Highly Correlated Recurrence Prognosis in Patients with Metastatic Colorectal Cancer by Synergistic Consideration of Circulating Tumor Cells/Microemboli and Tumor Markers CEA/CA19-9

Chu, Hsueh-Yao; Yang, Chih‐Yung; Yeh, Ping-Hao; Hsu, Chun-Jieh; Chang, Long‐Sen; Chan, Wai Meng; Lin, Chien-Ping; Lyu, You-You; Wu, Wei‐Cheng; Lee, Chun-Wei; Wu, Jen‐Kuei; Jiang, Jeng‐Kai; Tseng, Fan‐Gang

doi:10.3390/cells10051149

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…CEA/CA 19-9 are serum tumor biomarkers in CRC that are extensively deployed within clinic-based settings. CEA/ CA 19-9 are non-invasive and easily available cancer biomarkers concerning CRC immediate monitoring/prediction during early, advanced, and metastatic CRC [10][11][12]. Notwithstanding, to the best of our knowledge, clinical values within the normal range have not been assessed.…”

Section: Introductionmentioning

confidence: 99%

Elevated CEA and CA 19-9 Levels within the Normal Ranges Increase the Likelihood of CRC Recurrence in the Chinese Han Population

Wang¹,

Zhang²,

Shen³

et al. 2022

Applied Bionics and Biomechanics

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Objective. This study aimed to determine if variations in the expression profiles of CA 19-9 and carcinoembryonic antigen (CEA) within the reference range could serve as possible biomarkers for postoperative CRC recurrence. Method. This retrospective cohort investigation enrolled 2,596 cases of CRC that received curative surgery. Serum CEA/CA 19-9 were measured through chemiluminescence immunoassay (CLIA). Results. During follow-up (median follow-up = 5.2 years), in total, 837 patients experienced recurrence. The fully adjusted hazard ratios (HRs) were significantly higher, ≥1 standard deviation (±SD), in patients with upregulated CEA/CA 19-9 levels ( HRCEA = 7.06 ; HRCA 19 − 9 = 3.98 ) than in those with downregulated CEA/CA 19-9 levels. The likelihood of recurrence remained consistently greater in cases of elevated CEA/CA 19-9 levels during sensitivity analyses. Conclusions. The findings of this analysis showed that variations in CEA/CA 19-9 expression profiles within the reference range impact CRC recurrence.

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Section: Introductionmentioning

confidence: 99%

Elevated CEA and CA 19-9 Levels within the Normal Ranges Increase the Likelihood of CRC Recurrence in the Chinese Han Population

Wang¹,

Zhang²,

Shen³

et al. 2022

Applied Bionics and Biomechanics

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“…The clinical utility of identifying circulating tumour cells in colorectal cancer patients has already been described by several authors [ 15 , 22 , 23 , 25 , 27 , 38 , 39 ]. However, current protocols for the isolation and characterisation of CTCs are mainly limited to the microscopic evaluation of one or two markers, compromising the ability to identify different CTC subpopulations.…”

Section: Discussionmentioning

confidence: 99%

“…However, most studies on CTCs have relied solely on the expression of epithelial markers (EpCAM/CK) versus the absence of CD45 expression [ 12 , 24 ], reducing the ability to detect/characterise CTCs and thus weakening their prognostic value [ 26 ]. Furthermore, poor prognosis is associated not only with CTC counts but also with CTC clusters (also called microemboli), as they increase with disease stage and are significantly associated with worse outcomes [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Deep Phenotypic Characterisation of CTCs by Combination of Microfluidic Isolation (IsoFlux) and Imaging Flow Cytometry (ImageStream)

Ruiz-Rodríguez

Molina-Vallejo

Aznar-Peralta

et al. 2021

Cancers

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The isolation of circulating tumour cells (CTCs) in colorectal cancer (CRC) mostly relies on the expression of epithelial markers such as EpCAM, and phenotypic characterisation is usually performed under fluorescence microscopy with only one or two additional markers. This limits the ability to detect different CTC subpopulations based on multiple markers. The aim of this work was to develop a novel protocol combining two platforms (IsoFluxTM and ImageStream®X) to improve CTC evaluation. Cancer cell lines and peripheral blood from healthy donors were used to evaluate the efficiency of each platform independently and in combination. Peripheral blood was extracted from 16 early CRC patients (before loco-regional surgery) to demonstrate the suitability of the protocol for CTC assessment. Additionally, peripheral blood was extracted from nine patients one month after surgery to validate the utility of our protocol for identifying CTC subpopulation changes over time. Results: Our protocol had a mean recovery efficiency of 69.5% and a limit of detection of at least four cells per millilitre. We developed an analysis method to reduce noise from magnetic beads used for CTC isolation. CTCs were isolated from CRC patients with a median of 37 CTCs (IQ 13.0–85.5) at baseline. CTCs from CRC patients were significantly (p < 0.0001) larger than cytokeratin (CK)-negative cells, and patients were stratified into two groups based on BRAFV600E and PD-L1 expression on CK-positive cells. The changes observed over time included not only the number of CTCs but also their distribution into four different subpopulations defined according to BRAFV600E and PD-L1 positivity. We developed a novel protocol for semi-automatic CTC isolation and phenotypic characterisation by combining two platforms. Assessment of CTCs from early CRC patients using our protocol allowed the identification of two clusters of patients with changing phenotypes over time.

