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Hsiao CH, Li YL, Kiu KT, Yen MH, Chang TC. Clinical characteristics and prognostic impact of direct distant organ metastasis in colorectal cancer. Surg Oncol 2024; 53:102063. [PMID: 38492530 DOI: 10.1016/j.suronc.2024.102063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 02/20/2024] [Accepted: 03/07/2024] [Indexed: 03/18/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common type of cancer worldwide, and distant metastasis is frequently noted at diagnosis or follow-up. Notably, some patients with CRC can present with distant organ metastasis without any nodal involvement, which was defined as direct distant organ metastasis (DDOM). In this study, we evaluated the prognostic significance of DDOM for patients with CRC. METHODS This study included 325 patients who had undergone primary colorectal cancer resection between August 2008 and December 2021. The patients with and without DDOM were compared (Kaplan-Meier analysis) in terms of overall survival (OS) and time to recurrence. Furthermore, the patients' clinicopathological risk factors and protective factors were analyzed (multivariate Cox proportional hazards model). RESULTS Of the 325 patients, 65 (20%) had DDOM (Direct+ group) and 260 (80%) did not (Direct- group). The Kaplan-Meier analysis revealed that OS was significantly better in the Direct+ group than in the Direct- group (p < 0.01). A subgroup analysis by CRC stage was performed; for the patients with non-stage-IV CRC, the rate of OS was significantly higher in the Direct+ group than in the Direct- group (p = 0.02). However, DDOM did not affect the OS of the patients with stage IV CRC. The multivariate analysis indicated DDOM, left colon tumor location, and postoperative adjuvant chemotherapy were significant protective factors for disease-related mortality in the patients with non-stage-IV CRC; by contrast, body mass index, curative resection, and postoperative adjuvant chemotherapy were identified to be significant protective factors in the patients with stage IV CRC. CONCLUSIONS DDOM appears to be significantly associated with improved OS in patients with non-stage-IV CRC but not in those with stage IV CRC. Furthermore, the time to cancer recurrence may not vary significantly between patients with DDOM and those without it.
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Affiliation(s)
- Ching-Heng Hsiao
- Department of Medical Education, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan.
| | - Yen-Liang Li
- Department of Medical Education, National Cheng Kung University Hospital, No. 138,Sheng Li Road, Tainan, 704, Taiwan.
| | - Kee-Thai Kiu
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang-Ho Hospital, No. 291, Zhongzheng Road, Zhonghe District, Taipei, 235, Taiwan.
| | - Min-Hsuan Yen
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang-Ho Hospital, No. 291, Zhongzheng Road, Zhonghe District, Taipei, 235, Taiwan.
| | - Tung-Cheng Chang
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang-Ho Hospital, No. 291, Zhongzheng Road, Zhonghe District, Taipei, 235, Taiwan; Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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Vail E, Choubey AP, Alexander HR, August DA, Berry A, Boland PM, Eskander MF, Grandhi MS, Haliani B, In H, Kennedy TJ, Langan RC, Maggi JC, Pitt HA, Ganesan S, Ecker BL. Recurrence-free survival dynamics following adjuvant chemotherapy for resected colorectal cancer: A systematic review of randomized controlled trials. Cancer Med 2024; 13:e6884. [PMID: 38186327 PMCID: PMC10807601 DOI: 10.1002/cam4.6884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 11/15/2023] [Accepted: 12/17/2023] [Indexed: 01/09/2024] Open
Abstract
BACKGROUND Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence-free survival (RFS) following resection of Stage II-IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. METHODS The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan-Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t-tests. RESULTS The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0-0.5 years: 0.22 ± 0.21; 0.5-1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0-0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p < 0.001) and 0.5-1 years (0.14 ± 0.11 vs. 0.20 ± 0.09, p = 0.001) after randomization, but not at later intervals (1-5 years). In Stage IV trials, RFS event rates significantly differed for the interval 0-0.5 years (p = 0.012), corresponding with adjuvant treatment durations of 6 months. In Stage II/III trials, which included therapies of 6-24 months duration, there were marked differences in the RFS event rates between surgery and chemotherapy arms for the intervals 0-0.5 years (p < 0.001) and 0.5-1 years (p < 0.001) with smaller differences in the RFS event rates for the intervals 1-2 years (p = 0.012) and 2-3 years (p = 0.010). CONCLUSIONS In a systematic review of positive RCTs comparing adjuvant chemotherapy to surgery alone for Stage II-IV CRC, observed RFS improvements were driven by early divergences that occurred primarily during active cytotoxic chemotherapy. Late recurrence dynamics were not influenced by adjuvant therapy use. Such observations may have implications for the use of chemotherapy for micrometastatic clones detectable by cell-free DNA-based methodologies.
