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Ye W, Dong D, Shi X. Letter to the editor on "Laparoscopic pancreatoduodenectomy is safe for the treatment of pancreatic ductal adenocarcinoma treated by chemoradiotherapy compared with open pancreatoduodenectomy: A matched case-control study". Surgery 2025; 181:109135. [PMID: 39843299 DOI: 10.1016/j.surg.2024.109135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 12/23/2024] [Indexed: 01/24/2025]
Affiliation(s)
- Wei Ye
- Department of Vascular Surgery, Suzhou Ninth People's Hospital, Soochow University, Suzhou, Jiangsu, China
| | - Da Dong
- Department of Vascular Surgery, Suzhou Ninth People's Hospital, Soochow University, Suzhou, Jiangsu, China
| | - Xiaojia Shi
- Department of Thoracic Surgery, Suzhou Ninth People's Hospital, Soochow University, Suzhou, Jiangsu, China.
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2
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Juthani R, Manne A. Blood-based biomarkers in pancreatic ductal adenocarcinoma: developments over the last decade and what holds for the future- a review. Front Oncol 2025; 15:1555963. [PMID: 40330826 PMCID: PMC12052548 DOI: 10.3389/fonc.2025.1555963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/24/2025] [Indexed: 05/08/2025] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) accounts for a significant burden of global cancer deaths worldwide. The dismal outcomes associated with PDAC can be overcome by detecting the disease early and developing tools that predict response to treatment, allowing the selection of the most optimal treatment. Over the last couple of years, significant progress has been made in the development of novel biomarkers that aid in diagnosis, prognosis, treatment selection, and monitoring response. Blood-based biomarkers offer an alternative to tissue-based diagnosis and offer immense potential in managing PDAC. In this review, we have discussed the advances in blood-based biomarkers in PDAC, such as DNA (mutations and methylations), RNA, protein biomarkers and circulating tumor cells (CTC) over the last decade and also elucidated all aspects of practical implementation of these biomarkers in clinical practice. We have also discussed implementing multiomics utilizing more than one biomarker and targeted therapies that have been developed using these biomarkers.
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Affiliation(s)
- Ronit Juthani
- Department of Medicine, Saint Vincent Hospital, Worcester, MA, United States
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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3
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Jafari SH, Lajevardi ZS, Zamani Fard MM, Jafari A, Naghavi S, Ravaei F, Taghavi SP, Mosadeghi K, Zarepour F, Mahjoubin-Tehran M, Rahimian N, Mirzaei H. Imaging Techniques and Biochemical Biomarkers: New Insights into Diagnosis of Pancreatic Cancer. Cell Biochem Biophys 2024; 82:3123-3144. [PMID: 39026059 DOI: 10.1007/s12013-024-01437-z] [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] [Accepted: 07/12/2024] [Indexed: 07/20/2024]
Abstract
Pancreatic cancer (PaC) incidence is increasing, but our current screening and diagnostic strategies are not very effective. However, screening could be helpful in the case of PaC, as recent evidence shows that the disease progresses gradually. Unfortunately, there is no ideal screening method or program for detecting PaC in its early stages. Conventional imaging techniques, such as abdominal ultrasound, CT, MRI, and EUS, have not been successful in detecting early-stage PaC. On the other hand, biomarkers may be a more effective screening tool for PaC and have greater potential for further evaluation compared to imaging. Recent studies on biomarkers and artificial intelligence (AI)-enhanced imaging have shown promising results in the early diagnosis of PaC. In addition to proteins, non-coding RNAs are also being studied as potential biomarkers for PaC. This review consolidates the current literature on PaC screening modalities to provide an organized framework for future studies. While conventional imaging techniques have not been effective in detecting early-stage PaC, biomarkers and AI-enhanced imaging are promising avenues of research. Further studies on the use of biomarkers, particularly non-coding RNAs, in combination with imaging modalities may improve the accuracy of PaC screening and lead to earlier detection of this deadly disease.
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Affiliation(s)
- Seyed Hamed Jafari
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Radiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Sadat Lajevardi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Masoud Zamani Fard
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- Chronic Respiratory Diseases Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soroush Naghavi
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ravaei
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Pouya Taghavi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Kimia Mosadeghi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Zarepour
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran; Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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4
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Patel RK, Parappilly M, Farley HC, Latour EJ, Wang LG, Nair AM, Lu ES, Sims Z, Park B, Nelson K, Mayo SC, Mills GB, Sheppard BC, Chang YH, Gibbs SL, Kardosh A, Lopez CD, Wong MH. Circulating Neoplastic-Immune Hybrid Cells Are Biomarkers of Occult Metastasis and Treatment Response in Pancreatic Cancer. Cancers (Basel) 2024; 16:3650. [PMID: 39518088 PMCID: PMC11545756 DOI: 10.3390/cancers16213650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND/OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) presents significant diagnostic and prognostic challenges, as current biomarkers frequently fail to accurately stage disease, predict rapid metastatic recurrence (rPDAC), or assess response to neoadjuvant therapy (NAT). We investigated the potential for circulating neoplastic-immune hybrid cells (CHCs) as a non-invasive, multifunctional biomarker for PDAC. METHODS Peripheral blood specimens were obtained from patients diagnosed with PDAC. CHCs were detected by co-expression of pan-cytokeratin and CD45, normalized to 50,000 peripheral blood mononuclear cells. rPDAC was defined as metastatic recurrence within six months of margin-negative pancreatectomy. Cyclic immunofluorescence (CyCIF) analyses compared hybrid phenotypes in blood and tumors. RESULTS Blood samples were collected from 42 patients with PDAC prior to resection. Those with radiographically occult metastatic disease and rPDAC had higher preoperative CHC numbers compared to patients who did not (65.0 and 74.4, vs. 11.52 CHCs; p < 0.001). Patients with complete or near-complete pathologic responses to NAT had lower preoperative CHC numbers than partial and/or non-responders (1.7 vs. 13.1 CHCs; p = 0.008). When assessed longitudinally, those with partial pathologic response saw CHC levels become undetectable while on treatment but increase in the interval between NAT completion and resection. In contrast, patients with poor responses or development of metastatic disease experienced persistent CHC detection during therapy or rising levels prior to radiographic evidence of metastases. Further, in metastatic PDAC patients, treatment-induced phenotypic changes in hybrid cells mirrored those in paired metastatic tumor samples. CONCLUSIONS CHC enumeration and phenotyping display promise as a real-time indicator of disease burden, recurrence risk, and treatment response in PDAC. CHCs have great potential as tumor-derived biomarkers to optimize therapeutic strategies and improve survival in patients with PDAC.
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Affiliation(s)
- Ranish K. Patel
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University (OHSU), Portland, OR 97239, USA; (R.K.P.)
| | - Michael Parappilly
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
| | - Hannah C. Farley
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
| | - Emile J. Latour
- Biostatistics Shared Resource, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Lei G. Wang
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
| | - Ashvin M. Nair
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
| | - Ethan S. Lu
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
| | - Zachary Sims
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
| | - Byung Park
- Biostatistics Shared Resource, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
| | - Katherine Nelson
- Gastrointestinal Clinical Trials, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Skye C. Mayo
- Department of Surgery, Division of Surgical Oncology, Oregon Health & Science University (OHSU), Portland, OR 97239, USA; (R.K.P.)
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
| | - Gordon B. Mills
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
- Division of Oncological Sciences, Knight Cancer Institute, OHSU, Portland, OR 97239, USA
| | - Brett C. Sheppard
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
- Department of Surgery, Division of General Surgery, OHSU, Portland, OR 97239, USA
| | - Young Hwan Chang
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
| | - Summer L. Gibbs
- Department of Biomedical Engineering, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
| | - Adel Kardosh
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
- Department of Medicine, Division of Medical Oncology, OHSU, Portland, OR 97239, USA
| | - Charles D. Lopez
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
- Department of Medicine, Division of Medical Oncology, OHSU, Portland, OR 97239, USA
| | - Melissa H. Wong
- Department of Cell, Developmental and Cancer Biology, OHSU, Portland, OR 97201, USA
- Knight Cancer Institute, OHSU, Portland, OR 97201, USA
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5
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Li Z, Qin C, Zhao B, Li T, Zhao Y, Zhang X, Wang W. Circulating tumor cells in pancreatic cancer: more than liquid biopsy. Ther Adv Med Oncol 2024; 16:17588359241284935. [PMID: 39421679 PMCID: PMC11483845 DOI: 10.1177/17588359241284935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/03/2024] [Indexed: 10/19/2024] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells that slough off the primary lesions and extravasate into the bloodstream. By forming CTC clusters and interacting with other circulating cells (platelets, NK cells, macrophage, etc.), CTCs are able to survive in the circulatory system of tumor patients and colonize to metastatic organs. In recent years, the potential of CTCs in diagnosis, prognostic assessment, and individualized therapy of various types of tumors has been gradually explored, while advances in biotechnology have made it possible to extract CTCs from patient blood samples. These biological features of CTCs provide us with new insights into cancer vulnerabilities. With the advent of new immunotherapies and personalized medicines, disrupting the heterotypical interaction between CTCs and circulatory cells as well as direct CTCs targeting hold great promise. Pancreatic cancer (PC) is one of the most malignant cancers, in part because of early metastasis, difficult diagnosis, and limited treatment options. Although there is significant potential for CTCs as a biomarker to impact PC from diagnosis to therapy, there still remain a number of challenges to the routine implementation of CTCs in the clinical management of PC. In this review, we summed up the progress made in understanding biological characteristics and exceptional technological advances of CTCs and provided insight into exploiting these developments to design future clinical tools for improving the diagnosis and treatment of PC.
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Affiliation(s)
- Zeru Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Cheng Qin
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bangbo Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianyu Li
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yutong Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiangyu Zhang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weibin Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Wangfujing Street Dongcheng District Beijing China, Beijing 100730, China
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6
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Habib JR, Javed AA, Wolfgang CL. The Significance of Circulating Tumor Cells in Pancreatic Cancer. Adv Surg 2024; 58:135-142. [PMID: 39089773 DOI: 10.1016/j.yasu.2024.05.001] [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] [Indexed: 08/04/2024]
Abstract
The notion that technically resectable pancreatic ductal adenocarcinoma presents as localized disease is now known to be inaccurate. Evidence supports that most patients have subclinical systemic dissemination at the time of diagnosis. It is now widely accepted that both a local and systemic component of disease coexist, each requiring treatment of improved survival and potential cure. The advent of multiagent chemotherapy regimens has resulted in a modest improvement in survival. Consequently, this article will emphasize the expanding potential and significance of circulating tumor cells in the prognostication and management of patients with pancreatic cancer.
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Affiliation(s)
- Joseph R Habib
- Department of Surgery, New York University Langone Health, 550 First Avenue, New York, NY 10016, USA
| | - Ammar A Javed
- Department of Surgery, New York University Langone Health, 550 First Avenue, New York, NY 10016, USA
| | - Christopher L Wolfgang
- Department of Surgery, New York University Langone Health, 550 First Avenue, New York, NY 10016, USA.
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7
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Teja M, Ocanto A, Couñago F. Circulating tumor cells in pancreatic cancer: The prognostic impact in surgical patients. World J Clin Oncol 2024; 15:987-991. [PMID: 39193164 PMCID: PMC11346077 DOI: 10.5306/wjco.v15.i8.987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/27/2024] [Accepted: 07/03/2024] [Indexed: 08/16/2024] Open
Abstract
Pancreatic cancer is associated with a poor prognosis, even in the early stages, mainly due to metastatic progression. New diagnostic techniques that predict unfavorable outcomes are needed in order to improve treatment strategies. Circulating tumor cells (CTCs) are showing promising results as a predictive biomarker for various tumors. In this editorial we comment on the article by Zhang et al, who published the first systematic review and meta-analysis evaluating the prognostic value of CTCs as biomarkers in early-stage pancreatic cancer patients undergoing surgery. CTCs were detected in peripheral or central venous system blood, before or during surgery. Positive CTCs showed a correlation with decreased overall survival and decreased relapse-free, disease-free and progression-free survival in this meta-analysis. However, the heterogeneity was significant. The authors suggest that this result was related to the separation methods used between studies, but other differences such as the margin status or the neoadjuvant and adjuvant treatments used are also important to consider. CTCs may be a potential prognostic biomarker in pancreatic cancer patients, but it is necessary to compare and standardize the platforms used to isolate CTCs, to compare different biomarkers from liquid biopsy and to determine the impact on prognosis when therapeutic changes are made based on CTCs levels.
