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Simple Summary: Liquid biopsy is a technique that uses minimally invasive or noninvasive methods to detect disease biomarkers in biofluids, such as blood and urine. For childhood cancers, this approach is promising, especially when tissue biopsies are challenging. By analyzing tiny particles called extracellular vesicles, the small particles in biofluids which carry genetic and molecular information from cancer cells, this liquid biopsy technique can aid early diagnosis, treatment monitoring, and outcome prediction, potentially improving the outcomes of childhood cancers. This review article introduces the concept of extracellular vesicle liquid biopsy, summarizes the progress that is being made in the diagnosis of multiple types of pediatric malignancies, and provides prospects for using this extracellular vesicle method to guide the development of novel cancer therapeutics. Liquid biopsy involves the utilization of minimally invasive or noninvasive techniques to detect biomarkers in biofluids for disease diagnosis, monitoring, or guiding treatments. This approach is promising for the early diagnosis of childhood cancer, especially for brain tumors, where tissue biopsies are more challenging and cause late detection. Extracellular vesicles offer several characteristics that make them ideal resources for childhood cancer liquid biopsy. Extracellular vesicles are nanosized particles, primarily secreted by all cell types into body fluids such as blood and urine, and contain molecular cargos, i.e., lipids, proteins, and nucleic acids of original cells. Notably, the lipid bilayer-enclosed structure of extracellular vesicles protects their cargos from enzymatic degradation in the extracellular milieu. Proteins and nucleic acids of extracellular vesicles represent genetic alterations and molecular profiles of childhood cancer, thus serving as promising resources for precision medicine in cancer diagnosis, treatment monitoring, and prognosis prediction. This review evaluates the recent progress of extracellular vesicles as a liquid biopsy platform for various types of childhood cancer, discusses the mechanistic roles of molecular cargos in carcinogenesis and metastasis, and provides perspectives on extracellular vesicle-guided therapeutic intervention. Extracellular vesicle-based liquid biopsy for childhood cancer may ultimately contribute to improving patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cells can detach from a primary tumour and present in peripheral blood as circulating tumour cells, or in the widest sense, as circulating atypical cells (CAC). Although CAC are a promising biomarker for non-invasive cancer screening, they occur at very low frequency and their detection and characterization remains challenging. We here validated isolation and concentration of untouched CAC from spiked cancer cell blood samples and combined this with matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). This workflow was optimised to detect as little as six cancer cells per 5000 white blood cells. Future development of our workflow may cover a larger range of cancer types and further improvements to enable the use of MALDI-TOF MS as a cancer-screening platform in clinical settings. Circulating atypical cells (CAC) are released from a primary tumour site into peripheral blood and are indicators of cancer metastasis. CAC occur at very low frequency in circulating blood, and their detection remains challenging. Moreover, white blood cells (WBC) are the major contaminant in enriched CAC samples. Here, we developed matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) as a novel CAC characterization platform. Main spectra profiles (MSP) of normal and cancer cells were generated by MALDI-TOF MS, and a cell-main spectra database was then compiled and analysed using the MALDI Biotyper software. Logarithmic scores accurately predicted distinct cell types. The feasibility of this workflow was then validated using simulated samples, which were prepared by 5000 WBC of three healthy individuals spiked with varying numbers (3, 6, 12, 25, 50, and 100) of lung, colon, or prostate cancer cells. MALDI-TOF MS was able to detect cancer cells down to six cells over the background noise of 5000 WBC with significantly higher predictive scores as compared to WBC alone. Further development of cell-MSP database to cover all cancer types sourced from cell lines and patient tumours may enable the use of MALDI-TOF MS as a cancer-screening platform in clinical settings in the future. [ABSTRACT FROM AUTHOR]