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Lutfi A, Afghan MK, Kasi PM. CTCs and liquid biopsies in patients with colorectal cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2025; 392:101-117. [PMID: 40287217 DOI: 10.1016/bs.ircmb.2024.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
Liquid biopsy, which includes both circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) has become a valuable tool for cancer diagnosis and monitoring. It offers a less invasive approach than traditional tissue biopsy and recent technological advancements have enabled their use in comprehensive analysis of tumor molecular characteristics. By capturing the dynamic nature of tumors through repeated sampling, liquid biopsy addresses the limitations of tissue biopsy and provides insights into tumor heterogeneity over time. It is being extensively studied in patients with advanced colorectal cancer because it can aid in diagnosis, predict disease course, and guide treatment selection. Furthermore, as personalized medicine becomes more common, identifying genetic changes that cause cancer cells to become resistant to treatment is crucial. This chapter explores the emerging field of liquid biopsy, with a particular focus on the role and potential of circulating tumor cells (CTCs) in the context of colorectal cancer.
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Affiliation(s)
- Areeb Lutfi
- Department of Hematology and Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Maaz Khan Afghan
- Department of Hematology and Oncology, Weill Cornell Medicine, New York, NY, United States
| | - Pashtoon Murtaza Kasi
- Department of Oncology and Therapeutics Research, City of Hope, Irvine, CA, United States.
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Zhu T, Li Y, Li R, Zhang J, Zhang W. Predictive value of preoperative circulating tumor cells combined with hematological indexes for liver metastasis after radical resection of colorectal cancer. Medicine (Baltimore) 2025; 104:e41264. [PMID: 39792713 PMCID: PMC11730839 DOI: 10.1097/md.0000000000041264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 12/11/2024] [Indexed: 01/12/2025] Open
Abstract
Colorectal cancer is one of the most common malignant tumors in the world, and about 50% of its advanced patients will have liver metastasis. Preoperative assessment of the risk of liver metastasis in patients with colorectal cancer is of great significance for making individualized treatment plans. Traditional imaging examinations and tumor markers have some limitations in predicting the risk of liver metastasis. Therefore, it is of great clinical value to explore more sensitive and specific predictive indicators for improving early detection and treatment effect. In recent years, circulating tumor cells (CTCs), as a new biomarker, have attracted much attention because of their close relationship with tumor metastasis and prognosis. The purpose of this study is to collect and analyze the data of colorectal cancer patients treated in our hospital, so as to determine the predictive value of circulating tumor cells before operation and related hematological indexes for liver metastasis after radical resection of colorectal cancer, and to establish the corresponding prediction model to provide gastrointestinal surgeons with more accurate identification of high-risk patients and guidance for treatment. A total of 88 patients were included in this study, and 26 of whom developed liver metastasis after colorectal cancer surgery. The possible related factors are included in the single factor logistic regression, and the results are obtained after analysis. Body mass index, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9, tumor marker CA72-4 (CA72-4), cytokeratin-7 (CK-7), CTC count, and neutrophil-to-lymphocyte ratio (P < .2) are risk factors for liver metastasis after radical resection of colorectal cancer. Furthermore, the data obtained were included in multivariate regression analysis, and CEA, CA72-4, CK-7, and CTC counts were independent risk factors for liver metastasis after radical resection of colorectal cancer (P < .05). This study confirmed that CEA, CA72-4, CK-7, and CTC counts are independent risk factors for liver metastasis after radical resection of colorectal cancer. In addition, the prediction model of this study can help gastrointestinal surgeons accurately identify patients who are prone to liver metastasis after colorectal cancer surgery.
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Affiliation(s)
- Tianyi Zhu
- Department of Clinical Laboratory, The Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Yunsong Li
- Department of General Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Rui Li
- Department of Clinical Laboratory, The Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Jingjing Zhang
- Department of Clinical Laboratory, The Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Wentao Zhang
- Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
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Meyer YM, Wilting SM, Kraan J, Olthof P, Vermeulen P, Martens J, Grünhagen DJ, Sleijfer S, Verhoef C. Circulating tumour cells are associated with histopathological growth patterns of colorectal cancer liver metastases. Clin Exp Metastasis 2023; 40:69-77. [PMID: 36326981 PMCID: PMC9898367 DOI: 10.1007/s10585-022-10191-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022]
Abstract
Histopathological Growth Patterns (HGPs) have prognostic and predictive value in patients with Colorectal Liver Metastases (CRLM). This study examined whether preoperative measurement of Circulating Tumour Cells (CTCs) is associated with HGP. CTCs were prospectively enumerated in 7.5 ml of blood using the FDA-approved CellSearch system in patients who underwent local treatment of CRLM with curative intent between 2008 and 2021. All CTC samples were collected on the day of local treatment. Patients treated with neoadjuvant chemotherapy for CRLM or with extrahepatic disease at the time of CTC sampling were excluded. HGP was scored retrospectively following the current consensus guidelines. The association between CTCs and HGP was investigated through multivariable logistic regression. Data were available for 177 patients, desmoplastic HGP (dHGP) was observed in 34 patients (19%). There were no statistically significant differences in patient and tumour characteristics between dHGP and non-dHGP at baseline. Patients with dHGP had longer overall - and disease-free survival (logrank p = 0.003 and 0.003, respectively) compared to patients with non-dHGP. CTCs were not detected in 25(74%) of dHGP patients and in 68(48%) of non-dHGP patients (chi-squared p = 0.006). Preoperative absence of CTCs was the only significant predictor for dHGP in multivariable logistic regression (Odds Ratio 2.7, 95%CI 1.1-6.8, p = 0.028), Table 3. Preoperative absence of CTCs is associated with dHGP in chemo naive CRLM patients without extrahepatic disease. Based on our results, CTC count alone is not sufficient to preoperatively identify HGPs, but integration of CTC count in multivariable prediction models may aid the preoperative identification of HGPs of CRLM.
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Affiliation(s)
- Y M Meyer
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - S M Wilting
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - J Kraan
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - P Olthof
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - P Vermeulen
- Translational Cancer Research Unit (GZA Hospitals and University of Antwerp), Antwerp, Belgium
| | - J Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - D J Grünhagen
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - S Sleijfer
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - C Verhoef
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
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Yao Y, Zhu X, Liu W, Jiang J, Jiang H. Meta-analysis of the prognostic value of circulating tumor cells in gastrointestinal cancer. Medicine (Baltimore) 2022; 101:e31099. [PMID: 36281182 PMCID: PMC9592416 DOI: 10.1097/md.0000000000031099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Detecting circulating tumor cells (CTCs) has become a new strategy for predicting the prognosis of cancer patients. However, limited systematic research evidence is available for the detection of CTCs in various gastrointestinal tumors such as esophageal cancer (EC), colorectal cancer (CRC) and gastric cancer (GC). This topic was addressed to assess the prognostic significance of CTCs in gastrointestinal tumors. METHODS We conducted a literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist (from November 20, 2021). We performed a meta-analysis using the random effects model and Review Manager 5.3 software (The Cochrane Collaboration, Copenhagen, Denmark) according to the inclusion and exclusion criteria, data extraction and evaluation methods. RESULTS Twenty-four articles met the inclusion criteria for this study, and they included 3803 EC, CRC and GC patients, including 1189 CTC-positive and 2462 CTC-negative cases. The meta-analysis showed that the presence of CTCs was associated with worse OS (HR = 2.05, 95% CI = 1.75-2.40, P = .060) and PFS (HR = 2.27, 95% CI = 1.79-2.89, P < .001). Further meta-regression and subgroup analyses showed that CTC-positive patients also showed worse OS and PFS in different subgroups. CONCLUSION Our meta-analysis suggests that detecting CTCs in peripheral blood may be an important tool for improving the prognosis of patients with gastrointestinal tumors. Moreover, CTCs detection results could be used to develop personalized treatment plans in the future.
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Affiliation(s)
- Yuming Yao
- Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, China
| | - Xiang Zhu
- Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, China
| | - Weixin Liu
- Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, China
| | - Jiayi Jiang
- Mathematics Major, New York University, New York, NY, USA
| | - Han Jiang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- * Correspondence: Han Jiang, Department of Thoracic Surgery, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu, Nanchang 330006, Jiangxi, China (e-mail: )
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Defining A Liquid Biopsy Profile of Circulating Tumor Cells and Oncosomes in Metastatic Colorectal Cancer for Clinical Utility. Cancers (Basel) 2022; 14:cancers14194891. [PMID: 36230811 PMCID: PMC9563925 DOI: 10.3390/cancers14194891] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 09/30/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary Metastatic colorectal cancer (mCRC) is typified by its tumor heterogeneity and changing disease states, suggesting that personalized medicine approaches could be vital to improving clinical practice. As a minimally invasive approach, the liquid biopsy has the potential to be a powerful longitudinal prognostic tool. We investigated mCRC patients’ peripheral blood samples using an enrichment-free single-cell approach to capture the broader rare-event population beyond the conventionally detected epithelial-derived circulating tumor cell (CTC). Our analysis reveals a heterogenous profile of CTCs and oncosomes not commonly found in normal donor samples. We identified select rare cell types based on their distinct immunofluorescence expression and morphology across multiple assays. Lastly, we highlight correlations between enumerations of the blood-based analytes and progression-free survival. This study clinically validates an unbiased rare-event approach in the liquid biopsy, motivating future studies to further investigate these analytes for their prognostic potential. Abstract Metastatic colorectal cancer (mCRC) is characterized by its extensive disease heterogeneity, suggesting that individualized analysis could be vital to improving patient outcomes. As a minimally invasive approach, the liquid biopsy has the potential to longitudinally monitor heterogeneous analytes. Current platforms primarily utilize enrichment-based approaches for epithelial-derived circulating tumor cells (CTC), but this subtype is infrequent in the peripheral blood (PB) of mCRC patients, leading to the liquid biopsy’s relative disuse in this cancer type. In this study, we evaluated 18 PB samples from 10 mCRC patients using the unbiased high-definition single-cell assay (HDSCA). We first employed a rare-event (Landscape) immunofluorescence (IF) protocol, which captured a heterogenous CTC and oncosome population, the likes of which was not observed across 50 normal donor (ND) samples. Subsequent analysis was conducted using a colorectal-targeted IF protocol to assess the frequency of CDX2-expressing CTCs and oncosomes. A multi-assay clustering analysis isolated morphologically distinct subtypes across the two IF stains, demonstrating the value of applying an unbiased single-cell approach to multiple assays in tandem. Rare-event enumerations at a single timepoint and the variation of these events over time correlated with progression-free survival. This study supports the clinical utility of an unbiased approach to interrogating the liquid biopsy in mCRC, representing the heterogeneity within the CTC classification and warranting the further molecular characterization of the rare-event analytes with clinical promise.
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Chen FL, Wang YY, Liu W, Xing BC. Prognostic factors in colorectal liver metastases patients with various tumor numbers treated by liver resection: a single-center, retrospective study. World J Surg Oncol 2022; 20:237. [PMID: 35854361 PMCID: PMC9297581 DOI: 10.1186/s12957-022-02700-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Multiple liver metastases is considered a risk factor for overall survival of colorectal liver metastases patients (CRLM) after curative resection. However, whether the prognostic factors were constant in patients with various liver metastases (LM) numbers has not been adequately investigated. This retrospective study aimed to evaluate the changing of prognostic factors on overall survival (OS) in CRLM patients with various LM after curative resection. METHODS Patients who underwent liver resection for CRLM between January 2000 and November 2020 were retrospectively studied. They were divided into three subgroups according to LM numbers by X-tile analysis. Multivariable analysis identified prognostic factors in each subgroup. Nomograms were built using different prognostic factors in three subgroups, respectively. Performance of the nomograms was assessed according to the concordance index (C-index) and calibration plots. The abilities of different scoring systems predicting OS were compared by calculating the area under the time-dependent receiver operating characteristic (ROC) curve (AUC). RESULTS A total of 1095 patients were included. Multivariable analysis showed tumor number increasing was an independent risk factor. Patients were subsequently divided into 3 subgroups according to the number of LM by X-tile analysis, namely solitary (n = 375), 2-4 (n = 424), and ≥ 5 (n = 296). The 3-year and 5-year OS rates were 64.1% and 54.0% in solitary LM group, 58.1% and 41.7% in 2-4 LM group, and 50.9% and 32.0% in ≥ 5 LM group, respectively (p < 0.001). In multivariable analysis, RAS mutation was the only constant independent risk factor in all subgroups. The nomograms were built to predict survival based on independent factors in three subgroups. The C-index for OS prediction was 0.707 (95% CI 0.686-0.728) in the solitary LM group, 0.695 (95% CI 0.675-0.715) in the 2-4 LM group, and 0.687 (95% CI 0.664-0.710) in the ≥ 5 LM group. The time-dependent AUC values of nomograms developed using different risk factors after stratifying patients by tumor number were higher than the traditional scoring systems without patient stratification. CONCLUSIONS The prognostic factors varied among CRLM patients with different LM numbers. RAS mutation was the only constant risk factor. Building prediction models based on different prognostic factors improve patient stratification.
