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1
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Yun Y, Kim S, Lee SN, Cho HY, Choi JW. Nanomaterial-based detection of circulating tumor cells and circulating cancer stem cells for cancer immunotherapy. NANO CONVERGENCE 2024; 11:56. [PMID: 39671082 PMCID: PMC11645384 DOI: 10.1186/s40580-024-00466-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/04/2024] [Indexed: 12/14/2024]
Abstract
Nanomaterials have emerged as transformative tools for detecting circulating tumor cells (CTCs) and circulating cancer stem cells (CCSCs), significantly enhancing cancer diagnostics and immunotherapy. Nanomaterials, including those composed of gold, magnetic materials, and silica, have enhanced the sensitivity, specificity, and efficiency of isolating these rare cells from blood. These developments are of paramount importance for the early detection of cancer and for providing real-time insights into metastasis and treatment resistance, which are essential for the development of personalized immunotherapies. The combination of nanomaterial-based platforms with phenotyping techniques, such as Raman spectroscopy and microfluidics, enables researchers to enhance immunotherapy protocols targeting specific CTC and CCSC markers. Nanomaterials also facilitate the targeted delivery of immunotherapeutic agents, including immune checkpoint inhibitors and therapeutic antibodies, directly to tumor cells. This synergistic approach has the potential to enhance therapeutic efficacy and mitigate the risk of metastasis and relapse. In conclusion, this review critically examines the use of nanomaterial-driven detection systems for detecting CTCs and CCSCs, their application in immunotherapy, and suggests future directions, highlighting their potential to transform the integration of diagnostics and treatment, thereby paving the way for more precise and personalized cancer therapies.
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Affiliation(s)
- Yeochan Yun
- Department of Bio and Fermentation Convergence Technology, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul, 02707, Republic of Korea
| | - Seewoo Kim
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, Republic of Korea
| | - Sang-Nam Lee
- Uniance Gene Inc., 273, Digital-ro, Guro-gu, Seoul, 08381, Republic of Korea.
| | - Hyeon-Yeol Cho
- Department of Bio and Fermentation Convergence Technology, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul, 02707, Republic of Korea.
| | - Jeong-Woo Choi
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, Republic of Korea.
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2
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Gu J, Zhang J, Xia R, Wang X, Yang J, Xie F, Zhou Q, Li J, Zhang T, Chen Q, Fan Y, Guo S, Wang H. The role of histone H1.2 in pancreatic cancer metastasis and chemoresistance. Drug Resist Updat 2024; 73:101027. [PMID: 38290407 DOI: 10.1016/j.drup.2023.101027] [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: 08/14/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 02/01/2024]
Abstract
AIMS Pancreatic cancer (PC) is a highly metastatic malignant tumor of the digestive system. Drug resistance frequently occurs during cancer treatment process. This study aimed to explore the link between chemoresistance and tumor metastasis in PC and its possible molecular and cellular mechanisms. METHODS A Metastasis and Chemoresistance Signature (MCS) scoring system was built and validated based on metastasis- and chemoresistance-related genes using gene expression data of PC, and the model was applied to single-cell RNA sequencing data. The influence of linker histone H1.2 (H1-2) on PC was explored through in vitro and in vivo experiments including proliferation, invasion, migration, drug sensitivity, rescue experiments and immunohistochemistry, emphasizing its regulation with c-MYC signaling pathway. RESULTS A novel MCS scoring system accurately predicted PC patient survival and was linked to chemoresistance and epithelial-mesenchymal transition (EMT) in PC single-cell RNA sequencing data. H1-2 emerged as a significant prognostic factor, with its high expression indicating increased chemoresistance and EMT. This upregulation was mediated by c-MYC, which was also found to be highly expressed in PC tissues. CONCLUSION The MCS scoring system offers insights into PC chemoresistance and metastasis potential. Targeting H1-2 could enhance therapeutic strategies and improve PC patient outcomes.
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Affiliation(s)
- Jianyou Gu
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China; Chongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing 401147, China
| | - Junfeng Zhang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China; University of Chinese Academy of Sciences (UCAS) Chongqing School, Chongqing Medical University, Chongqing, China
| | - Renpei Xia
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China
| | - Xianxing Wang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China; Chongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing 401147, China
| | - Jiali Yang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China
| | - Fuming Xie
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China
| | - Qiang Zhou
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China
| | - Jinghe Li
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China
| | - Tao Zhang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China; University of Chinese Academy of Sciences (UCAS) Chongqing School, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing 401147, China
| | - Qing Chen
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China
| | - Yingfang Fan
- Department of Biliary Surgery, the Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China.
| | - Shixiang Guo
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China; Chongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing 401147, China; Chongqing School, University of Chinese Academy of Sciences, Chongqing 400714, China.
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing, China; University of Chinese Academy of Sciences (UCAS) Chongqing School, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing 401147, China.
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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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Stosic K, Senar OA, Tarfouss J, Bouchart C, Navez J, Van Laethem JL, Arsenijevic T. A Comprehensive Review of the Potential Role of Liquid Biopsy as a Diagnostic, Prognostic, and Predictive Biomarker in Pancreatic Ductal Adenocarcinoma. Cells 2023; 13:3. [PMID: 38201207 PMCID: PMC10778087 DOI: 10.3390/cells13010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most lethal malignant diseases, with a mortality rate being close to incidence. Due to its heterogeneity and plasticity, as well as the lack of distinct symptoms in the early phases, it is very often diagnosed at an advanced stage, resulting in poor prognosis. Traditional tissue biopsies remain the gold standard for making a diagnosis, but have an obvious disadvantage in their inapplicability for frequent sampling. Blood-based biopsies represent a non-invasive method which potentially offers easy and repeated sampling, leading to the early detection and real-time monitoring of the disease and hopefully an accurate prognosis. Given the urgent need for a reliable biomarker that can estimate a patient's condition and response to an assigned treatment, blood-based biopsies are emerging as a potential new tool for improving patients' survival and surveillance. In this article, we discuss the current advances and challenges in using liquid biopsies for pancreatic cancer, focusing on circulating tumour DNA (ctDNA), extracellular vesicles (EVs), and circulating tumour cells (CTCs), and compare the performance and reliability of different biomarkers and combinations of biomarkers.
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Affiliation(s)
- Kosta Stosic
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Oier Azurmendi Senar
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Jawad Tarfouss
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
| | - Christelle Bouchart
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Radiation Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Julie Navez
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Hepato-Biliary-Pancreatic Surgery, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Jean-Luc Van Laethem
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
| | - Tatjana Arsenijevic
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, 1070 Brussels, Belgium (O.A.S.); (C.B.)
- Department of Gastroenterology, Hepatology and Digestive Oncology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium
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Tanishima Y, Takahashi K, Nishikawa K, Ishikawa Y, Yuda M, Tanaka Y, Matsumoto A, Yano F, Eto K. Microscopic venous invasion is a predictor of prognosis in patients with esophageal squamous cell carcinoma undergoing ineffective neoadjuvant chemotherapy and surgery. Esophagus 2023; 20:651-659. [PMID: 37081314 DOI: 10.1007/s10388-023-01005-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 04/14/2023] [Indexed: 04/22/2023]
Abstract
BACKGROUND Neoadjuvant chemotherapy followed by surgery is Japan's most effective treatment modality for advanced thoracic esophageal squamous cell carcinoma. However, the prognosis is not as expected. This study aimed to examine prognostic factors in patients with pathologically ineffective neoadjuvant chemotherapy followed by surgery for esophageal squamous cell carcinoma. METHODS We retrospectively analyzed patients who underwent neoadjuvant chemotherapy followed by curative esophagectomy for esophageal squamous cell carcinoma between December 2008 and July 2021. The patients were divided into the neoadjuvant chemotherapy effective group and the neoadjuvant chemotherapy ineffective group according to the pathological diagnosis. Clinicopathological data, prognosis, and recurrence were analyzed. RESULTS A total of 143 patients (121 males, 22 females; median age, 67 years) were included in this study. Of these, 34 patients were classified into the effective group and the remaining 109 patients were assigned to the ineffective group. The ineffective group had significantly worse overall survival and recurrence-free survival than the effective group (p = 0.0192 and p = 0.0070, respectively). In the ineffective group, multivariate analysis demonstrated that microscopic venous invasion was an independent prognostic factor for overall survival (hazard ratio 2.44; 95% confidence interval 1.13-5.30) and recurrence-free survival (hazard ratio 2.43; 95% confidence interval 1.24-4.73). CONCLUSIONS Microscopic venous invasion was associated with poor survival and cancer recurrence in the neoadjuvant chemotherapy ineffective group of patients who underwent esophagectomy for esophageal squamous cell carcinoma.