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Affiliation(s)
- Emma Vail
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
| | - Ankur P. Choubey
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - H. Richard Alexander
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - David A. August
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Abril Berry
- Cooperman Barnabas Medical CenterLivingstonNew JerseyUSA
| | - Patrick M. Boland
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
- Division of Medical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
| | - Mariam F. Eskander
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Miral S. Grandhi
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | | | - Haejin In
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Timothy J. Kennedy
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Russell C. Langan
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
- Cooperman Barnabas Medical CenterLivingstonNew JerseyUSA
| | - Jason C. Maggi
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Cooperman Barnabas Medical CenterLivingstonNew JerseyUSA
| | - Henry A. Pitt
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
| | - Shridar Ganesan
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
- Division of Medical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
| | - Brett L. Ecker
- Division of Surgical OncologyRutgers Cancer Institute of New Jersey, Rutgers HealthNew BrunswickNew JerseyUSA
- Rutgers Robert Wood Johnson University Medical SchoolNew BrunswickNew JerseyUSA
- Cooperman Barnabas Medical CenterLivingstonNew JerseyUSA
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Cai JW, Huang XM, Li XL, Qin S, Rong YM, Chen X, Weng JR, Zou YF, Lin XT. An 11-gene signature for the prediction of systemic recurrences in colon adenocarcinoma. Gastroenterol Rep (Oxf) 2021; 9:451-460. [PMID: 34733531 PMCID: PMC8560041 DOI: 10.1093/gastro/goab023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 05/16/2021] [Accepted: 05/16/2021] [Indexed: 11/16/2022] Open
Abstract
Background Prognosis varies among patients within the same colon adenocarcinoma (COAD) stage, indicating the need for reliable molecular markers to enable individualized treatment. This study aimed to investigate gene signatures that can be used for better prognostic prediction of COAD. Methods Gene-expression profiles of COAD patients were obtained from the Gene Expression Omnibus database (n = 332) and The Cancer Genome Atlas database (n = 431). The relationship between gene signature and relapse-free survival was analysed in the training set (n = 93) and validated in the internal validation set (n = 94) and external validation sets (n = 145 and 431). Results Overall, 11 genes (N-myc downstream regulated gene 1 [NDRG1], fms-like tyrosine kinase 1 [FLT1], lipopolysaccharide binding protein [LBP], fatty acid binding protein 4 [FABP4], adiponectin gene [ADIPOQ], angiotensinogen gene [AGT], activin A receptor, type II-like kinase 1 [ACVRL1], CC chemokine ligand 11 [CCL11], cell division cycle 42 [CDC42], T-cell receptor alpha variable 9_2 [TRAV9_2], and proopiomelanocortin [POMC]) were identified by univariable and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. Based on the risk-score model, the patients were grouped into the high-risk or low-risk groups using the median risk score as the cut-off. The area under the curve (AUC) values for 1-, 3-, and 5-year recurrence were 0.970, 0.849, and 0.859, respectively. Patients in the high-risk group had significantly poorer relapse-free survival than did those in the low-risk group. The predictive accuracy of the 11-gene signature was proven in the validation sets. Our gene signature showed better predictive performance for 1-, 3-, and 5-year recurrence than did the other four models. Conclusions The 11-gene signature showed good performance in predicting recurrence in COAD. The accuracy of the signature for prognostic classification requires further confirmation.
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Affiliation(s)
- Jia-Wei Cai
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiao-Ming Huang
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiao-Lan Li
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Department of Reproductive Medicine, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Si Qin
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Department of Medical Ultrasonics, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yu-Ming Rong
- Department of VIP Region, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Xi Chen
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jing-Rong Weng
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yi-Feng Zou
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xu-Tao Lin
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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Kerboeuf M, Koppang EO, Haaland AH, Lingaas F, Bruland ØS, Teige J, Moe L. Early immunohistochemical detection of pulmonary micrometastases in dogs with osteosarcoma. Acta Vet Scand 2021; 63:41. [PMID: 34732227 PMCID: PMC8565451 DOI: 10.1186/s13028-021-00608-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/19/2021] [Indexed: 11/18/2022] Open
Abstract
Background Despite decades of research, the early phases of metastatic development are still not fully understood. Canine osteosarcoma (OS) is a highly aggressive cancer, with a high metastatic rate (> 90%), despite a low overt metastatic prevalence at initial diagnosis (< 15%). Canine OS is generally regarded as a good clinically relevant model for human OS. The aim of this hypothesis-generating study was to evaluate a method to detect pulmonary micrometastases and study their prevalence in dogs with OS without macroscopic metastases. We prospectively enrolled dogs with OS that received no cancer-specific treatment (n = 12) and control dogs without cancer (n = 2). Dogs were necropsied and sampled immediately after euthanasia. The OS dogs were classified as having macroscopic metastases (n = 2) or not (n = 10). We immunohistochemically stained one tissue sample from each of the seven lung lobes from each dog with a monoclonal antibody (TP-3) to identify micrometastases (defined as clusters of 5–50 tumour cells), microscopic metastases (> 50 tumour cells) and TP-3 positive single cells (< 5 tumour cells). Results We showed that pulmonary micrometastases easily overseen on routine histology could be detected with TP-3. Pulmonary micrometastases and microscopic metastases were present in two dogs with OS without macroscopic metastases (20%). Micrometastases were visualised in three (43%) and four (57%) of seven samples from these two dogs, with a mean of 0.6 and 1.7 micrometastases per sample. Microscopic metastases were present in one (14%) and four (57%) of seven samples from the same two dogs, with a mean of 0.14 and 1.0 microscopic metastases per sample. There were four (57%) and two (29%) samples with neither microscopic metastases nor micrometastases for each of these two dogs. The prevalence of pulmonary micrometastases (20%) was significantly lower than expected (> 90%) based on commonly expected metastatic rates after amputation (P < 0.0001). There was no statistically significant difference in the number of TP-3 positive single cells in between groups (P = 0.85). Conclusions Pulmonary micrometastases could be detected with TP-3 immunohistochemistry in a subset of dogs with OS before macroscopic metastases had developed. We propose that dogs with spontaneous OS represent clinically relevant models to study early micrometastatic disease.
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Vafaei S, Fattahi F, Ebrahimi M, Janani L, Shariftabrizi A, Madjd Z. Common molecular markers between circulating tumor cells and blood exosomes in colorectal cancer: a systematic and analytical review. Cancer Manag Res 2019; 11:8669-8698. [PMID: 31576171 PMCID: PMC6768129 DOI: 10.2147/cmar.s219699] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Nearly half of patients with colorectal cancer (CRC), the third leading cause of cancer deaths worldwide, are diagnosed in the late stages of the disease. Appropriate treatment is not applied in a timely manner and nearly 90% of the patients who experience metastasis ultimately die. Timely detection of CRC can increase the five-year survival rate of patients. Existing histopathological and molecular classifications are insufficient for prediction of metastasis, which limits approaches to treatment. Detection of reliable cancer-related biomarkers can improve early diagnosis, prognosis, and treatment response prediction and recurrence risk. Circulating tumor cells (CTCs) and exosomes in peripheral blood can be used in a liquid biopsy to assess the status of a tumor. Exosomes are abundant and available in all fluids of the body, have a high half-life and are released by most cells. Tumor-derived exosomes are released from primary tumors or CTCs with selective cargo that represents the overall tumor. The current systematic review highlights new trends and approaches in the detection of CRC biomarkers to determine tumor signatures using CTC and exosomes. When these are combined, they could be used to guide molecular pathology and can revolutionize detection tools. Relevant observational studies published until July 24, 2019 which evaluated the expression of tumor markers in CTCs and exosomes were searched in PubMed, Scopus, Embase, and ISI Web of Science databases. The extracted biomarkers were analyzed using String and EnrichR tools.