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Affiliation(s)
- Feng-Lin Chen
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Hepatopancreatobiliary Surgery Department I, Beijing Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Yan-Yan Wang
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Hepatopancreatobiliary Surgery Department I, Beijing Cancer Hospital and Institute, Beijing, People's Republic of China
| | - Wei Liu
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Hepatopancreatobiliary Surgery Department I, Beijing Cancer Hospital and Institute, Beijing, People's Republic of China.
| | - Bao-Cai Xing
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Hepatopancreatobiliary Surgery Department I, Beijing Cancer Hospital and Institute, Beijing, People's Republic of China.
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Guadagni S, Masedu F, Fiorentini G, Sarti D, Fiorentini C, Guadagni V, Apostolou P, Papasotiriou I, Parsonidis P, Valenti M, Ricevuto E, Bruera G, Farina AR, Mackay AR, Clementi M. Circulating tumour cell gene expression and chemosensitivity analyses: predictive accuracy for response to multidisciplinary treatment of patients with unresectable refractory recurrent rectal cancer or unresectable refractory colorectal cancer liver metastases. BMC Cancer 2022; 22:660. [PMID: 35710393 PMCID: PMC9202660 DOI: 10.1186/s12885-022-09770-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 06/08/2022] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs). METHODS In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected. RESULTS Our analyses resulted in evaluations of 94.12% (95% CI 0.71-0.99) for sensitivity, 5.26% (95% CI 0.01-0.26) for specificity, a predictive value of 47.06% (95% CI 0.29-0.65) for a positive response, a predictive value of 50% (95% CI 0.01-0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30-0.64). CONCLUSIONS This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials.
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Affiliation(s)
- Stefano Guadagni
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100, L'Aquila, Italy.
| | - Francesco Masedu
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | - Giammaria Fiorentini
- Department of Oncology and Hematology, Azienda Ospedaliera "Ospedali Riuniti Marche Nord", Pesaro, Italy
| | - Donatella Sarti
- Department of Oncology and Hematology, Azienda Ospedaliera "Ospedali Riuniti Marche Nord", Pesaro, Italy
| | - Caterina Fiorentini
- Department of Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Veronica Guadagni
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | | | | | | | - Marco Valenti
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | - Enrico Ricevuto
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | - Gemma Bruera
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | - Antonietta R Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | - Andrew R Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100, L'Aquila, Italy
| | - Marco Clementi
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100, L'Aquila, Italy
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Hong XC, Liang QL, Chen M, Yang HX, Huang J, Yi SL, Wang ZW, Liang HY, Zhang DY, Huang ZY. PRL-3 and MMP9 Expression and Epithelial-Mesenchymal Transition Markers in Circulating Tumor Cells From Patients With Colorectal Cancer: Potential Value in Clinical Practice. Front Oncol 2022; 12:878639. [PMID: 35574414 PMCID: PMC9104807 DOI: 10.3389/fonc.2022.878639] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/04/2022] [Indexed: 12/01/2022] Open
Abstract
Objective To evaluate the clinical correlation of epithelial-mesenchymal transition (EMT) with PRL-3 and MMP9 expression in the circulating tumor cells (CTCs) of patients with colorectal cancer (CRC). Materials and Methods Between January 2016 and December 2018, the EMT phenotype-based subsets of CTCs and the expression levels of PRL-3 and MMP9 in CTCs were identified, and their clinical values in 172 patients were evaluated. The CTCs were isolated, classified, and counted using the CanPatrol™ CTC filtration system. The CTC subsets (epithelial cells, mesenchymal cells and biphenotypic cells), as well as PRL-3 and MMP9 expression, were detected by RNA in situ hybridization. Results CTCs were detected in 93.0% (160/172) of the included patients with CRC. Positive PRL-3 and MMP9 expression in CTC and M-CTC was found in 75.0% (102/136) and 80.8% (97/120) of the patients, respectively. The proportion of patients with positive PRL-3 and MMP9 expression in M-CTC was significantly associated with distant metastasis (p<0.05). The patients with ≥6 CTCs tended to show poorer progression-free survival (PFS) and overall survival (OS) rates (p=0.016, 0.02, respectively), and the patients with ≥3 M-CTC also showed poor PFS (p=0.0013). Additionally, the patients with positive PRL-3 and MMP9 expression in CTCs had significantly poorer PFS (p=0.0024) and OS (p=0.095) than the patients with negative PRL-3 and MMP9 expression. Multivariate Cox analysis uncovered that positive PRL-3 and MMP9 expression in CTCs may be an independent prognostic factor for worse PFS. Conclusion EMT phenotypes and CTC numbers can be used as prognostic indicators for metastasis and survival in patients with CRC, and the combination of PRL-3 and MMP9 expression in CTCs is a promising clinical marker for patients with CRC.
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Affiliation(s)
- Xiao-Cui Hong
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Qi-Lian Liang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- *Correspondence: Qi-Lian Liang,
| | - Man Chen
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hai-Xia Yang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jie Huang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Si-Lin Yi
- Pathology Department, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhen-Wei Wang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hai-Yan Liang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Ding-Yue Zhang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zeng-Yi Huang
- Oncology Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as a Liquid Biopsy Marker in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13184500. [PMID: 34572727 PMCID: PMC8469158 DOI: 10.3390/cancers13184500] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/25/2021] [Accepted: 08/30/2021] [Indexed: 01/05/2023] Open
Abstract
Simple Summary Colorectal cancer is one of the most frequent malignant tumors worldwide and the spread of tumor cells through the blood circulation followed by the colonization of distant organs (“metastases”) is the main cause of cancer-related death. The blood is, therefore, an important fluid that can be explored for diagnostic purposes. Liquid biopsy is a new diagnostic concept defined as the analysis of circulating tumor cells or cellular products such as cell-free DNA in the blood or other body fluids of cancer patients. In this review, we summarize and discuss the latest findings using circulating tumor cells and cell-free DNA derived from tumor lesions in the blood of patients with colorectal cancer. Clinical applications include early detection of cancer, identification of patients with a high risk for disease progression after curative surgery, monitoring for disease progression in the context of cancer therapies, and discovery of mechanisms of resistance to therapy. Abstract Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. It is a heterogeneous tumor with a wide genomic instability, leading to tumor recurrence, distant metastasis, and therapy resistance. Therefore, adjunct non-invasive tools are urgently needed to help the current classical staging systems for more accurate prognostication and guiding personalized therapy. In recent decades, there has been an increasing interest in the diagnostic, prognostic, and predictive value of circulating cancer-derived material in CRC. Liquid biopsies provide direct non-invasive access to tumor material, which is shed into the circulation; this enables the analysis of circulating tumor cells (CTC) and genomic components such as circulating free DNA (cfDNA), which could provide the key for personalized therapy. Liquid biopsy (LB) allows for the identification of patients with a high risk for disease progression after curative surgery, as well as longitudinal monitoring for disease progression and therapy response. Here, we will review the most recent studies on CRC, demonstrating the clinical potential and utility of CTCs and ctDNA. We will discuss some of the advantages and limitations of LBs and the future perspectives in the field of CRC management.
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Abdalla TSA, Meiners J, Riethdorf S, König A, Melling N, Gorges T, Karstens KF, Izbicki JR, Pantel K, Reeh M. Prognostic value of preoperative circulating tumor cells counts in patients with UICC stage I-IV colorectal cancer. PLoS One 2021; 16:e0252897. [PMID: 34111181 PMCID: PMC8191913 DOI: 10.1371/journal.pone.0252897] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. There is an urgent need to identify prognostic markers for patients undergoing curative resection of CRC. The detection of circulating tumor cells in peripheral blood is a promising approach to identify high-risk patients with disseminated disease in colorectal cancer. This study aims to evaluate the prognostic relevance of preoperative CTCs using the Cellsearch® system (CS) in patients, who underwent resection with curative intent of different stages (UICC I-IV) of colorectal cancer. Out of 91 Patients who underwent colorectal resection, 68 patients were included in this study. CTC analysis was performed in patients with CRC UICC stages I-IV immediately before surgery. Data were correlated with clinicopathological parameters and patient outcomes. One or more CTCs/7.5 mL were detected in 45.6% (31/68) of patients. CTCs were detected in all stages of the Union of International Cancer Control (UICC), in stage I (1/4, 25%), in stage II (4/12, 33.3%), in stage III (5/19, 26.3%) and in stage IV (21/33, 63.6%). The detection of ≥ 1 CTCs/ 7.5ml correlated to the presence of distant overt metastases (p = 0.014) as well as with shorter progression-free (p = 0.008) and overall survival (p = 0.008). Multivariate analyses showed that the detection of ≥ 1 CTCs/ 7.5ml is an independent prognostic indicator for overall survival (HR, 3.14; 95% CI, 1.18-8.32; p = 0.021). The detection of CTCs is an independent and strong prognostic factor in CRC, which might improve the identification of high-risk patients in future clinical trials.
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Affiliation(s)
- Thaer S. A. Abdalla
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- * E-mail:
| | - Jan Meiners
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Riethdorf
- Department of Tumor Biology, University Cancer Center Hamburg, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexandra König
- Department of General Surgery, Hospital Wilhelmshaven, Wilhelmshaven, Germany
| | - Nathaniel Melling
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tobias Gorges
- Department of Tumor Biology, University Cancer Center Hamburg, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karl-F. Karstens
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R. Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, University Cancer Center Hamburg, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias Reeh
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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11
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Patelli G, Vaghi C, Tosi F, Mauri G, Amatu A, Massihnia D, Ghezzi S, Bonazzina E, Bencardino K, Cerea G, Siena S, Sartore-Bianchi A. Liquid Biopsy for Prognosis and Treatment in Metastatic Colorectal Cancer: Circulating Tumor Cells vs Circulating Tumor DNA. Target Oncol 2021; 16:309-324. [PMID: 33738696 PMCID: PMC8105246 DOI: 10.1007/s11523-021-00795-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2021] [Indexed: 02/06/2023]
Abstract
Liquid biopsy recently gained widespread attention as a noninvasive alternative/complementary technique to tissue biopsy in patients with cancer. As technological advances have improved both feasibility and turnaround time, liquid biopsy has expanded tumor molecular analysis with acknowledgement of both spatial and temporal heterogeneity, overcoming many limitations of traditional tissue biopsy. Because of its diagnostic, prognostic, and predictive value, liquid biopsy has been extensively studied also in metastatic colorectal cancer. Indeed, as personalized medicine establishes its role in cancer treatment, genetic biomarkers unveiling the emergence of early resistance are needed. Among the wide variety of tumor analytes amenable to collection, circulating DNA and circulating tumor cells are the most adopted approaches, and both carry clinical relevance in colorectal cancer. However, few studies focused on comparing feasibility between these two approaches. In this review, we discuss the potential implications of liquid biopsy in metastatic colorectal cancer, assessing the advantages and drawbacks of circulating DNA and circulating tumor cells, and highlighting the most relevant trials for clinical practice.
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Affiliation(s)
- Giorgio Patelli
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Piazza Ospedale Maggiore, 3, 20162, Milan, Italy
| | - Caterina Vaghi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Piazza Ospedale Maggiore, 3, 20162, Milan, Italy
| | - Federica Tosi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Gianluca Mauri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Piazza Ospedale Maggiore, 3, 20162, Milan, Italy
| | - Alessio Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Daniela Massihnia
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Piazza Ospedale Maggiore, 3, 20162, Milan, Italy
| | - Silvia Ghezzi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Erica Bonazzina
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Katia Bencardino
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giulio Cerea
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Piazza Ospedale Maggiore, 3, 20162, Milan, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano (La Statale), Piazza Ospedale Maggiore, 3, 20162, Milan, Italy.