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Affiliation(s)
- Yuichiro Tanishima
- Division of Gastrointestinal Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
| | - Keita Takahashi
- Division of Gastrointestinal Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Katsunori Nishikawa
- Division of Gastrointestinal Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Yoshitaka Ishikawa
- Division of Gastrointestinal Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Masami Yuda
- Division of Gastrointestinal Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Yujiro Tanaka
- Division of Gastrointestinal Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Akira Matsumoto
- Division of Gastrointestinal Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Fumiaki Yano
- Division of Gastrointestinal Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Ken Eto
- Division of Gastrointestinal Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan
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Ei S, Takahashi S, Ogasawara T, Mashiko T, Masuoka Y, Nakagohri T. Neoadjuvant and Adjuvant Treatments for Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma: The Current Status of Pancreatic Ductal Adenocarcinoma Treatment in Japan. Gut Liver 2023; 17:698-710. [PMID: 36843421 PMCID: PMC10502496 DOI: 10.5009/gnl220311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/30/2022] [Accepted: 10/30/2022] [Indexed: 02/28/2023] Open
Abstract
Resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Although the outcome of technically resectable PDAC has improved with advances in surgery and adjuvant therapy, the 5-year survival rate remains low at 20% to 40%. More effective therapy is needed. Almost 15 years ago, the National Comprehensive Cancer Network guidelines proposed a resectability classification of PDAC based on preoperative imaging. Since then, treatment strategies for PDAC have been devised based on resectability. The standard of care for resectable PDAC is adjuvant chemotherapy after R0 resection, as shown by the results of pivotal clinical trials. With regard to neoadjuvant treatment, several recent clinical trials comparing neoadjuvant treatment with upfront resection have been conducted on resectable PDAC and borderline resectable PDAC, and the benefits and efficacy of neoadjuvant treatment for pancreatic cancer has become clearer. The significance of neoadjuvant treatment for resectable PDAC remains controversial, but in borderline resectable PDAC the efficacy of neoadjuvant treatment has been further recognised, although the standard of care has not yet been established. Several promising clinical trials for PDAC are ongoing. This review presents previous and ongoing trials of perioperative treatment for resectable and borderline resectable PDAC, focusing on the difference between Asian and Western countries.
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Affiliation(s)
- Shigenori Ei
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Shinichiro Takahashi
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Toshihito Ogasawara
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Taro Mashiko
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Yoshihito Masuoka
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Toshio Nakagohri
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
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Goel N, Rhim AD, Xi H, Olive KP, Thomas AS, Kwon W, Schwartz J, Sugahara KN, Schrope BA, Chabot JA, Kluger MD. Transfusion of salvaged red blood cells during pancreatic ductal adenocarcinoma operations. Br J Surg 2023; 110:917-919. [PMID: 36461883 PMCID: PMC10361671 DOI: 10.1093/bjs/znac393] [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: 01/03/2022] [Revised: 04/26/2022] [Accepted: 10/24/2022] [Indexed: 07/20/2023]
Affiliation(s)
- Neha Goel
- Department of Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Andrew D Rhim
- Department of Gastroenterology, Hepatology & Nutrition, MD Anderson Cancer Center, Houston, Texas, USA
| | - Huaqing Xi
- Department of Surgery, Division of Gastrointestinal and Endocrine Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Kenneth P Olive
- Department of Medicine, Division of Digestive and Liver Diseases, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Alexander S Thomas
- Department of Surgery, Division of Gastrointestinal and Endocrine Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Wooil Kwon
- Department of Surgery, Division of Gastrointestinal and Endocrine Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Joseph Schwartz
- Department of Anatomic Pathology and Clinical Pathology, The Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kazuki N Sugahara
- Department of Surgery, Division of Gastrointestinal and Endocrine Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Beth A Schrope
- Department of Surgery, Division of Gastrointestinal and Endocrine Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - John A Chabot
- Department of Surgery, Division of Gastrointestinal and Endocrine Surgery, Columbia University Irving Medical Center, New York, New York, USA
| | - Michael D Kluger
- Department of Surgery, Division of Gastrointestinal and Endocrine Surgery, Columbia University Irving Medical Center, New York, New York, USA
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Anoop TM, Basu PK, Chandramohan K, Thomas A, Manoj S. Evolving utility of exosomes in pancreatic cancer management. World J Methodol 2023; 13:46-58. [PMID: 37456979 PMCID: PMC10348087 DOI: 10.5662/wjm.v13.i3.46] [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: 03/22/2023] [Revised: 05/02/2023] [Accepted: 05/31/2023] [Indexed: 06/20/2023] Open
Abstract
Despite the development of newer oncological treatment, the survival of patients with pancreatic cancer (PC) remains poor. Recent studies have identified exosomes as essential mediators of intercellular communications and play a vital role in tumor initiation, metastasis and chemoresistance. Thus, the utility of liquid biopsies using exosomes in PC management can be used for early detection, diagnosis, monitoring as well as drug delivery vehicles for cancer therapy. This review summarizes the function, and clinical applications of exosomes in cancers as minimally invasive liquid biomarker in diagnostic, prognostic and therapeutic roles.
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Affiliation(s)
- Thattungal Manoharan Anoop
- Department of Medical Oncology, Regional Cancer Center, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - Palash Kumar Basu
- Department of Avionics, Indian Institute of Space Science & Technology (IIST), Thiruvananthapuram 695547, Kerala, India
| | - K Chandramohan
- Surgical Oncology, Regional Cancer Center, Thiruvananthapuram 695011, Kerala, India
| | - Ajai Thomas
- Department of Medical Oncology, Regional Cancer Center, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
| | - S Manoj
- Department of Medical Oncology, Regional Cancer Center, Medical College Campus, Thiruvananthapuram 695011, Kerala, India
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9
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Cheng R, Peng Y, Sun X, Zhang S, Li P. Circulating Tumor Cells as Diagnostic Markers of Early Gastric Cancer and Gastric Precancerous Lesions. Oncology 2023; 101:512-519. [PMID: 37263263 DOI: 10.1159/000531323] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 04/21/2023] [Indexed: 06/03/2023]
Abstract
INTRODUCTION Circulating tumor cells (CTCs) may be potential diagnostic biomarkers of various malignancies including gastric cancer. This study aimed to evaluate whether CTCs could be used to facilitate the diagnosis of early gastric cancer (EGC) or precancerous gastric lesions. METHODS The diagnostic study included consecutive patients with EGC, gastric precancerous lesions, or fundic gland polyps admitted to the Gastroenterology Department, Beijing Friendship Hospital Affiliated to Capital Medical University (National Center for Digestive Diseases) between October 2016 and January 2018. RESULTS A total of 92 patients were enrolled, including 57 patients with EGC, 14 patients with gastric precancerous lesions, and 21 patients with fundic gland polyps (control group). CTCs were detected in 47.89% (34/71) of patients with EGC/gastric precancerous lesions and 4.76% (1/21) of patients with fundic gland polyps (p < 0.001). CTC detection distinguished EGC/precancerous lesions from fundic gland polyps with an area under the receiver operating characteristic curve of 0.740 (95% confidence interval, 0.640-0.840; p = 0.001), a sensitivity of 49.10%, a specificity of 95.00%, a positive predictive value of 97.00%, and a negative predictive value of 64.90%. CONCLUSIONS Peripheral blood CTCs are more common in patients with EGC or gastric precancerous lesions than in patients with fundic gland polyps. Measurement of CTCs may be a useful tool to aid in the diagnosis of EGC and precancerous lesions.