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Affiliation(s)
- Macarena Teja
- Department of Radiation Oncology, GenesisCare-San Francisco de Asís University Hospital, Madrid 28002, Spain
- Department of Radiation Oncology, GenesisCare-Vithas La Milagrosa University Hospital, Madrid 28010, Spain
| | - Abrahams Ocanto
- Department of Radiation Oncology, GenesisCare-San Francisco de Asís University Hospital, Madrid 28002, Spain
- Department of Radiation Oncology, GenesisCare-Vithas La Milagrosa University Hospital, Madrid 28010, Spain
| | - Felipe Couñago
- Department of Radiation Oncology, GenesisCare-San Francisco de Asís University Hospital, Madrid 28002, Spain
- Department of Radiation Oncology, GenesisCare-Vithas La Milagrosa University Hospital, Madrid 28010, Spain
- National Director, GenesisCare Spain, Madrid 28043, Spain
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8
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Koti S, Demyan L, Deutsch G, Weiss M. Surgery for Oligometastatic Pancreatic Cancer: Defining Biologic Resectability. Ann Surg Oncol 2024; 31:4031-4041. [PMID: 38502293 PMCID: PMC11076395 DOI: 10.1245/s10434-024-15129-8] [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: 12/14/2023] [Accepted: 02/17/2024] [Indexed: 03/21/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is most often metastatic at diagnosis. As systemic therapy continues to improve alongside advanced surgical techniques, the focus has shifted toward defining biologic, rather than technical, resectability. Several centers have reported metastasectomy for oligometastatic PDAC, yet the indications and potential benefits remain unclear. In this review, we attempt to define oligometastatic disease in PDAC and to explore the rationale for metastasectomy. We evaluate the existing evidence for metastasectomy in liver, peritoneum, and lung individually, assessing the safety and oncologic outcomes for each. Furthermore, we explore contemporary biomarkers of biological resectability in oligometastatic PDAC, including radiographic findings, biochemical markers (such as CA 19-9 and CEA), inflammatory markers (including neutrophil-to-lymphocyte ratio, C-reactive protein, and scoring indices), and liquid biopsy techniques. With careful consideration of existing data, we explore the concept of biologic resectability in guiding patient selection for metastasectomy in PDAC.
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Affiliation(s)
- Shruti Koti
- Department of General Surgery, Northwell Health, Queens, NY, USA.
- Northwell Health Cancer Institute, Northwell Health, New Hyde Park, NY, USA.
| | - Lyudmyla Demyan
- Department of General Surgery, Northwell Health, Queens, NY, USA
| | - Gary Deutsch
- Northwell Health Cancer Institute, Northwell Health, New Hyde Park, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Matthew Weiss
- Northwell Health Cancer Institute, Northwell Health, New Hyde Park, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
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9
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Mondal D, Shinde S, Sinha V, Dixit V, Paul S, Gupta RK, Thakur S, Vishvakarma NK, Shukla D. Prospects of liquid biopsy in the prognosis and clinical management of gastrointestinal cancers. Front Mol Biosci 2024; 11:1385238. [PMID: 38770216 PMCID: PMC11103528 DOI: 10.3389/fmolb.2024.1385238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 04/08/2024] [Indexed: 05/22/2024] Open
Abstract
Gastrointestinal (GI) cancers account for one-fourth of the global cancer incidence and are incriminated to cause one-third of cancer-related deaths. GI cancer includes esophageal, gastric, liver, pancreatic, and colorectal cancers, mostly diagnosed at advanced stages due to a lack of accurate markers for early stages. The invasiveness of diagnostic methods like colonoscopy for solid biopsy reduces patient compliance as it cannot be frequently used to screen patients. Therefore, minimally invasive approaches like liquid biopsy may be explored for screening and early identification of gastrointestinal cancers. Liquid biopsy involves the qualitative and quantitative determination of certain cancer-specific biomarkers in body fluids such as blood, serum, saliva, and urine to predict disease progression, therapeutic tolerance, toxicities, and recurrence by evaluating minimal residual disease and its correlation with other clinical features. In this review, we deliberate upon various tumor-specific cellular and molecular entities such as circulating tumor cells (CTCs), tumor-educated platelets (TEPs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), exosomes, and exosome-derived biomolecules and cite recent advances pertaining to their use in predicting disease progression, therapy response, or risk of relapse. We also discuss the technical challenges associated with translating liquid biopsy into clinical settings for various clinical applications in gastrointestinal cancers.
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Affiliation(s)
- Deepankar Mondal
- Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
| | - Sapnita Shinde
- Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
| | - Vibha Sinha
- Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
| | - Vineeta Dixit
- Department of Botany, Sri Sadguru Jagjit Singh Namdhari College, Garhwa, Jharkhand, India
| | - Souvik Paul
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
| | - Rakesh Kumar Gupta
- Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
| | | | | | - Dhananjay Shukla
- Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India
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10
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Yakar M, Etiz D. Circulating tumor cells as prognostic marker in pancreatic cancer. World J Clin Oncol 2024; 15:165-168. [PMID: 38455127 PMCID: PMC10915936 DOI: 10.5306/wjco.v15.i2.165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 12/16/2023] [Accepted: 01/09/2024] [Indexed: 02/20/2024] Open
Abstract
In this editorial we comment on the article by Zhang et al published in the recent issue of the World Journal of Clinical Oncology. Pancreatic cancer is the fourth most common cause of cancer-related mortality and has the lowest survival rate among all solid cancers. It causes 227000 deaths annually worldwide, and the 5-year survival rate is very low due to early metastasis, which is 4.6%. Cancer survival increases with better knowledge of risk factors and early and accurate diagnosis. Circulating tumor cells (CTCs) are tumor cells that intravasate from the primary tumor or metastasis foci into the peripheral blood circulation system spontaneously or during surgical operations. Detection of CTC in blood is promising for early diagnosis. In addition, studies have associated high CTC levels with a more advanced stage, and more intensive treatments should be considered in cases with high CTC. In tumors that are considered radiologically resectable, it may be of critical importance in detecting occult metastases and preventing unnecessary surgeries.
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Affiliation(s)
- Melek Yakar
- Department of Radiation Oncology, Osmangazi University, Eskişehir 26040, Turkey
| | - Durmuş Etiz
- Department of Radiation Oncology, Eskisehir Osmangazi University Faculty of Medicine, Eskişehir 26040, Turkey
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11
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Schläpfer M, Schadde E, Braun J, Soll C, Breitenstein S, Weber M, Gutknecht S, Ganter MT, Filipovic M, Beck-Schimmer B. Effect of volatile versus total intravenous anaesthesia on circulating tumour cells after pancreatic adenocarcinoma resection: multicentre randomized clinical trial. Br J Surg 2024; 111:znad357. [PMID: 37963143 PMCID: PMC10771133 DOI: 10.1093/bjs/znad357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/08/2023] [Accepted: 06/13/2023] [Indexed: 11/16/2023]
Affiliation(s)
- Martin Schläpfer
- Institute of Anaesthesiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Institute of Physiology, University of Zurich, Zurich, Switzerland
| | - Erik Schadde
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Department of Surgery, Rush University Medical Centre, Chicago, Illinois, USA
- Department of Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland
| | - Julia Braun
- Departments of Epidemiology and Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
| | - Christopher Soll
- Department of Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland
| | - Stefan Breitenstein
- Department of Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland
| | - Markus Weber
- Department of Surgery, Triemli Hospital Zurich, Zurich, Switzerland
| | - Stefan Gutknecht
- Department of Surgery, Triemli Hospital Zurich, Zurich, Switzerland
| | - Michael T Ganter
- Institute of Anaesthesiology, Cantonal Hospital Winterthur, Winterthur, Switzerland
| | - Miodrag Filipovic
- Department for Anaesthesiology, Intensive, Rescue and Pain Medicine, Cantonal Hospital St Gallen, St Gallen, Switzerland
| | - Beatrice Beck-Schimmer
- Institute of Anaesthesiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Institute of Physiology, University of Zurich, Zurich, Switzerland
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12
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Kolbeinsson HM, Chandana S, Wright GP, Chung M. Pancreatic Cancer: A Review of Current Treatment and Novel Therapies. J INVEST SURG 2023; 36:2129884. [PMID: 36191926 DOI: 10.1080/08941939.2022.2129884] [Citation(s) in RCA: 173] [Impact Index Per Article: 86.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Pancreatic cancer is one of the leading causes for cancer-related deaths in the United States. Majority of patients present with unresectable or metastatic disease. For those that present with localized disease, a multidisciplinary approach is necessary to maximize survival and optimize outcomes. The quality and safety of surgery for pancreatic cancer have improved in recent years with increasing adoption of minimally invasive techniques and surgical adjuncts. Systemic chemotherapy has also evolved to impact survival. It is now increasingly being utilized in the neoadjuvant setting, often with concomitant radiation. Increased utilization of genomic testing in metastatic pancreatic cancer has led to better understanding of their biology, thereby allowing clinicians to consider potential targeted therapies. Similarly, targeted agents such as PARP inhibitors and immune checkpoint- inhibitors have emerged with promising results. In summary, pancreatic cancer remains a disease with poor long-term survival. However, recent developments have led to improved outcomes and have changed practice in the past decade. This review summarizes current practices in pancreatic cancer treatment and the milestones that brought us to where we are today, along with emerging therapies.
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Affiliation(s)
- Hordur Mar Kolbeinsson
- Spectrum Health General Surgery Residency, Grand Rapids, Michigan, USA.,Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA
| | - Sreenivasa Chandana
- Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA.,Cancer and Hematology Centers of Western Michigan, PC, Grand Rapids, Michigan, USA
| | - G Paul Wright
- Spectrum Health General Surgery Residency, Grand Rapids, Michigan, USA.,Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA.,Division of Surgical Oncology, Spectrum Health Medical Group, Grand Rapids, Michigan, USA
| | - Mathew Chung
- Spectrum Health General Surgery Residency, Grand Rapids, Michigan, USA.,Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA.,Division of Surgical Oncology, Spectrum Health Medical Group, Grand Rapids, Michigan, USA
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Zhang ZH, Bao YW, Zhao YJ, Wang JQ, Guo JT, Sun SY. Circulating tumor cells as potential prognostic biomarkers for early-stage pancreatic cancer: A systematic review and meta-analysis. World J Clin Oncol 2023; 14:504-517. [PMID: 38059182 PMCID: PMC10696218 DOI: 10.5306/wjco.v14.i11.504] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/14/2023] [Accepted: 10/26/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Pancreatic cancer is difficult to be diagnosed early clinically, while often leads to poor prognosis. If optimal personalized treatment plan can be provided to pancreatic cancer patient at an earlier stage, this can greatly improve overall survival (OS). Circulating tumor cells (CTCs) are a collective term for various types of tumor cells present in the peripheral blood (PB), which are formed by detachment during the development of solid tumor lesions. Most CTCs undergo apoptosis or are phagocytosed after entering the PB, whereas a few can escape and anchor at distal sites to develop metastasis, increasing the risk of death for patients with malignant tumors. AIM To investigate the significance of CTCs in predicting the prognosis of early pancreatic cancer patients. METHODS The PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine, and ChinaInfo databases were searched for articles published through December 2022. Studies were considered qualified if they included patients with early pancreatic cancer, analyzed the prognostic value of CTCs, and were full papers reported in English or Chinese. Researches were selected and assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and the Newcastle-Ottawa Scale criteria. We used a funnel plot to assess publication bias. RESULTS From 1595 publications, we identified eight eligible studies that collectively enrolled 355 patients with pancreatic cancer. Among these original studies, two were carried out in China; three in the United States; and one each in Italy, Spain, and Norway. All eight studies analyzed the relevance between CTCs and the prognosis of patients with early-stage pancreatic cancer after surgery. A meta-analysis showed that the patients that were positive pre-treatment or post-treatment for CTCs were associated with decreased OS [hazard ratio (HR) = 1.93, 95% confidence interval (CI): 1.197-3.126, P = 0.007] and decreased relapse-free/disease-free/progression-free survival (HR = 1.27, 95%CI: 1.137-1.419, P < 0.001) in early-stage pancreatic cancer. Additionally, the results suggest no statistically noticeable publication bias for overall, disease-free, progression-free, and recurrence-free survival. CONCLUSION This pooled meta-analysis shows that CTCs, as biomarkers, can afford reliable prognostic information for patients with early-stage pancreatic cancer and help develop individualized treatment plans.