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Affiliation(s)
- Somayeh Vafaei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fahimeh Fattahi
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Leila Janani
- Department of Biostatistics, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | | | - Zahra Madjd
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
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Zhao Y, Ma W, Zou S, Chen B, Cheng H, He X, Wang K. Terminal deoxynucleotidyl transferase-initiated molecule beacons arrayed aptamer probe for sensitive detection of metastatic colorectal cancer cells. Talanta 2019; 202:152-158. [PMID: 31171163 DOI: 10.1016/j.talanta.2019.04.065] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 04/18/2019] [Accepted: 04/23/2019] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world, which can lead to considerably high mortality rate. It was reported that the prognosis is extremely poor and survival is often measured in months once CRC metastases become clinically evident. Therefore, the development of effective approach for metastatic CRC cells detection and imaging may potentially be significant and helpful for CRC prognosis and treatment. Therefore, we proposed a sensitive and specific approach for high-metastatic CRC LoVo cells detection and imaging by using terminal deoxynucleotidyl transferase (TdT)-initiated molecule beacons (MBs) arrayed fluorescent aptamer probes (denoted as TMAP). In this approach, the aptamer W3 targeting high-metastatic CRC LoVo cells was elongated to form W3-poly A at the 3'-hydroxyl terminus with repeated A bases in the presence of TdT and dATP. The MBs designed with poly T sequence in the loop were then hybridized with the poly A in the aptamer W3. The TMAP was easily constructed without the need of aptamer modification. It was demonstrated that this approach could specifically detect and image the high-metastatic CRC LoVo cells from the mixture of high-metastatic CRC LoVo cells and non-metastatic HCT-8 cells. Compared with 6-carboxyfluorescein (6-FAM) labeled aptamer W3, the TMAP was demonstrated to have a much stronger fluorescence signal on the target cells, realizing a 4-fold increase in signal-to-background ratio (SBR). Determination by flow cytometry allowed for detection of as low as 23 CRC LoVo cells in 200 μL cell culture medium. The high sensitivity and the capability for using in complicate biological samples imply that this approach holds considerable potential for metastatic CRC detection and therapy.
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Affiliation(s)
- Yujie Zhao
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecule Engineering of Hunan Province, Changsha, 410082, China
| | - Wenjie Ma
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecule Engineering of Hunan Province, Changsha, 410082, China
| | - Shanzi Zou
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecule Engineering of Hunan Province, Changsha, 410082, China
| | - Biao Chen
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecule Engineering of Hunan Province, Changsha, 410082, China
| | - Hong Cheng
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecule Engineering of Hunan Province, Changsha, 410082, China
| | - Xiaoxiao He
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecule Engineering of Hunan Province, Changsha, 410082, China.
| | - Kemin Wang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Hunan University, Key Laboratory for Bio-Nanotechnology and Molecule Engineering of Hunan Province, Changsha, 410082, China.
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Dai W, Li Y, Mo S, Feng Y, Zhang L, Xu Y, Li Q, Cai G. A robust gene signature for the prediction of early relapse in stage I-III colon cancer. Mol Oncol 2018; 12:463-475. [PMID: 29377588 PMCID: PMC5891048 DOI: 10.1002/1878-0261.12175] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 12/23/2017] [Accepted: 12/23/2017] [Indexed: 01/09/2023] Open
Abstract
Colon cancer patients experiencing early relapse consistently exhibited poor survival. The aim of our study was to develop an mRNA signature that can help to detect early relapse cases in stage I-III colon cancer. Public microarray datasets of stage I-III colon cancer samples were extracted from the Gene Expression Omnibus database. Propensity score matching analysis was performed between patients in the early relapse group and the long-term survival group from GSE39582 discovery series (N = 386), and patients were 1 : 1 matched. Global mRNA expression changes were then analyzed between the paired groups to identify the differentially expressed genes. Lasso Cox regression modeling analysis was conducted for the selection of prognostic mRNA. Fifteen mRNA were finally identified to build an early relapse classifier. With specific risk score formula, patients were classified into a high-risk group and a low-risk group. Relapse-free survival was significantly different between the two groups in every series, including discovery [hazard ratio (HR): 2.547, 95% confidence interval (CI): 1.708-3.797, P < 0.001)], internal validation (HR: 5.146, 95% CI: 1.968-13.457, P < 0.001), and external validation (HR: 1.977, 95% CI: 1.295-3.021, P < 0.001) sets of patients. Time-dependent receiver-operating characteristic at 1 year suggested more prognostic accuracy of the classifier [area under curve (AUC = 0.703)] than the American Joint Commission on Cancer tumor-node-metastasis staging system (AUC = 0.659) in all 951 patients. In conclusion, we developed a robust mRNA signature that can effectively classify colon cancer patients into groups with low and high risks of early relapse. This mRNA signature may help select high-risk colon cancer patients who require more aggressive therapeutic intervention.
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Affiliation(s)
- Weixing Dai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Yaqi Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Shaobo Mo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Yang Feng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Long Zhang
- Shanghai Medical College, Collaborative Innovation Center of Cancer Medicine, Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, China
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, China.,Department of Oncology, Shanghai Medical College, Fudan University, China
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Märkl B, Wilhelms N, Anthuber M, Schenkirsch G, Schlimok G, Oruzio D. Circulating cytokeratin-positive cells and tumor budding in colorectal cancer. World J Clin Oncol 2016; 7:433-440. [PMID: 28008384 PMCID: PMC5143437 DOI: 10.5306/wjco.v7.i6.433] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 09/10/2016] [Accepted: 10/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether circulating cytokeratin-positive (CK+) cells in the mesenteric blood of resected colorectal specimens are prognostic and correlate with tumor budding.