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Affiliation(s)
- Rui Cheng
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yang Peng
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Department of Gastroenterology, Suining First People's Hospital, Suining, China
| | - Xiujing Sun
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Peng Li
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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10
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Kara N, Ayoub N, Ilgu H, Fotiadis D, Ilgu M. Aptamers Targeting Membrane Proteins for Sensor and Diagnostic Applications. Molecules 2023; 28:molecules28093728. [PMID: 37175137 PMCID: PMC10180177 DOI: 10.3390/molecules28093728] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/07/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
Many biological processes (physiological or pathological) are relevant to membrane proteins (MPs), which account for almost 30% of the total of human proteins. As such, MPs can serve as predictive molecular biomarkers for disease diagnosis and prognosis. Indeed, cell surface MPs are an important class of attractive targets of the currently prescribed therapeutic drugs and diagnostic molecules used in disease detection. The oligonucleotides known as aptamers can be selected against a particular target with high affinity and selectivity by iterative rounds of in vitro library evolution, known as Systematic Evolution of Ligands by EXponential Enrichment (SELEX). As an alternative to antibodies, aptamers offer unique features like thermal stability, low-cost, reuse, ease of chemical modification, and compatibility with various detection techniques. Particularly, immobilized-aptamer sensing platforms have been under investigation for diagnostics and have demonstrated significant value compared to other analytical techniques. These "aptasensors" can be classified into several types based on their working principle, which are commonly electrochemical, optical, or mass-sensitive. In this review, we review the studies on aptamer-based MP-sensing technologies for diagnostic applications and have included new methodological variations undertaken in recent years.
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Affiliation(s)
- Nilufer Kara
- Department of Biological Sciences, Middle East Technical University, Ankara 06800, Turkey
| | - Nooraldeen Ayoub
- Department of Biological Sciences, Middle East Technical University, Ankara 06800, Turkey
- Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland
| | - Huseyin Ilgu
- Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland
| | - Dimitrios Fotiadis
- Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland
| | - Muslum Ilgu
- Department of Biological Sciences, Middle East Technical University, Ankara 06800, Turkey
- Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA
- Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, IA 50011, USA
- Aptalogic Inc., Ames, IA 50014, USA
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11
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Thomas AS, Belli A, Salceda J, López-Ben S, Lee SY, Kwon W, Pawlik TM, Kluger MD. Contemporary practice and perception of autologous blood salvage in hepato-pancreatico-biliary operations: an international survey. HPB (Oxford) 2023:S1365-182X(23)00122-3. [PMID: 37117066 DOI: 10.1016/j.hpb.2023.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 04/04/2023] [Accepted: 04/11/2023] [Indexed: 04/30/2023]
Abstract
BACKGROUND This study aimed to assess contemporary knowledge, attitudes and behaviors around transfusion of intraoperative salvaged blood (sRBCt) during hepato-pancreatico-biliary (HPB) operations. Findings are meant to inform the design of future studies that address provider concerns to change behaviors and improve patient outcomes. METHODS A survey was designed and assessed for relevance, readability and content, and distributed to an international audience of surgeons performing HPB operations. RESULTS The 237 respondents were predominantly distributed across North America (37.55%), Europe (27.43%) and Asia (19.83%). Roughly one-half (52.74%) of respondents had used sRBCt in HPB surgery before. Transplantation surgeons were more likely than HPB surgeons to have previously used sRBCt [odds ratio = 5.18 (95% CI 1.89-14.20)]. More respondents believed sRBCt was safe for non-cancer versus cancer operations (68.57% vs. 24.17%, p < 0.0001). Less than half (45.71%) of respondents believed that sRBCt was safe in clean-contaminated fields. Most did not utilize preoperative strategies to avoid donor transfusion. CONCLUSION Practices related to sRBCt in HPB operations vary widely and there is no consensus on its use. Concerns seem primarily related to cancer-specific and infectious outcomes. While further studies are pursued, surgeons may increase their utilization of preoperative strategies to boost hemoglobin levels for at risk patients.
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Affiliation(s)
- Alexander S Thomas
- Division of Gastrointestinal and Endocrine Surgery, Department of Surgery, Columbia University Irving Medical Center, Herbert Irving Pavilion, 8th Floor, 161 Fort Washington Avenue, New York, NY, 10032, USA.
| | - Andrea Belli
- Hepatobiliary Surgical Oncology Division, "Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italia", Via Mariano Semmola, 53, 80131, Napoli, NA, Italy
| | - Juan Salceda
- Department of Surgery, Ramon Santamarina Hospital, Gral. Paz 1406, B7000, Tandil, Provincia de Buenos Aires, Argentina
| | - Santiago López-Ben
- General Surgery Department, Hospital Universitari de Girona Dr Josep Trueta, Avinguda de França, S/N, 17007, 168753, Girona, Spain
| | - Ser Y Lee
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, 31 Third Hospital Ave, Singapore
| | - Wooil Kwon
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 101, Daehak-ro Jongno-gu, Seoul, 03080, Republic of Korea
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Cancer Hospital and Solove Research Institute, 395 W 12th Ave #670, Columbus, OH, 43210, USA
| | - Michael D Kluger
- Division of Gastrointestinal and Endocrine Surgery, Department of Surgery, Columbia University Irving Medical Center, Herbert Irving Pavilion, 8th Floor, 161 Fort Washington Avenue, New York, NY, 10032, USA
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12
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Masterson AN, Chowdhury NN, Fang Y, Yip-Schneider MT, Hati S, Gupta P, Cao S, Wu H, Schmidt CM, Fishel ML, Sardar R. Amplification-Free, High-Throughput Nanoplasmonic Quantification of Circulating MicroRNAs in Unprocessed Plasma Microsamples for Earlier Pancreatic Cancer Detection. ACS Sens 2023; 8:1085-1100. [PMID: 36853001 DOI: 10.1021/acssensors.2c02105] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that is often detected at an advanced stage. Earlier diagnosis of PDAC is key to reducing mortality. Circulating biomarkers such as microRNAs are gaining interest, but existing technologies require large sample volumes, amplification steps, extensive biofluid processing, lack sensitivity, and are low-throughput. Here, we present an advanced nanoplasmonic sensor for the highly sensitive, amplification-free detection and quantification of microRNAs (microRNA-10b, microRNA-let7a) from unprocessed plasma microsamples. The sensor construct utilizes uniquely designed -ssDNA receptors attached to gold triangular nanoprisms, which display unique localized surface plasmon resonance (LSPR) properties, in a multiwell plate format. The formation of -ssDNA/microRNA duplex controls the nanostructure-biomolecule interfacial electronic interactions to promote the charge transfer/exciton delocalization processes and enhance the LSPR responses to achieve attomolar (10-18 M) limit of detection (LOD) in human plasma. This improve LOD allows the fabrication of a high-throughput assay in a 384-well plate format. The performance of nanoplasmonic sensors for microRNA detection was further assessed by comparing with the qRT-PCR assay of 15 PDAC patient plasma samples that shows a positive correlation between these two assays with the Pearson correlation coefficient value >0.86. Evaluation of >170 clinical samples reveals that oncogenic microRNA-10b and tumor suppressor microRNA-let7a levels can individually differentiate PDAC from chronic pancreatitis and normal controls with >94% sensitivity and >94% specificity at a 95% confidence interval (CI). Furthermore, combining both oncogenic and tumor suppressor microRNA levels significantly improves differentiation of PDAC stages I and II versus III and IV with >91% and 87% sensitivity and specificity, respectively, in comparison to the sensitivity and specificity values for individual microRNAs. Moreover, we show that the level of microRNAs varies substantially in pre- and post-surgery PDAC patients (n = 75). Taken together, this ultrasensitive nanoplasmonic sensor with excellent sensitivity and specificity is capable of assaying multiple biomarkers simultaneously and may facilitate early detection of PDAC to improve patient care.