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Affiliation(s)
- Zi-Han Zhang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Yi-Wen Bao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Ya-Jun Zhao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Jian-Quan Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Jin-Tao Guo
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Si-Yu Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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14
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Wang K, Wang X, Pan Q, Zhao B. Liquid biopsy techniques and pancreatic cancer: diagnosis, monitoring, and evaluation. Mol Cancer 2023; 22:167. [PMID: 37803304 PMCID: PMC10557192 DOI: 10.1186/s12943-023-01870-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/25/2023] [Indexed: 10/08/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most common malignancies. Surgical resection is a potential curative approach for PC, but most patients are unsuitable for operations when at the time of diagnosis. Even with surgery, some patients may still experience tumour metastasis during the operation or shortly after surgery, as precise prognosis evaluation is not always possible. If patients miss the opportunity for surgery and resort to chemotherapy, they may face the challenging issue of chemotherapy resistance. In recent years, liquid biopsy has shown promising prospects in disease diagnosis, treatment monitoring, and prognosis assessment. As a noninvasive detection method, liquid biopsy offers advantages over traditional diagnostic procedures, such as tissue biopsy, in terms of both cost-effectiveness and convenience. The information provided by liquid biopsy helps clinical practitioners understand the molecular mechanisms underlying tumour occurrence and development, enabling the formulation of more precise and personalized treatment decisions for each patient. This review introduces molecular biomarkers and detection methods in liquid biopsy for PC, including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), noncoding RNAs (ncRNAs), and extracellular vesicles (EVs) or exosomes. Additionally, we summarize the applications of liquid biopsy in the early diagnosis, treatment response, resistance assessment, and prognostic evaluation of PC.
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Affiliation(s)
- Kangchun Wang
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Xin Wang
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Qi Pan
- Department of Organ Transplantation and Hepatobiliary, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
| | - Bei Zhao
- Department of Ultrasound, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
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15
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Lee HS, Jung EH, Shin H, Park CS, Park SB, Jung DE, Leem G, Kim SJ, Jo JH, Chung MJ, Park JY, Bang S, Park SW, Song SY. Phenotypic characteristics of circulating tumor cells and predictive impact for efficacy of chemotherapy in patients with pancreatic cancer: a prospective study. Front Oncol 2023; 13:1206565. [PMID: 37736542 PMCID: PMC10509470 DOI: 10.3389/fonc.2023.1206565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Accepted: 08/14/2023] [Indexed: 09/23/2023] Open
Abstract
Objective Early chemoresistance and tumor mass progression are associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor cells (CTCs) have been studied as potential predictors of treatment response and prognosis in PDAC; however, this approach has yet to be applied in clinical practice. The aim of our study was to investigate the phenotypic characteristics of CTCs and determine their predictive value for PDAC progression. Methods We prospectively enrolled 40 patients who were pathologically diagnosed with PDAC and collected blood samples at diagnosis, 2 months after diagnosis, and during disease progression or recurrence. We used a microfabricated filter-based enrichment system to retrieve and analyze CTCs, which were classified using immunofluorescence staining (CD45, EpCAM, and vimentin). Results Our study included 20 women and 20 men (median age, 66 years). Overall, 45% of the patients (18/40) had disseminated disease, and 77.5% (31/40) received chemotherapy. Multivariate analysis revealed that the total CTC count and carbohydrate antigen 19-9 level at 2 months after diagnosis were associated with disease progression (P<0.05). Linear mixed model analysis revealed that the total CTC count and vimentin-positive CTCs were significantly correlated with treatment response during chemotherapy (P=0.024 and 0.017, respectively). Kaplan-Meier analysis showed that total CTC positivity at 2 months was significantly associated with poor progression-free survival (P=0.038). Conclusion Our study's findings suggest that CTCs can serve as predictive biomarkers of clinical outcomes in patients with PDAC receiving palliative chemotherapy. In particular, the total CTC count and vimentin-positive CTCs showed changes associated with the chemotherapy response.
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Affiliation(s)
- Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Hye Jung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyejung Shin
- Biostatistics Collaboration Unit, Medical Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chan Su Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Been Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dawoon E. Jung
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Galam Leem
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - So Jung Kim
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung Hyun Jo
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Moon Jae Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Youp Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Si Young Song
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
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16
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Wang Q, Šabanović B, Awada A, Reina C, Aicher A, Tang J, Heeschen C. Single-cell omics: a new perspective for early detection of pancreatic cancer? Eur J Cancer 2023; 190:112940. [PMID: 37413845 DOI: 10.1016/j.ejca.2023.112940] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 06/04/2023] [Indexed: 07/08/2023]
Abstract
Pancreatic cancer is one of the most lethal cancers, mostly due to late diagnosis and limited treatment options. Early detection of pancreatic cancer in high-risk populations bears the potential to greatly improve outcomes, but current screening approaches remain of limited value despite recent technological advances. This review explores the possible advantages of liquid biopsies for this application, particularly focusing on circulating tumour cells (CTCs) and their subsequent single-cell omics analysis. Originating from both primary and metastatic tumour sites, CTCs provide important information for diagnosis, prognosis and tailoring of treatment strategies. Notably, CTCs have even been detected in the blood of subjects with pancreatic precursor lesions, suggesting their suitability as a non-invasive tool for the early detection of malignant transformation in the pancreas. As intact cells, CTCs offer comprehensive genomic, transcriptomic, epigenetic and proteomic information that can be explored using rapidly developing techniques for analysing individual cells at the molecular level. Studying CTCs during serial sampling and at single-cell resolution will help to dissect tumour heterogeneity for individual patients and among different patients, providing new insights into cancer evolution during disease progression and in response to treatment. Using CTCs for non-invasive tracking of cancer features, including stemness, metastatic potential and expression of immune targets, provides important and readily accessible molecular insights. Finally, the emerging technology of ex vivo culturing of CTCs could create new opportunities to study the functionality of individual cancers at any stage and develop personalised and more effective treatment approaches for this lethal disease.
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Affiliation(s)
- Qi Wang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Berina Šabanović
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Azhar Awada
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy; Molecular Biotechnology Center, University of Turin (UniTO), Turin, Italy
| | - Chiara Reina
- Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy
| | - Alexandra Aicher
- Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Jiajia Tang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China; South Chongqing Road 227, Shanghai, China.
| | - Christopher Heeschen
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute FPO-IRCCS, Candiolo, Turin, Italy; South Chongqing Road 227, Shanghai, China.
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Javed AA, Ding D, Hasanain A, van Oosten F, Yu J, Cameron JL, Burkhart RA, Zheng L, He J, Wolfgang CL. Persistent Circulating Tumor Cells at 1 Year After Oncologic Resection Predict Late Recurrence in Pancreatic Cancer. Ann Surg 2023; 277:859-865. [PMID: 36111892 DOI: 10.1097/sla.0000000000005708] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The aim of the study was to assess the association between persistent circulating tumor cells (CTCs) and subsequent recurrence in patients who were clinically recurrence free ~12 months postoperatively. BACKGROUND Circulating tumor cells have been proposed as biomarkers to predict survival in pancreatic cancer. Some patients demonstrate persistent CTCs postoperatively, which could represent minimal residual disease. METHODS Patients from previously published prospective circulating tumor cell in pancreatic cancer trial without clinical evidence of recurrence 12 months postoperatively and CTC testing performed 9 to 15 months postoperatively were included. The presence of epithelial and transitional CTCs (trCTCs) was evaluated as predictor of recurrence. Kaplan-Meier curve, log-rank test, and Cox model were used for survival analysis. RESULTS Thirty-three of 129 eligible patients (circulating tumor cell in pancreatic cancer trial) were included. The trCTC-positive and negative patients were well balanced in clinicopathologic features. Patients with trCTCs had a recurrence rate per-person-month of 10.3% compared with 3.1% in trCTCs-negative patients with a median time to recurrence of 3.9 versus 27.1 months, respectively. On multivariable analysis, trCTCs positivity was associated with higher risk of late recurrence (hazard ratio: 4.7, 95% CI, 1.2-18.3, P =0.024). Fourteen (42.4%) patients recurred during the second postoperative year. One-year postoperative trCTCs positivity was associated with a higher rate of recurrence during the second year (odds ratio:13.1, 95% CI, 1.6-1953.4, P =0.028, area under curve=0.72). Integrating clinicopathologic features with trCTCs increased the area under curve to 0.80. A majority of trCTCs-positive patients (N=5, 62.5%) had multisite recurrence, followed by local-only (N=2, 25.0%) and liver-only (N=1, 12.5%) recurrence. This was in striking contrast to trCTCs-negative patients, where a majority (N=6, 66.7%) had a local-only recurrence, followed by liver-only (N=2, 22.2%) and multisite (N=1, 11.1%) recurrence. CONCLUSIONS In patients deemed to be clinically disease-free 12 months postoperatively, trCTCs positivity is associated with higher rates of subsequent recurrence with distinct patterns of recurrence. CTCs could be used a putative biomarker to guide patient prognostication and management in pancreatic cancer.
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Affiliation(s)
- Ammar A Javed
- Department of Surgery, New York University Langone Hospital, New York City, NY
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ding Ding
- Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Alina Hasanain
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Floortje van Oosten
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Surgery, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St. Antonius Hospital Nieuwegein, Utrecht University, The Netherlands
| | - Jun Yu
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - John L Cameron
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Richard A Burkhart
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Lei Zheng
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jin He
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD
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18
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Zheng S, Girgis MD, Tomlinson JS. Circulating Tumor Cells: Metastases Caught in the Act. Ann Surg 2023; 277:873-876. [PMID: 36994706 DOI: 10.1097/sla.0000000000005846] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 02/11/2023] [Indexed: 03/31/2023]
Affiliation(s)
- Serena Zheng
- Department of Surgery, University of California, Los Angeles
| | - Mark D Girgis
- Department of Surgery, University of California, Los Angeles
- Department of Surgery, Greater Los Angeles VA Medical Center, Los Angeles
| | - James S Tomlinson
- Department of Surgery, University of California, Los Angeles
- Department of Surgery, Greater Los Angeles VA Medical Center, Los Angeles
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19
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Kung H, Yu J. Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study. MedComm (Beijing) 2023; 4:e216. [PMID: 36814688 PMCID: PMC9939368 DOI: 10.1002/mco2.216] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 02/21/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with a high rate of recurrence and a dismal 5-year survival rate. Contributing to the poor prognosis of PDAC is the lack of early detection, a complex network of signaling pathways and molecular mechanisms, a dense and desmoplastic stroma, and an immunosuppressive tumor microenvironment. A recent shift toward a neoadjuvant approach to treating PDAC has been sparked by the numerous benefits neoadjuvant therapy (NAT) has to offer compared with upfront surgery. However, certain aspects of NAT against PDAC, including the optimal regimen, the use of radiotherapy, and the selection of patients that would benefit from NAT, have yet to be fully elucidated. This review describes the major signaling pathways and molecular mechanisms involved in PDAC initiation and progression in addition to the immunosuppressive tumor microenvironment of PDAC. We then review current guidelines, ongoing research, and future research directions on the use of NAT based on randomized clinical trials and other studies. Finally, the current use of and research regarding targeted therapy for PDAC are examined. This review bridges the molecular understanding of PDAC with its clinical significance, development of novel therapies, and shifting directions in treatment paradigm.
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Affiliation(s)
- Heng‐Chung Kung
- Krieger School of Arts and SciencesJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Jun Yu
- Departments of Medicine and OncologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
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20
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David P, Mittelstädt A, Kouhestani D, Anthuber A, Kahlert C, Sohn K, Weber GF. Current Applications of Liquid Biopsy in Gastrointestinal Cancer Disease-From Early Cancer Detection to Individualized Cancer Treatment. Cancers (Basel) 2023; 15:cancers15071924. [PMID: 37046585 PMCID: PMC10093361 DOI: 10.3390/cancers15071924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Worldwide, gastrointestinal (GI) cancers account for a significant amount of cancer-related mortality. Tests that allow an early diagnosis could lead to an improvement in patient survival. Liquid biopsies (LBs) due to their non-invasive nature as well as low risk are the current focus of cancer research and could be a promising tool for early cancer detection. LB involves the sampling of any biological fluid (e.g., blood, urine, saliva) to enrich and analyze the tumor's biological material. LBs can detect tumor-associated components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs). These components can reflect the status of the disease and can facilitate clinical decisions. LBs offer a unique and new way to assess cancers at all stages of treatment, from cancer screenings to prognosis to management of multidisciplinary therapies. In this review, we will provide insights into the current status of the various types of LBs enabling early detection and monitoring of GI cancers and their use in in vitro diagnostics.