METHODS Fifty-six colorectal specimens were collected between 9/2007 and 7/2008. Blood from the mesenteric vein was drawn immediately after receiving the fresh and unfixed specimens in the pathology department. After separation of the mononuclear cells by Ficoll-Hypaque density-gradient centrifugation, cytological smears were immunocytochemically stained for CK18. Tumor budding was evaluated on slides stained for pan-cytokeratin. The identification of ≥ 30 buds/1.3 mm2 was defined as high grade budding.
RESULTS CK+ cells and clusters were identified in 29 (48%) and 14 (25%) of the samples, respectively. Two cells were identified in one of three non-malignant cases. Clusters were found exclusively in malignant cases. The occurrence of CK+ cells or clusters was not associated with any of the evaluated clinicopathological factors, including surgical technique and tumor budding. Moreover, the occurrence of CK+ cells or clusters had no influence on the cancer-specific survival [75 mo (CI: 61; 88) vs 83 mo (CI: 72; 95) and 80 mo (CI: 63; 98) vs 79 mo (CI: 69; 89), respectively].
CONCLUSION CK+ cells and showed neither prognostic significance nor an association with tumor budding. It is very likely that CK18-staining is not specific enough to identify the relevant cells.
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Bünger S, Zimmermann M, Habermann JK. Diversity of assessing circulating tumor cells (CTCs) emphasizes need for standardization: a CTC Guide to design and report trials. Cancer Metastasis Rev 2016; 34:527-45. [PMID: 26323491 DOI: 10.1007/s10555-015-9582-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Hematogenous spreading of tumor cells from primary tumors is a crucial step in the cascade to metastasis, the latter being the most limiting factor for patients' survival prognosis. Therefore, circulating tumor cells (CTCs) have become a field of intensive research. However, the process of isolation and identification of CTCs lacks standardization. This article presents an overview of 71 CTC studies reported in PUBMED since 2000 and focusing on colorectal cancer. These studies are evaluated regarding standardization of CTC isolation and identification, marker proteins used, study population and blood sample quality management, clinical performance, and quality measures. Overall, standardization of CTC assessment seems insufficient. Thus, comparability of CTC studies is hampered and results should be interpreted carefully. We here propose a standardized CTC guideline (CTC Guide) to prospectively design and report studies/trials in a harmonized form. Despite the current interstudy heterogeneity, the data indicate that CTC detection is of clinical relevance and CTCs should be considered as a surrogate prognostic marker. Many studies indicate the high potential for CTCs as prognostic markers, e.g., in colorectal cancer treatment. However, standardized, large-scale multicenter validation studies are still needed to pave the way for clinical implementation of CTC detection that could ameliorate individualized medicine regimes.
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Affiliation(s)
- S Bünger
- Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
| | - M Zimmermann
- Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
| | - J K Habermann
- Section for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
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10
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Karimi S, Mohamadnia A, Nadji SA, Yadegarazari R, Khosravi A, Bahrami N, Saidijam M. Expression of two basic mRNA biomarkers in peripheral blood of patients with non-small cell lung cancer detected by real-time rt-PCR, individually and simultaneously. IRANIAN BIOMEDICAL JOURNAL 2015; 19:17-22. [PMID: 25605485 PMCID: PMC4322228 DOI: 10.6091/ibj.1397.2014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 05/14/2014] [Accepted: 05/19/2014] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Although extensive research has been conducted on lung cancer markers, a singular clinically applicable marker has not been found yet. The objective of this study was to evaluate the sensitivity and the specificity of carcinoembryonic antigen (CEA) mRNA and lung-specific X protein (LUNX) mRNA biomarkers in peripheral blood to detect lung cancer individually and simultaneously. METHODS Thirty patients affected by lung cancer and 30 healthy individuals were studied in this research. Three vials of cDNA were made from each sample after taking peripheral blood samples and extracting total RNA. Each sample was examined by the real-time RT-PCR technique. The result from each vial was then compared with the sensitivity of overall marker. RESULTS The CEA mRNA was positive in 24 out of 30 lung cancer patients. Hence, its sensitivity was determined at 80%, differing significantly from that observed in healthy individuals, where 11 positive cases were seen. The overall sensitivity of this marker was significantly associated with positivity in vials 2 and 3 but not in vial 1. The LUNX mRNA was positive in 21 out of 30 patients, indicating 70% sensitivity. This finding significantly differed from that in healthy individuals. The overall sensitivity of this marker was significantly associated with positivity in vials 1 and 3, but not in vial 2. In 93.3% of the patients, at least one positive marker was observed. CONCLUSION The mentioned mRNA could be suggested as sensitive and specific markers in peripheral blood for primary diagnosis of lung cancer.