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Affiliation(s)
- Adrianna N Masterson
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University, Indianapolis, Indiana 46202, United States
| | - Nayela N Chowdhury
- Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
| | - Yue Fang
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Michele T Yip-Schneider
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Sumon Hati
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University, Indianapolis, Indiana 46202, United States
| | - Prashant Gupta
- Department of Mechanical Engineering, Washington University, St. Louis, Missouri 63130, United States
| | - Sha Cao
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Huangbing Wu
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - C Max Schmidt
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Melissa L Fishel
- Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Rajesh Sardar
- Department of Chemistry and Chemical Biology, Indiana University-Purdue University, Indianapolis, Indiana 46202, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana 46202, United States
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13
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Lee SH, Cha B, Ko J, Afzal M, Park J. Acoustofluidic separation of proteins from platelets in human blood plasma using aptamer-functionalized microparticles. BIOMICROFLUIDICS 2023; 17:024105. [PMID: 37153865 PMCID: PMC10162022 DOI: 10.1063/5.0140096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/20/2023] [Indexed: 05/10/2023]
Abstract
Microfluidic liquid biopsy has emerged as a promising clinical assay for early diagnosis. Herein, we propose acoustofluidic separation of biomarker proteins from platelets in plasma using aptamer-functionalized microparticles. As model proteins, C-reactive protein and thrombin were spiked in human platelet-rich plasma. The target proteins were selectively conjugated with their corresponding aptamer-functionalized microparticles of different sizes, and the particle complexes served as a mobile carrier for the conjugated proteins. The proposed acoustofluidic device was composed of an interdigital transducer (IDT) patterned on a piezoelectric substrate and a disposable polydimethylsiloxane (PDMS) microfluidic chip. The PDMS chip was placed in a tilted arrangement with the IDT to utilize both vertical and horizontal components of surface acoustic wave-induced acoustic radiation force (ARF) for multiplexed assay at high-throughput. The two different-sized particles experienced the ARF at different magnitudes and were separated from platelets in plasma. The IDT on the piezoelectric substrate could be reusable, while the microfluidic chip can be replaceable for repeated assays. The sample processing throughput with the separation efficiency >95% has been improved such that the volumetric flow rate and flow velocity were 1.6 ml/h and 37 mm/s, respectively. For the prevention of platelet activation and protein adsorption to the microchannel, polyethylene oxide solution was introduced as sheath flows and coating on to the walls. We conducted scanning electron microscopy, x-ray photoemission spectroscopy , and sodium dodecyl sulfate- analysis before and after the separation to confirm the protein capture and separation. We expect that the proposed approach will provide new prospects for particle-based liquid biopsy using blood.
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Affiliation(s)
- Song Ha Lee
- Department of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea
| | - Beomseok Cha
- Department of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea
| | - Jeongu Ko
- Department of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea
| | - Muhammad Afzal
- Center of Immunology Marseille-Luminy, Aix-Marseille University, 171 Av, De Luminy, 13009 Marseille, France
| | - Jinsoo Park
- Department of Mechanical Engineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea
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Li Z, Xu S, Chen L, Huang S, Kuerban X, Li T. Prognostic significance of ING3 expression in patients with cancer: A systematic review and meta-analysis. Front Oncol 2023; 13:1090860. [PMID: 36845697 PMCID: PMC9948604 DOI: 10.3389/fonc.2023.1090860] [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: 11/06/2022] [Accepted: 01/19/2023] [Indexed: 02/11/2023] Open
Abstract
Background It has been reported that ING3 inhibits the progression of various cancers. However, some studies have shown that it promotes the development of prostate cancer. The purpose of this study was to investigate whether ING3 expression is associated with the prognosis of patients with cancer. Materials and methods PubMed, Cochrane Database, Embase, Medline, ScienceDirect, Scopus and Web of Science were searched until September 2022. The hazard ratio (HR)/odds ratio (OR) and 95% confidence interval (95% CI) were calculated using Stata 17 software. We used the Newcastle-Ottawa Scale (NOS) to assess the risk of bias. Result Seven studies involving 2371 patients with five types of cancer were included. The results showed that high expression of ING3 was negatively associated with a more advanced TNM stage (III-IV vs. I-II) (OR=0.61, 95% CI: 0.43-0.86), lymph node metastasis (OR=0.67, 95% CI: 0.49-0.90) and disease-free survival (HR=0.63, 95% CI: 0.37-0.88). However, ING3 expression was not associated with overall survival (HR=0.77, 95% CI: 0.41-1.12), tumor size (OR=0.67, 95% CI: 0.33-1.37), tumor differentiation (OR=0.86, 95% CI: 0.36-2.09) and gender (OR=1.14, 95% CI: 0.78-1.66). Conclusion This study showed that the expression of ING3 was associated with better prognosis, suggesting that ING3 may be a potential biomarker for cancer prognosis. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier (CRD42022306354).
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Affiliation(s)
- Zehan Li
- The Department of Surgery, the First Dongguan Affiliated Hospital of Guangdong Medical University, Guangdong, China
| | - Shengchao Xu
- The Department of Surgery, Guangzhou Medical University, Guangdong, China
| | - Lin Chen
- The Department of Surgery, the First Dongguan Affiliated Hospital of Guangdong Medical University, Guangdong, China
| | - Shuqi Huang
- The Department of Surgery, the First Dongguan Affiliated Hospital of Guangdong Medical University, Guangdong, China
| | - Xieyida Kuerban
- The Department of Surgery, the First Dongguan Affiliated Hospital of Guangdong Medical University, Guangdong, China
| | - Tianyu Li
- The Department of Surgery, the First Dongguan Affiliated Hospital of Guangdong Medical University, Guangdong, China,*Correspondence: Tianyu Li,
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The mesenchymal circulating tumor cells as biomarker for prognosis prediction and supervision in hepatocellular carcinoma. J Cancer Res Clin Oncol 2023:10.1007/s00432-022-04526-9. [PMID: 36633681 PMCID: PMC10356895 DOI: 10.1007/s00432-022-04526-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/07/2022] [Indexed: 01/13/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. Accurate prognosis prediction tools are urgently needed. While the use of circulating tumor cells (CTCs) as prognostic prediction tool has a clear potential. METHODS We established a comprehensive, negative enrichment-based strategy for CTCs analysis in patients with HCC, involving identification of epithelial CTCs (E-CTCs) and mesenchymal CTCs (M-CTCs) through specific biomarker. This strategy was performed in 127 HCC cases, 21 nonmalignant liver disease (NMLD) patients and 42 health control to analyze the relevance between CTCs and tumor recurrence. RESULTS The total CTC number and M-CTC percent were positively correlated with tumor malignancy and high recurrence risk. Individually, preoperative total CTC number and M-CTC percent could robustly distinguish relapse cases from those with no relapse, with sensitivity of 80.95% and 90.48%, specificity of 74.12% and 84.71%, respectively. Levels of preoperative total CTC number and M-CTC percent can both be regarded as independent risk factors for HCC with early recurrence (P = 0.0053, P < 0.0001), and are both significantly correlated with worse recurrence-free survival (RFS) (log rank P < 0.0001; HR 7.78, 95% CI = 3.59-16.87; log rank P < 0.0001; HR 24.4, 95% CI = 8.67-68.77). The levels of total CTC number and M-CTC number had higher effectiveness than alpha fetal protein (AFP) in HCC longitudinal supervision (77.78% vs 88.89% vs 22.22%). CONCLUSION Preoperative and postoperative CTCs with higher effectiveness than AFP in prognosis prediction and recurrence supervision, indicating that CTCs could work as the biomarker for HCC clinical management.