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12
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Abstract
Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), pancreatic cancer, melanoma, lung cancer and breast cancer, although CRC is the most common primary cancer that metastasizes to the liver. Interactions between tumour cells and the tumour microenvironment play an important part in the engraftment, survival and progression of the metastases. Various cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, parenchymal hepatocytes, dendritic cells, resident natural killer cells as well as other immune cells such as monocytes, macrophages and neutrophils are implicated in promoting and sustaining metastases in the liver. Four key phases (microvascular, pre-angiogenic, angiogenic and growth phases) have been identified in the process of liver metastasis. Imaging modalities such as ultrasonography, CT, MRI and PET scans are typically used for the diagnosis of liver metastases. Surgical resection remains the main potentially curative treatment among patients with resectable liver metastases. The role of liver transplantation in the management of liver metastasis remains controversial. Systemic therapies, newer biologic agents (for example, bevacizumab and cetuximab) and immunotherapeutic agents have revolutionized the treatment options for liver metastases. Moving forward, incorporation of genetic tests can provide more accurate information to guide clinical decision-making and predict prognosis among patients with liver metastases.
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13
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Ono K, Abe T, Oshita A, Sumi Y, Yano T, Okuda H, Kurayoshi M, Kobayashi T, Ohdan H, Noriyuki T, Nakahara M. Efficacy of upfront hepatectomy without neoadjuvant chemotherapy for resectable colorectal liver metastasis. World J Surg Oncol 2021; 19:97. [PMID: 33820549 PMCID: PMC8022388 DOI: 10.1186/s12957-021-02210-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/22/2021] [Indexed: 12/17/2022] Open
Abstract
Background Hepatectomy for resectable colorectal liver metastasis (CRLM) is recommended. However, the efficacy of upfront hepatectomy without neoadjuvant chemotherapy (NAC) is unclear due to the uncertainty of perioperative systemic chemotherapy. Moreover, it is crucial to predict the prognosis when considering perioperative chemotherapy. This study evaluated the impact of neoadjuvant chemotherapy on the prognosis of patients with resectable CRLM and assessed the usefulness of Beppu’s nomogram for predicting prognosis. Methods This retrospective study identified 88 consecutive inpatients who underwent primary hepatic resection for CRLM; 58 received neoadjuvant chemotherapy and 30 underwent upfront surgery. Factors associated with recurrence-free survival were identified via univariate and multivariate analysis. Furthermore, propensity score analysis using inverse probability of treatment weighting (IPTW) was performed. Results On univariate analysis, poor recurrence-free survival was associated with multiple tumors, advanced primary tumor stage, vascular invasion by the primary tumor, a Beppu’s nomogram score ≥ 6, and neoadjuvant chemotherapy. On multivariate analysis, a Beppu’s nomogram score ≥ 6 and neoadjuvant chemotherapy were independent risk factors for recurrence. Neoadjuvant chemotherapy recipients had a higher incidence of lymph node metastasis and vascular invasion than non-recipients. Propensity score analysis revealed no significant difference in the recurrence-free survival rate between these groups. Conclusions Our results show that upfront hepatectomy without neoadjuvant chemotherapy can be considered for resectable CRLM treatment. Beppu’s nomogram score can be a tool for predicting the prognosis of patients with CRLM.
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Affiliation(s)
- Kosuke Ono
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara Onomichi, Hiroshima, 722-8508, Japan
| | - Tomoyuki Abe
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara Onomichi, Hiroshima, 722-8508, Japan.
| | - Akihiko Oshita
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara Onomichi, Hiroshima, 722-8508, Japan.,Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Hiroshima, 734-8551, Japan
| | - Yusuke Sumi
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara Onomichi, Hiroshima, 722-8508, Japan
| | - Takuya Yano
- Department of Surgery, Hiroshima Citizens Hospital, 7-33 Motomachi, Hiroshima, 730-8518, Japan
| | - Hiroshi Okuda
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara Onomichi, Hiroshima, 722-8508, Japan
| | - Manabu Kurayoshi
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara Onomichi, Hiroshima, 722-8508, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Hiroshima, 734-8551, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Hiroshima, 734-8551, Japan
| | - Toshio Noriyuki
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara Onomichi, Hiroshima, 722-8508, Japan.,Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Hiroshima, 734-8551, Japan
| | - Masahiro Nakahara
- Department of Surgery, Onomichi General Hospital, 1-10-23 Hirahara Onomichi, Hiroshima, 722-8508, Japan
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14
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Memarpour S, Khalili-Tanha G, Ghannad AA, Razavi MS, Joudi M, Joodi M, Ferns GA, Hassanian SM, Khazaei M, Avan A. The Clinical Application of Circulating Tumor Cells and DNAs as Prognostic and Predictive Biomarkers in Gastrointestinal Cancer. Curr Cancer Drug Targets 2021; 21:676-688. [PMID: 33719973 DOI: 10.2174/1568009621666210311090531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/21/2020] [Accepted: 01/31/2021] [Indexed: 11/22/2022]
Abstract
Gastrointestinal (GI) cancer is one of the most common cancers globally. Genetic and epigenetic mechanisms are involved in its pathogenesis. The conventional methods for diagnosis and screening for GI cancers are often invasive and have other limitations. In the era of personalized medicine, a novel non-invasive approach called liquid biopsy has been introduced for the detection and management of GI cancers, which focuses on the analysis of circulating tumor cells (CTCs) and circulating cell-free tumor DNA (ctDNA). Several studies have shown that this new approach allows for an improved understanding of GI tumor biology and will lead to an improvement in clinical management. The aim of the current review is to explore the clinical applications of CTCs and ctDNA in patients with GI cancer.
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Affiliation(s)
- Sara Memarpour
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Awa Alizadeh Ghannad
- Department of biological sciences, California state University, Sacramento, California. United States
| | - Masoud Sharifian Razavi
- Department of Gastroenterology, Ghaem Medical Center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Mona Joudi
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Marjan Joodi
- Sarvar Children's Hospital, Endoscopic and Minimally Invasive Surgery Research Center, Mashhad. Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH. United Kingdom
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Majid Khazaei
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad. Iran
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15
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White MG, Lee A, Vicente D, Hall C, Kim MP, Katz MHG, Lee JE, Ikoma N, Lucci A, Tzeng CWD. Measurement of Portal Vein Blood Circulating Tumor Cells is Safe and May Correlate With Outcomes in Resected Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol 2021; 28:4615-4622. [PMID: 33415562 DOI: 10.1245/s10434-020-09518-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/05/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND This study investigated the safety and feasibility of intraoperative portal vein blood (PVB) collection at the time of pancreatic ductal adenocarcinoma (PDAC) resection. Relationships of circulating tumor cells (CTCs) in PVB and peripheral blood (PB) with overall survival (OS) and recurrence-free survival were studied. METHODS Patients undergoing PDAC resection were offered enrollment in a prospective liquid biopsy protocol. The patients had PB drawn before incision and PVB drawn before tumor mobilization, then again immediately after resection. Using standard CellSearch protocols, CTCs were identified and compared with OS. RESULTS Of the 34 patients enrolled in this study, 23 (68%) underwent pancreaticoduodenectomy, 8 (23%) underwent distal pancreatectomy, and 3 (9%) underwent total pancreatectomy. Peripheral blood was available for 22 (65%) and PVB for 31 (91%) of the patients. No bleeding or thrombotic complications occurred with the PVB draws. The CTC counts per 7.5 mL of PVB collected before and after resection were highly correlated (R2 = 0.89). The study found CTCs in 11 (50%) of 22 PB samples and 22 (71%) of 31 PVB samples. The OS rate at 18 months was 92% for the patients with < 3 CTCs, 71% for the patients with ≥ 3 CTCs per 7.5 mL of PB (p = 0.30), 100% for the patients without PVB CTCs, and 70% for the patients with PVB CTCs (p < 0.01). CONCLUSIONS Collection of PVB during PDAC resection is safe. In this pilot study, PVB CTC counts but not PB CTC counts were significantly correlated with OS. This opens the door for future studies on selective omission of adjuvant chemotherapy for patients treated preoperatively and tailored surveillance intensity for patients without PVB CTCs at PDAC resection.
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Affiliation(s)
- Michael G White
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew Lee
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Diego Vicente
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Carolyn Hall
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael P Kim
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Matthew H G Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeffrey E Lee
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naruhiko Ikoma
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anthony Lucci
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ching-Wei D Tzeng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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16
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Rahbari NN, Birgin E, Bork U, Mehrabi A, Reißfelder C, Weitz J. Anterior Approach vs Conventional Hepatectomy for Resection of Colorectal Liver Metastasis: A Randomized Clinical Trial. JAMA Surg 2021; 156:31-40. [PMID: 33147332 DOI: 10.1001/jamasurg.2020.5050] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Importance Tumor relapse after partial hepatectomy for colorectal liver metastasis (CRLM) remains an unsolved issue. Intraoperative manipulation of the liver during conventional hepatectomy might enhance hematogenous tumor cell spread. The anterior approach is an alternative approach that may reduce intraoperative tumor cell dissemination. Objective To determine the efficacy and safety of the anterior approach compared with conventional hepatectomy in patients undergoing resection for CRLM. Design, Setting, and Participants This randomized clinical study evaluated the efficacy and safety of the anterior approach compared with conventional hepatectomy in adult patients with CRLM who were scheduled for hepatectomy from February 1, 2003, to March 31, 2012, at a tertiary-care hospital. A total of 80 patients with CRLM were randomized to the anterior approach and conventional hepatectomy groups in a 1:1 ratio. Bone marrow and blood samples were analyzed for disseminated tumor cells and circulating tumor cells (CTC) using cytokeratin 20 reverse transcriptase-polymerase chain reaction analysis. Data were analyzed from April 1 to December 1, 2018, using intention to treat. Interventions Anterior approach vs conventional hepatectomy. Main Outcomes and Measures The primary end point was intraoperative CTC detection in central blood samples after liver resection. Secondary end points included postoperative morbidity, mortality, and long-term survival. Results Among the 80 patients included in the analysis (48 men [60%]; mean [SD] age, 61 [10] years), baseline characteristics, including preoperative CTC detection, were comparable between both groups. There was no statistically significant difference in intraoperative CTC detection between patients in the conventional hepatectomy (5 of 21 [24%]) and anterior approach (6 of 22 [27%]) groups (P = .54). Except for a longer operating time in the anterior approach group (mean [SD], 171 [53] vs 221 [53] minutes; P < .001), there were no significant differences in intraoperative and postoperative outcomes between both study groups. Although detection of CTC was associated with poor overall (median, 46 [95% CI, 40-52] vs 81 [95% CI, 54-107] months; P = .03) and disease-free (median, 40 [95% CI, 34-46] vs 60 [95% CI, 46-74] months; P = .04) survival, there was no significant difference in overall (median, 73 [95% CI, 42-104] vs 55 [95% CI, 35-75] months; P = .43) and disease-free (median, 48 [95% CI, 40-56] vs 40 [95% CI, 28-52] months; P = .88) survival between the conventional hepatectomy and anterior approach groups. Also, there was no significant difference in patterns of recurrence between both groups. Conclusions and Relevance This randomized clinical trial found that the anterior approach was not superior to conventional hepatectomy in reducing intraoperative tumor cell dissemination in patients undergoing resection of CRLM. Trial Registration isrctn.org Identifier: ISRCTN45066244.
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Affiliation(s)
- Nuh N Rahbari
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.,now affiliated with Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Emrullah Birgin
- Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ulrich Bork
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Christoph Reißfelder
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.,now affiliated with Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jürgen Weitz
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
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17
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Zhang Z, Li Q, Du X, Liu M. Application of electrochemical biosensors in tumor cell detection. Thorac Cancer 2020; 11:840-850. [PMID: 32101379 PMCID: PMC7113062 DOI: 10.1111/1759-7714.13353] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/19/2020] [Accepted: 01/21/2020] [Indexed: 01/05/2023] Open
Abstract
Conventional methods for detecting tumors, such as immunological methods and histopathological diagnostic techniques, often request high analytical costs, complex operation, long turnaround time, experienced personnel and high false-positive rates. In addition, these assays are difficult to obtain an early diagnosis and prognosis quickly for malignant tumors. Compared with traditional technology, electrochemical technology has realized the study of interface charge transfer behavior at the atomic and molecular levels, which has become an important analytical and detection tool in contemporary analytical science. Electrochemical technique has the advantages of rapid detection, high sensitivity (single cell) and specificity in the detection of tumor cells, which has not only been successful in differentiating tumor cells from normal cells, but has also achieved targeted detection of localized tumor cells and circulating tumor cells. Electrochemical biosensors provide powerful tools for early diagnosis, staging and prognosis of tumors in clinical medicine. Therefore, this review mainly discusses the development and application of electrochemical biosensors in tumor cell detection in recent years.