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Affiliation(s)
- Paul David
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Anke Mittelstädt
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Dina Kouhestani
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Anna Anthuber
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Christoph Kahlert
- Department of Surgery, Carl Gustav Carus University Hospital, 01307 Dresden, Germany
| | - Kai Sohn
- Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, 70569 Stuttgart, Germany
| | - Georg F Weber
- Department of Surgery, University Hospital of Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany
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Asawa S, Nüesch M, Gvozdenovic A, Aceto N. Circulating tumour cells in gastrointestinal cancers: food for thought? Br J Cancer 2023; 128:1981-1990. [PMID: 36932192 DOI: 10.1038/s41416-023-02228-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/17/2023] [Accepted: 03/02/2023] [Indexed: 03/19/2023] Open
Abstract
Gastrointestinal (GI) cancers account for 35% of cancer-related deaths, predominantly due to their ability to spread and generate drug-tolerant metastases. Arising from different locations in the GI system, the majority of metastatic GI malignancies colonise the liver and the lungs. In this context, circulating tumour cells (CTCs) are playing a critical role in the formation of new metastases, and their presence in the blood of patients has been correlated with a poor outcome. In addition to their prognostic utility, prospective targeting of CTCs may represent a novel, yet ambitious strategy in the fight against metastasis. A better understanding of CTC biology, mechanistic underpinnings and weaknesses may facilitate the development of previously underappreciated anti-metastasis approaches. Here, along with related clinical studies, we outline a selection of the literature describing biological features of CTCs with an impact on their metastasis forming ability in different GI cancers.
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Affiliation(s)
- Simran Asawa
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Manuel Nüesch
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Ana Gvozdenovic
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland
| | - Nicola Aceto
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), Zurich, Switzerland.
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Sugawara T, Rodriguez Franco S, Sherman S, Kirsch MJ, Colborn K, Ishida J, Grandi S, Al-Musawi MH, Gleisner A, Schulick RD, Del Chiaro M. Association of Adjuvant Chemotherapy in Patients With Resected Pancreatic Adenocarcinoma After Multiagent Neoadjuvant Chemotherapy. JAMA Oncol 2023; 9:316-323. [PMID: 36480190 PMCID: PMC9857517 DOI: 10.1001/jamaoncol.2022.5808] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/13/2022] [Indexed: 12/13/2022]
Abstract
Importance The total number of patients with pancreatic ductal adenocarcinoma (PDAC) who receive neoadjuvant chemotherapy (NAC) is increasing. However, the added role of adjuvant chemotherapy (AC) in these patients remains unknown. Objective To evaluate the association of AC with overall survival (OS) in patients with PDAC who received multiagent NAC followed by curative-intent surgery. Design, Setting, and Participants This retrospective, matched-cohort study used data from the National Cancer Database and included patients with PDAC diagnosed between 2010 and 2018. The study included patients at least 18 years of age who received multiagent NAC followed by surgical resection and had available records of the pathological findings. Patients were excluded if they had clinical or pathological stage IV disease or died within 90 days of their operation. Exposures All included patients received NAC and underwent resection for primary PDAC. Some patients received adjuvant chemotherapy. Main Outcomes and Measures The main outcome was the OS of patients who received AC (AC group) vs those who did not (non-AC group). Interactions between pathological findings and AC were investigated in separate multivariable Cox regression models. Results In total, 1132 patients (mean [SD] age, 63.5 [9.4] years; 577 [50.1%] male; 970 [85.7%] White) were included, 640 patients in the non-AC group and 492 patients in the AC group. After being matched by propensity score according to demographic and pathological characteristics, 444 patients remained in each group. The multivariable Cox regression model adjusted for all covariates revealed an association between AC and improved survival (hazard ratio, 0.71; 95% CI, 0.59-0.85; P < .001). Subgroup interaction analysis revealed that AC was significantly associated with better OS (26.6 vs 21.2 months; P = .002), but the benefit varied by age, pathological T category, and tumor differentiation. Of note, AC was associated with better survival in patients with any pathological N category and positive margin status. Conclusions and Relevance In this cohort study, AC following multiagent NAC and resection in patients with PDAC was associated with significant survival benefit compared with that in patients who did not receive AC. These findings suggest that patients with aggressive tumors may benefit from AC to achieve prolonged survival, even after multiagent NAC and curative-intent resection.
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Affiliation(s)
- Toshitaka Sugawara
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Salvador Rodriguez Franco
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora
| | - Samantha Sherman
- Department of Surgery, Parkview Hospital Randallia, Fort Wayne, Indiana
| | - Michael J. Kirsch
- Department of Surgery, University of Colorado School of Medicine, Aurora
| | - Kathryn Colborn
- Department of Biostatistics and Informatics, University of Colorado School of Medicine, Aurora
- Surgical Outcomes and Applied Research Program, University of Colorado School of Medicine, Aurora
| | - Jun Ishida
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora
| | - Samuele Grandi
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora
| | - Mohammed H. Al-Musawi
- Clinical Trials Office, Department of Surgery, University of Colorado School of Medicine, Aurora
| | - Ana Gleisner
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora
- University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora
| | - Richard D. Schulick
- Department of Surgery, University of Colorado School of Medicine, Aurora
- University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora
| | - Marco Del Chiaro
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora
- University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora
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23
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Lin SY, Lu LK, Hsu WF, Peng WC, Tseng HW, Li CC, Chen CL, Huang GS, Lee CN, Wo AM. A Systemic Approach to Isolate, Retrieve, and Characterize Trophoblasts from the Maternal Circulation Using a Centrifugal Microfluidic Disc and a Multiple Single-Cell Retrieval Strategy. Anal Chem 2023; 95:3274-3282. [PMID: 36736312 DOI: 10.1021/acs.analchem.2c04260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Rare cells in the blood often have rich clinical significance. Although their isolation is highly desirable, this goal remains elusive due to their rarity. This paper presents a systemic approach to isolate and characterize trophoblasts from the maternal circulation. A microfluidic rare cell disc assay (RaCDA) was designed to process an extremely large volume of up to 15 mL of blood in 30 min, depleting red blood cells (RBCs) and RBC-bound white blood cells (WBC) while isolating trophoblasts in the collection chip. To minimize cell loss, on-disc labeling of cells with fluorescent immuno-staining identified the trophoblasts. Retrieval of trophoblasts utilized an optimized strategy in which multiple single cells were retrieved within the same micropipette column, with each cell encapsulated in a fluid volume (50 nL) separated by an air pocket (10 nL). Further, whole-genome amplification (WGA) amplified contents from a few retrieved cells, followed by quality control (QC) on the success of WGA via housekeeping genes. For definitive confirmation of trophoblasts, short-tandem repeat (STR) of the WGA-amplified content was compared against STR from maternal WBC and amniocytes from amniocentesis. Results showed a mean recovery rate (capture efficiency) of 91.0% for spiked cells with a WBC depletion rate of 99.91%. The retrieval efficiency of single target cells of 100% was achieved for up to four single cells retrieved per micropipette column. Comparison of STR signatures revealed that the RaCDA can retrieve trophoblasts from the maternal circulation.
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Affiliation(s)
- Shin-Yu Lin
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei 100226, Taiwan
| | - Li-Kuo Lu
- Institute of Applied Mechanics, National Taiwan University, Taipei 10617, Taiwan
| | - Wei-Fan Hsu
- Institute of Applied Mechanics, National Taiwan University, Taipei 10617, Taiwan.,Reliance Biosciences, Inc., New Taipei City 23141, Taiwan
| | - Wei-Chieh Peng
- Institute of Applied Mechanics, National Taiwan University, Taipei 10617, Taiwan.,Reliance Biosciences, Inc., New Taipei City 23141, Taiwan
| | - Hua-Wei Tseng
- Institute of Applied Mechanics, National Taiwan University, Taipei 10617, Taiwan
| | - Chih-Chi Li
- Reliance Biosciences, Inc., New Taipei City 23141, Taiwan.,Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan
| | - Chen-Lin Chen
- Institute of Applied Mechanics, National Taiwan University, Taipei 10617, Taiwan
| | - Guan-Syuan Huang
- Institute of Applied Mechanics, National Taiwan University, Taipei 10617, Taiwan.,Reliance Biosciences, Inc., New Taipei City 23141, Taiwan
| | - Chien-Nan Lee
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei 100226, Taiwan.,Department of Obstetrics and Gynecology, National Taiwan University College of Medicine, Taipei 100233, Taiwan
| | - Andrew M Wo
- Institute of Applied Mechanics, National Taiwan University, Taipei 10617, Taiwan.,Reliance Biosciences, Inc., New Taipei City 23141, Taiwan
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24
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Nishiwada S, Cui Y, Sho M, Jun E, Akahori T, Nakamura K, Sonohara F, Yamada S, Fujii T, Han IW, Tsai S, Kodera Y, Park JO, Von Hoff D, Kim SC, Li W, Goel A. Transcriptomic Profiling Identifies an Exosomal microRNA Signature for Predicting Recurrence Following Surgery in Patients With Pancreatic Ductal Adenocarcinoma. Ann Surg 2022; 276:e876-e885. [PMID: 34132691 PMCID: PMC8674379 DOI: 10.1097/sla.0000000000004993] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE We performed genome-wide expression profiling to develop an exosomal miRNA panel for predicting recurrence following surgery in patients with PDAC. SUMMARY OF BACKGROUND DATA Pretreatment risk stratification is essential for offering individualized treatments to patients with PDAC, but predicting recurrence following surgery remains clinically challenging. METHODS We analyzed 210 plasma and serum specimens from 4 cohorts of PDAC patients. Using a discovery cohort (n = 25), we performed genome-wide sequencing to identify candidate exosomal miRNAs (exo-miRNAs). Subsequently, we trained and validated the predictive performance of the exo-miRNAs in two clinical cohorts (training cohort: n = 82, validation cohort: n = 57) without neoadjuvant therapy (NAT), followed by a post-NAT clinical cohort (n = 46) as additional validation. RESULTS We performed exo-miRNA expression profiling in plasma specimens obtained before any treatment in a discovery cohort. Subsequently we optimized and trained a 6-exo-miRNA risk-prediction model, which robustly discriminated patients with recurrence [area under the curve (AUC): 0.81, 95% confidence interval (CI): 0.70-0.89] and relapse-free survival (RFS, P < 0.01) in the training cohort. The identified exo-miRNA panel was successfully validated in an independent validation cohort (AUC: 0.78, 95% CI: 0.65- 0.88, RFS: P < 0.01), where it exhibited comparable performance in the post-NAT cohort (AUC: 0.72, 95% CI: 0.57-0.85, RFS: P < 0.01) and emerged as an independent predictor for RFS (hazard ratio: 2.84, 95% CI: 1.30-6.20). CONCLUSIONS We identified a novel, noninvasive exo-miRNA signature that robustly predicts recurrence following surgery in patients with PDAC; highlighting its potential clinical impact for optimized patient selection and improved individualized treatment strategies.