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Guan S, Deng G, Sun J, Han Q, Lv Y, Xue T, Ding L, Yang T, Qian N, Dai G. Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma. Front Oncol 2022; 12:926260. [PMID: 36081557 PMCID: PMC9446234 DOI: 10.3389/fonc.2022.926260] [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: 04/25/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
PurposePancreatic cancer is an aggressive solid tumor with a severe prognosis. Although tumor biomarkers are often used to identify advanced pancreatic cancer, this is not accurate, and the currently used biomarkers are not indicative of prognosis. The present study evaluated circulating tumor DNA (ctDNA) as a biomarker for prognosis prediction and disease monitoring in metastatic pancreatic adenocarcinoma (PAC).MethodsFrom 2017 to 2018, 40 patients with metastatic PAC were enrolled, and tumor tissue and blood samples were collected from 40 and 35 patients, respectively. CtDNA was sequenced by next-generation sequencing (NGS) with a 425-gene capture panel. The association of clinical characteristics, laboratory indicators, and dynamic ctDNA with patient outcomes was analyzed.ResultsMutations in KRAS (87.5%, N = 35) and TP53 (77.5%, N = 31) were most common in 40 tumor tissue. Patients’ ECOG score, CA19-9, CEA, neutrophil-lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR) levels and mutations in ≥ 3 driver genes were strongly correlated with patients’ overall survival (OS). Patients’ gender, ECOG score, CA19-9, and CEA levels were associated with progression-free survival (PFS) (P<0.05). In 35 blood samples, univariate analysis showed a significant association between ECOG score, CA19-9, KRAS or CDKN2A mutation in ctDNA and OS and between CA19-9, CDKN2A or SMAD4 mutation in ctDNA and PFS. Cox hazard proportion model showed that patients’ CDKN2A mutation in ctDNA (HR=16.1, 95% CI=4.4-59.1, P<0.001), ECOG score (HR=6.2, 95% CI=2.4-15.7, P<0.001) and tumor location (HR=0.4, 95% CI=0.1-0.9, P=0.027) were significantly associated with OS. Patients’ CDKN2A mutation in ctDNA (HR=6.8, 95% CI=2.3-19.9, P=0.001), SMAD4 mutation in ctDNA (HR=3.0, 95% CI=1.1-7.9, P=0.031) and metastatic organ (HR=0.4, 95% CI=0.2-1.0, P=0.046) were significantly associated with PFS. Longitudinal changes in gene mutation allelic frequency (MAF) value were evaluated in 24 patients. Detection of progression disease (PD) by ctDNA was 0.9 months earlier than by radiological imaging (mean PFS: 4.6m vs 5.5m, P=0.004, paired t-test).ConclusionsThe ctDNA has the potential as a specific survival predictive marker for metastatic PAC patients. Longitudinal ctDNA tracking could potentially help identify disease progression and be a valuable complement for routine clinical markers and imaging.
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Affiliation(s)
- Shasha Guan
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Guochao Deng
- Senior Department of Oncology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Jingjie Sun
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Quanli Han
- Senior Department of Oncology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Yao Lv
- Senior Department of Oncology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Tianhui Xue
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Lijuan Ding
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Tongxin Yang
- Department of Oncology, Hainan Hospital of Chinese People’s Liberation Army (PLA) General Hospital, Sanya, China
| | - Niansong Qian
- Department of Thoracic Oncology, The Eighth Medical Center, Chinese People’ Liberation Army (PLA) General Hospital, Beijing, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- *Correspondence: Niansong Qian, ; Guanghai Dai,
| | - Guanghai Dai
- Senior Department of Oncology, The Fifth Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- *Correspondence: Niansong Qian, ; Guanghai Dai,
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Liu Z, Han Y, Dang Q, Xu H, Zhang Y, Duo M, Lv J, Li H, Kong Y, Han X. Roles of circulating tumor DNA in PD-1/PD-L1 immune checkpoint Inhibitors: Current evidence and future directions. Int Immunopharmacol 2022; 111:109173. [PMID: 35998502 DOI: 10.1016/j.intimp.2022.109173] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/11/2022] [Accepted: 08/14/2022] [Indexed: 12/18/2022]
Abstract
Circulating tumor DNA (ctDNA) sequencing holds considerable promise for early diagnosis and detection of surveillance and minimal residual disease. Blood ctDNA monitors specific cancers by detecting the alterations found in cancer cells, such as apoptosis and necrosis. Due to the short half-life, ctDNA reflects the actual burden of other treatments on tumors. In addition, ctDNA might be preferable to monitor tumor development and treatment compared with invasive tissue biopsy. ctDNA-based liquid biopsy brings remarkable strength to targeted therapy and precision medicine. Notably, multiple ctDNA analysis platforms have been broadly applied in clinical immunotherapy. Through targeted sequencing, early variations in ctDNA could predict response to immune checkpoint inhibitor (ICI). Several studies have demonstrated a correlation between ctDNA kinetics and anti-PD1 antibodies. The need for further research and development remains, although this biomarker holds significant prospects for early cancer detection. This review focuses on describing the basis of ctDNA and its current utilities in oncology and immunotherapy, either for clinical management or early detection, highlighting its advantages and inherent limitations.
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Affiliation(s)
- Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China.
| | - Yilin Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Qin Dang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Mengjie Duo
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jinxiang Lv
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Huanyun Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ying Kong
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052, China; Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052, China.
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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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Sankar K, Zeinali M, Nagrath S, Ramnath N. Molecular biomarkers and liquid biopsies in lung cancer. Semin Oncol 2022; 49:275-284. [PMID: 35820969 DOI: 10.1053/j.seminoncol.2022.06.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 06/13/2022] [Accepted: 06/13/2022] [Indexed: 12/27/2022]
Abstract
Liquid biopsy refers to the identification of tumor-derived materials in body fluids including in blood circulation. In the age of immunotherapy and targeted therapies used for the treatment of advanced malignancies, molecular analysis of the tumor is considered a crucial step to guide management. In lung cancer, the concept of liquid biopsies is particularly relevant given the invasiveness of tumor biopsies in certain locations, and the potential risks of biopsy in a patient population with significant co-morbidities. Liquid biopsies have many advantages including non-invasiveness, lower cost, potential for genomic testing, ability to monitor tumor evolution through treatment, and the ability to overcome spatial and temporal intertumoral heterogeneity. The potential clinical applications of liquid biopsy are vast and include screening, detection of minimal residual disease and/or early relapse after curative intent treatment, monitoring response to immunotherapy, and identifying mutations that might be targetable or can confer resistance. Herein, we review the potential role of circulating tumor DNA and circulating tumor cells as forms of liquid biopsies and blood biomarkers in non-small cell lung cancer. We discuss the methodologies/platforms available for each, clinical applications, and limitations/challenges in incorporation into clinical practice. We additionally review emerging forms of liquid biopsies including tumor educated platelets, circular RNA, and exosomes.
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Affiliation(s)
- Kamya Sankar
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Mina Zeinali
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI; Biointerfaces Institute, University of Michigan, Ann Arbor, MI; Rogel Cancer Center, University of Michigan, Ann Arbor, MI
| | - Sunitha Nagrath
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI; Biointerfaces Institute, University of Michigan, Ann Arbor, MI; Rogel Cancer Center, University of Michigan, Ann Arbor, MI
| | - Nithya Ramnath
- Division of Medical Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI.
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Circulating Tumor Cells and the Non-Touch Isolation Technique in Surgery for Non-Small-Cell Lung Cancer. Cancers (Basel) 2022; 14:cancers14061448. [PMID: 35326603 PMCID: PMC8946695 DOI: 10.3390/cancers14061448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/18/2022] [Accepted: 03/09/2022] [Indexed: 11/16/2022] Open
Abstract
Circulating tumor cells (CTCs) are dislodged from the primary tumor into the bloodstream, travel within the bloodstream to distant organs, and finally extravasate and proliferate as epithelial metastatic deposits. The relationship between the existence of CTCs and tumor prognosis has been demonstrated by many researchers. In surgery for malignancies, the surgical manipulation of tumors and tissues around the tumor may lead to the release of CTCs into the bloodstream. The non-touch isolation technique (NTIT) has been advocated to prevent the release of CTCs during surgery. The concept of NTIT is the prevention of intraoperative increment of CTCs from the primary tumor by the early blockade of outflow vessels, and ‘pulmonary vein (PV)-first lobectomy’ during surgery for non-small-cell lung cancer (NSCLC) corresponds to this technique. The concept of PV-first lobectomy is well known among thoracic surgeons, but evidence of its efficacy for preventing the increase of intra- and postoperative CTCs and for improving postoperative prognosis is still uncertain. Our study summarizes evidence regarding the relationship between NTIT and CTCs in NSCLC and suggests the need for further research on CTCs and CTC-detecting modalities.