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Affiliation(s)
- Zhenhua Zhang
- Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life SciencesShandong Normal UniversityJinanChina
| | - Qingchao Li
- Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life SciencesShandong Normal UniversityJinanChina
| | - Xin Du
- Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life SciencesShandong Normal UniversityJinanChina
| | - Min Liu
- Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life SciencesShandong Normal UniversityJinanChina
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18
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Ding Y, Li W, Wang K, Xu C, Hao M, Ding L. Perspectives of the Application of Liquid Biopsy in Colorectal Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6843180. [PMID: 32258135 PMCID: PMC7085834 DOI: 10.1155/2020/6843180] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 02/25/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal tumors and the second leading cause of cancer death worldwide. Since traditional biopsies are invasive and do not reflect tumor heterogeneity or monitor the dynamic progression of tumors, there is an urgent need for new noninvasive methods that can supplement and improve the current management strategies of CRC. Blood-based liquid biopsies are a promising noninvasive biomarker that can detect disease early, assist in staging, monitor treatment responses, and predict relapse and metastasis. Over time, an increasing number of experiments have indicated the clinical utility of liquid biopsies in CRC. In this review, we mainly focus on the development of circulating tumor cells and circulating tumor DNA as key components of liquid biopsies in CRC and introduce the potential of exosomal microRNAs as emerging liquid biopsy markers in clinical application for CRC.
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Affiliation(s)
- Yuhan Ding
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Wenxia Li
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Kun Wang
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Chang Xu
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Mengdi Hao
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
| | - Lei Ding
- Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing 100038, China
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19
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Yang C, Chen F, Wang S, Xiong B. Circulating Tumor Cells in Gastrointestinal Cancers: Current Status and Future Perspectives. Front Oncol 2019; 9:1427. [PMID: 31921680 PMCID: PMC6923205 DOI: 10.3389/fonc.2019.01427] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/29/2019] [Indexed: 12/24/2022] Open
Abstract
Circulating tumor cells (CTCs), which are now defined as the "break away" cancer cells that derive from primary- or metastatic-tumor sites and present in the bloodstream, are considered to be the precursors of metastases. Considering the key role of CTCs in cancer progression, researchers are committed to analyze them in the past decades and many technologies have been proposed for achieving CTCs isolation and characterization with highly sensitivity and specificity until now. On this basis, clinicians gradually realize the clinical values of CTCs' detection through various clinical studies. As a "liquid biopsy," CTCs' detection and measurement can supply important information for predicting patient's survival, monitoring of response/resistance, assessment of minimal residual disease, evaluating distant metastasis, and sometimes, customizing therapy choices. Nowadays, eliminating CTCs of the blood circulation has been regarded as a promising method to prevent tumor metastasis. However, research on CTCs still faces many challenges. Herein, we present an overview to discuss the current concept of CTCs, summarize the available techniques for CTCs detection, and provide an update on the clinical significance of CTCs in gastrointestinal malignancies, especially focus on gastric and colorectal cancer.
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Affiliation(s)
- Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.,Hubei Cancer Clinical Study Center, Wuhan, China
| | - Fangfang Chen
- Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.,Hubei Cancer Clinical Study Center, Wuhan, China.,Department of Breast and Thyroid Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.,Hubei Cancer Clinical Study Center, Wuhan, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.,Hubei Cancer Clinical Study Center, Wuhan, China
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20
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Christou N, Meyer J, Popeskou S, David V, Toso C, Buchs N, Liot E, Robert J, Ris F, Mathonnet M. Circulating Tumour Cells, Circulating Tumour DNA and Circulating Tumour miRNA in Blood Assays in the Different Steps of Colorectal Cancer Management, a Review of the Evidence in 2019. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5953036. [PMID: 31930130 PMCID: PMC6942724 DOI: 10.1155/2019/5953036] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 08/02/2019] [Accepted: 08/17/2019] [Indexed: 12/24/2022]
Abstract
Despite many advances in the diagnosis and treatment of colorectal cancer (CRC), its incidence and mortality rates continue to make an impact worldwide and in some countries rates are mounting. Over the past decade, liquid biopsies have been the object of fundamental and clinical research with regard to the different steps of CRC patient care such as screening, diagnosis, prognosis, follow-up, and therapeutic response. They are attractive because they are considered to encompass both the cellular and molecular heterogeneity of tumours. They are easily accessible and can be applied to large-scale settings despite the cost. However, liquid biopsies face drawbacks in detection regardless of whether we are testing for circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), or miRNA. This review highlights the different advantages and disadvantages of each type of blood-based biopsy and underlines which specific one may be the most useful and informative for each step of CRC patient care.
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Affiliation(s)
- Niki Christou
- Endocrine, General and Digestive Surgery Department, CHU de Limoges, Limoges Cedex 87042, France
- Laboratoire EA3842 Contrôle de l'Activation cellulaire, Progression Tumorale et Résistances thérapeutiques «CAPTuR», Faculté de médecine, 2 Rue du Docteur Marcland, 87025 Limoges, France
- Department of Visceral Surgery, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland
| | - Jeremy Meyer
- Department of Visceral Surgery, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland
| | - Sotirios Popeskou
- Department of Visceral Surgery, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland
| | - Valentin David
- Laboratoire EA3842 Contrôle de l'Activation cellulaire, Progression Tumorale et Résistances thérapeutiques «CAPTuR», Faculté de médecine, 2 Rue du Docteur Marcland, 87025 Limoges, France
| | - Christian Toso
- Department of Visceral Surgery, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland
| | - Nicolas Buchs
- Department of Visceral Surgery, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland
| | - Emilie Liot
- Department of Visceral Surgery, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland
| | - Joan Robert
- Department of Visceral Surgery, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland
| | - Frederic Ris
- Department of Visceral Surgery, University Hospital of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland
| | - Muriel Mathonnet
- Endocrine, General and Digestive Surgery Department, CHU de Limoges, Limoges Cedex 87042, France
- Laboratoire EA3842 Contrôle de l'Activation cellulaire, Progression Tumorale et Résistances thérapeutiques «CAPTuR», Faculté de médecine, 2 Rue du Docteur Marcland, 87025 Limoges, France
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21
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Arrazubi V, Mata E, Antelo ML, Tarifa A, Herrera J, Zazpe C, Teijeira L, Viudez A, Suárez J, Hernández I, Vera R. Circulating Tumor Cells in Patients Undergoing Resection of Colorectal Cancer Liver Metastases. Clinical Utility for Long-Term Outcome: A Prospective Trial. Ann Surg Oncol 2019; 26:2805-2811. [PMID: 31209673 DOI: 10.1245/s10434-019-07503-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Patients with resected colorectal cancer liver metastases display heterogeneous clinical behavior. The identification of new prognostic factors would help in making more accurate decisions. OBJECTIVE The aim of this study was to evaluate the survival impact of circulating tumor cells (CTCs) in this setting. METHODS We conducted a prospective study of patients with resected liver metastases of colorectal cancer. Patients were included in the study from February 2009 to January 2013. The CellSearch System™ was employed for the detection of pre- and postsurgery CTCs. A positive test was defined as two or more CTCs/7.5 mL of blood. Recurrence rate, disease-free survival, and overall survival were calculated, and univariate and multivariate analyses were performed. RESULTS Forty-four patients were included in our study. After a median follow-up of 60 months (range 28-74), 32 patients experienced recurrence (72.7%). The CTCs number was determined and the test was positive in 8 patients (18.6%) before surgery and 13 patients (29.5%) after surgery. The postoperative detection of CTCs was not related to any clinical outcome; however, the preoperative detection of CTCs was significantly related to behavior. All patients in the preoperative CTC-positive group relapsed, versus 65% in the CTC-negative group (p = 0.051). Disease-free survival was 19 months in the preoperative CTC-negative group versus 7 months in the CTC-positive group (p = 0.01). Additionally, overall survival was 69 months in the preoperative CTC-negative group versus 17 months in the CTC-positive group (p = 0.004). Preoperative CTC count remained significant in multivariate analysis. CONCLUSIONS In this cohort of colorectal cancer liver metastases patients, the presence of two or more preoperative CTCs was associated with disease progression and poor survival despite complete resection.
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Affiliation(s)
- Virginia Arrazubi
- Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain.
| | - Elena Mata
- Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - María Luisa Antelo
- Department of Hematology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Antonio Tarifa
- Department of Gastrointestinal Surgery, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Javier Herrera
- Department of Gastrointestinal Surgery, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Cruz Zazpe
- Department of Gastrointestinal Surgery, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Lucía Teijeira
- Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Antonio Viudez
- Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Javier Suárez
- Department of Gastrointestinal Surgery, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Irene Hernández
- Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Ruth Vera
- Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain
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22
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Chow FCL, Chok KSH. Colorectal liver metastases: An update on multidisciplinary approach. World J Hepatol 2019; 11:150-172. [PMID: 30820266 PMCID: PMC6393711 DOI: 10.4254/wjh.v11.i2.150] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/24/2018] [Accepted: 12/04/2018] [Indexed: 02/06/2023] Open
Abstract
Liver metastasis is the commonest form of distant metastasis in colorectal cancer. Selection criteria for surgery and liver-directed therapies have recently been extended. However, resectability remains poorly defined. Tumour biology is increasingly recognized as an important prognostic factor; hence molecular profiling has a growing role in risk stratification and management planning. Surgical resection is the only treatment modality for curative intent. The most appropriate surgical approach is yet to be established. The primary cancer and the hepatic metastasis can be removed simultaneously or in a two-step approach; these two strategies have comparable long-term outcomes. For patients with a limited future liver remnant, portal vein embolization, combined ablation and resection, and associating liver partition and portal vein ligation for staged hepatectomy have been advocated, and each has their pros and cons. The role of neoadjuvant and adjuvant chemotherapy is still debated. Targeted biological agents and loco-regional therapies (thermal ablation, intra-arterial chemo- or radio-embolization, and stereotactic radiotherapy) further improve the already favourable results. The recent debate about offering liver transplantation to highly selected patients needs validation from large clinical trials. Evidence-based protocols are missing, and therefore optimal management of hepatic metastasis should be personalized and determined by a multi-disciplinary team.
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Affiliation(s)
| | - Kenneth Siu-Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, the University of Hong Kong, Hong Kong, China.
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23
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Brudvik KW, Jones RP, Giuliante F, Shindoh J, Passot G, Chung MH, Song J, Li L, Dagenborg VJ, Fretland ÅA, Røsok B, De Rose AM, Ardito F, Edwin B, Panettieri E, Larocca LM, Yamashita S, Conrad C, Aloia TA, Poston GJ, Bjørnbeth BA, Vauthey JN. RAS Mutation Clinical Risk Score to Predict Survival After Resection of Colorectal Liver Metastases. Ann Surg 2019; 269:120-126. [PMID: 28549012 DOI: 10.1097/sla.0000000000002319] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM). BACKGROUND The t-CS relies on the following factors: primary tumor nodal status, disease-free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS. METHODS Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analyses were used to compare the t-CS and the m-CS. The m-CS was validated in an international multicenter cohort of 608 patients. RESULTS A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis >50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not. CONCLUSIONS Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM.