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Affiliation(s)
- Satoshi Nishiwada
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Department of Surgery, Nara Medical University, Nara, Japan
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Ya Cui
- Department of Biological Chemistry, University of California, Irvine, CA, USA
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, Nara, Japan
| | - Eunsung Jun
- Department of Convergence Medicine and Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Institute for Life Sciences, AMIST, Asan Medical Center, Seoul, Korea
| | | | - Kota Nakamura
- Department of Surgery, Nara Medical University, Nara, Japan
| | - Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsutomu Fujii
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - In Woong Han
- Division of Hepato-Biliary Pancreatic Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Susan Tsai
- Pancreatic Cancer Program, Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - Song Cheol Kim
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Biomedical Engineering Research Center, AMIST, Asan Medical Center, Seoul, Korea
| | - Wei Li
- Department of Biological Chemistry, University of California, Irvine, CA, USA
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
- Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
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25
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Mechanism of selective induction of apoptosis of HCT116 tumor cells in circulating blood by riboflavin photochemistry. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B: BIOLOGY 2022; 237:112588. [DOI: 10.1016/j.jphotobiol.2022.112588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 10/14/2022] [Accepted: 10/18/2022] [Indexed: 11/28/2022]
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26
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Epithelial to Mesenchymal Transition as Mechanism of Progression of Pancreatic Cancer: From Mice to Men. Cancers (Basel) 2022; 14:cancers14235797. [PMID: 36497278 PMCID: PMC9735867 DOI: 10.3390/cancers14235797] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 11/26/2022] Open
Abstract
Owed to its aggressive yet subtle nature, pancreatic cancer remains unnoticed till an advanced stage so that in most cases the diagnosis is made when the cancer has already spread to other organs with deadly efficiency. The progression from primary tumor to metastasis involves an intricate cascade of events comprising the pleiotropic process of epithelial to mesenchymal transition (EMT) facilitating cancer spread. The elucidation of this pivotal phenotypic change in cancer cell morphology, initially heretic, moved from basic studies dissecting the progression of pancreatic cancer in animal models to move towards human disease, although no clinical translation of the concept emerged yet. Despite this transition, a full-blown mesenchymal phenotype may not be accomplished; rather, the plasticity of the program and its dependency on heterotopic signals implies a series of fluctuating modifications of cancer cells encompassing mesenchymal and epithelial features. Despite the evidence supporting the activation of EMT and MET during cancer progression, our understanding of the relationship between tumor microenvironment and EMT is not yet mature for a clinical application. In this review, we attempt to resume the knowledge on EMT and pancreatic cancer, aiming to include the EMT among the hallmarks of cancer that could potentially modify our clinical thinking with the purpose of filling the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers, as well as their application for prognostic and predictive purposes.
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27
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Smolkova B, Kataki A, Earl J, Ruz-Caracuel I, Cihova M, Urbanova M, Buocikova V, Tamargo S, Rovite V, Niedra H, Schrader J, Kohl Y. Liquid biopsy and preclinical tools for advancing diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms. Crit Rev Oncol Hematol 2022; 180:103865. [PMID: 36334880 DOI: 10.1016/j.critrevonc.2022.103865] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
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28
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Cheng H, Yang J, Fu X, Mao L, Chu X, Lu C, Li G, Qiu Y, He W. Folate receptor-positive circulating tumor cells predict survival and recurrence patterns in patients undergoing resection for pancreatic cancer. Front Oncol 2022; 12:1012609. [PMID: 36313690 PMCID: PMC9606765 DOI: 10.3389/fonc.2022.1012609] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/26/2022] [Indexed: 12/03/2022] Open
Abstract
Objective To evaluate the prognostic impact of folate receptor (FR)-positive circulating tumor cells (FR+ CTCs) for patients with pancreatic cancer (PC). Background Risk stratification before surgery for PC patients remains challenging as there are no reliable prognostic markers currently. FR+ CTCs, detected by ligand-targeted polymerase chain reaction (LT-PCR), have shown excellent diagnostic value for PC in our previous study and prognostic value in a variety of cancer types. Methods Peripheral blood samples from 44 consecutive patients diagnosed with PC were analyzed for FR+ CTCs. 25 patients underwent tumor resection and were assigned to the surgical group. 19 patients failed to undergo radical resection because of local advance or distant metastasis and were assigned to the non-surgical group. The impact of CTCs on relapse and survival were explored. Results For the prognostic stratification, the optimal cut-off value of CTCs analyzed by receiver operating characteristic (ROC) curve was 14.49 folate units (FU)/3 ml. High CTC levels (> 14.49 FU/3 ml) were detected in 52.0% (13/25) of the patients in the surgical group and 63.2% (12/19) in the non-surgical group. In the surgical group, median disease-free survival (DFS) for patients with high CTC levels versus low CTC levels (< 14.49 FU/3 ml) was 8.0 versus 26.0 months (P = 0.008). In multivariable analysis, CTCs were an independent risk factor for DFS (HR: 4.589, P = 0.012). Concerning the recurrence patterns, patients with high CTC levels showed a significantly frequent rate of distant and early recurrence (P = 0.017 and P = 0.011). CTC levels remained an independent predictor for both distant (OR: 8.375, P = 0.014) and early recurrence (OR: 8.412, P = 0.013) confirmed by multivariable logistic regression. However, CTCs did not predict survival in the non-surgical group (P = 0.220). Conclusion FR+ CTCs in resected PC patients could predict impaired survival and recurrence patterns after surgery. Preoperative CTC levels detected by LT-PCR may help guide treatment strategies and further studies in a larger cohort are warranted.
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Affiliation(s)
- Hao Cheng
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jun Yang
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xu Fu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Liang Mao
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xuehui Chu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chenglin Lu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Gang Li
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yudong Qiu
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Yudong Qiu, ; Wei He,
| | - Wei He
- Institute of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Yudong Qiu, ; Wei He,
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Andersson R, Haglund C, Seppänen H, Ansari D. Pancreatic cancer - the past, the present, and the future. Scand J Gastroenterol 2022; 57:1169-1177. [PMID: 35477331 DOI: 10.1080/00365521.2022.2067786] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Pancreatic cancer has been and still is associated with a very poor prognosis. This is due to a lack of major breakthroughs with respect to early diagnosis, prognostication, prediction, as well as novel, targeted therapies. The benefits of surgery and chemotherapy are evident, but the fact that only some 10% of all patients have early, localized disease highlights the unmet need for new early detection methods. An improved understanding of tumor biology and the development of molecular markers detectable both in the circulation and in cancer tissues may underlie the development of new tools for optimizing both diagnosis and treatment. MATERIAL AND METHODS Review of the literature. RESULTS AND CONCLUSION If we do not improve precision oncology for pancreatic ductal adenocarcinoma, the prognosis will still remain dismal and the" burden" on society will increase substantially.
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Affiliation(s)
- Roland Andersson
- Surgery, Department of Clinical Sciences Lund Lund University, Skåne University Hospital, Lund, Sweden
| | - Caj Haglund
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hanna Seppänen
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Daniel Ansari
- Surgery, Department of Clinical Sciences Lund Lund University, Skåne University Hospital, Lund, Sweden
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30
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Sutton TL, Patel RK, Anderson AN, Bowden SG, Whalen R, Giske NR, Wong MH. Circulating Cells with Macrophage-like Characteristics in Cancer: The Importance of Circulating Neoplastic-Immune Hybrid Cells in Cancer. Cancers (Basel) 2022; 14:cancers14163871. [PMID: 36010865 PMCID: PMC9405966 DOI: 10.3390/cancers14163871] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary In cancer, disseminated neoplastic cells circulating in blood are a source of tumor DNA, RNA, and protein, which can be harnessed to diagnose, monitor, and better understand the biology of the tumor from which they are derived. Historically, circulating tumor cells (CTCs) have dominated this field of study. While CTCs are shed directly into circulation from a primary tumor, they remain relatively rare, particularly in early stages of disease, and thus are difficult to utilize as a reliable cancer biomarker. Neoplastic-immune hybrid cells represent a novel subpopulation of circulating cells that are more reliably attainable as compared to their CTC counterparts. Here, we review two recently identified circulating cell populations in cancer—cancer-associated macrophage-like cells and circulating hybrid cells—and discuss the future impact for the exciting area of disseminated hybrid cells. Abstract Cancer remains a significant cause of mortality in developed countries, due in part to difficulties in early detection, understanding disease biology, and assessing treatment response. If effectively harnessed, circulating biomarkers promise to fulfill these needs through non-invasive “liquid” biopsy. While tumors disseminate genetic material and cellular debris into circulation, identifying clinically relevant information from these analytes has proven difficult. In contrast, cell-based circulating biomarkers have multiple advantages, including a source for tumor DNA and protein, and as a cellular reflection of the evolving tumor. While circulating tumor cells (CTCs) have dominated the circulating cell biomarker field, their clinical utility beyond that of prognostication has remained elusive, due to their rarity. Recently, two novel populations of circulating tumor-immune hybrid cells in cancer have been characterized: cancer-associated macrophage-like cells (CAMLs) and circulating hybrid cells (CHCs). CAMLs are macrophage-like cells containing phagocytosed tumor material, while CHCs can result from cell fusion between cancer and immune cells and play a role in the metastatic cascade. Both are detected in higher numbers than CTCs in peripheral blood and demonstrate utility in prognostication and assessing treatment response. Additionally, both cell populations are heterogeneous in their genetic, transcriptomic, and proteomic signatures, and thus have the potential to inform on heterogeneity within tumors. Herein, we review the advances in this exciting field.
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Affiliation(s)
- Thomas L. Sutton
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Ranish K. Patel
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Ashley N. Anderson
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Stephen G. Bowden
- Department of Neurological Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Riley Whalen
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Nicole R. Giske
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Melissa H. Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
- Correspondence: ; Tel.: +1-503-494-8749; Fax: +1-503-494-4253
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31
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Luo K, Wang X, Zhang X, Liu Z, Huang S, Li R. The Value of Circulating Tumor Cells in the Prognosis and Treatment of Pancreatic Cancer. Front Oncol 2022; 12:933645. [PMID: 35860591 PMCID: PMC9293050 DOI: 10.3389/fonc.2022.933645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 05/31/2022] [Indexed: 12/21/2022] Open
Abstract
In the past few decades, tumor diagnosis and treatment theory have developed in a variety of directions. The number of people dying from pancreatic cancer increases while the mortality rate of other common tumors decreases. Traditional imaging methods show the boundaries of pancreatic tumor, but they are not sufficient to judge early micrometastasis. Although carcinoembryonic antigen (CEA) and carbohydrate antigen19-9 (CA19-9) have the obvious advantages of simplicity and minimal invasiveness, these biomarkers obviously lack sensitivity and specificity. Circulating tumor cells (CTCs) have attracted attention as a non-invasive, dynamic, and real-time liquid biopsy technique for analyzing tumor characteristics. With the continuous development of new CTCs enrichment technologies, substantial progress has been made in the basic research of CTCs clinical application prospects. In many metastatic cancers, CTCs have been studied as an independent prognostic factor. This article reviews the research progress of CTCs in the treatment and prognosis of pancreatic cancer.
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Chen J, Wang H, Zhou L, Liu Z, Tan X. A combination of circulating tumor cells and CA199 improves the diagnosis of pancreatic cancer. J Clin Lab Anal 2022; 36:e24341. [PMID: 35334495 PMCID: PMC9102772 DOI: 10.1002/jcla.24341] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/29/2022] [Accepted: 02/27/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to the lack of effective screening tests. CA199, the standard biomarker for PDAC management, is not sufficiently reliable for early diagnosis. This prospective study aimed to evaluate whether circulating tumor cells (CTCs) could complement or perform better than CA199 in determining PDAC. METHODS A total of 168 blood samples were collected from 80 patients with PDAC, 32 patients with acute pancreatitis, 22 patients with benign pancreatic masses, and 34 healthy donors. CTCs were detected by a novel system combining negative enrichment with immunostaining and fluorescence in situ hybridization (NE-imFISH). Next, ROC curves and AUC analyses were conducted to assess diagnostic abilities of CA199, CTCs, and the combination of the two biomarkers in PDAC. RESULTS CTCs were stained as CD45-/DAPI+/CEP8 ≥3. With 2 CTCs/3.2 ml as the cut-off value, the sensitivity/specificity of the CTC number was 0.76/0.94, which was comparable to that of CA199 (0.78/0.83; Delong test p = 0.3360). Improved performance was achieved through a logistic regression model integrating CA199 and CTC number (AUCCTC+CA199 = 0.95, AUCCA199 = 0.80, AUCCTC number = 0.85; Delong test p vs . CA199 < 0.0001 and p vs . CTC number = 0.0002). CTC subtype was inferior to CTC number as a diagnostic marker (AUCCTC subtype = 0.73; Delong test p vs . CTC number < 0.0001). CONCLUSION The dual-marker panel consisting of CA199 and CTC number can significantly improve upon the diagnostic performance of CA199 alone, highlighting the promising clinical utilization as an effective strategy for PDAC surveillance.
