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Galli E, Patelli G, Villa F, Gri N, Mazzarelli C, Mangoni I, Sgrazzutti C, Ghezzi S, Sartore-Bianchi A, Belli LS, De Carlis L, Vanzulli A, Siena S, Bencardino K. Circulating blood biomarkers for minimal residual disease in hepatocellular carcinoma: A systematic review. Cancer Treat Rev 2025; 135:102908. [PMID: 40058162 DOI: 10.1016/j.ctrv.2025.102908] [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: 11/09/2024] [Revised: 02/24/2025] [Accepted: 02/25/2025] [Indexed: 04/08/2025]
Abstract
BACKGROUND Relapse after radical treatment remains a major concern in hepatocellular carcinoma (HCC), affecting 50-75 % of early-stage cases within 5 years. Early recurrence prediction is a clinical unmet need. Circulating blood biomarkers could provide a minimally invasive approach to detect minimal residual disease (MRD) post-intervention. Although alpha-fetoprotein has been the primary biomarker in this setting, its MRD sensitivity is limited to 50-70 %. This systematic review aims to summarize available evidence regarding the clinical validity and potential utility of emerging circulating blood biomarkers for MRD detection in HCC patients. METHODS We searched PubMed and Embase for peer-reviewed articles and abstracts published up to 2025, and ClinicalTrials.gov for ongoing trials on circulating blood biomarkers for MRD in HCC. RESULTS A total of 91 studies (74 with results and 17 ongoing, out of 2,386) were retrieved. We evaluated various blood biomarkers, including circulating DNA (cDNA, N = 24), circulating tumor cells (CTCs, N = 20), circulating RNA (cRNA, N = 8), and other miscellaneous (N = 22) for MRD detection in HCC. These biomarkers demonstrated encouraging results, albeit with notable heterogeneity. In particular, circulating tumor DNA (ctDNA) and CTCs stand as the most robust novel approaches, with 50-80 % sensitivity and specificity up to 94 %. Nonetheless, none of the 17 ongoing studies involve biomarker-driven intervention to prove clinical utility. CONCLUSIONS Novel circulating blood biomarkers are mature for MRD detection in HCC. However, variability in methodologies and results highlights the need for further validation. We encourage the investigation of CTCs and/or ctDNA in interventional trials to assess clinical utility. This biomarker-driven approach may enhance adjuvant treatment effectiveness in MRD-positive cases while minimizing toxicity in MRD-negative patients.
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Affiliation(s)
- Edoardogregorio Galli
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giorgio Patelli
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy; IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy.
| | - Federica Villa
- Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Nicole Gri
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Chiara Mazzarelli
- Hepatology and Gastroenterology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Iacopo Mangoni
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | | | - Silvia Ghezzi
- Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Andrea Sartore-Bianchi
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Division of Clinical Research and Innovation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Luca Saverio Belli
- Hepatology and Gastroenterology Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Angelo Vanzulli
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Department of Radiology, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Salvatore Siena
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano (La Statale), Milan, Italy; Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Katia Bencardino
- Niguarda Cancer Center, Department of Hematology, Oncology and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
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Salehi M, Lavasani ZM, Keshavarz Alikhani H, Shokouhian B, Hassan M, Najimi M, Vosough M. Circulating Tumor Cells as a Promising Tool for Early Detection of Hepatocellular Carcinoma. Cells 2023; 12:2260. [PMID: 37759483 PMCID: PMC10527869 DOI: 10.3390/cells12182260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/27/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Liver cancer is a significant contributor to the cancer burden, and its incidence rates have recently increased in almost all countries. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is the second leading cause of cancer-related deaths worldwide. Because of the late diagnosis and lack of efficient therapeutic modality for advanced stages of HCC, the death rate continues to increase by ~2-3% per year. Circulating tumor cells (CTCs) are promising tools for early diagnosis, precise prognosis, and follow-up of therapeutic responses. They can be considered to be an innovative biomarker for the early detection of tumors and targeted molecular therapy. In this review, we briefly discuss the novel materials and technologies applied for the practical isolation and detection of CTCs in HCC. Also, the clinical value of CTC detection in HCC is highlighted.
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Affiliation(s)
- Mahsa Salehi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran 1665666311, Iran; (M.S.); (B.S.)
| | - Zohre Miri Lavasani
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1983969411, Iran;
| | - Hani Keshavarz Alikhani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran 1665666311, Iran; (M.S.); (B.S.)
| | - Bahare Shokouhian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran 1665666311, Iran; (M.S.); (B.S.)
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, 171 77 Stockholm, Sweden;
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, B-1200 Brussels, Belgium
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran 1665666311, Iran; (M.S.); (B.S.)