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Mangieri CW, Valenzuela CD, Erali RA, Shen P, Howerton R, Clark CJ. Prognostic Effect of Aberrant Right Hepatic Artery with Pancreaticoduodenectomy: Focus on Hepatic Recurrence. Ann Surg Oncol 2022; 29:3219-3228. [DOI: 10.1245/s10434-022-11341-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/31/2021] [Indexed: 11/18/2022]
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22
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Turanli B, Yildirim E, Gulfidan G, Arga KY, Sinha R. Current State of "Omics" Biomarkers in Pancreatic Cancer. J Pers Med 2021; 11:127. [PMID: 33672926 PMCID: PMC7918884 DOI: 10.3390/jpm11020127] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most fatal malignancies and the seventh leading cause of cancer-related deaths related to late diagnosis, poor survival rates, and high incidence of metastasis. Unfortunately, pancreatic cancer is predicted to become the third leading cause of cancer deaths in the future. Therefore, diagnosis at the early stages of pancreatic cancer for initial diagnosis or postoperative recurrence is a great challenge, as well as predicting prognosis precisely in the context of biomarker discovery. From the personalized medicine perspective, the lack of molecular biomarkers for patient selection confines tailored therapy options, including selecting drugs and their doses or even diet. Currently, there is no standardized pancreatic cancer screening strategy using molecular biomarkers, but CA19-9 is the most well known marker for the detection of pancreatic cancer. In contrast, recent innovations in high-throughput techniques have enabled the discovery of specific biomarkers of cancers using genomics, transcriptomics, proteomics, metabolomics, glycomics, and metagenomics. Panels combining CA19-9 with other novel biomarkers from different "omics" levels might represent an ideal strategy for the early detection of pancreatic cancer. The systems biology approach may shed a light on biomarker identification of pancreatic cancer by integrating multi-omics approaches. In this review, we provide background information on the current state of pancreatic cancer biomarkers from multi-omics stages. Furthermore, we conclude this review on how multi-omics data may reveal new biomarkers to be used for personalized medicine in the future.
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Affiliation(s)
- Beste Turanli
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
| | - Esra Yildirim
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
| | - Gizem Gulfidan
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
| | - Kazim Yalcin Arga
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
- Turkish Institute of Public Health and Chronic Diseases, 34718 Istanbul, Turkey
| | - Raghu Sinha
- Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA
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23
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Xu W, Yang W, Wu C, Ma X, Li H, Zheng J. Enolase 1 Correlated With Cancer Progression and Immune-Infiltrating in Multiple Cancer Types: A Pan-Cancer Analysis. Front Oncol 2021; 10:593706. [PMID: 33643901 PMCID: PMC7902799 DOI: 10.3389/fonc.2020.593706] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 12/22/2020] [Indexed: 12/13/2022] Open
Abstract
Enolase 1 (ENO1) is an oxidative stress protein expressed in endothelial cells. This study aimed to investigate the correlation of ENO1 with prognosis, tumor stage, and levels of tumor-infiltrating immune cells in multiple cancers. ENO1 expression and its influence on tumor stage and clinical prognosis were analyzed by UCSC Xena browser, Gene Expression Profiling Interactive Analysis (GEPIA), The Cancer Genome Atlas (TCGA), and GTEx Portal. The ENO1 mutation analysis was performed by cBio Portal, and demonstrated ENO1 mutation (1.8%) did not impact on tumor prognosis. The relationship between ENO1 expression and tumor immunity was analyzed by Tumor Immune Estimation Resource (TIMER) and GEPIA. The potential functions of ENO1 in pathways were investigated by Gene Set Enrichment Analysis. ENO1 expression was significantly different in tumor and corresponding normal tissues. ENO1 expression in multiple tumor tissues correlated with prognosis and stage. ENO1 showed correlation with immune infiltrates including B cells, CD8+ and CD4+ T cells, macrophages, neutrophils, and dendritic cells, and tumor purity. ENO1 was proved to be involved in DNA replication, cell cycle, apoptosis, glycolysis process, and other processes. These findings indicate that ENO1 is a potential prognostic biomarker that correlates with cancer progression immune infiltration.
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Affiliation(s)
- Wenhua Xu
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Wenna Yang
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Chunfeng Wu
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Xiaocong Ma
- Graduate School, Guangxi University of Chinese Medicine, Nanning City, China
| | - Haoyu Li
- Department of Ophthalmology, Jingliang Eye Hospital Affiliated to Guangxi Medical University, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Jinghui Zheng
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
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24
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White MG, Lee A, Vicente D, Hall C, Kim MP, Katz MHG, Lee JE, Ikoma N, Lucci A, Tzeng CWD. Measurement of Portal Vein Blood Circulating Tumor Cells is Safe and May Correlate With Outcomes in Resected Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol 2021; 28:4615-4622. [PMID: 33415562 DOI: 10.1245/s10434-020-09518-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/05/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND This study investigated the safety and feasibility of intraoperative portal vein blood (PVB) collection at the time of pancreatic ductal adenocarcinoma (PDAC) resection. Relationships of circulating tumor cells (CTCs) in PVB and peripheral blood (PB) with overall survival (OS) and recurrence-free survival were studied. METHODS Patients undergoing PDAC resection were offered enrollment in a prospective liquid biopsy protocol. The patients had PB drawn before incision and PVB drawn before tumor mobilization, then again immediately after resection. Using standard CellSearch protocols, CTCs were identified and compared with OS. RESULTS Of the 34 patients enrolled in this study, 23 (68%) underwent pancreaticoduodenectomy, 8 (23%) underwent distal pancreatectomy, and 3 (9%) underwent total pancreatectomy. Peripheral blood was available for 22 (65%) and PVB for 31 (91%) of the patients. No bleeding or thrombotic complications occurred with the PVB draws. The CTC counts per 7.5 mL of PVB collected before and after resection were highly correlated (R2 = 0.89). The study found CTCs in 11 (50%) of 22 PB samples and 22 (71%) of 31 PVB samples. The OS rate at 18 months was 92% for the patients with < 3 CTCs, 71% for the patients with ≥ 3 CTCs per 7.5 mL of PB (p = 0.30), 100% for the patients without PVB CTCs, and 70% for the patients with PVB CTCs (p < 0.01). CONCLUSIONS Collection of PVB during PDAC resection is safe. In this pilot study, PVB CTC counts but not PB CTC counts were significantly correlated with OS. This opens the door for future studies on selective omission of adjuvant chemotherapy for patients treated preoperatively and tailored surveillance intensity for patients without PVB CTCs at PDAC resection.
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Affiliation(s)
- Michael G White
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew Lee
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Diego Vicente
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Carolyn Hall
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael P Kim
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Matthew H G Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeffrey E Lee
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naruhiko Ikoma
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anthony Lucci
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ching-Wei D Tzeng
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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25
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Pelle M, Das AAK, Madden LA, Paunov VN. Bioimprint Mediated Label-Free Isolation of Pancreatic Tumor Cells from a Healthy Peripheral Blood Cell Population. ADVANCED BIOSYSTEMS 2020; 4:e2000054. [PMID: 33016004 DOI: 10.1002/adbi.202000054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 09/22/2020] [Indexed: 11/11/2022]
Abstract
New techniques are required for earlier diagnosis and response to treatment of pancreatic cancer. Here, a label-free approach is reported in which circulating pancreatic tumor cells are isolated from healthy peripheral blood cells via cell bioimprinting technology. The method involves pre-fabrication of pancreatic cell layers and sequential casting of cell surfaces with a series of custom-made resins to produce negative cell imprints. The imprint is functionalized with a combination of polymers to engineer weak attraction to the cells which is further amplified by the increased area of contact with the matching cells. A flow-through bioimprint chip is designed and tested for selectivity toward two pancreatic tumor cell lines, ASPC-1 and Mia-PaCa-2. Healthy human peripheral blood mononuclear cells (PBMCs) are spiked with pancreatic tumor cells at various concentrations. Bioimprints are designed for preferential retention of the matching pancreatic tumor cells and with respect to PBMCs. Tumor bioimprints are capable of capturing and concentrating pancreatic tumor cells from a mixed cell population with increased retention observed with the number of seedings. ASPC-1 bioimprints preferentially retain both types of pancreatic tumor cells. This technology could be relevant for the collection and interrogation of liquid biopsies, early detection, and relapse monitoring of pancreatic cancer patients.