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Affiliation(s)
- Junliang Chen
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Huaitao Wang
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Lei Zhou
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Zhihao Liu
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
| | - Xiaodong Tan
- Department of General SurgeryShengjing Hospital of China Medical UniversityShenyangChina
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Dopico PJ, Le MCN, Burgess B, Yang Z, Zhao Y, Wang Y, George TJ, Fan ZH. Longitudinal Study of Circulating Biomarkers in Patients with Resectable Pancreatic Ductal Adenocarcinoma. BIOSENSORS 2022; 12:206. [PMID: 35448266 PMCID: PMC9028387 DOI: 10.3390/bios12040206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/23/2022] [Accepted: 03/28/2022] [Indexed: 05/12/2023]
Abstract
While patients with resectable pancreatic ductal adenocarcinoma (PDAC) show improved survival compared to their non-resectable counterparts, survival remains low owing to occult metastatic disease and treatment resistance. Liquid biopsy based on circulating tumor cells (CTCs) and cell-free DNA (cfDNA) has been shown to predict recurrence and treatment resistance in various types of cancers, but their utility has not been fully demonstrated in resectable PDAC. We have simultaneously tracked three circulating biomarkers, including CTCs, cfDNA, and circulating tumor DNA (ctDNA), over a period of cancer treatment using a microfluidic device and droplet digital PCR (ddPCR). The microfluidic device is based on the combination of filtration and immunoaffinity mechanisms. We have measured CTCs, cfDNA, and ctDNA in a cohort of seven resectable PDAC patients undergoing neoadjuvant therapy followed by surgery, and each patient was followed up to 10 time points over a period of 4 months. CTCs were detectable in all patients (100%) at some point during treatment but were detectable in only three out of six patients (50%) prior to the start of treatment. Median cfDNA concentrations remained comparable to negative controls throughout treatment. ddPCR was able to find KRAS mutations in six of seven patients (86%); however, these mutations were present in only two of seven patients (29%) prior to treatment. Overall, the majority of circulating biomarkers (81% for CTCs and 91% for cfDNA/ctDNA) were detected after the start of neoadjuvant therapy but before surgery. This study suggests that a longitudinal study of circulating biomarkers throughout treatment provides more useful information than those single time-point tests for resectable PDAC patients.
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Affiliation(s)
- Pablo J. Dopico
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL 32611, USA; (P.J.D.); (M.-C.N.L.)
| | - Minh-Chau N. Le
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL 32611, USA; (P.J.D.); (M.-C.N.L.)
| | - Benjamin Burgess
- UF Health Cancer Center, University of Florida, 2033 Mowry Rd., Gainesville, FL 32610, USA;
| | - Zhijie Yang
- Atila Biosystems, 740 Sierra Vista Ave., Unit E, Mountain View, CA 94043, USA; (Z.Y.); (Y.Z.); (Y.W.)
| | - Yu Zhao
- Atila Biosystems, 740 Sierra Vista Ave., Unit E, Mountain View, CA 94043, USA; (Z.Y.); (Y.Z.); (Y.W.)
| | - Youxiang Wang
- Atila Biosystems, 740 Sierra Vista Ave., Unit E, Mountain View, CA 94043, USA; (Z.Y.); (Y.Z.); (Y.W.)
| | - Thomas J. George
- UF Health Cancer Center, University of Florida, 2033 Mowry Rd., Gainesville, FL 32610, USA;
- Department of Medicine, University of Florida, 1600 SW Archer Rd., Gainesville, FL 32610, USA
| | - Z. Hugh Fan
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL 32611, USA; (P.J.D.); (M.-C.N.L.)
- UF Health Cancer Center, University of Florida, 2033 Mowry Rd., Gainesville, FL 32610, USA;
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
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Zeng CDD, Jin CC, Gao C, Xiao AT, Tong YX, Zhang S. Preoperative Folate Receptor-Positive Circulating Tumor Cells Are Associated With Occult Peritoneal Metastasis and Early Recurrence in Gastric Cancer Patients: A Prospective Cohort Study. Front Oncol 2022; 12:769203. [PMID: 35425708 PMCID: PMC9002093 DOI: 10.3389/fonc.2022.769203] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 02/21/2022] [Indexed: 12/27/2022] Open
Abstract
Background The aim of this study is to explore the clinical feasibility of detecting folate receptor-positive circulating tumor cells (FR+ CTCs) for predicting peritoneal metastasis and short-term outcome in gastric cancer patients. Methods This is a prospective, single-center, observational study. We applied ligand-targeted enzyme-linked polymerization method to detect preoperative FR+ CTC levels in peripheral blood. We evaluated the diagnostic value of FR+ CTCs and other biomarkers in predicting peritoneal metastasis. Prognostic factors for recurrence-free survival (RFS) were investigated in univariate and multivariate analyses. Results A total of 132 patients with gastric cancer and 9 patients with benign disease were recruited. Gastric cancer patients had a significantly higher CTC level compared to that of patients with benign disease (p < 0.01). Combined model including CTC level and other biomarkers presented high sensitivity (100%) and moderate specificity (59.3%) in predicting peritoneal metastasis. Univariate analysis revealed that decreased serum prealbumin, decreased peripheral lymphocyte count, FR+ CTCs, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and lymph node metastasis were significantly associated with shorter RFS. FR+ CTC level [≥12.6 folate units (FU)/3 ml, hazard ratio (HR) = 6.957, p = 0.005] and CA19-9 (>34 ng/ml, HR = 3.855, p = 0.037) were independent prognostic factors in multivariate analysis. Conclusions Our findings for the first time suggested the diagnostic value of preoperative CTC levels in predicting peritoneal metastasis in gastric cancer. Moreover, the FR+ CTC level could be a novel and promising prognostic factor for the recurrence of gastric cancer in patients who underwent surgery. Clinical Trial Registration Chinese Clinic Trial Registry, identifier ChiCTR2100050514.
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Affiliation(s)
| | | | | | | | | | - Sheng Zhang
- Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Sun N, Yang Y, Miao H, Redublo P, Liu H, Liu W, Huang YW, Teng PC, Zhang C, Zhang RY, Smalley M, Yang P, Chou SJ, Huai K, Zhang Z, Lee YT, Wang JJ, Wang J, Liang IY, Zhang TX, Zhang D, Liang L, Weiss PS, Posadas EM, Donahue T, Hecht JR, Allen-Auerbach MS, Bergsland EK, Hope TA, Pei R, Zhu Y, Tseng HR, Heaney AP. Discovery and characterization of circulating tumor cell clusters in neuroendocrine tumor patients using nanosubstrate-embedded microchips. Biosens Bioelectron 2022; 199:113854. [PMID: 34896918 PMCID: PMC8900541 DOI: 10.1016/j.bios.2021.113854] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 10/25/2021] [Accepted: 11/27/2021] [Indexed: 01/19/2023]
Abstract
Circulating tumor cell (CTC) clusters are present in cancer patients with severe metastasis, resulting in poor clinical outcomes. However, CTC clusters have not been studied as extensively as single CTCs, and the clinical utility of CTC clusters remains largely unknown. In this study, we aim sought to explore the feasibility of NanoVelcro Chips to simultaneously detect both single CTCs and CTC clusters with negligible perturbation to their intrinsic properties in neuroendocrine tumors (NETs). We discovered frequent CTC clusters in patients with advanced NETs and examined their potential roles, together with single NET CTCs, as novel biomarkers of patient response following peptide receptor radionuclide therapy (PRRT). We observed dynamic changes in both total NET CTCs and NET CTC cluster counts in NET patients undergoing PRRT which correlated with clinical outcome. These preliminary findings suggest that CTC clusters, along with single CTCs, offer a potential non-invasive option to monitor the treatment response in NET patients undergoing PRRT.
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Affiliation(s)
- Na Sun
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States; Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Suzhou, 215123, PR China
| | - Yingying Yang
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States; Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, PR China
| | - Hui Miao
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States; Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, PR China
| | - Peter Redublo
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Hongtao Liu
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Wenfei Liu
- Department of Chemistry and Biochemistry, Department of Bioengineering, Department of Materials Science and Engineering, California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, 90095, United States
| | - Yen-Wen Huang
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Pai-Chi Teng
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, United States
| | - Ceng Zhang
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States; Department of Pathology, Southern Medical University, Guangzhou, 510515, Guangdong Province, PR China
| | - Ryan Y Zhang
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Matthew Smalley
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Peng Yang
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Shih-Jie Chou
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Kevin Huai
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Zhicheng Zhang
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Yi-Te Lee
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Jasmine J Wang
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, United States
| | - Jing Wang
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Icy Y Liang
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Tiffany X Zhang
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Dongyun Zhang
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Li Liang
- Department of Pathology, Southern Medical University, Guangzhou, 510515, Guangdong Province, PR China
| | - Paul S Weiss
- Department of Chemistry and Biochemistry, Department of Bioengineering, Department of Materials Science and Engineering, California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA, 90095, United States
| | - Edwin M Posadas
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, United States
| | - Timothy Donahue
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - J Randolph Hecht
- Department of Medicine, Division of Hematology Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Martin S Allen-Auerbach
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States
| | - Emily K Bergsland
- Department of Clinical Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94158, United States
| | - Thomas A Hope
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, 94158, United States
| | - Renjun Pei
- Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Suzhou, 215123, PR China.
| | - Yazhen Zhu
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States.
| | - Hsian-Rong Tseng
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States.
| | - Anthony P Heaney
- Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, United States.
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Xing Y, Zhang X, Qin F, Yang J, Ai L, Wang Q, Zhai Y. The clinical significance of circulating tumor cells and T lymphocyte subtypes in pancreatic cancer patients. Bioengineered 2022; 13:2130-2138. [PMID: 35034581 PMCID: PMC8973992 DOI: 10.1080/21655979.2021.2023800] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Circulating tumor cells (CTCs) are sensitive and reliable biomarkers for tracing relapsed and metastatic cancer. Here, we explore the clinical significance of CTCs and T lymphocyte subtypes in patients with pancreatic cancer. A total of 106 patients with the pancreatic cancer were enrolled in this study. The enrichment and identification of CTCs were achieved before treatment by a PatrolCTC detection technique. Flow cytometry (FACS) was used to characterize CD4, CD8, natural killer (NK) cells, and Tregulatory (Treg) lymphocyte subtypes. Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-17A (IL-17A), Interleukin-10 (IL-10), and Interferon γ (IFN-γ) were measured by meso-scale discovery (MSD) assay. Among these patients, 44 (41.5%) patients with pancreatic ductal adenocarcinoma (PDAC) were female and 62 (58.5%) cases were male. Case numbers with II-IV tumor-node-metastasis (TNM) stages were 32 (30.2%), 50 (47.2%), and 24 (22.6%), respectively. The positive rate of CTCs before surgery was 37.5% (12/32), 88.0% (44/50) and 100% (24/24) in stage II, III, and IV patients, respectively. Total CTCs, mixed CTCs, and mesenchymal CTCs (MCTCs) were strongly relevant to shorter progression-free survival (PFS) of the patients. In addition, total CTCs (≥6) and positive MCTCs were also significantly correlated with recurrence and metastasis. The patients with high CTCs also had low levels of CD4, CD4/CD8 ratio, NK cells, IL-2, and IFNγ. In contrast, Treg cells had significant elevation in PDAC patients. These results indicated that CTCs number in PDAC patients was an independent indicator for worse PFS. High CTCs also had strong correlation with weak cellular immunity functions.
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Affiliation(s)
- Yasi Xing
- Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Xinfa Zhang
- General Surgery, Shandong Provincial Coal Taishan Sanatorium, Taian, Shandong, China
| | - Fangyuan Qin
- Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Jingwen Yang
- Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Lei Ai
- Department of Clinical Laboratory, Shandong Provincial Coal Taishan Sanitarium, Taian, Shandong, China
| | - Qingsong Wang
- General Surgery, Shandong Provincial Coal Taishan Sanatorium, Taian, Shandong, China
| | - Yaping Zhai
- Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
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Exploring the Clinical Utility of Pancreatic Cancer Circulating Tumor Cells. Int J Mol Sci 2022; 23:ijms23031671. [PMID: 35163592 PMCID: PMC8836025 DOI: 10.3390/ijms23031671] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 01/27/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type, characterized by a dismal prognosis due to late diagnosis, frequent metastases, and limited therapeutic response to standard chemotherapy. Circulating tumor cells (CTCs) are a rare subset of tumor cells found in the blood of cancer patients. CTCs has the potential utility for screening, early and definitive diagnosis, prognostic and predictive assessment, and offers the potential for personalized management. However, a gold-standard CTC detection and enrichment method remains elusive, hindering comprehensive comparisons between studies. In this review, we summarize data regarding the utility of CTCs at different stages of PDAC from early to metastatic disease and discuss the molecular profiling and culture of CTCs. The characterization of CTCs brings us closer to defining the specific CTC subpopulation responsible for metastasis with the potential to uncover new therapies and more effective management options for PDAC.