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, 171 77 Stockholm, Sweden;
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Niu ZS, Wang WH, Niu XJ. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J Gastroenterol 2022; 28:6433-6477. [PMID: 36569275 PMCID: PMC9782839 DOI: 10.3748/wjg.v28.i46.6433] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/31/2022] [Accepted: 11/21/2022] [Indexed: 12/08/2022] Open
Abstract
Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Department of Internal Medicine, Qingdao Shibei District People's Hospital, Qingdao 266033, Shandong Province, China
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Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review. Cancers (Basel) 2022; 14:cancers14143373. [PMID: 35884432 PMCID: PMC9322939 DOI: 10.3390/cancers14143373] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary One of the major problems regarding hepatocellular carcinoma (HCC) is the development of metastasis and recurrence, even in patients with an early stage. Recently, circulating tumor cells (CTCs) enumeration has been intensively studied as a diagnostic and prognostic biomarker in HCC. Nevertheless, increasing evidence suggests the role of metastasis-associated CTC phenotypes, including epithelial–mesenchymal transition (EMT)-CTCs and circulating cancer stem cells (CCSCs). We performed a systematic review to investigate the correlation of different CTC subtypes with HCC characteristics and their prognostic relevance to clinical outcomes. A preliminary meta-analysis found that CTC subtypes had prognostic power for predicting the probability of early recurrence. This study highlights the potential of CTC subtyping analysis as a biomarker for HCC management and provides information on metastasis-associated CTCs for a deeper molecular characterization of specific CTC subtypes. Abstract Circulating tumor cells (CTCs) play a key role in hematogenous metastasis and post-surgery recurrence. In hepatocellular carcinoma (HCC), CTCs have emerged as a valuable source of therapeutically relevant information. Certain subsets or phenotypes of CTCs can survive in the bloodstream and induce metastasis. Here, we performed a systematic review on the importance of epithelial–mesenchymal transition (EMT)-CTCs and circulating cancer stem cells (CCSCs) in metastatic processes and their prognostic power in HCC management. PubMed, Scopus, and Embase databases were searched for relevant publications. PRISMA criteria were used to review all studies. Twenty publications were eligible, of which 14, 5, and 1 study reported EMT-CTCs, CCSCs, and both phenotypes, respectively. Most studies evaluated that mesenchymal CTCs and CCSCs positivity were statistically associated with extensive clinicopathological features, including larger size and multiple numbers of tumors, advanced stages, micro/macrovascular invasion, and metastatic/recurrent disease. A preliminary meta-analysis showed that the presence of mesenchymal CTCs in pre- and postoperative blood significantly increased the risk of early recurrence. Mesenchymal-CTCs positivity was the most reported association with inferior outcomes based on the prognosis of HCC recurrence. Our finding could be a step forward, conveying additional prognostic values of CTC subtypes as promising biomarkers in HCC management.
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Lu S, Duplat D, Benitez-Bolivar P, León C, Villota SD, Veloz-Villavicencio E, Arévalo V, Jaenes K, Guo Y, Cicek S, Robinson L, Peidis P, Pearson JD, Woodgett J, Mazzulli T, Ponce P, Restrepo S, González JM, Bernal A, Guevara-Suarez M, Pardee K, Cevallos VE, González C, Bremner R. Multicenter international assessment of a SARS-CoV-2 RT-LAMP test for point of care clinical application. PLoS One 2022; 17:e0268340. [PMID: 35544541 PMCID: PMC9094544 DOI: 10.1371/journal.pone.0268340] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/27/2022] [Indexed: 12/19/2022] Open
Abstract
Continued waves, new variants, and limited vaccine deployment mean that SARS-CoV-2 tests remain vital to constrain the coronavirus disease 2019 (COVID-19) pandemic. Affordable, point-of-care (PoC) tests allow rapid screening in non-medical settings. Reverse-transcription loop-mediated isothermal amplification (RT-LAMP) is an appealing approach. A crucial step is to optimize testing in low/medium resource settings. Here, we optimized RT-LAMP for SARS-CoV-2 and human β-actin, and tested clinical samples in multiple countries. "TTTT" linker primers did not improve performance, and while guanidine hydrochloride, betaine and/or Igepal-CA-630 enhanced detection of synthetic RNA, only the latter two improved direct assays on nasopharygeal samples. With extracted clinical RNA, a 20 min RT-LAMP assay was essentially as sensitive as RT-PCR. With raw Canadian nasopharygeal samples, sensitivity was 100% (95% CI: 67.6% - 100%) for those with RT-qPCR Ct values ≤ 25, and 80% (95% CI: 58.4% - 91.9%) for those with 25 < Ct ≤ 27.2. Highly infectious, high titer cases were also detected in Colombian and Ecuadorian labs. We further demonstrate the utility of replacing thermocyclers with a portable PoC device (FluoroPLUM). These combined PoC molecular and hardware tools may help to limit community transmission of SARS-CoV-2.