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Affiliation(s)
- Marie Pelle
- Department of Chemistry and Biochemistry, University of Hull, Hull, HU6 7RX, UK
| | - Anupam A K Das
- Department of Chemistry and Biochemistry, University of Hull, Hull, HU6 7RX, UK
| | - Leigh A Madden
- Department of Biomedical Sciences, University of Hull, Hull, HU6 7RX, UK
| | - Vesselin N Paunov
- Department of Chemistry and Biochemistry, University of Hull, Hull, HU6 7RX, UK
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26
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Nagai M, Sho M, Akahori T, Nakagawa K, Nakamura K. Application of liquid biopsy for surgical management of pancreatic cancer. Ann Gastroenterol Surg 2020; 4:216-223. [PMID: 32490335 PMCID: PMC7240145 DOI: 10.1002/ags3.12317] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 12/19/2019] [Accepted: 01/17/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Although drug development over the past decade has gradually improved the prognosis of PDAC, the prognosis remains extremely poor. The predominant determinant of a poor prognosis is that patients are already at the advanced stage when they are diagnosed. Therefore, it is essential to detect early-stage PDAC to ensure a good prognosis. However, in general, being asymptomatic at the early stage makes the detection of early-stage PDAC very difficult. Recently, much attention has been focused on the utility of a liquid biopsy as a biomarker. Theoretically, early-stage tumors can be detected even under asymptomatic conditions. A number of studies on liquid biopsies have been reported so far. Several biomarkers, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCS), and exosomes, are used in liquid biopsies, with the potential to be applied to the clinical setting. Each biomarker is reported to have different utilities, such as the detection of early-stage disease, the differential diagnosis of PDAC from other types of pancreatic tumors, the prediction of the prognosis or risk of recurrence, and monitoring the treatment response. In this review, we focus on ctDNA, CTCS, and exosomes as representative liquid biopsy biomarkers and describe the specific functions of each biomarker in the treatment of PDAC. Furthermore, we discuss the application of liquid biopsies, especially for the surgical management of PDAC.
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Affiliation(s)
- Minako Nagai
- Department of Surgery Nara Medical University Kashihara Japan
| | - Masayuki Sho
- Department of Surgery Nara Medical University Kashihara Japan
| | | | - Kenji Nakagawa
- Department of Surgery Nara Medical University Kashihara Japan
| | - Kota Nakamura
- Department of Surgery Nara Medical University Kashihara Japan
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27
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Duan X, Zhao L, Dong H, Zhao W, Liu S, Sui G. Microfluidic Immunoassay System for Rapid Detection and Semi-Quantitative Determination of a Potential Serum Biomarker Mesothelin. ACS Sens 2019; 4:2952-2957. [PMID: 31602975 DOI: 10.1021/acssensors.9b01430] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Mesothelin (MSLN) is considered as a potential serological tumor biomarker for early diagnosis of pancreatic cancer. Nevertheless, low sensibility, high reagent consumption, and time costs of traditional detection methods limit their utility in clinical disease diagnoses. Here, we combined the immunoassay technique with microfluidic chips to develop a microfluidic immunoassay system (MIAS) that can be used for rapid semi-quantitative detection of serum MSLN levels. The MIAS was composed of 12 uniform structures, including 12 inlets, 12 reaction chambers, and one outlet allowing measurement of four samples with three repeats, simultaneously. A unique microarray cylinder was located at the end of each reaction chamber where immunoassay was performed to trap microspheres. A feasible interception efficiency (∼80%) was attained, with microspheres filling the reaction column. It has been demonstrated that fluorescence intensity is proportional to the MSLN concentration on the MIAS (R2 = 0.95). Subsequently, 16 clinical serum samples collected from Changhai Hospital, Shanghai were selected from eight patients with pancreatic cancers, four with pancreatitis, and four with other digestive system diseases (2 gastric cancer, 1 bile duct stricture, and 1 bile duct stones). MSLN levels for these samples were detected via MIAS. The results showed a significant correlation between MIAS and traditional enzyme-linked immunosorbent assay (ELISA), with the correlation coefficient, 0.93. The detection limit of MSLN fluorescence intensity and concentration was ∼6 a.u. and ∼20 pg/mL, respectively. The entire duration of analysis by MIAS decreased to ∼40 min compared to 2 h by ELISA. Statistical analysis of MIAS data revealed that MSLN was overexpressed in pancreatic cancer than in the others (P value = 0.0014). Moreover, the diagnostic accuracies of MSLN detected by MIAS and CA19-9 detected by ELISA in hospitals were 87.5 and 81.3%, respectively. MSLN is helpful for the early diagnosis of pancreatic cancer and other diseases, and it had a significant ability to discriminate between pancreatic and nonpancreatic cancers (P value = 0.0159). The results from this study show that MIAS has the potential to become a new serological tumor marker detection platform for rapid detection and semi-quantitative determination of MSLN and would have broad applications in early clinical diagnosis.
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Affiliation(s)
- Xiaoxiao Duan
- Shanghai Key Laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
| | - Linlin Zhao
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
| | - Heng Dong
- Shanghai Key Laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
| | - Wang Zhao
- Shanghai Key Laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
| | - Sixiu Liu
- Shanghai Key Laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
| | - Guodong Sui
- Shanghai Key Laboratory of Atmospheric Particle Pollution Prevention (LAP3), Department of Environmental Science & Engineering, Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
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28
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Vicente D, Lee AJ, Hall CS, Lucci A, Lee JE, Kim MP, Katz MH, Hurd MW, Maitra A, Rhim, MD AD, Tzeng CWD. Circulating Tumor Cells and Transforming Growth Factor Beta in Resected Pancreatic Adenocarcinoma. J Surg Res 2019; 243:90-99. [DOI: 10.1016/j.jss.2019.04.090] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/05/2019] [Accepted: 04/30/2019] [Indexed: 12/22/2022]
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29
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Wei T, Zhang X, Zhang Q, Yang J, Chen Q, Wang J, Li X, Chen J, Ma T, Li G, Gao S, Lou J, Que R, Wang Y, Dang X, Zheng L, Liang T, Bai X. Vimentin-positive circulating tumor cells as a biomarker for diagnosis and treatment monitoring in patients with pancreatic cancer. Cancer Lett 2019; 452:237-243. [DOI: 10.1016/j.canlet.2019.03.009] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 03/04/2019] [Accepted: 03/10/2019] [Indexed: 12/12/2022]
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30
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Zeinali M, Murlidhar V, Fouladdel S, Shao S, Zhao L, Cameron H, Bankhead A, Shi J, Cuneo KC, Sahai V, Azizi E, Wicha MS, Hafner M, Simeone DM, Nagrath S. Profiling Heterogeneous Circulating Tumor Cells (CTC) Populations in Pancreatic Cancer Using a Serial Microfluidic CTC Carpet Chip. ADVANCED BIOSYSTEMS 2018; 2. [DOI: 10.1002/adbi.201800228] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Indexed: 01/24/2023]
Abstract
AbstractAlthough isolation of circulating tumor cells (CTCs) from pancreatic adenocarcinoma patients is feasible, investigating their clinical utility has proven less successful than other cancers due to the limitations of epithelial cellular adhesion molecule (EpCAM)‐only based CTC assays. An integrated technology‐ and biology‐based approach using a microfluidic “Carpet Chip” is presented to study the biological relevance of heterogeneous CTC populations. Both epithelial CTCs (EpCs) and epithelial‐to‐mesenchymal transition (EMT)‐like CTCs (EMTCs) are isolated simultaneously from the whole blood of pancreatic cancer (PaCa) patients (n = 35) by separately targeting two surface markers: EpCAM and CD133. Recovery of cancer cell lines spiked into whole blood is ≥97% with >76% purity. Thirty‐four patients had ≥5 EpCs mL−1 and 35 patients had ≥15 EMTCs mL−1. Overall, significantly higher numbers of EMTCs than EpCs are recovered, reflecting the aggressive nature of PaCa. Furthermore, higher numbers of EMTCs are observed in patients with lymph node involvement compared to patients without. Gene expression profiling of CTCs from 17 patients reveals that CXCR1 is significantly upregulated in EpCs, while known stem cell markers POU5F1/Oct‐4 and MYC are upregulated in EMTCs. In conclusion, successful isolation and genomic profiling of heterogeneous CTC populations are demonstrated, revealing genetic signatures relevant to patient outcomes.