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Schreyer D, Neoptolemos JP, Barry ST, Bailey P. Deconstructing Pancreatic Cancer Using Next Generation-Omic Technologies-From Discovery to Knowledge-Guided Platforms for Better Patient Management. Front Cell Dev Biol 2022; 9:795735. [PMID: 35096825 PMCID: PMC8793685 DOI: 10.3389/fcell.2021.795735] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Comprehensive molecular landscaping studies reveal a potentially brighter future for pancreatic ductal adenocarcinoma (PDAC) patients. Blood-borne biomarkers obtained from minimally invasive "liquid biopsies" are now being trialled for early disease detection and to track responses to therapy. Integrated genomic and transcriptomic studies using resectable tumour material have defined intrinsic patient subtypes and actionable genomic segments that promise a shift towards genome-guided patient management. Multimodal mapping of PDAC using spatially resolved single cell transcriptomics and imaging techniques has identified new potentially therapeutically actionable cellular targets and is providing new insights into PDAC tumour heterogeneity. Despite these rapid advances, defining biomarkers for patient selection remain limited. This review examines the current PDAC cancer biomarker ecosystem (identified in tumour and blood) and explores how advances in single cell sequencing and spatially resolved imaging modalities are being used to uncover new targets for therapeutic intervention and are transforming our understanding of this difficult to treat disease.
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Affiliation(s)
- Daniel Schreyer
- Institute of Cancer Sciences, University of Glasgow, Scotland, United Kingdom
| | - John P. Neoptolemos
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Simon T. Barry
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Peter Bailey
- Institute of Cancer Sciences, University of Glasgow, Scotland, United Kingdom
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Section Surgical Research, University Clinic Heidelberg, Heidelberg, Germany
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Lin D, Shen L, Luo M, Zhang K, Li J, Yang Q, Zhu F, Zhou D, Zheng S, Chen Y, Zhou J. Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther 2021; 6:404. [PMID: 34803167 PMCID: PMC8606574 DOI: 10.1038/s41392-021-00817-8] [Citation(s) in RCA: 472] [Impact Index Per Article: 118.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/06/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.
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Affiliation(s)
- Danfeng Lin
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Breast Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lesang Shen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Meng Luo
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kun Zhang
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinfan Li
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Yang
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fangfang Zhu
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dan Zhou
- Department of Surgery, Traditional Chinese Medical Hospital of Zhuji, Shaoxing, China
| | - Shu Zheng
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiding Chen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jiaojiao Zhou
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Perales S, Torres C, Jimenez-Luna C, Prados J, Martinez-Galan J, Sanchez-Manas JM, Caba O. Liquid biopsy approach to pancreatic cancer. World J Gastrointest Oncol 2021; 13:1263-1287. [PMID: 34721766 PMCID: PMC8529923 DOI: 10.4251/wjgo.v13.i10.1263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/18/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to pose a major clinical challenge. There has been little improvement in patient survival over the past few decades, and it is projected to become the second leading cause of cancer mortality by 2030. The dismal 5-year survival rate of less than 10% after the diagnosis is attributable to the lack of early symptoms, the absence of specific biomarkers for an early diagnosis, and the inadequacy of available chemotherapies. Most patients are diagnosed when the disease has already metastasized and cannot be treated. Cancer interception is vital, actively intervening in the malignization process before the development of a full-blown advanced tumor. An early diagnosis of PC has a dramatic impact on the survival of patients, and improved techniques are urgently needed to detect and evaluate this disease at an early stage. It is difficult to obtain tissue biopsies from the pancreas due to its anatomical position; however, liquid biopsies are readily available and can provide useful information for the diagnosis, prognosis, stratification, and follow-up of patients with PC and for the design of individually tailored treatments. The aim of this review was to provide an update of the latest advances in knowledge on the application of carbohydrates, proteins, cell-free nucleic acids, circulating tumor cells, metabolome compounds, exosomes, and platelets in blood as potential biomarkers for PC, focusing on their clinical relevance and potential for improving patient outcomes.
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Affiliation(s)
- Sonia Perales
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Carolina Torres
- Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Joaquina Martinez-Galan
- Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, Granada 18011, Spain
| | | | - Octavio Caba
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
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Li LS, Guo XY, Sun K. Recent advances in blood-based and artificial intelligence-enhanced approaches for gastrointestinal cancer diagnosis. World J Gastroenterol 2021; 27:5666-5681. [PMID: 34629793 PMCID: PMC8473600 DOI: 10.3748/wjg.v27.i34.5666] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/14/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancers are among the most common cancer types and leading causes of cancer-related deaths worldwide. There is a tremendous clinical need for effective early diagnosis for better healthcare of GI cancer patients. In this article, we provide a short overview of the recent advances in GI cancer diagnosis. In the first part, we discuss the applications of blood-based biomarkers, such as plasma circulating cell-free DNA, circulating tumor cells, extracellular vesicles, and circulating cell-free RNA, for cancer liquid biopsies. In the second part, we review the current trends of artificial intelligence (AI) for pathology image and tissue biopsy analysis for GI cancer, as well as deep learning-based approaches for purity assessment of tissue biopsies. We further provide our opinions on the future directions in blood-based and AI-enhanced approaches for GI cancer diagnosis, and we think that these fields will have more intensive integrations with clinical needs in the near future.
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Affiliation(s)
- Li-Shi Li
- School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, Guangdong Province, China
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, Guangdong Province, China
| | - Xiang-Yu Guo
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, Guangdong Province, China
| | - Kun Sun
- Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen 518132, Guangdong Province, China
- BGI-Shenzhen, Shenzhen 518083, Guangdong Province, China
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Pappalardo A, Giunta EF, Tirino G, Pompella L, Federico P, Daniele B, De Vita F, Petrillo A. Adjuvant Treatment in Pancreatic Cancer: Shaping the Future of the Curative Setting. Front Oncol 2021; 11:695627. [PMID: 34485130 PMCID: PMC8415474 DOI: 10.3389/fonc.2021.695627] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/16/2021] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease even in the early stages, despite progresses in surgical and pharmacological treatment in recent years. High potential for metastases is the main cause of therapeutic failure in localized disease, highlighting the current limited knowledge of underlying pathological processes. However, nowadays research is focusing on the search for personalized approaches also in the adjuvant setting for PDAC, by implementing the use of biomarkers and investigating new therapeutic targets. In this context, the aim of this narrative review is to summarize the current treatment scenario and new potential therapeutic approaches in early stage PDAC, from both a preclinical and clinical point of view. Additionally, the review examines the role of target therapies in localized PDAC and the influence of neoadjuvant treatments on survival outcomes.
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Affiliation(s)
- Annalisa Pappalardo
- Medical Oncology Unit, Ospedale del Mare, Naples, Italy
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of study of Campania “L. Vanvitelli”, Naples, Italy
| | - Emilio Francesco Giunta
- Medical Oncology Unit, Ospedale del Mare, Naples, Italy
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of study of Campania “L. Vanvitelli”, Naples, Italy
| | - Giuseppe Tirino
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of study of Campania “L. Vanvitelli”, Naples, Italy
| | - Luca Pompella
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of study of Campania “L. Vanvitelli”, Naples, Italy
| | | | - Bruno Daniele
- Medical Oncology Unit, Ospedale del Mare, Naples, Italy
| | - Ferdinando De Vita
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of study of Campania “L. Vanvitelli”, Naples, Italy
| | - Angelica Petrillo
- Medical Oncology Unit, Ospedale del Mare, Naples, Italy
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of study of Campania “L. Vanvitelli”, Naples, Italy
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Dietz MS, Sutton TL, Walker BS, Gast CE, Zarour L, Sengupta SK, Swain JR, Eng J, Parappilly M, Limbach K, Sattler A, Burlingame E, Chin Y, Gower A, Mira JLM, Sapre A, Chiu YJ, Clayburgh DR, Pommier SJ, Cetnar JP, Fischer JM, Jaboin JJ, Pommier RF, Sheppard BC, Tsikitis VL, Skalet AH, Mayo SC, Lopez CD, Gray JW, Mills GB, Mitri Z, Chang YH, Chin K, Wong MH. Relevance of circulating hybrid cells as a non-invasive biomarker for myriad solid tumors. Sci Rep 2021; 11:13630. [PMID: 34211050 PMCID: PMC8249418 DOI: 10.1038/s41598-021-93053-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/09/2021] [Indexed: 02/06/2023] Open
Abstract
Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. The heterogeneity in disseminated tumor cell populations capable of seeding and growing in distant organ sites contributes to the development of treatment resistant disease. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. It is unknown if CHCs represent a generalized cancer mechanism for cell dissemination, or if this population is relevant to the metastatic cascade. Herein, we detect CHCs in the peripheral blood of patients with cancer in myriad disease sites encompassing epithelial and non-epithelial malignancies. Further, we demonstrate that in vivo-derived hybrid cells harbor tumor-initiating capacity in murine cancer models and that CHCs from human breast cancer patients express stem cell antigens, features consistent with the potential to seed and grow at metastatic sites. Finally, we reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression. Importantly, this novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease.
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Affiliation(s)
- Matthew S Dietz
- Department of Pediatrics, Oregon Health & Science University (OHSU), Portland, OR, 97239, USA.,Department of Pediatrics, University of Utah, Salt Lake City, UT, 84113, USA
| | | | | | - Charles E Gast
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - Luai Zarour
- Department of Surgery, OHSU, Portland, OR, 97239, USA.,Department of General Surgery, Legacy Medical Group, Gresham, OR, 97030, USA
| | - Sidharth K Sengupta
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - John R Swain
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - Jennifer Eng
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA
| | - Michael Parappilly
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | | | - Ariana Sattler
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - Erik Burlingame
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,Computational Biology Program, OHSU, Portland, OR, 97239, USA
| | - Yuki Chin
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA
| | - Austin Gower
- Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA
| | - Jose L Montoya Mira
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA
| | - Ajay Sapre
- Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA
| | - Yu-Jui Chiu
- Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA
| | - Daniel R Clayburgh
- Department of Otolaryngology, OHSU, Portland, OR, 97239, USA.,Operative Care Division, Portland Veterans Affairs Medical Center, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | | | - Jeremy P Cetnar
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Medicine, OHSU, Portland, OR, 97239, USA
| | - Jared M Fischer
- Cancer Early Detection Advanced Research Center, OHSU, Portland, OR, 97201, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Molecule and Medical Genetics, OHSU, Portland, OR, 97239, USA
| | - Jerry J Jaboin
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Radiation Medicine, OHSU, Portland, OR, 97239, USA
| | - Rodney F Pommier
- Department of Surgery, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Brett C Sheppard
- Department of Surgery, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | | | - Alison H Skalet
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Casey Eye Institute, OHSU, Portland, OR, 97239, USA
| | - Skye C Mayo
- Department of Surgery, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Charles D Lopez
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Medicine, OHSU, Portland, OR, 97239, USA
| | - Joe W Gray
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Gordon B Mills
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Zahi Mitri
- The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.,Department of Medicine, OHSU, Portland, OR, 97239, USA
| | - Young Hwan Chang
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,Computational Biology Program, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Koei Chin
- Department of Biomedical Engineering, OHSU, Portland, OR, 97239, USA.,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA
| | - Melissa H Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, 2720 S. Moody Ave., Mailcode KC-CDCB, Portland, OR, 97201, USA. .,The Knight Cancer Institute, OHSU, Portland, OR, 97201, USA.