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Affiliation(s)
- Kristoffer W Brudvik
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Robert P Jones
- Liverpool Hepatobiliary Unit, Aintree University Hospital, Liverpool, United Kingdom
| | - Felice Giuliante
- Hepatobiliary Surgery Unit, A. Gemelli Medical School, Rome, Italy
| | - Junichi Shindoh
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
- Hepatobiliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Guillaume Passot
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael H Chung
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Juhee Song
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Liang Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Vegar J Dagenborg
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - Åsmund A Fretland
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Bård Røsok
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | | | - Francesco Ardito
- Hepatobiliary Surgery Unit, A. Gemelli Medical School, Rome, Italy
| | - Bjørn Edwin
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Elena Panettieri
- Hepatobiliary Surgery Unit, A. Gemelli Medical School, Rome, Italy
| | | | - Suguru Yamashita
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Claudius Conrad
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Thomas A Aloia
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Graeme J Poston
- Liverpool Hepatobiliary Unit, Aintree University Hospital, Liverpool, United Kingdom
| | - Bjørn A Bjørnbeth
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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24
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Bahnassy AA, Salem SE, Mohanad M, Abulezz NZ, Abdellateif MS, Hussein M, Zekri CAN, Zekri ARN, Allahloubi NMA. Prognostic significance of circulating tumor cells (CTCs) in Egyptian non-metastatic colorectal cancer patients: A comparative study for four different techniques of detection (Flowcytometry, CellSearch, Quantitative Real-time PCR and Cytomorphology). Exp Mol Pathol 2018; 106:90-101. [PMID: 30578762 DOI: 10.1016/j.yexmp.2018.12.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 11/16/2018] [Accepted: 12/17/2018] [Indexed: 12/21/2022]
Abstract
PURPOSE We assessed CTCs counts in NMCRC patients using four different techniques. METHODS CTCs were detected in 63 NMCRC patients, 40 benign bowel diseases (BBD) and 40 normal controls (NC) using, flow-cytometry (FCM), CellSearch (CS), cytomorphology and quantitative real time (qPCR) for CK19, MUC1, CD44, CD133, ALDH1 expression. Results were correlated to progression free (PFS) and overall (OS). RESULTS Positive CTCs (≥4 cells /7.5 mL blood) were detected in 50.8% (32/63) NMCRC by FCM and 7.5% (3/40) BBD (p < .001). CTCs were detected in 34/63 (54%) NMCRC, 4/40 (10%) BBD (p < .001) by CS. CK19, MUC1, CD44, CD133 and ALDH1 were expressed in 35 (55.6%), 29 (46.0%), 28 (44.4%), 26 (41.3%) and 25 (41.3%) cases of NMCRC. In BBD 4/40 (10%) cases expressed CK19, MUC1 and CD44, while 2/40 (5%) expressed CD133. Cytomorphology showed the lowest sensitivity (47.6%) and specificity (90%) for CTCs detection. The combined use of FCM or CS with CTCs-mRNA markers improved the sensitivity and specificity to 68.3%, and 95.0%; respectively. Positive CTCs and mRNA markers expression were significantly associated with shorter 5-yr PFS and OS. In multivariate analysis, CTCs mRNA markers were independent prognostic factors for PFS and OS. CONCLUSIONS Enumeration of CTCs by FCM and RNA expression for specific colon cancer markers are comparable to CS regarding sensitivity and specificity. CTCs also represent novel therapeutic targets for NMCRC cases.
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Affiliation(s)
- Abeer A Bahnassy
- Tissue culture and Cytogenetics Unit, Pathology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt.
| | - Salem E Salem
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Marwa Mohanad
- Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6(th) of October 12945, Egypt
| | - Nermeen Z Abulezz
- Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6(th) of October 12945, Egypt
| | - Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Marwa Hussein
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Chahd A N Zekri
- Faculty of Medicine, 6(th) of October University, 6(th) of October, Egypt
| | - Abdel-Rahman N Zekri
- Virology and Immunology unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
| | - Nasr M A Allahloubi
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo 11976, Egypt
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Prognostic significance of CEACAM5mRNA-positive circulating tumor cells in patients with metastatic colorectal cancer. Cancer Chemother Pharmacol 2018; 82:767-775. [DOI: 10.1007/s00280-018-3666-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Accepted: 08/04/2018] [Indexed: 01/04/2023]
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26
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Wang W, Wan L, Wu S, Yang J, Zhou Y, Liu F, Wu Z, Cheng Y. Mesenchymal marker and LGR5 expression levels in circulating tumor cells correlate with colorectal cancer prognosis. Cell Oncol (Dordr) 2018; 41:495-504. [PMID: 29949050 DOI: 10.1007/s13402-018-0386-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/29/2018] [Indexed: 12/18/2022] Open
Abstract
PURPOSE The presence of circulating tumor cells (CTCs) has been found to correlate with colorectal cancer (CRC) prognosis, whereas epithelial-mesenchymal transition (EMT) in CTCs has been found to be associated with CRC metastasis. LGR5 is a known target of Wnt signaling and plays an important role in CRC development. The aim of this study was to assess the clinical relevance of EMT and LGR5 expression in CTCs from CRC patients. METHODS Sixty-six CRC patients were included in this study. The detection and expression of EMT phenotypes in CTCs from these patients were assessed using CanPatrol™ CTC enrichment and mRNA in situ hybridization (ISH), respectively. LGR5 expression in the CTCs was assessed using mRNA ISH. RESULTS CTCs were detected in 86.4% (57/66) of the CRC patients included. Both the numbers of total CTCs and of CTCs displaying a mesenchymal phenotype (M+ CTCs) were found to significantly correlate with advanced disease stages and the occurrence of metastasis (p < 0.05). An adjusted multivariate analysis also indicated that the number of M+ CTCs significantly correlated with the occurrence of metastasis (p = 0.031). Additionally, we found that a high LGR5 expression level significantly correlated with the occurrence of metastasis (p < 0.05). We also found that the presence of ≥ 6 CTCs or ≥ 3 M+ CTCs per 5 ml blood significantly correlated with disease progression (p < 0.05). Patients with ≥ 6 CTCs or ≥ 3 M+ CTCs per 5 ml blood were found to exhibit poorer progression-free survival (PFS) and overall survival (OS) rates (p < 0.05 in all cases). Using Cox regression analyses, we found that only total CTC numbers remained as independent prognostic factors for a worse PFS (p = 0.043). CONCLUSIONS From our data we conclude that CTC numbers and EMT phenotypes may serve as prognostic markers for disease progression and metastasis in CRC patients. In addition, we conclude that LGR5 expression in CTCs may serve as a marker for CRC metastasis.
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Affiliation(s)
- Wuyi Wang
- Department of Gastrointestinal Surgery, The 1st Affiliated Hospital of CQMU, Chongqing, China
| | - Lin Wan
- Department of Gastrointestinal Surgery, The 1st Affiliated Hospital of CQMU, Chongqing, China
| | | | - Jianguo Yang
- Department of Gastrointestinal Surgery, The 1st Affiliated Hospital of CQMU, Chongqing, China
| | - Yang Zhou
- Department of Gastrointestinal Surgery, The 1st Affiliated Hospital of CQMU, Chongqing, China
| | - Fang Liu
- SurExam Bio-Tech Co., Guangzhou, China
| | | | - Yong Cheng
- Department of Gastrointestinal Surgery, The 1st Affiliated Hospital of CQMU, Chongqing, China.
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Tan Y, Wu H. The significant prognostic value of circulating tumor cells in colorectal cancer: A systematic review and meta-analysis. Curr Probl Cancer 2018; 42:95-106. [DOI: 10.1016/j.currproblcancer.2017.11.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 10/19/2017] [Accepted: 11/27/2017] [Indexed: 12/18/2022]
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Lopez A, Harada K, Mizrak Kaya D, Dong X, Song S, Ajani JA. Liquid biopsies in gastrointestinal malignancies: when is the big day? Expert Rev Anticancer Ther 2017; 18:19-38. [PMID: 29202614 DOI: 10.1080/14737140.2018.1403320] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Anthony Lopez
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Gastroenterology and Hepatology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Kazuto Harada
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dilsa Mizrak Kaya
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaochuan Dong
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shumei Song
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A. Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Yang C, Zou K, Zheng L, Xiong B. Prognostic and clinicopathological significance of circulating tumor cells detected by RT-PCR in non-metastatic colorectal cancer: a meta-analysis and systematic review. BMC Cancer 2017; 17:725. [PMID: 29115932 PMCID: PMC5688806 DOI: 10.1186/s12885-017-3704-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 10/25/2017] [Indexed: 01/08/2023] Open
Abstract
Background Circulating tumor cells (CTCs) have been accepted as a prognostic marker in patients with metastatic colorectal cancer (mCRC, UICC stage IV). However, the prognostic value of CTCs in patients with non-metastatic colorectal cancer (non-mCRC, UICC stage I-III) still remains in dispute. A meta-analysis was performed to investigate the prognostic significance of CTCs detected by the RT-PCR method in patients diagnosed with non-mCRC patients. Methods A comprehensive literature search for relevant articles was performed in the EmBase, PubMed, Ovid, Web of Science, Cochrane library and Google Scholar databases. The studies were selected according to predetermined inclusion/exclusion criteria. Using the random-effects model of Stata software, version12.0 (2011) (Stata Corp, College Station, TX, USA), to conduct the meta-analysis, and the hazard ratio (HR), risk ratio (RR) and their 95% confidence intervals (95% CIs) were regarded as the effect measures. Subgroup analyses and meta-regression were also conducted to clarify the heterogeneity. Results Twelve eligible studies, containing 2363 patients with non-mCRC, were suitable for final analyses. The results showed that the overall survival (OS) (HR = 3.07, 95% CI: [2.05–4.624], P < 0.001; I2 = 55.7%, P = 0.008) and disease-free survival (DFS) (HR = 2.58, 95% CI: [2.00–3.32], P < 0.001; I2 = 34.0%, P = 0.085) were poorer in patients with CTC-positive, regardless of the sampling time, adjuvant therapy and TNM stage. CTC-positive was also significantly associated with regional lymph nodes (RLNs) metastasis (RR = 1.62, 95% CI: [1.17–2.23], P = 0.003; I2 = 74.6%, P<0.001), depth of infiltration (RR = 1.41, 95% CI: [1.03–1.92], P = 0.03; I2 = 38.3%, P = 0.136), vascular invasion (RR = 1.66, 95% CI: [1.17–2.36], P = 0.004; I2 = 46.0%, P = 0.135), tumor grade (RR = 1.19, 95% CI: [1.02–1.40], P = 0.029; I2 = 0%, P = 0.821) and tumor-node-metastasis (TNM) stage(I, II versus III) (RR = 0.76, 95% CI 0.71–0.81, P < 0.001; I2 = 0%, P = 0.717). However, there was no significant relationship between CTC-positive and tumor size (RR = 1.08, 95% CI: [0.94–1.24], P = 0.30; I2 = 0%, P = 0.528). Conclusions Detection of CTCs by RT-PCR method has prognostic value for non-mCRC patients, and CTC-positive was associated with poor prognosis and poor clinicopathological prognostic factors. However, the prognostic value of CTCs supports the use of CTCs as an indicator of metastatic disease prior to the current classification of mCRC meaning it is detectable by CT/MRI.
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Affiliation(s)
- Chaogang Yang
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University; Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Kun Zou
- Department of Oncology, Central Hospital of Wuhan, No.16 Gusaoshu Road, Jianghan District, Wuhan, 430014, China
| | - Liang Zheng
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University; Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Bin Xiong
- Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University; Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, No.169 Donghu Road, Wuchang District, Wuhan, 430071, China.
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Margonis GA, Sasaki K, Andreatos N, Pour MZ, Shao N, Ghasebeh MA, Buettner S, Antoniou E, Wolfgang CL, Weiss M, Kamel IR, Pawlik TM. Increased kinetic growth rate during late phase liver regeneration impacts the risk of tumor recurrence after colorectal liver metastases resection. HPB (Oxford) 2017; 19:808-817. [PMID: 28602644 DOI: 10.1016/j.hpb.2017.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 03/26/2017] [Accepted: 05/08/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Although experimental data strongly support the pro-tumorigenic role of postoperative liver regeneration, this hypothesis has not been clinically investigated. We aimed to examine the impact of liver regeneration determined by volumetric imaging on recurrence following resection of colorectal liver metastasis (CRLM). METHODS Resected liver volume was subtracted from total liver volume (TLV) to define postoperative remnant liver volume (RLVp). Early and late kinetic growth rates (KGR) were defined as the postoperative increases in liver volume within 2-3 and 8-10 months from surgery, respectively, divided by the corresponding time interval. RESULTS Median early and late KGR was 2.6%/month (IQR: -0.9 to 12.3) and 1.0%/month (IQR: -0.64 to 2.91), respectively. Late KGR predicted intrahepatic recurrence after 1 year from surgery (AUC 0.677, P = 0.011). Specifically, patients with a late KGR ≥1% had a higher cumulative risk of recurrence compared with patients with a KGR <1% (P = 0.038). In multivariate analysis, KGR ≥1% independently predicted recurrence (P = 0.027). DISCUSSION A KGR ≥1% during the late regeneration phase was associated with increased risk of intrahepatic recurrence. These data may inform the timing of adjuvant therapy administration and focus surveillance strategies for high-risk patients.