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Affiliation(s)
- Shirin Karimi
- Mycobacteriology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran;
| | - Abdolreza Mohamadnia
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran;
- Dept. of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran;
| | - Seyed Alireza Nadji
- Virology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran;
| | - Reza Yadegarazari
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran;
- Dept. of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran;
| | - Adnan Khosravi
- Tobacco Prevention and Control Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran;
| | - Naghmeh Bahrami
- Iranian Tissue Bank and Research Center Tehran University of Medical Sciences, Tehran;
- Dental Biomaterial Dept. of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran;
- Dept. of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran;
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11
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Detection of cytokeratin-20-positive cells in preoperative and postoperative blood samples from colorectal cancer patients by real-time RT-PCR. Int J Biol Markers 2013; 28:174-81. [PMID: 23558939 DOI: 10.5301/jbm.5000003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND Detection of circulating cancer cells by reverse transcription polymerase chain reaction (RT-PCR) has been studied as a prognostic marker in patients with colorectal cancer (CRC) but so far with conflicting results regarding specificity and prognostic value. In this study cytokeratin-20 (CK20) was evaluated by real-time RT-PCR as a marker for circulating CRC cell detection and the influence of surgical tumor resection on the presence of circulating CRC cells was analyzed. METHODS RNA was isolated from the mononuclear cell fraction of blood samples taken from 95 CRC patients before and after tumor resection and from 23 healthy volunteers and assayed by real-time RT-PCR for CK20 expression. RESULTS Among 23 healthy volunteers one was positive for CK20. Among 95 CRC patients, 25 were positive for CK20 before and 23 after surgery. Sixteen patients positive before surgery became negative after surgery, while 14 patients negative before surgery became positive after surgery. An increase in the proportion of CK20-positive samples with increasing stage of disease was observed for preoperative but not postoperative blood samples. CONCLUSIONS Its association with clinical stage indicates that CK20 might have prognostic value as a marker for detection of circulating CRC cells. Surgical tumor resection can both reduce and induce the presence of circulating CRC cells.
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12
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Tänzer M, Liebl M, Quante M. Molecular biomarkers in esophageal, gastric, and colorectal adenocarcinoma. Pharmacol Ther 2013; 140:133-47. [PMID: 23791941 DOI: 10.1016/j.pharmthera.2013.06.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023]
Abstract
Cancers of the esophagus, stomach and colon contribute to a major health burden worldwide and over 20% of all cancer deaths. Biomarkers that should indicate pathogenic process and are measureable in an objective manner for these tumors are rare and not established in the clinical setting. In general biomarkers can be very useful for cancer management as they can improve clinical decision-making regarding diagnosis, surveillance, and therapy. Biomarkers can be different types of molecular entities (such as DNA, RNA or proteins), which can be detected, in different tissues or body fluids. However, more important is the type of biomarker itself, which allows diagnostic, prognostic or predictive analyses for different clinical problems. This review aims to systematically summarize the recent findings of genetic and epigenetic markers for gastrointestinal tumors within the last decade. While many biomarkers seem to be very promising, especially if used as panels, further development is urgently needed to address practical considerations of biomarkers in cancer treatment.
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Affiliation(s)
- Marc Tänzer
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany
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13
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Akagi Y, Kinugasa T, Adachi Y, Shirouzu K. Prognostic significance of isolated tumor cells in patients with colorectal cancer in recent 10-year studies. Mol Clin Oncol 2013; 1:582-592. [PMID: 24649214 DOI: 10.3892/mco.2013.116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 04/18/2013] [Indexed: 12/14/2022] Open
Abstract
Circulating tumor cells (CTCs) that detach from the primary tumor and move into the circulation are detected in patients with metastatic cancer. The discovery of such cancer cells has been used as a predictor of recurrence and prognosis, although a consensus regarding such applications has not been reached. Peritoneal cytology may be used for identifying high risk of recurrence or mortality, whereas the intraoperative presence of tumor cells in drainage veins, bone marrow, or the liver is not always useful for evaluating the prognosis. The reported positive rate for tumor cells in the peripheral blood of patients with colorectal cancer, including metastasis, has varied from 10 to 80%; however, numerous studies have demonstrated significant differences in the recurrence and mortality rates between patients with and without isolated tumor cells (ITCs) in the peripheral blood. However, the clinical significance of CTCs as an absolute prognostic factor has not been elucidated, since the measurement methodologies and/or the number of cases differed between the studies. Future prospective studies including larger patient populations may elucidate the utility of routine detection of ITCs in daily practice.
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Affiliation(s)
- Yoshito Akagi
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Tetsushi Kinugasa
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Yosuke Adachi
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Kazuo Shirouzu
- Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
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14
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Yadegarazari R, Hassanzadeh T, Majlesi A, Keshvari A, Monsef Esfahani A, Tootoonchi A, Shabab N, Saidijam M. Improved real-time rt-PCR assays of two colorectal cancer peripheral blood mRNA biomarkers: a pilot study. IRANIAN BIOMEDICAL JOURNAL 2013; 17:15-21. [PMID: 23279830 PMCID: PMC3600971 DOI: 10.6091/ibj.1104.2012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/07/2012] [Revised: 10/08/2012] [Accepted: 10/10/2012] [Indexed: 12/21/2022]
Abstract
BACKGROUND Efficient screening for detection of colorectal cancer (CRC) at earlier stages reduces its mortality. The purpose of this study was to investigate expression of carcinoembryonic antigen (CEA) and human telomerase reverse transcriptase (hTERT) mRNA in peripheral blood of CRC patients and to present strategies for early detection screen test. METHODS Twenty seven patients in non-metastatic stage and 27 healthy individuals were studied. Expression of CEA, hTERT mRNA and 18srRNA (18s subunit of ribosomal RNA, as reference gene) were determined based on real-time RT-PCR on 3 µg of total RNA from blood in 3 separate vials (1 µg per vial). RESULTS Positive expression rate of CEA mRNA (78%) and hTERT mRNA (81%) were higher in patient group (P<0.001). These rates were meaningfully higher than the results of individual vials containing only 1 µg of total RNA. Difference between Ct values of markers with 18srRNA ΔCt) was higher in healthy group than patient one. Therefore, a ΔCt cut-off value was determined for distinguishing between true- and false-positive results. Concurrent expression of both markers was found in 67% of the patients, which was higher than healthy cases (11%). Combination of concurrent marker expression with cut-off point strategy increased specificity to 100%. CONCLUSION These results showed that concurrent evaluation of marker expression and performing the test on 3 µg of samples in 3 separate vials may increase specificity and sensitivity of real-time RT-PCR for early detection of non-metastatic CRC. However, more investigations with larger numbers of samples are needed to verify these results.