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Liberko M, Kolostova K, Szabo A, Gurlich R, Oliverius M, Soumarova R. Circulating Tumor Cells, Circulating Tumor DNA and Other Blood-based Prognostic Scores in Pancreatic Ductal Adenocarcinoma - Mini-Review. In Vivo 2021; 35:31-39. [PMID: 33402447 DOI: 10.21873/invivo.12229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/19/2020] [Accepted: 11/21/2020] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma represents a disease with increasing incidence. Its prognosis is the worst among all malignancies despite the aggressive combined multimodal treatment across all stages. In metastatic disease, median survival is approximatelly one year. The mainstay of treatment is chemotherapy (neo/adjuvant, palliative) and in selected subgroups of patients even radiotherapy. Nevertheless, nowadays there are very few prognostic and/or predictive biomarkers available that can be used to identify and better stratify patients based on risk to tailored treatment. Potentially, promising areas of research are circulating tumor cells and circulating tumor DNA, which can be easily obtained from peripheral blood - so called liquid biopsy. They may serve as a tool to assess response to applied treatment, and to detect the emergence of treatment-resistant clones or early disease relapse. Moreover, their study may allow identification of potentially tumor-specific alterations, which may serve as target structures for targeted (tailored) therapy. Alternatively, different prognostic indexes/scores calculated by analysis of selected parameters of blood and/or biochemistry can be used to better stratify patients based on risk and better predict prognosis. The aim of this mini-review is to provide a basic overview of the current state of the art in this area and its potential significance for clinical practice.
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Affiliation(s)
- Marian Liberko
- Department of Radiotherapy and Oncology, University Hospital Kralovske Vinohorady, Prague, Czech Republic; .,Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | - Katarina Kolostova
- Department of Laboratory Genetics, Laboratory Diagnostics, University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - Arpad Szabo
- Department of Pathology, Third Faculty of Medicine, Charles University in Prague and University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - Robert Gurlich
- Department of General Surgery, University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - Martin Oliverius
- Department of General Surgery, University Hospital Kralovske Vinohrady, Prague, Czech Republic
| | - Renata Soumarova
- Department of Radiotherapy and Oncology, University Hospital Kralovske Vinohorady, Prague, Czech Republic.,Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
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Heredia-Soto V, Rodríguez-Salas N, Feliu J. Liquid Biopsy in Pancreatic Cancer: Are We Ready to Apply It in the Clinical Practice? Cancers (Basel) 2021; 13:1986. [PMID: 33924143 PMCID: PMC8074327 DOI: 10.3390/cancers13081986] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/14/2021] [Accepted: 04/16/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC.
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Affiliation(s)
- Victoria Heredia-Soto
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
| | - Nuria Rodríguez-Salas
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain
| | - Jaime Feliu
- Translational Oncology Research Laboratory, Biomedical Research Institute, La Paz University Hospital, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain; (V.H.-S.); (N.R.-S.)
- Centro de Investigación Biomédica en Red de Cáncer, CIBERONC, Instituto de Salud Carlos III, Monforte de Lemos 5, 28029 Madrid, Spain
- Cátedra UAM-AMGEN, Medical Oncology Department, La Paz University Hospital, Paseo de la Castellana 261, 28046 Madrid, Spain
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Park Y, Jun HR, Choi HW, Hwang DW, Lee JH, Song KB, Lee W, Kwon J, Ha SH, Jun E, Kim SC. Circulating tumour cells as an indicator of early and systemic recurrence after surgical resection in pancreatic ductal adenocarcinoma. Sci Rep 2021; 11:1644. [PMID: 33462311 PMCID: PMC7814057 DOI: 10.1038/s41598-020-80383-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
Early recurrence in pancreatic ductal adenocarcinoma (PDAC) is a decisive factor in determining a patient's prognosis. We determined in our current study whether circulating tumour cells (CTCs) exist in the blood of PDAC patients and can be used as a predictor of recurrence patterns (i.e. time and site) after surgical resection. Between December 2017 and November 2018, the mononuclear cell layer was obtained from the peripheral blood of 36 patients diagnosed with PDAC. CTCs were then isolated using the CD-PRIME™ platform and detected via immunostaining. The patient records were analyzed to correlate these data with survival and recurrence patterns. Twelve patients were CTC-positive (33.3%) and showed a significantly frequent rate of systemic recurrence (distant metastases and peritoneal dissemination) (p = 0.025). On multi-variable logistic regression analysis, CTC positivity was an independent risk factor for early recurrence (p = 0.027) and for systemic recurrence (p = 0.033). In summary, the presence or absence of CTC in the blood of the patients with PDAC could help predict the recurrence pattern after surgery. PDAC patients with CTC positivity at tumour diagnosis should therefore undergo a comprehensive strategy for systemic therapy and active monitoring to detect possible early recurrence.
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MESH Headings
- Aged
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Carcinoma, Pancreatic Ductal/blood
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/surgery
- Humans
- Male
- Middle Aged
- Neoplasm Recurrence, Local/blood
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/surgery
- Neoplastic Cells, Circulating/pathology
- Prognosis
- Survival Rate
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Affiliation(s)
- Yejong Park
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye Ryeong Jun
- Biomedical Engineering Research Center, Asan Medical Center, Seoul, Republic of Korea
| | - Hwi Wan Choi
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
| | - Dae Wook Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Hoon Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ki Byung Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Woohyung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jaewoo Kwon
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Su Hyeon Ha
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eunsung Jun
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea.
- Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea.
| | - Song Cheol Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Ishido K, Hakamada K, Kimura N, Miura T, Wakiya T. Essential updates 2018/2019: Current topics in the surgical treatment of pancreatic ductal adenocarcinoma. Ann Gastroenterol Surg 2021; 5:7-23. [PMID: 33532676 PMCID: PMC7832965 DOI: 10.1002/ags3.12379] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/23/2020] [Accepted: 06/25/2020] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is highly malignant. While cancers in other organs have shown clear improvements in 5-year survival, the 5-year survival rate of pancreatic cancer is approximately 10%. Early relapse and metastasis are not uncommon, making it difficult to achieve an acceptable prognosis even after complete surgical resection of the pancreas. Studies have been performed on various treatments to improve the prognosis of PDAC, and multidisciplinary approaches including non-surgical treatments have led to gradual improvement. In the present literature review, we have described the significance of anatomical and biological resectability criteria, the concept of R0 resection in surgical treatment, the feasibility of minimally invasive surgery, the remarkable development of perioperative chemotherapy, the effectiveness of conversion surgery for unresectable PDAC, and ongoing challenges in PDAC treatment. We also provide an essential update on these subjects by focusing on recent trends and topics.
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Affiliation(s)
- Keinosuke Ishido
- Department of Gastroenterological SurgeryHirosaki University Graduate School of MedicineHirosakiJapan
| | - Kenichi Hakamada
- Department of Gastroenterological SurgeryHirosaki University Graduate School of MedicineHirosakiJapan
| | - Norihisa Kimura
- Department of Gastroenterological SurgeryHirosaki University Graduate School of MedicineHirosakiJapan
| | - Takuya Miura
- Department of Gastroenterological SurgeryHirosaki University Graduate School of MedicineHirosakiJapan
| | - Taiichi Wakiya
- Department of Gastroenterological SurgeryHirosaki University Graduate School of MedicineHirosakiJapan
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48
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Pang TCY, Po JW, Becker TM, Goldstein D, Pirola RC, Wilson JS, Apte MV. Circulating tumour cells in pancreatic cancer: A systematic review and meta-analysis of clinicopathological implications. Pancreatology 2021; 21:103-114. [PMID: 33309014 DOI: 10.1016/j.pan.2020.11.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The detection and quantification of circulating tumour cells (CTCs) in pancreatic cancer (PC) has the potential to provide prognostic information. The aim of this review was to provide an overview of the literature surrounding CTCs in PC. METHODS A systematic literature review on CTCs in PC between 2005-2020 was performed. Data based on peripheral vein samples were used to determine the positivity rate of CTCs, their prognostic significance and their relative numbers compared to portal vein (PV) samples. RESULTS The overall CTC detection rate in forty-four articles was 65% (95%CI: 55-75%). Detection rate for CellSearch was 26% (95%CI: 14-38%), which was lower than for both filtration and microfluidic techniques. In nine studies with >50 patients, overall survival was worse with CTC positivity (HR 1.82; 95%CI: 1.61-2.05). Five of seven studies which described PV CTC collection provided patient-level data. PV CTC yield was 7.7-fold (95%CI 1.35-43.9) that of peripheral blood. CONCLUSIONS CTCs were detected in the peripheral circulation of most patients with PC and may be related to prognosis and disease stage. PV blood contains more CTCs than peripheral blood sampling. This review points to the maturation of techniques of CTC enrichment, and its evidence base for eventual clinical deployment.
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Affiliation(s)
- Tony C Y Pang
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia; Surgical Innovations Unit, Westmead Hospital, Westmead, Australia; Westmead Clinical School, University of Sydney, Westmead, Australia
| | - Joseph W Po
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, South Western Clinical School, University of New South Wales, School of Medicine, Western Sydney University, Australia; Surgical Innovations Unit, Westmead Hospital, Westmead, Australia; Westmead Clinical School, University of Sydney, Westmead, Australia
| | - Therese M Becker
- Centre for Circulating Tumour Cell Diagnostics and Research, Ingham Institute for Applied Medical Research, South Western Clinical School, University of New South Wales, School of Medicine, Western Sydney University, Australia
| | - David Goldstein
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Romano C Pirola
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia
| | - Minoti V Apte
- Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia.
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49
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GAS2L1 Is a Potential Biomarker of Circulating Tumor Cells in Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12123774. [PMID: 33333841 PMCID: PMC7765300 DOI: 10.3390/cancers12123774] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/10/2020] [Accepted: 12/13/2020] [Indexed: 12/25/2022] Open
Abstract
Pancreatic cancer is a malignant disease with high mortality and a dismal prognosis. Circulating tumor cell (CTC) detection and characterization have emerged as essential techniques for early detection, prognostication, and liquid biopsy in many solid malignancies. Unfortunately, due to the low EPCAM expression in pancreatic cancer CTCs, no specific marker is available to identify and isolate this rare cell population. This study analyzed single-cell RNA sequencing profiles of pancreatic CTCs from a genetically engineered mouse model (GEMM) and pancreatic cancer patients. Through dimensionality reduction analysis, murine pancreatic CTCs were grouped into three clusters with different biological functions. CLIC4 and GAS2L1 were shown to be overexpressed in pancreatic CTCs in comparison with peripheral blood mononuclear cells (PBMCs). Further analyses of PBMCs and RNA-sequencing datasets of enriched pancreatic CTCs were used to validate the overexpression of GAS2L1 in pancreatic CTCs. A combinatorial approach using both GAS2L1 and EPCAM expression leads to an increased detection rate of CTCs in PDAC in both GEMM and patient samples. GAS2L1 is thus proposed as a novel biomarker of pancreatic cancer CTCs.
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50
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Gao T, Ding P, Li W, Wang Z, Lin Q, Pei R. Isolation of DNA aptamers targeting N-cadherin and high-efficiency capture of circulating tumor cells by using dual aptamers. NANOSCALE 2020; 12:22574-22585. [PMID: 33174555 DOI: 10.1039/d0nr06180h] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Circulating tumor cells (CTCs) acquire mesenchymal markers (e.g., N-cadherin) and lose epithelial markers (e.g., epithelial cell adhesion molecule, EpCAM) during the epithelial-mesenchymal transition (EMT) and are therefore ideal biomarkers of tumor metastasis. However, it is still a challenge to efficiently capture and detect circulating tumor cells with different phenotypes simultaneously. In this work, to obtain aptamers targeting N-cadherin in the native conformation on live cells, we established stable N-cadherin overexpressing cells (N-cadherin cells) and used these cells to identify a panel of N-cadherin-specific aptamers through the cell-SELEX approach. Two aptamer candidates obtained after 12 rounds of selection showed a low equilibrium dissociation constant in the nanomolar range, indicating high binding affinity. The truncated aptamer candidate NC3S showed the highest binding affinity to N-cadherin cells with a low Kd value of 20.08 nM. The SYL3C aptamer was reported to target cancer cell surface biomarker EpCAM. Then, we synthesized two kinds of aptamer-modified magnetic nanoparticles (SYL3C-MNPs and NC3S-MNPs). Both SYL3C and NC3S aptamers possess excellent capture specificity and efficiency for the target cells. The aptamer-MNP cocktail exhibits a considerable capture efficiency and sensitivity for rare cancer cells of epithelial and mesenchymal phenotypes. Furthermore, no CTCs were found in blood samples from healthy donors, while CTCs were successfully isolated by using the aptamer-MNP cocktail for 15 out of 16 samples collected from patients. In summary, the two kinds of aptamer-modified MNPs could be utilized as a promising tool for capturing CTCs from clinical samples.
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Affiliation(s)
- Tian Gao
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei 230026, China
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