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Affiliation(s)
- Georgios A Margonis
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kazunari Sasaki
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nikolaos Andreatos
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Manijeh Zargham Pour
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nannan Shao
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Stefan Buettner
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Efstathios Antoniou
- Second Department of Propaedeutic Surgery, Athens University Medical School, Athens, Greece
| | | | - Matthew Weiss
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ihab R Kamel
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Timothy M Pawlik
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Wang S, Du H, Li G. Significant prognostic value of circulating tumor cells in esophageal cancer patients: A meta-analysis. Oncotarget 2017; 8:15815-15826. [PMID: 28178659 PMCID: PMC5362525 DOI: 10.18632/oncotarget.15012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 01/03/2017] [Indexed: 01/24/2023] Open
Abstract
Esophageal cancer is the sixth leading cause of cancer death worldwide. Detection of circulating tumor cells (CTCs) is emerging as a novel strategy for predicting cancer patient prognosis. Here we performed a comprehensive literature search to identify relevant articles in EMbase, PubMed, EBSCO, OVID, Cochrane Database, CNKI, WanFangdata and VIPdata. Meta-analysis was conducted using Stata12.0 software, according to the inclusion and exclusion criteria, extracted data and assessment methodology. Thirteen eligible literature studies were included with a total of 979 esophageal squamous cell carcinoma patients, including 424 CTC-positive and 684 CTC-negative cases. Meta-analysis showed that the presence of CTCs was associated with both worse progression-free/disease-free survival [hazard ration (HR) = 2.32, 95% confidence interval (CI) = 1.57 - 3.43, p < 0.001] and poorer overall survival [HR = 2.64, 95% CI = 1.69 - 4.14, p < 0.001]. Further subgroup analyses demonstrated that CTC-positive patients also showed worse progression-free/disease-free survival and poorer overall survival in different subsets. In summary, our meta-analysis provides strong evidence that detection of CTCs in the peripheral blood is an independent prognostic indicator of poor outcome for esophageal squamous cell carcinoma patients.
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Affiliation(s)
- Shuyu Wang
- Medical Laboratory Department, Heze Municipal Hospital, Heze, Shandong, 274031 China
| | - Hongyang Du
- Heze Centre for Adverse Drug Reactions Monitoring, Heze, Shangdong, 274000, China
| | - Guixia Li
- Medical Laboratory Department, Heze Municipal Hospital, Heze, Shandong, 274031 China
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Wu W, Zhang Z, Gao XH, Shen Z, Jing Y, Lu H, Li H, Yang X, Cui X, Li Y, Lou Z, Liu P, Zhang C, Zhang W. Clinical significance of detecting circulating tumor cells in colorectal cancer using subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH). Oncotarget 2017; 8:21639-21649. [PMID: 28423493 PMCID: PMC5400612 DOI: 10.18632/oncotarget.15452] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 01/27/2017] [Indexed: 12/18/2022] Open
Abstract
Circulating tumor cells (CTC) are useful in early detection of colorectal cancer. This study described a newly developed platform, integrated subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH), to assess CTCs in colorectal cancer. CTCs were detected by SE-iFISH in 40 of 44 preoperative colorectal cancer patients, and yielded a sensitivity of 90.9%, which was significantly higher than CellSearch system (90.9% vs. 43.2%, P=0.033). No significant association was found between tumor stage, survival and preoperative CTC number. CTCs were detected in 10 colorectal cancer patients one week after surgery; seven patients with decreased CTC numbers (compared with preoperative CTC number) were free of recurrence; whereas two of the three patients with increased CTC numbers had tumor recurrence. Moreover, CTCs were detected in 34 colorectal cancer patients three months after surgery; patients with CTC<2 at three months after surgery had significantly longer Progression Free Survival than those with CTC>=2 (P=0.019); patients with decreased CTC number (compared with preoperative CTC number) had significantly longer Progression Free Survival than those with increased CTC number (P=0.003). In conclusion, CTCs could be detected in various stages of colorectal cancer using SE-iFISH. Dynamic monitoring of CTC numbers could predict recurrence and prognosis.
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Affiliation(s)
- Wei Wu
- Department of General Surgery, The Aviation Hanzhong 3201 Hospital, Xi’an Jiao Tong University, Hanzhong 723000, Shaanxi, China
| | - Zhenzhen Zhang
- Zhangjiang Center for Translational Medicine, Shanghai 200120, China
| | - Xian Hua Gao
- Department of Colorectal Surgery, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Zhen Shen
- Department of General Surgery, The Aviation Hanzhong 3201 Hospital, Xi’an Jiao Tong University, Hanzhong 723000, Shaanxi, China
| | - Yan Jing
- Department of General Surgery, The Aviation Hanzhong 3201 Hospital, Xi’an Jiao Tong University, Hanzhong 723000, Shaanxi, China
| | - Haibo Lu
- Department of General Surgery, The Aviation Hanzhong 3201 Hospital, Xi’an Jiao Tong University, Hanzhong 723000, Shaanxi, China
| | - Heng Li
- Department of General Surgery, The Aviation Hanzhong 3201 Hospital, Xi’an Jiao Tong University, Hanzhong 723000, Shaanxi, China
| | - Xiaoye Yang
- Department of General Surgery, The Aviation Hanzhong 3201 Hospital, Xi’an Jiao Tong University, Hanzhong 723000, Shaanxi, China
| | - Xiangbin Cui
- Department of General Surgery, The Aviation Hanzhong 3201 Hospital, Xi’an Jiao Tong University, Hanzhong 723000, Shaanxi, China
| | - Yuqing Li
- Department of General Surgery, The Aviation Hanzhong 3201 Hospital, Xi’an Jiao Tong University, Hanzhong 723000, Shaanxi, China
| | - Zheng Lou
- Department of Colorectal Surgery, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Peng Liu
- Department of Colorectal Surgery, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China
| | - Cun Zhang
- Department of General Surgery, The Aviation Hanzhong 3201 Hospital, Xi’an Jiao Tong University, Hanzhong 723000, Shaanxi, China
| | - Wei Zhang
- Department of Colorectal Surgery, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China
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Jones RP, Brudvik KW, Franklin JM, Poston GJ. Precision surgery for colorectal liver metastases: Opportunities and challenges of omics-based decision making. Eur J Surg Oncol 2017; 43:875-883. [PMID: 28302330 DOI: 10.1016/j.ejso.2017.02.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 02/24/2017] [Indexed: 12/17/2022] Open
Abstract
Precision surgery involves improving patient selection to ensure that surgical intervention that is proven to benefit on a population level is the optimal treatment for each individual patient. For patients with colorectal liver metastases (CRLM), existing prognostic scoring systems rely on well-recognised histopathological features such as size and number of lesions. Advances in preoperative imaging algorithms mean that increasingly low volume disease can be detected, improving assessment of these factors. In addition, novel imaging modalities mean that underlying tumour biology and metabolic behaviour during therapy can be assessed. Molecular analysis of tumours can provide crucial prognostic information, with the critical role of RAS/RAF mutations in prognosis well recognised. The optimal source of tissue for this level of analysis is debated, with good concordance between primary and metastatic lesions for some recognised prognostic factors but marked discrepancies for a variety of other relevant mutations. As well as mutational heterogeneity between primary and metastatic lesions, heterogeneity within tumours and dynamic changes in tumour biology over time present a significant challenge in assessing tumour for prognostic biomarkers. Circulating tumour cells offer one potential method of longitudinal tumour analysis, but are limited by current technologies. This review article summarises some of the key advances in prognostication for patients with resectable colorectal liver metastases, as well as highlighting the potential limitations of such an approach.
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Affiliation(s)
- R P Jones
- North Western Hepatobiliary Unit, Aintree University Hospital, Liverpool, UK; School of Cancer Studies, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
| | - K W Brudvik
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - J M Franklin
- Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - G J Poston
- North Western Hepatobiliary Unit, Aintree University Hospital, Liverpool, UK
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Seeberg LT, Brunborg C, Waage A, Hugenschmidt H, Renolen A, Stav I, Bjørnbeth BA, Borgen E, Naume B, Brudvik KW, Wiedswang G. Survival Impact of Primary Tumor Lymph Node Status and Circulating Tumor Cells in Patients with Colorectal Liver Metastases. Ann Surg Oncol 2017; 24:2113-2121. [PMID: 28258416 PMCID: PMC5491630 DOI: 10.1245/s10434-017-5818-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Indexed: 12/25/2022]
Abstract
OBJECTIVE The aim of this study was to analyse the survival impact of primary tumor nodal status (N0/N+) in patients with resectable colorectal liver metastases (CLM), and to determine the value of circulating and disseminated tumor cells (CTCs/DTCs) in this setting. METHODS In this prospective study of patients undergoing resection of CLM from 2008 to 2011, peripheral blood was analyzed for CTCs using the CellSearch System®, and bone marrow was sampled for DTC analyses just prior to hepatic resection. The presence of one or more tumor cells was scored as CTC/DTC-positive. Following resection of the primary tumor, the lymph nodes (LNs) were examined by routine histopathological examination. RESULTS A total of 140 patients were included in this study; 38 patients (27.1%) were negative at the primary colorectal LN examination (N0). CTCs were detected in 12.1% of all patients; 5.3% of patients in the N0 group and 14.7% of patients in the LN-positive (N+) group (p = 0.156), with the LN-positive group (N+) consisting of both N1 and N2 patients. There was a significant difference in recurrence-free survival (RFS) when analysing the N0 group versus the N+ group (p = 0.007) and CTC-positive versus CTC-negative patients (p = 0.029). In multivariate analysis, CTC positivity was also significantly associated with impaired overall survival (OS) [p = 0.05], whereas DTC positivity was not associated with survival. CONCLUSION In this cohort of resectable CLM patients, 27% had primary N0 colorectal cancer. Assessment of CTC in addition to nodal status may contribute to improved classification of patients into high- and low-risk groups, which has the potential to guide and improve treatment strategies.
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Affiliation(s)
- Lars Thomas Seeberg
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway. .,Department of Gastrointestinal Surgery, Vestfold Hospital Trust, Tønsberg, Norway.
| | - Cathrine Brunborg
- Oslo Centre of Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway
| | - Anne Waage
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
| | - Harald Hugenschmidt
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
| | - Anne Renolen
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Ingunn Stav
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Bjørn A Bjørnbeth
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
| | - Elin Borgen
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Bjørn Naume
- Department of Oncology, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Oslo University Hospital, Oslo, Norway
| | | | - Gro Wiedswang
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
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Schulz A, Viktil E, Godt JC, Johansen CK, Dormagen JB, Holtedahl JE, Labori KJ, Bach-Gansmo T, Kløw NE. Diagnostic performance of CT, MRI and PET/CT in patients with suspected colorectal liver metastases: the superiority of MRI. Acta Radiol 2016; 57:1040-8. [PMID: 26622057 DOI: 10.1177/0284185115617349] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 10/21/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Meticulous imaging of colorectal liver metastases (CRLM) is mandatory to optimize outcome after liver resection. However, the detection of CRLM is still challenging. PURPOSE To evaluate prospectively if magnetic resonance imaging (MRI) with diffusion-weighted and Gd-EOB-DTPA-enhanced sequences had a better diagnostic performance for CRLM compared to computed tomography (CT) and fluorine-18 fluorodeoxyglucose positron emission tomography (PET/CT). MATERIAL AND METHODS Forty-six patients scheduled for resection of suspected CRLM were evaluated prospectively from September 2011 to January 2013. None of the patients had undergone previous treatment for their CRLM. Multiphase CT, liver MRI with diffusion-weighted and dynamic Gd-EOB-DTPA-enhanced sequences and low-dose PET/CT were performed. Two independent, blinded readers evaluated the examinations. The reference standard was histopathological confirmation (81/140 CRLM) or follow-up. RESULTS A total of 140 CRLM and 196 benign lesions were identified. On a per-lesion basis, MRI had the significantly highest sensitivity overall and for CRLM < 10 mm (P < 0.001). Overall sensitivity/specificity and PPV/NPV were 68%/94% and 89%/81% for CT, 90%/87% and 82%/93% for MRI, and 61%/99% and 97%/78% for PET/CT. For CRLM < 10 mm it was 16%/96% and 54%/80% for CT, 74%/88% and 64%/93% for MRI, and 9%/98% and 57%/79% for PET/CT. CONCLUSION MRI had the significantly highest sensitivity compared with CT and PET/CT, particularly for CRLM < 10 mm. Therefore, detection of CRLM should be based on MRI.
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Affiliation(s)
- Anselm Schulz
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Ellen Viktil
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Johannes Clemens Godt
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Cathrine K Johansen
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | | | | | - Knut Jørgen Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Tore Bach-Gansmo
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Nils-Einar Kløw
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
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36
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Liver metastatic disease: new concepts and biomarker panels to improve individual outcomes. Clin Exp Metastasis 2016; 33:743-755. [PMID: 27541751 DOI: 10.1007/s10585-016-9816-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 08/10/2016] [Indexed: 12/11/2022]
Abstract
Liver cancer, one of the leading causes of all cancer related deaths, belongs to the most malignant cancer types. In fact, the secondary hepatic malignancies (liver metastases) are more common than the primary ones. Almost all solid malignancies can metastasise to the liver. It is well justified that the "treat and wait" approach in the overall management of the liver cancer is not up-to-date and so creation of complex individual patient profiles is needed. This review is specifically focused on the liver metastases originating from the colorectum, breast and prostate cancer. Innovative multilevel diagnostics may procure specific panels of validated biomarkers for predisposition, development and progression of metastatic disease. Creation of the patient specific "molecular portrait" is an essential part of the diagnostic strategy. Contextually, analysis of molecular and cellular patterns in blood samples as the minimally invasive diagnostic tool and construction of diagnostic windows based on individual patient profiling is highly recommended for patient cohorts predisposed to and affected by the liver metastatic disease. Summarised information on risk assessment, predictive and prognostic panels for diagnosis and treatments of the liver metastatic disease in colorectal, breast and prostate cancer is provided.