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Affiliation(s)
- Suying Lu
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada
| | - David Duplat
- Centro de Investigaciones en Microbiología y Parasitología Tropical (CIMPAT), Department of Biological Sciences, Universidad de los Andes, Bogotá, Colombia
| | - Paula Benitez-Bolivar
- Centro de Investigaciones en Microbiología y Parasitología Tropical (CIMPAT), Department of Biological Sciences, Universidad de los Andes, Bogotá, Colombia
| | - Cielo León
- Centro de Investigaciones en Microbiología y Parasitología Tropical (CIMPAT), Department of Biological Sciences, Universidad de los Andes, Bogotá, Colombia
| | - Stephany D. Villota
- Centro de Investigación en Enfermedades Infecciosas y Vectoriales (CIREV), Instituto Nacional de Investigación en Salud Pública, Quito, Ecuador
| | - Eliana Veloz-Villavicencio
- Centro de Investigación en Enfermedades Infecciosas y Vectoriales (CIREV), Instituto Nacional de Investigación en Salud Pública, Quito, Ecuador
| | - Valentina Arévalo
- Centro de Investigación en Enfermedades Infecciosas y Vectoriales (CIREV), Instituto Nacional de Investigación en Salud Pública, Quito, Ecuador
| | - Katariina Jaenes
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
| | - Yuxiu Guo
- LSK Technologies Inc., Kitchener, Canada
| | | | | | - Philippos Peidis
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada
| | - Joel D. Pearson
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada
| | - Jim Woodgett
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Tony Mazzulli
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Microbiology, Sinai Health System/University Health Network, Toronto, Canada
| | - Patricio Ponce
- Centro de Investigación en Enfermedades Infecciosas y Vectoriales (CIREV), Instituto Nacional de Investigación en Salud Pública, Quito, Ecuador
| | - Silvia Restrepo
- Department of Food and Chemical Engineering, Universidad de los Andes, Bogotá, Colombia
| | - John M. González
- Grupo de Ciencias Básicas Médicas, School of Medicine, Universidad de los Andes, Bogotá, Colombia
| | - Adriana Bernal
- Laboratory of Molecular Interactions of Agricultural Microbes (LIMMA), Department of Biological Sciences, Universidad de Los Andes, Bogotá, Colombia
| | - Marcela Guevara-Suarez
- Applied genomics research group, Vicerrectoría de Investigación y Creación, Universidad de los Andes, Bogotá, Colombia
| | - Keith Pardee
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada
- LSK Technologies Inc., Kitchener, Canada
- Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada
| | - Varsovia E. Cevallos
- Centro de Investigación en Enfermedades Infecciosas y Vectoriales (CIREV), Instituto Nacional de Investigación en Salud Pública, Quito, Ecuador
| | - Camila González
- Centro de Investigaciones en Microbiología y Parasitología Tropical (CIMPAT), Department of Biological Sciences, Universidad de los Andes, Bogotá, Colombia
| | - Rod Bremner
- Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Sinai Health System, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada
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Mao R, Wang T, Zhao Y, Wu X, Zhang S, Cai T. Closed dumbbell mediated isothermal amplification of nucleic acids for DNA diagnostic assays. Talanta 2022; 240:123217. [PMID: 35033926 DOI: 10.1016/j.talanta.2022.123217] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/05/2021] [Accepted: 01/05/2022] [Indexed: 12/12/2022]
Abstract
Nucleic acid amplification tests have been widely applied in clinical diagnostics, food safety monitoring, and molecular biology. As a well-established isothermal amplification method, Loop-mediated isothermal amplification (LAMP) has gained recognition. However, the need for specifically designed four to six primers and non-specific amplification pose challenges for further application of LAMP based detection methods. Here, a novel isothermal amplification method, termed closed dumbbell mediated isothermal amplification (CDA) of nucleic acids, was developed. The primers are easily designed by adding two different parts of middle sequence to the canonical PCR primers at 5'-ends. CDA method was demonstrated in detecting MERS-CoV orf1a gene and H1N1 gene fragments with merits of short core primer, simple primer design process and high amplification efficiency. In addition, CDA showed excellent amplification efficacy over LAMP and competitive annealing mediated isothermal amplification (CAMP) by slight modification of primers targeting at same sequence. Furthermore, real-time and HNB based colorimetric CDA detection of Shigella were developed for practical application, both exhibited 100% success. In all, the developed CDA method with high specificity, simplicity, efficiency and rapidity has shown its great potential for point of care nucleic acids diagnostic.
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Affiliation(s)
- Rui Mao
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, 315010, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315010, China.
| | - Tianzuo Wang
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, 315010, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315010, China
| | - Yue Zhao
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, 315010, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315010, China
| | - Xinyao Wu
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, 315010, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315010, China
| | - Shun Zhang
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, 315010, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315010, China
| | - Ting Cai
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, 315010, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, 315010, China.
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