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Affiliation(s)
- Reza Yadegarazari
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan;
- Dept. of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan;
| | - Taghi Hassanzadeh
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan;
| | - Amir Majlesi
- Dept. of Gastrointestinal Disease, Beheshti Hospital of Hamadan University of Medical Sciences, Hamadan;
| | - Amir Keshvari
- Dept. of General Surgery, Imam Khomeini Hospital of Tehran University of Medical Sciences, Tehran;
| | | | - Amirsasan Tootoonchi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan;
| | - Nooshin Shabab
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan;
- Dept. of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan;
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan;
- Dept. of Genetics and Molecular Medicine, Hamadan University of Medical Sciences, Hamadan;
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Bosch LJW, Carvalho B, Fijneman RJA, Jimenez CR, Pinedo HM, van Engeland M, Meijer GA. Molecular tests for colorectal cancer screening. Clin Colorectal Cancer 2011; 10:8-23. [PMID: 21609931 DOI: 10.3816/ccc.2011.n.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Detecting and removing high-risk adenomas and early colorectal cancer (CRC) can reduce mortality of this disease. The noninvasive fecal occult blood test (FOBT; guaiac-based or immunochemical) is widely used in screening programs and although effective, it leaves room for improvement in terms of test accuracy. Molecular tests are expected to be more sensitive, specific and informative than current detection tests, and are promising future tools for CRC screening. This review provides an overview of the performances of DNA, RNA, and protein markers for CRC detection in stool and blood. Most emphasis currently is on DNA and protein markers. Among DNA markers there is trend to move away from mutation markers in favor of methylation markers. The recent boost in proteomics research leads to many new candidate protein markers. Usually in small series, some markers show better performance than the present FOBT. Evaluation in large well-controlled randomized trials is the next step needed to take molecular markers for CRC screening to the next level and warrant implementation in a screening setting.
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Affiliation(s)
- Linda J W Bosch
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
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16
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Lu CY, Uen YH, Tsai HL, Chuang SC, Hou MF, Wu DC, Hank Juo SH, Lin SR, Wang JY. Molecular detection of persistent postoperative circulating tumour cells in stages II and III colon cancer patients via multiple blood sampling: prognostic significance of detection for early relapse. Br J Cancer 2011; 104:1178-1184. [PMID: 21343933 PMCID: PMC3068492 DOI: 10.1038/bjc.2011.40] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Revised: 01/19/2011] [Accepted: 01/25/2011] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND The purpose of this study was to detect postoperative persistent circulating tumour cells (CTCs) in stages II and III colon cancer patients undergoing curative resection and so identify a subgroup of patients who are at high risk for early relapse. METHODS Four mRNA molecular markers including human telomerase reverse transcriptase, cytokeratin-19, cytokeratin-20, and carcinoembryonic antigen (CEA) mRNA were used to detect CTCs in 141 stages II and III colon cancer patients undergoing curative resection to determine the significance of CTCs in postoperative early relapse. RESULTS Out of 141 patients, postoperative early relapse and non-early relapse/no relapse was found in 48 (34.0%) patients and 93 (66.0%) patients, respectively. Univariately, postoperative early relapse was significantly correlated with lymph node metastasis (P=0.025), vascular invasion (P=0.002), perineural invasion (P=0.001), laparoscopic surgery (P=0.019), high postoperative serum CEA levels (P=0.001), and presence of persistent postoperative CTCs (P<0.001). Using a multivariate proportional hazards regression analysis, the presence of perineural invasion (P=0.034; HR, 1.974; 95% CI: 1.290-3.861), high postoperative serum CEA levels (P=0.020; HR, 2.377; 95% CI: 1.273-4.255), and the presence of persistent postoperative CTCs (P<0.001; HR, 11.035; 95% CI: 4.396-32.190), were demonstrated to be independent predictors for postoperative early relapse. Furthermore, the presence of persistent postoperative CTCs was strongly correlated with a poorer disease-free and overall survival (both P<0.001). CONCLUSIONS This study suggests that molecular detection of persistent postoperative CTCs is a prognostic predictor of early relapse in UICC stage II/III colon cancer patients, and thus could help to define patients with this tumour entity for an enhanced follow-up and therapeutic program.
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Affiliation(s)
- C-Y Lu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Y-H Uen
- Division of General Surgery, Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan
- Department of Electrical Engineering, Southern Taiwan University, Tainan, Taiwan
| | - H-L Tsai
- Department of Emergency Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Program of Bachelor of Health Beauty, School of Medical and Health Sciences, Fooyin University, Kaohsiung County, Taiwan
| | - S-C Chuang
- Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - M-F Hou
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - D-C Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - S-H Hank Juo
- Department of Medical Genetics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - S-R Lin
- Department of Medical Research, Fooyin University Hospital, Pingtung County, Taiwan
- Department of Medical Technology, School of Medical and Health Sciences, Fooyin University, Kaohsiung County, Taiwan
| | - J-Y Wang
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Genetics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung, Taiwan
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Tsouma A, Aggeli C, Lembessis P, Zografos GN, Korkolis DP, Pectasides D, Skondra M, Pissimissis N, Tzonou A, Koutsilieris M. Multiplex RT-PCR-based detections of CEA, CK20 and EGFR in colorectal cancer patients. World J Gastroenterol 2010; 16:5965-74. [PMID: 21157973 PMCID: PMC3007112 DOI: 10.3748/wjg.v16.i47.5965] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a multiplex reverse transcription polymerase chain reaction (RT-PCR) method detecting circulating tumor cells in the peripheral blood of colorectal cancer (CRC) patients.
METHODS: Peripheral blood samples were collected from 88 CRC patients and 40 healthy individuals from the blood donors’ clinic and subsequently analyzed by multiplex RT-RCR for the expression of carcinoembryonic antigen (CEA), cytokeratin 20 (CK20) and epidermal growth factor receptor (EGFR) mRNA. The analysis involved determining the detection rates of CEA, CK20 and EGFR transcripts vs disease stage and overall survival. Median follow-up period was 19 mo (range 8-28 mo).