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Søreide K, Watson MM, Lea D, Nordgård O, Søreide JA, Hagland HR. Assessment of clinically related outcomes and biomarker analysis for translational integration in colorectal cancer (ACROBATICC): study protocol for a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastasis. J Transl Med 2016; 14:192. [PMID: 27357108 PMCID: PMC4928276 DOI: 10.1186/s12967-016-0951-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 06/21/2016] [Indexed: 02/08/2023] Open
Abstract
Background More accurate predictive and prognostic biomarkers for patients with colorectal cancer (CRC) primaries or colorectal liver metastasis (CLM) are needed. Outside clinical trials, the translational integration of emerging pathways and novel techniques should facilitate exploration of biomarkers for improved staging and prognosis. Methods An observational study exploring predictive and prognostic biomarkers in a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastases. Long-term outcomes will be cancer-specific survival, recurrence-free survival and overall survival at 5 years from diagnosis. Beyond routine clinicopathological and anthropometric characteristics and laboratory and biochemistry results, the project allows for additional blood samples and fresh-frozen tumour and normal tissue for investigation of circulating tumour cells (CTCs) and novel biomarkers (e.g. immune cells, microRNAs etc.). Tumour specimens will be investigated by immunohistochemistry in full slides. Extracted DNA/RNA will be analysed for genomic markers using specific PCR techniques and next-generation sequencing (NGS) panels. Flow cytometry will be used to characterise biomarkers in blood. Collaboration is open and welcomed, with particular interest in mutual opportunities for validation studies. Status and perspectives The project is ongoing and recruiting at an expected rate of 120–150 patients per year, since January 2013. A project on circulating tumour cells (CTCs) has commenced, with analysis being prepared. Investigating molecular classes beyond the TNM staging is under way, including characteristics of microsatellite instability (MSI) and elevated microsatellite alterations in selected tetranucleotides (EMAST). Hot spot panels for known mutations in CRC are being investigated using NGS. Immune-cell characteristics are being performed by IHC and flow cytometry in tumour and peripheral blood samples. The project has ethical approval (REK Helse Vest, #2012/742), is financially supported with a Ph.D.-Grant (EMAST project; Folke Hermansen Cancer Fund) and a CTC-project (Norwegian Research Council; O. Nordgård). The ACROBATICC clinical and molecular biobank repository will serve as a long-term source for novel exploratory analysis and invite collaborators for mutual validation of promising biomarker results. The project aims to generate results that can help better discern prognostic groups in stage II/III cancers; explore prognostic and predictive biomarkers, and help detail the biology of colorectal liver metastasis for better patient selection and tailored treatment. The project is registered at http://www.ClinicalTrials.gov NCT01762813.
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Affiliation(s)
- Kjetil Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, POB 8100, 4068, Stavanger, Norway. .,Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway. .,Department of Clinical Medicine, University of Bergen, Bergen, Norway.
| | - Martin M Watson
- Department of Gastrointestinal Surgery, Stavanger University Hospital, POB 8100, 4068, Stavanger, Norway.,Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway
| | - Dordi Lea
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway.,Department of Pathology, Stavanger University Hospital, Stavanger, Norway
| | - Oddmund Nordgård
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - Jon Arne Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, POB 8100, 4068, Stavanger, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Hanne R Hagland
- Gastrointestinal Translational Research Unit, Laboratory for Molecular Biology, Stavanger University Hospital, Stavanger, Norway.,Centre of Organelle Research (CORE), University of Stavanger, Stavanger, Norway
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Connor AA, McNamara K, Al-Sukhni E, Diskin J, Chan D, Ash C, Lowes LE, Allan AL, Zogopoulos G, Moulton CA, Gallinger S. Central, But Not Peripheral, Circulating Tumor Cells are Prognostic in Patients Undergoing Resection of Colorectal Cancer Liver Metastases. Ann Surg Oncol 2015; 23:2168-75. [PMID: 26714949 DOI: 10.1245/s10434-015-5038-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND Colorectal cancer liver metastases (CRLMs) are potentially curable with resection, but most patients recur and succumb to their disease. Clinical covariates do not account for all outcomes. Circulating tumor cells (CTCs) are prognostic in the primary and metastatic settings of breast, prostate and colorectal cancer (CRC), and evolving evidence supports their role in CRLMs. Our objective was to determine whether CTCs in peripheral (PV) and hepatic venous (HV) compartments are associated with disease-free survival (DFS) and overall survival (OS) post-CRLM resection. METHODS CTCs were measured by CellSearch assay from intraoperative HV and PV samples from 63 patients who underwent CRLM resection from June 2007 to August 2012 at a single center. DFS and OS were primary endpoints. RESULTS HV CTCs > 3 were associated with shorter DFS and OS, but not PV CTCs, although no significant difference was found between CTC measurements in the two compartments. By univariate analysis, CRC stage and site, CRLM recurrence, and hepatic capsule invasion were also associated with OS, but only HV CTCs and CRC site were significant by multivariate Cox. Only HV CTCs were associated with DFS by multivariate analysis. Cases with elevated HV CTCs had hepatic vein invasion and lymph node metastases, and were younger with larger tumors. CONCLUSIONS Elevated HV CTCs are prognostic for DFS and OS following CRLM resection. Clinicopathologic features associated with HV CTCs are identifiable preoperatively and should be considered in CRLM surgical decision making. We found no evidence that PV CTCs are prognostic in this setting.
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Affiliation(s)
- Ashton A Connor
- Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada.,The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Kate McNamara
- The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Eisar Al-Sukhni
- The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Jacob Diskin
- The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - David Chan
- Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada
| | - Colleen Ash
- The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Lori E Lowes
- Departments of Oncology, and Anatomy and Cell Biology, Western University, London, ON, Canada.,London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada
| | - Alison L Allan
- Departments of Oncology, and Anatomy and Cell Biology, Western University, London, ON, Canada.,London Regional Cancer Program, London Health Sciences Centre, London, ON, Canada
| | - George Zogopoulos
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Carol-Anne Moulton
- Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada
| | - Steven Gallinger
- Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada. .,The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
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Brudvik KW, Seeberg LT, Hugenschmidt H, Renolen A, Schirmer CB, Brunborg C, Bjørnbeth BA, Borgen E, Naume B, Waage A, Wiedswang G. Detection of Circulating Tumor Cells at Surgery and at Follow-Up Assessment to Predict Survival After Two-Stage Liver Resection of Colorectal Liver Metastases. Ann Surg Oncol 2015; 22:4029-4037. [DOI: 10.1245/s10434-015-4482-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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40
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Schulz A, Godt JC, Dormagen JB, Holtedahl JE, Bogsrud TV, Labori KJ, Kløw NE, Bach-Gansmo T. Respiratory gated PET/CT of the liver: A novel method and its impact on the detection of colorectal liver metastases. Eur J Radiol 2015; 84:1424-1431. [PMID: 26044293 DOI: 10.1016/j.ejrad.2015.05.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 05/05/2015] [Indexed: 12/27/2022]
Abstract
PURPOSE To evaluate the diagnostic performance of a new method for respiratory gated positron emission tomography (rgPET/CT) for colorectal liver metastases (CRLM), secondly, to assess its additional value to standard PET/CT (PET/CT). MATERIALS AND METHODS Forty-three patients scheduled for resection of suspected CRLM were prospectively included from September 2011 to January 2013. None of the patients had previously undergone treatment for their CRLM. All patients underwent PET/CT and rgPET/CT in the same session. For rgPET/CT an in-house developed electronic circuit was used which displayed a color-coded countdown for the patient. The patients held their breath according to the countdown and only the data from the inspiration breath-hold period was used for image reconstruction. Two independent and blinded readers evaluated both PET/CT and rgPET/CT separately. The reference standard was histopathological confirmation for 73 out of 131 CRLM and follow-up otherwise. RESULTS Reference standard identified 131 CRLM in 39/43 patients. Nine patients accounted for 25 mucinous CRLM. The overall per-lesion sensitivity for detection of CRLM was for PET/CT 60.0%, for rgPET/CT 63.1%, and for standard+rgPET/CT 67.7%, respectively. Standard+rgPET/CT was overall significantly more sensitive for CRLM compared to PET/CT (p=0.002) and rgPET/CT (p=0.031). The overall positive predictive value (PPV) for detection of CRLM was for PET/CT 97.5%, for rgPET/CT 95.3%, and for standard+rgPET/CT 93.6%, respectively. CONCLUSION Combination of PET/CT and rgPET/CT improved the sensitivity significantly for CRLM. However, high patient compliance is mandatory to achieve optimal performance and further improvements are needed to overcome these limitations. The diagnostic performance of the evaluated new method for rgPET/CT was comparable to earlier reported technically more complex and expensive methods.
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Affiliation(s)
- Anselm Schulz
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Postboks Pb 4956 Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway.
| | - Johannes Clemens Godt
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Postboks Pb 4956 Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway.
| | - Johann Baptist Dormagen
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Postboks Pb 4956 Nydalen, 0424 Oslo, Norway.
| | - Jon Erik Holtedahl
- The Intervention Centre, Oslo University Hospital, Postboks 4950 Nydalen, 0424 Oslo, Norway.
| | - Trond Velde Bogsrud
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Postboks Pb 4956 Nydalen, 0424 Oslo, Norway; Department of Nuclear Medicine and PET-Center, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus C, Denmark.
| | - Knut Jørgen Labori
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Postboks 4950 Nydalen, 0424 Oslo, Norway.
| | - Nils-Einar Kløw
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Postboks Pb 4956 Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171 Blindern, 0318 Oslo, Norway.
| | - Tore Bach-Gansmo
- Department of Radiology and Nuclear Medicine, Oslo University Hospital, Postboks Pb 4956 Nydalen, 0424 Oslo, Norway.
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Circulating tumour cells and outcome in non-metastatic colorectal cancer: a prospective study. Br J Cancer 2015; 112:1306-13. [PMID: 25867263 PMCID: PMC4402459 DOI: 10.1038/bjc.2015.88] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 01/13/2015] [Accepted: 02/09/2015] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Circulating tumour cells (CTC) in the blood have been accepted as a prognostic marker in patients with metastatic colorectal cancer (CRC). Only limited data exist on the prognostic impact of CTC in patients with early stage CRC using standardised detection assays. The aim of this study was to elucidate the role of CTC in patients with non-metastatic CRC. METHODS A total of 287 patients with potentially curable CRC were enrolled, including 239 patients with UICC stage I-III. CTC were measured in the blood using the CellSearch system preoperatively and on postoperative days 3 and 7. The complete patient group (UICC I-IV) and the non-metastatic cohort (UICC I-III) were analysed independently. Patients were followed for 28 (0-53) months. Prognostic factors for overall and progression-free survival were analysed using univariate and multivariate analyses. RESULTS CTC were detected more frequently in patients with metastatic disease. No clinicopathological variables were associated with CTC detection in non-metastatic patients. CTC detection (⩾1 CTC per 7.5 ml blood) in the blood was significantly associated with worse overall survival (49.8 vs 38.4 months; P<0.001) in the non-metastatic group (UICC I-III), as well as in the complete cohort (48.4 vs 33.6 months; P<0.001). On multivariate analysis CTC were the strongest prognostic factor in non-metastatic patients (hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.3-13.6) as well as in the entire study group (HR 5.6; 95% CI 2.6-12.0). CONCLUSIONS Preoperative CTC detection is a strong and independent prognostic marker in non-metastatic CRC.