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“…And secondly, they are larger than single CTCs, and more likely to be trapped in blood vessels, leading to greater colonization efficiency. Previous studies have reported the presence of homotypic CTC clusters causes significantly worse progression or poor prognosis in breast, [43,52,56] colorectal, [57,58] gastric cancer, [59,60] pancreatic ductal adenocarcinoma, [61] and small-cell lung cancers. [31] Heterotypic CTC clusters consists of aggregates of cancer cells with non-malignant stromal or immune cells.…”

Section: Ctcs Exist In Circulation Either As Individual Cells or As C...mentioning

confidence: 99%

The Discovery of Novel Circulating Cancer‐Related Cells in Circulation Poses New Challenges to Microfluidic Devices for Enrichment and Detection

Huang

Zhou

et al. 2022

Small Methods

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cells (CTCs) are precursors of metastasis in various cancers. They are detached cells slough off the edges of a solid tumor, and then enter the bloodstream or lymphatic system, moving from the primary site to distal organs via the lymphatic channels or the circulation. Although an estimated number of 3.2 × 10 6 tumor cells detach from one gram of tumor tissues per day, [2] CTCs have a relatively short life span that most of them begin to apoptosis within 24 h due to the loss of adhesion to the extracellular matrix, the shear forces of blood flow, or attacks from the immune cells. [3,4] Only a tiny fraction of CTCs that have undergone epithelial-mesenchymal transition (EMT) or CTC clusters formation survive in the bloodstream. [5] After EMT, epithelial CTCs acquire a mesenchymal phenotype, and become invasive and motile. CTCs hold the genetic information of the primary tumor, due to their same origin, thus can act as the surrogate of primary tumor for the monitoring of tumor phenotype/genotype. [6] CTCs counts have been reported correlate to overall survival and/or metastatic relapse, and suggested as a surrogate predictive marker for early diagnoses, the evaluation of chemotherapy efficacy, and cancer prognosis. [7] However, CTCs detection and analysis have two major challenges: their rarity in a typically sampled blood volume (10-50 mL), as well as genetical and phenotypical heterogeneity. [8] Thus, enrichment and detection procedures are the foundation for developing the technologies of CTCs detection. Microfluidic chip is a promising technology for CTCs isolation, identification, and characterization by using their biological and physical properties. It owes unique advantages, such as low-cost, simplicity, reduction in reagent consumption, miniaturization, fast and precise control.The substantial heterogeneity of CTCs determines their variability in expression patterns, [9] which causes difficulties to define a CTC by using specific markers. The most widely used markers to identify CTCs are EpCAM and cytokeratins (CKs). Thus, a long time in the early days, CTCs are defined as EpCAM or CKs positive and CD45 negative. But only epithelial CTCs express these two proteins. CTCs undergoing EMT gradually lose their epithelial features, having no or very low expression of epithelial markers (e.g., EpCAM, CKs, Circulating tumor cells (CTCs) enumeration has been widely used as a surrogate predictive marker for early diagnoses, the evaluation of chemotherapy efficacy, and cancer prognosis. Microfluidic technologies for CTCs enrichment and detection have been developed and commercialized as automation platforms. Currently, in addition to CTCs, some new types of circulating cancer-related cells (e.g., CCSCs, CTECs, CAMLs, and heterotypic CTC clusters) in circulation are also reported to be correlated to cancer diagnosis, metastasis, or prognosis. And they widely differ from the conventional CTCs in positive markers, cellular morphology, or size, which presents a new technological challenge to microfluidic devices that use ...

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Highly Correlated Recurrence Prognosis in Patients with Metastatic Colorectal Cancer by Synergistic Consideration of Circulating Tumor Cells/Microemboli and Tumor Markers CEA/CA19-9

Cited by 19 publications

References 29 publications

Elevated CEA and CA 19-9 Levels within the Normal Ranges Increase the Likelihood of CRC Recurrence in the Chinese Han Population

Elevated CEA and CA 19-9 Levels within the Normal Ranges Increase the Likelihood of CRC Recurrence in the Chinese Han Population

Deep Phenotypic Characterisation of CTCs by Combination of Microfluidic Isolation (IsoFlux) and Imaging Flow Cytometry (ImageStream)

The Discovery of Novel Circulating Cancer‐Related Cells in Circulation Poses New Challenges to Microfluidic Devices for Enrichment and Detection

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