RESULTS: Rates of CEA, CK20 and EGFR detection in CRC patients were 95.5%, 78.4% and 19.3%, respectively. CEA transcripts were detected in 3 healthy volunteer samples (7.5%), whereas all control samples were tested negative for CK20 and EGFR transcripts. The increasing number of positive detections for CEA, CK20 and EGFR transcripts in each blood sample was positively correlated with Astler-Coller disease stage (P < 0.001) and preoperative serum levels of CEA (P = 0.029) in CRC patients. Data analysis using Kaplan-Meier estimator documented significant differences in the overall survival of the different CRC patient groups as formed according to the increasing number of positivity for CEA, CK20 and EGFR transcripts.
CONCLUSION: These data suggest that multiplex RT-PCR assay can provide useful information concerning disease stage and overall survival of CRC patients.
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Peach G, Kim C, Zacharakis E, Purkayastha S, Ziprin P. Prognostic significance of circulating tumour cells following surgical resection of colorectal cancers: a systematic review. Br J Cancer 2010; 102:1327-34. [PMID: 20389297 PMCID: PMC2865760 DOI: 10.1038/sj.bjc.6605651] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: The role of adjuvant chemotherapy after resection of colorectal cancers (CRCs) is well understood for patients with stage-I or stage-III disease. Its efficacy for those with stage-II disease remains much less clear. Many investigators have sought to identify prognostic markers that might clarify which patients have the highest risk of recurrence and would, therefore, be most likely to benefit from chemotherapy. This systematic review examines evidence for the use of peripherally sampled, circulating tumour cells (CTCs) as such a prognostic marker. Methods: A comprehensive literature search was used to identify studies reporting on the significance of CTCs in the postoperative blood of CRC patients. Results: Fourteen studies satisfied the inclusion criteria. Six of the nine studies that took blood samples 24 h or more postoperatively found detection of postoperative CTCs to be an independent predictor of cancer recurrence. Conclusion: The presence of CTCs in peripheral blood at least 24 h after resection of CRCs is an independent prognostic marker of recurrence. Further studies are needed to clarify the optimal time point for blood sampling and determine the benefit of chemotherapy in CTC-positive patients with stage-II disease.
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Affiliation(s)
- G Peach
- Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, St Mary's Campus, Imperial College London, Praed Street, London W2 1NY, UK.
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Serrano Fernádez MJ, Alvarez Merino JC, Martínez Zubiaurre I, Fernández García A, Sánchez Rovira P, Lorente Acosta JA. Clinical relevance associated to the analysis of circulating tumour cells in patients with solid tumours. Clin Transl Oncol 2010; 11:659-68. [PMID: 19828408 DOI: 10.1007/s12094-009-0421-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
The distant growth of tumour cells escaping from primary tumours, a process termed metastasis, represents the leading cause of death among patients affected by malignant neoplasias from breast and colon. During the metastasis process, cancer cells liberated from primary tumour tissue, also termed circulating tumour cells (CTCs), travel through the circulatory and/or lymphatic systems to reach distant organs. The early detection and the genotypic and phenotypic characterisation of such CTCs could represent a powerful diagnostic tool of the disease, and could also be considered an important predictive and prognostic marker of disease progression and treatment response. In this article we discuss the potential relevance in the clinic of monitoring CTCs from patients suffering from solid epithelial tumours, with emphasis on the impact of such analyses as a predictive marker for treatment response.
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Affiliation(s)
- María José Serrano Fernádez
- Center GENYO (Pfizer-University of Granada-Andalucian Goverment Center for Genomics and Oncological Research), Armilla, Granada, Spain.
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Katsuno H, Zacharakis E, Aziz O, Rao C, Deeba S, Paraskeva P, Ziprin P, Athanasiou T, Darzi A. Does the presence of circulating tumor cells in the venous drainage of curative colorectal cancer resections determine prognosis? A meta-analysis. Ann Surg Oncol 2008; 15:3083-91. [PMID: 18787906 DOI: 10.1245/s10434-008-0131-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2008] [Revised: 07/09/2008] [Accepted: 07/10/2008] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatic metastasis can occur following curative colorectal cancer surgery despite favorable prognostic indicators, raising the question of whether detecting circulating tumor cells in the venous drainage of colorectal cancers at resection using reverse-transcriptase polymerase chain reaction would help determine prognosis. This study compares lymph node positivity, hepatic metastasis rates, and disease-free survival in circulating tumor positive versus negative patients. METHODS A Medline, Embase, Ovid, and Cochrane database search was conducted on all studies between 1999 and 2006 reporting the outcomes of interest. Meta-analysis was performed in line with recommendations from the Cochrane Collaboration and the Quality of Reporting of Meta-Analyses guidelines. RESULTS Nine studies reporting on 646 subjects published between 1998 and 2006 matched the selection criteria and were suitable for inclusion in this meta-analysis. There was a significantly higher incidence of circulating tumor cells (50%) in lymph node positive compared with negative groups (21%) [odds ratio (OR) = 3.83, confidence interval (CI) = 2.46-5.94], and a significantly increased hepatic metastases rate (21%) in circulating tumor cells positive compared with in negative patients (8%, OR = 6.38; CI = 2.67-15.25. Disease-free survival was significantly higher in the circulating tumor cell negative versus positive groups at 1 year [hazard ratio (HR) = 0.04, CI = 0-0.46], 2 years (HR = 0.05, CI = 0.01-0.31), and 3 years (HR = 0.08, CI = 0.02-0.34) post resection. CONCLUSION This study highlights the potential importance of free cancer cell detection in the venous drainage of colorectal cancers as a prognostic indicator and a mode of staging colorectal cancers.