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Huang X, Gao P, Song Y, Sun J, Chen X, Zhao J, Xu H, Wang Z. Meta-analysis of the prognostic value of circulating tumor cells detected with the CellSearch System in colorectal cancer. BMC Cancer 2015; 15:202. [PMID: 25880692 PMCID: PMC4389311 DOI: 10.1186/s12885-015-1218-9] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 03/19/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The prognostic value of circulating tumor cells (CTCs) detected with the CellSearch System in patients with colorectal cancer (CRC) is controversial. The aim of our meta-analysis was to evaluate whether the detection of CTCs in the peripheral blood with the standardized CellSearch System has prognostic utility for patients with CRC. METHODS The PubMed, Science Citation Index, Cochrane Database, Embase, and the references in relevant studies were systematically searched (up to December, 2014). No search restrictions were imposed. Our meta-analysis was performed in Stata software, version 12.0 (2011) (Stata Corp, College Station, TX, USA), with the odds ratio (OR), risk ratio (RR), hazard ratio (HR), and 95% confidence interval (95% CI) as the effect measures. Subgroup and sensitivity analyses were also conducted. RESULTS Eleven studies containing 1847 patients with CRC were analyzed. There was a significantly higher incidence of CTCs in the metastasis-positive group than in the metastasis-negative group (OR = 4.06, 95% CI [1.74, 9.50], P < 0.01, I(2) = 0%). For hepatic metastasis, a type of metastasis, a higher incidence of CTCs was observed in the hepatic-metastasis-positive group than in the -negative group (OR = 2.61, 95% CI [1.73, 3.96], P < 0.01, I(2) = 0%). The presence of CTCs was significantly related to overall survival (HR = 2.00, 95% CI [1.49, 2.69], P < 0.01, I(2) = 67.1%) and progression-free survival (HR = 1.80, 95% CI [1.52, 2.13], P < 0.01, I(2) = 43.9%) of patients with CRC, regardless of the sampling time. The response rate for the CTC(+) groups was significantly lower than that for the CTC(-) groups at baseline and during treatment (baseline: 33% versus 39%, RR = 0.79, 95% CI [0.63, 0.99], P = 0.04, I(2) = 7.0%; during treatment: 17% versus 46%, RR = 0.41, 95% CI [0.22, 0.77], P = 0.01, I(2) = 0.0%;). CONCLUSIONS Our meta-analysis indicates that the detection of CTCs in the peripheral blood with the CellSearch System has prognostic utility for patients with CRC.
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Affiliation(s)
- Xuanzhang Huang
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, 110001, Shenyang City, People's Republic of China.
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, 110001, Shenyang City, People's Republic of China.
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, 110001, Shenyang City, People's Republic of China.
| | - Jingxu Sun
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, 110001, Shenyang City, People's Republic of China.
| | - Xiaowan Chen
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, 110001, Shenyang City, People's Republic of China.
| | - Junhua Zhao
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, 110001, Shenyang City, People's Republic of China.
| | - Huimian Xu
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, 110001, Shenyang City, People's Republic of China.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, 155 North Nanjing Street, Heping District, 110001, Shenyang City, People's Republic of China.
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Lalmahomed ZS, Mostert B, Onstenk W, Kraan J, Ayez N, Gratama JW, Grünhagen D, Verhoef C, Sleijfer S. Prognostic value of circulating tumour cells for early recurrence after resection of colorectal liver metastases. Br J Cancer 2015; 112:556-61. [PMID: 25562435 PMCID: PMC4453661 DOI: 10.1038/bjc.2014.651] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 12/01/2014] [Accepted: 12/08/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Despite good outcomes for many, a substantial group of patients undergoing metastasectomy for isolated liver metastases from colorectal cancer (CRC) experience early recurrence. We have investigated whether circulating tumour cell (CTC) detection can identify patients developing disease recurrence within 1 year after liver metastasectomy. METHODS In CRC patients undergoing liver metastasectomy, 30 ml peripheral blood was withdrawn preoperatively. CTCs were detected by the CellSearch system after a density-gradient-based enrichment step. RESULTS One hundred and seventy-three samples from 151 individual patients were analysed. In 75 samples (43%), CTCs were detected, 16% had ⩾3 CTCs/7.5 ml of blood. Eighty-two patients (47%) experienced early disease recurrence (<1 year). The 1-year recurrence rate between patients with or without detectable CTCs were similar (47% vs 48%) or with a low or high CTC count (<3 or ⩾3 CTCs/7.5 ml of blood) (50% vs 47%). Also disease-free and overall survival were similar between patients with or without CTCs. CONCLUSIONS The presence of CTCs in preoperative peripheral blood samples does not identify patients at risk for early disease recurrence after curative resection of colorectal liver metastases. Other parameters are needed to better identify patients at high risk to relapse after liver metastasectomy for CRC.
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Affiliation(s)
- Z S Lalmahomed
- Division of Transplantation and Hepatobiliary Surgery, Department of Surgery, PO Box 2040, Erasmus MC, 3000 CA Rotterdam, The Netherlands
| | - B Mostert
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, PO Box 5201, Erasmus MC, 3008 AE Rotterdam, The Netherlands
| | - W Onstenk
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, PO Box 5201, Erasmus MC, 3008 AE Rotterdam, The Netherlands
| | - J Kraan
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, PO Box 5201, Erasmus MC, 3008 AE Rotterdam, The Netherlands
| | - N Ayez
- Division of Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, PO Box 5201, Erasmus MC, 3008 CA Rotterdam, The Netherlands
| | - J W Gratama
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, PO Box 5201, Erasmus MC, 3008 AE Rotterdam, The Netherlands
| | - D Grünhagen
- Division of Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, PO Box 5201, Erasmus MC, 3008 CA Rotterdam, The Netherlands
| | - C Verhoef
- Division of Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, PO Box 5201, Erasmus MC, 3008 CA Rotterdam, The Netherlands
| | - S Sleijfer
- Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, PO Box 5201, Erasmus MC, 3008 AE Rotterdam, The Netherlands
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Fosså SD, Hess SL, Paus E, Borgen E. Circulating tumor cells in patients with metastatic castration resistant prostate cancer: exploratory findings at a tertiary referral hospital. Res Rep Urol 2014; 6:121-6. [PMID: 25328865 PMCID: PMC4199652 DOI: 10.2147/rru.s68477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Objectives In patients with metastatic castration-resistant prostate cancer (mCRPC), the finding of less than five circulating tumor cells (CTCs)/7.5 mL blood before start of cytotoxic treatment or shortly thereafter indicates prolonged survival. In this descriptive pilot study, we investigated whether this association depends on the sequence of the therapeutic attempts. Patients and methods CTCs were determined in 41 mCRPC patients before and 2–3 months after starting first-line treatment with docetaxel (group 1) or second-line treatment with either radium-223 (group 2) or placebo/best supportive care (group 3). A “favorable” CTC count was defined as <5 CTC/7.5 mL blood. The results were related to overall survival. Results Pretreatment, six of ten men in group 1, three of 19 in group 2, and three of 12 patients in group 3 had a favorable CTC count, leading to a significant difference between first- and second-line therapy (P=0.04). Decrease of pretreatment elevated CTCs to a favorable CTC count was significantly more often observed in patients on first-line therapy (three of four patients) than on second-line treatment (two of 26 men) (P=0.03). A favorable CTC count before or shortly after treatment start was observed in nine of ten patients on first-line and in eight of 31 men on second-line therapy (P=0.01). A favorable CTC count pretreatment or 2–3 months after therapy start was associated with beneficial overall survival in the three groups combined and in each group analyzed separately. Conclusion In mCRPC, a favorable CTC count before or 2–3 months after start of therapy is associated with length of overall survival, though such favorable CTC counts are observed significantly less often in patients on second- than on first-line therapy.
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Affiliation(s)
- Sophie D Fosså
- National Resource Center for Late Effects after Cancer Treatment, Norwegian Radium Hospital, Oslo University Hospital, Radiumhospital, Oslo, Norway
| | - Siri L Hess
- National Resource Center for Late Effects after Cancer Treatment, Norwegian Radium Hospital, Oslo University Hospital, Radiumhospital, Oslo, Norway
| | - Elisabeth Paus
- Department of Medical Biochemistry, Norwegian Radium Hospital, Oslo University Hospital, Radiumhospital, Oslo, Norway
| | - Elin Borgen
- Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Radiumhospital, Oslo, Norway
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Microenvironmental Influences on Metastasis Suppressor Expression and Function during a Metastatic Cell's Journey. CANCER MICROENVIRONMENT 2014; 7:117-31. [PMID: 24938990 DOI: 10.1007/s12307-014-0148-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 06/08/2014] [Indexed: 12/21/2022]
Abstract
Metastasis is the process of primary tumor cells breaking away and colonizing distant secondary sites. In order for a tumor cell growing in one microenvironment to travel to, and flourish in, a secondary environment, it must survive a series of events termed the metastatic cascade. Before departing the primary tumor, cells acquire genetic and epigenetic changes that endow them with properties not usually associated with related normal differentiated cells. Those cells also induce a subset of bone marrow-derived stem cells to mobilize and establish pre-metastatic niches [1]. Many tumor cells undergo epithelial-to-mesenchymal transition (EMT), where they transiently acquire morphologic changes, reduced requirements for cell-cell contact and become more invasive [2]. Invasive tumor cells eventually enter the circulatory (hematogenous) or lymphatic systems or travel across body cavities. In transit, tumor cells must resist anoikis, survive sheer forces and evade detection by the immune system. For blood-borne metastases, surviving cells then arrest or adhere to endothelial linings before either proliferating or extravasating. Eventually, tumor cells complete the process by proliferating to form a macroscopic mass [3].Up to 90 % of all cancer related morbidity and mortality can be attributed to metastasis. Surgery manages to ablate most primary tumors, especially when combined with chemotherapy and radiation. But if cells have disseminated, survival rates drop precipitously. While multiple parameters of the primary tumor are predictive of local or distant relapse, biopsies remain an imperfect science. The introduction of molecular and other biomarkers [4, 5] continue to improve the accuracy of prognosis. However, the invasive procedure introduces new complications for the patient. Likewise, the heterogeneity of any tumor population [3, 6, 7] means that sampling error (i.e., since it is impractical to examine the entire tumor) necessitates further improvements.In the case of breast cancer, for example, women diagnosed with stage I diseases (i.e., no evidence of invasion through a basement membrane) still have a ~30 % likelihood of developing distant metastases [8]. Many physicians and patients opt for additional chemotherapy in order to "mop up" cells that have disseminated and have the potential to grow into macroscopic metastases. This means that ~ 70 % of patients receive unnecessary therapy, which has undesirable side effects. Therefore, improving prognostic capability is highly desirable.Recent advances allow profiling of primary tumor DNA sequences and gene expression patterns to define a so-called metastatic signature [9-11], which can be predictive of patient outcome. However, the genetic changes that a tumor cell must undergo to survive the initial events of the metastatic cascade and colonize a second location belie a plasticity that may not be adequately captured in a sampling of heterogeneous tumors. In order to tailor or personalize patient treatments, a more accurate assessment of the genetic profile in the metastases is needed. Biopsy of each individual metastasis is not practical, safe, nor particularly cost-effective. In recent years, there has been a resurrection of the notion to do a 'liquid biopsy,' which essentially involves sampling of circulating tumor cells (CTC) and/or cell free nucleic acids (cfDNA, including microRNA (miRNA)) present in blood and lymph [12-16].The rationale for liquid biopsy is that tumors shed cells and/or genetic fragments into the circulation, theoretically making the blood representative of not only the primary tumor but also distant metastases. Logically, one would predict that the proportion of CTC and/or cfDNA would be proportionate to the likelihood of developing metastases [14]. While a linear relationship does not exist, the information within CTC or cfDNA is beginning to show great promise for enabling a global snapshot of the disease. However, the CTC and cfDNA are present at extremely low levels. Nonetheless, newer technologies capture enough material to enrich and sequence the patient's DNA or quantification of some biomarkers.Among the biomarkers showing great promise are metastasis suppressors which, by definition, block a tumor cell's ability to complete the metastatic process without prohibiting primary tumor growth [17]. Since the discovery of the first metastasis suppressor, Nm23, more than 30 have been functionally characterized. They function at various stages of the metastatic cascade, but their mechanisms of action, for the most part, remain ill-defined. Deciphering the molecular interactions of functional metastasis suppressors may provide insights for targeted therapies when these regulators cease to function and result in metastatic disease.In this brief review, we summarize what is known about the various metastasis suppressors and their functions at individual steps of the metastatic cascade (Table 1). Some of the subdivisions are rather arbitrary in nature, since many metastasis suppressors affect more than one step in the metastatic cascade. Nonetheless what emerges is a realization that metastasis suppressors are intimately associated with the microenvironments in which cancer cells find themselves [18].
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The Evolving Use of Prognostic Factors After Resection of Colorectal Liver Metastases. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0220-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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