DNA in Pediatric Cancer

Doculara

Trahair

Bayat

et al. 2022

Front. Mol. Biosci.

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The measurement of circulating tumor DNA (ctDNA) has gained increasing prominence as a minimally invasive tool for the detection of cancer-specific markers in plasma. In adult cancers, ctDNA detection has shown value for disease-monitoring applications including tumor mutation profiling, risk stratification, relapse prediction, and treatment response evaluation. To date, there are ctDNA tests used as companion diagnostics for adult cancers and it is not understood why the same cannot be said about childhood cancer, despite the marked differences between adult and pediatric oncology. In this review, we discuss the current understanding of ctDNA as a disease monitoring biomarker in the context of pediatric malignancies, including the challenges associated with ctDNA detection in liquid biopsies. The data and conclusions from pediatric cancer studies of ctDNA are summarized, highlighting treatment response, disease monitoring and the detection of subclonal disease as applications of ctDNA. While the data from retrospective studies highlight the potential of ctDNA, large clinical trials are required for ctDNA analysis for routine clinical use in pediatric cancers. We outline the requirements for the standardization of ctDNA detection in pediatric cancers, including sample handling and reproducibility of results. With better understanding of the advantages and limitations of ctDNA and improved detection methods, ctDNA analysis may become the standard of care for patient monitoring in childhood cancers.

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“…THNSL2 was chosen as it is positioned near the centromere of the same chromosome arm as MYCN, to control for a false positive result due to numerical change of whole chromosome 2. We also included evaluation of ALK gene levels as: (a) ALK amplification is known to occur in 3-4% of neuroblastoma sporadic cases [16] almost exclusively in the context of MNA due to their close proximity on chromosome 2p23-24 [17], and (b) to increase the robustness for normalization by using both ALK and THNSL2 as reference genes. Simultaneous detection of the three target genes using only two fluorophores included strategies to optimize primer/probe-sets concentration that allow a clean segregation of the droplets by levels of fluorescence in the data output [18] (Figure S1).…”

Section: Ddpcrmentioning

confidence: 99%

“…Published studies comparing different blood collection tubes demonstrated that testing for point mutations in ctDNA is optimally performed on plasma collected in DNA and cell stabilization tubes (e.g., Streck, PAXgene) or EDTA tubes, provided EDTA specimens are processed within 6 h of collection and stored at 4 • C (reviewed in [17]). However, the pre-analytical conditions suitable for copy number detection require further investigation.…”

Section: Pre-analytical Considerations For Optimized Mna Ddpcr Detectionmentioning

confidence: 99%

Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and ALK Genotyping via Cell-Free Circulating Tumor DNA Profiling

Kahana-Edwin

Cain

McCowage

et al. 2021

Cancers

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Background: MYCN amplification (MNA), segmental chromosomal aberrations (SCA) and ALK activating mutations are biomarkers for risk-group stratification and for targeted therapeutics for neuroblastoma, both of which are currently assessed on tissue biopsy. Increase in demand for tumor genetic testing for neuroblastoma diagnosis is posing a challenge to current practice, as the small size of the core needle biopsies obtained are required for multiple molecular tests. We evaluated the utility of detecting these biomarkers in the circulation. Methods: Various pre-analytical conditions tested to optimize circulating-tumor DNA (ctDNA) copy number changes evaluations. Plasma samples from 10 patients diagnosed with neuroblastoma assessed for SCA and MNA using single nucleotide polymorphism (SNP) array approach currently used for neuroblastoma diagnosis, with MNA status assessed independently using digital-droplet PCR (ddPCR). Three patients (one in common with the previous 10) tested for ALK activating mutations p.F1174L and p.F1245I using ddPCR. Results: Copy number detection is highly affected by physical perturbations of the blood sample (mimicking suboptimal sample shipment), which could be overcome using specialized preservative collection tubes. Pre-analytical DNA repair procedures on ctDNA before SNP chromosome microarray processing improved the lower limit of detection for SCA and MNA, defined as 20% and 10%, respectively. We detected SCA in 10/10 (100%) patients using SNP array, 7 of which also presented MNA. Circulating-free DNA (cfDNA) and matched tumor DNA profiles were generally identical. MNA was detected using ddPCR in 7/7 (100%) of MNA and 0/12 (0%) non-MNA cases. MNA and ALK mutation dynamic change was assessed in longitudinal samples from 4 and 3 patients (one patient with both), respectively, accurately reflected response to treatment in 6/6 (100%) and disease recurrence in 5/6 (83%) of cases. Samples taken prior to targeted treatment with the ALK inhibitor Lorlatinib and 6–8 weeks on treatment showed reduction/increase in ALK variants according to response to treatment. Conclusions: These results demonstrate the feasibility of ctDNA profiling for molecular risk-stratification, and treatment monitoring in a clinically relevant time frame and the potential to reduce fresh tissue requirements currently embedded in the management of neuroblastoma.

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Roadmap to Liquid Biopsy Biobanking from Pediatric Cancers–Challenges and Opportunities

Cited by 12 publications

References 28 publications

Gaps and Opportunities of Artificial Intelligence Applications for Pediatric Oncology in European Research: A Systematic Review of Reviews and a Bibliometric Analysis

Gaps and Opportunities of Artificial Intelligence Applications for Pediatric Oncology in European Research: A Systematic Review of Reviews and a Bibliometric Analysis

Circulating Tumor DNA in Pediatric Cancer

Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and ALK Genotyping via Cell-Free Circulating Tumor DNA Profiling

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