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Affiliation(s)
- Hidetoshi Katsuno
- Department of Biosurgery and Surgical Technology, Imperial College London, St Mary's Hospital, 10th Floor, QEQM Wing, St Mary's Campus, Praed Street, London W2 1NY, UK
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Maruthachalam K, Lash GE, Shenton BK, Horgan AF. Tumour cell dissemination following endoscopic stent insertion. Br J Surg 2007; 94:1151-4. [PMID: 17541987 DOI: 10.1002/bjs.5790] [Citation(s) in RCA: 190] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND This study examined whether colonoscopy or endoscopic stent insertion increases levels of carcinoembryonic antigen (CEA) and/or cytokeratin (CK) 20 mRNA expression in the peripheral circulation of patients with colorectal cancer. METHODS Peripheral venous blood samples were obtained before and after colonoscopy (38 patients) or colonic stent insertion (20). Twenty patients undergoing colonoscopy for benign conditions served as controls. Expression of mRNA was quantified using real-time reverse transcriptase-polymerase chain reaction. RESULTS Circulating CK20 mRNA was detected in 13 of 38 patients who had a colonoscopy and eight of 20 patients with stent insertion. CK20 mRNA expression was increased following stent insertion (P = 0.007) but not after staging colonoscopy (P = 0.454). CEA mRNA was detected in one patient who had colonoscopy and two who had a stent inserted. Neither CEA nor CK20 mRNA was found in blood samples from controls. CONCLUSION Endoscopic insertion of colonic stents but not staging colonoscopy results in increased levels of CK20 mRNA in the peripheral circulation.
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Affiliation(s)
- K Maruthachalam
- Department of Colorectal Surgery, Freeman Hospital, Newcastle upon Tyne, UK
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Sadahiro S, Suzuki T, Maeda Y, Yurimoto S, Yasuda S, Makuuchi H, Kamijo A, Murayama C. Detection of carcinoembryonic antigen messenger RNA-expressing cells in peripheral blood 7 days after curative surgery is a novel prognostic factor in colorectal cancer. Ann Surg Oncol 2007; 14:1092-8. [PMID: 17200912 DOI: 10.1245/s10434-006-9289-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2006] [Revised: 11/02/2006] [Accepted: 11/09/2006] [Indexed: 12/19/2022]
Abstract
BACKGROUND The significance of detection of circulating cancer cells in blood during surgery in patients with colorectal cancer (CRC) remains controversial. Experimental study revealed that the cancer cells injected from the vein disappeared completely until 7 days. The aim of this study was to clarify that the detection of circulating cancer cells in blood taken later than 7 days after curative surgery may be a prognostic factor. METHODS Two hundred consecutive patients with CRC who underwent potentially curative surgery were the subjects. Peripheral blood was collected between 7 and 10 days after resection. Cancer cells were detected using reverse transcriptase-polymerase chain reaction targeting carcinoembryonic antigen (CEA) messenger RNA (mRNA). The median follow-up period was 52 months (range: 34-69 months). RESULTS The overall positive incidence of CEA mRNA was 22%. Detection of CEA mRNA was not significantly related to conventional clinicopathological findings. Recurrence has been confirmed in 55 patients (28%). The recurrence rate was significantly higher in patients with rectal cancer, deep penetration, lymph node metastasis, preoperative chemoradiotherapy and positive CEA mRNA. The CEA mRNA positive patients showed significantly poorer disease free survival (DFS) and overall survival (OS) than the negative patients (DFS, P = 0.007; OS, P = 0.04). Multivariate analysis revealed that the positive expression of CEA mRNA (P < 0.01) as well as the tumor location and TNM stage classification was identified as the significant risk factors for recurrence. CONCLUSIONS Detection of CEA mRNA expressing cells in peripheral blood 7 days after curative surgery is a novel independent factor predicting recurrence in patients with CRC.
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MESH Headings
- Adenocarcinoma, Mucinous/blood
- Adenocarcinoma, Mucinous/secondary
- Adenocarcinoma, Mucinous/surgery
- Carcinoembryonic Antigen/genetics
- Carcinoma, Signet Ring Cell/blood
- Carcinoma, Signet Ring Cell/secondary
- Carcinoma, Signet Ring Cell/surgery
- Colorectal Neoplasms/blood
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/surgery
- Female
- Humans
- Lymphatic Metastasis
- Male
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/surgery
- Prognosis
- RNA, Messenger/blood
- RNA, Neoplasm/analysis
- Reverse Transcriptase Polymerase Chain Reaction
- Survival Rate
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Affiliation(s)
- Sotaro Sadahiro
- Department of Surgery, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, Japan.
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Wolfrum F, Vogel I, Fändrich F, Kalthoff H. Detection and clinical implications of minimal residual disease in gastro-intestinal cancer. Langenbecks Arch Surg 2005; 390:430-41. [PMID: 15991048 DOI: 10.1007/s00423-005-0558-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2005] [Accepted: 03/23/2005] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Metastatic dissemination is an important factor for the prognosis of patients with gastro-intestinal cancer. Exact staging is crucial to determine appropriate multimodal therapeutic strategies. At present, the sensitivity of routinely performed diagnostic techniques is suboptimal for the detection of minimal residual disease (MRD) and occult metastases since the number of disseminated tumour cells (DTCs) is mostly marginal. To amend the verification of DTCs, immunohistochemical and molecular methods were applied to retrieve epithelial cell-specific proteins in non-epithelial tissue of different body compartments or fluids. Many groups have eagerly focussed on the identification of new markers and novel tests, yet specificity and sensitivity of these methods as well as robustness in the clinical setting are frequently missing. MATERIALS AND METHODS This review critically evaluates the prognostic impact of MRD in patients with pancreatic, colorectal and gastric cancer by outlining those studies showing diagnostic results of DTC detection in lymph nodes, bone marrow, venous blood and peritoneal lavage, some of which present novel strategies. CONCLUSION The analysed data concerning MRD in gastro-intestinal cancers reveal that results are undesirably heterogeneous. From a critical point of view, many clinical studies missed their chance because of small cohort size; moreover, methodological standardisation is generally lacking. On the other hand, the very encouraging results achieved so far, together with the comprehensive analyses of a few research groups, foster the prediction that DTC/MRD issues will soon expand the standard TNM classification.
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Affiliation(s)
- Fabian Wolfrum
- Department of General and Thoracic Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 7, 24105, Kiel, Germany
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