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Affiliation(s)
- Mina Zeinali
- Department of Chemical Engineering and Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC B10‐A184 Ann Arbor MI 48109 USA
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
- Institute for Medical Technology of Heidelberg University & University of Applied Sciences Mannheim Mannheim 68163 Germany
| | - Vasudha Murlidhar
- Department of Chemical Engineering and Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC B10‐A184 Ann Arbor MI 48109 USA
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
| | - Shamileh Fouladdel
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
- Department of Internal Medicine University of Michigan Ann Arbor MI 48109 USA
| | - Shimeng Shao
- Department of Chemical Engineering and Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC B10‐A184 Ann Arbor MI 48109 USA
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
| | - Lili Zhao
- Biostatistics Department University of Michigan Ann Arbor MI 48109 USA
| | - Heather Cameron
- Department of Surgery and Molecular and Integrative Physiology University of Michigan 1500 E. Medical Center Drive, 2210B Taubman Center Ann Arbor MI 48109 USA
| | - Armand Bankhead
- Biostatistics Department University of Michigan Ann Arbor MI 48109 USA
- Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI 48109 USA
| | - Jiaqi Shi
- Department of Pathology University of Michigan Ann Arbor MI 48109 USA
| | - Kyle C. Cuneo
- Department of Radiation Oncology University of Michigan Ann Arbor MI 48109 USA
| | - Vaibhav Sahai
- Department of Internal Medicine University of Michigan Ann Arbor MI 48109 USA
| | - Ebrahim Azizi
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
- Department of Internal Medicine University of Michigan Ann Arbor MI 48109 USA
| | - Max S. Wicha
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
- Department of Internal Medicine University of Michigan Ann Arbor MI 48109 USA
| | - Mathias Hafner
- Institute for Medical Technology of Heidelberg University & University of Applied Sciences Mannheim Mannheim 68163 Germany
| | - Diane M. Simeone
- Department of Surgery and Molecular and Integrative Physiology University of Michigan 1500 E. Medical Center Drive, 2210B Taubman Center Ann Arbor MI 48109 USA
| | - Sunitha Nagrath
- Department of Chemical Engineering and Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC B10‐A184 Ann Arbor MI 48109 USA
- Biointerfaces Institute University of Michigan 2800 Plymouth Road, NCRC Ann Arbor MI 48109 USA
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31
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Samandari M, Julia MG, Rice A, Chronopoulos A, Del Rio Hernandez AE. Liquid biopsies for management of pancreatic cancer. Transl Res 2018; 201:98-127. [PMID: 30118658 DOI: 10.1016/j.trsl.2018.07.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/17/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is one of the main causes of cancer-related deaths worldwide. It is asymptomatic at an early stage, and most diagnosis occurs when the disease is already at a late stage, by which time the tumor is nonresectable. In order to increase the overall survival of patients with pancreatic cancer, as well as to decrease the cancer burden, it is necessary to perform early diagnosis, prognosis stratifications and cancer monitoring using accurate, minimally invasive, and cost-effective methods. Liquid biopsies seek to detect tumor-associated biomarkers in a variety of extractable body fluids and can help to monitor treatment response and disease progression, and even predict patient outcome. In patients with pancreatic cancer, tumor-derived materials, primarily circulating tumor DNA, circulating tumor cells and exosomes, are being studied for inclusion in the management of the disease. This review focuses on describing the biology of these biomarkers, methods for their enrichment and detection, as well as their potential for clinical application. Moreover, we discuss the future direction of liquid biopsies and introduce how they can be exploited toward point of care personalized medicine for the management of pancreatic cancer.
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Affiliation(s)
- Mohamadmahdi Samandari
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - María Gil Julia
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Alistair Rice
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Antonios Chronopoulos
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
| | - Armando E Del Rio Hernandez
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom.
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32
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Vilhav C, Engström C, Naredi P, Novotny A, Bourghardt-Fagman J, Iresjö BM, Asting AG, Lundholm K. Fractional uptake of circulating tumor cells into liver-lung compartments during curative resection of periampullary cancer. Oncol Lett 2018; 16:6331-6338. [PMID: 30405768 PMCID: PMC6202519 DOI: 10.3892/ol.2018.9435] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 08/02/2018] [Indexed: 12/25/2022] Open
Abstract
Circulating tumor cells (CTCs) are able to predict outcome in patients with breast, colon and prostate cancer and appear to be promising biomarkers of pancreatic carcinoma. The aim of the present study was to demonstrate a statistically significant portal-arterial difference of CTCs during curative resection of periampullary cancer. A commercially available instrument (IsofluxR) was used to quantify blood content of CTC in 10 patients with periampullary cancer according to preoperative diagnostics. Portal and arterial blood samples (~8 ml each) were simultaneously collected intra-operatively following surgical dissection prior to division of the pancreas for tumor removal. Quantitative CTC analyses were performed according to standardized protocols for immune-magnetic enrichment of CTC. Flow cytometry was applied for qualitative evaluations of various CTC markers in 7 patients. There was a statistically significant difference in the number of CTCs collected in the portal blood [58±14 cells per 100 ml; mean ± standard error (SE)] vs. arterial blood [24±7 cells per 100 ml (SE), P<0.025]. A fractional uptake of ≥40% across liver and lung compartments of assumed malignant CTC was estimated to correspond to the appearance of ~410 tumor cells per minute during pancreatic resections based on estimated hepatic blood flow, measured tumor cell mass and tumor cell proliferation activity. Complications in the collection of portal blood were not observed. A significant uptake across liver or lung compartments of potentially malignant tumor CTCs from periampullary carcinoma may represent a model to capture, define and characterize cell clones with metastatic potential in liver and lung tissues following surgical resection.
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Affiliation(s)
- Caroline Vilhav
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-41346, Sweden
| | - Cecilia Engström
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-41346, Sweden
| | - Peter Naredi
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-41346, Sweden
| | - Ann Novotny
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-41346, Sweden
| | - Johan Bourghardt-Fagman
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-41346, Sweden
| | - Britt-Marie Iresjö
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-41346, Sweden
| | - Annika G Asting
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-41346, Sweden
| | - Kent Lundholm
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-41346, Sweden
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Ou H, Huang Y, Xiang L, Chen Z, Fang Y, Lin Y, Cui Z, Yu S, Li X, Yang D. Circulating Tumor Cell Phenotype Indicates Poor Survival and Recurrence After Surgery for Hepatocellular Carcinoma. Dig Dis Sci 2018; 63:2373-2380. [PMID: 29926241 DOI: 10.1007/s10620-018-5124-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 05/11/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Circulating tumors cells (CTCs) may be a promising prognostic marker for patients with malignant tumors. However, there are few reports regarding its value for hepatocellular carcinoma (HCC) patients. AIMS To investigate CTCs with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for HCC patients. METHODS Peripheral blood samples were obtained from 165 HCC patients before radical surgery. CTCs were isolated via the CanPatrol CTC enrichment technique and classified using epithelial-mesenchymal transition (EMT) markers. The relationship of CTC phenotype with clinicopathological factors and HCC recurrence in patients was analyzed. RESULTS CTC-positive status (count ≥ 2/5 mL) was found in 70.9% of the 165 HCC patients. Increased CTC number was more common in patients with higher AFP levels, multiple tumors, advanced TNM and BCLC staging, and presence of embolus or microembolus (P < 0.05). CTCs heterogeneity was noted using EMT markers. Mesenchymal CTCs were significantly correlated with high AFP levels, multiple tumors, advanced TNM and BCLC stage, presence of embolus or microembolus, and earlier recurrence (P < 0.05). The presence of mesenchymal CTCs predicted the shortest relapse-free survival, followed by mixed phenotypic CTCs, and then epithelial CTCs (P < 0.001). CONCLUSION CTC phenotype may serve as a prognostic indicator for HCC patients. CTCs assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers.
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Affiliation(s)
- Huohui Ou
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Yu Huang
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Leyang Xiang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Zhanjun Chen
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Yinghao Fang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Yixiong Lin
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Zhonglin Cui
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Sheng Yu
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Xianghong Li
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
| | - Dinghua Yang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
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Garcia-Algar M, Fernandez-Carrascal A, Olano-Daza A, Guerrini L, Feliu N, Parak WJ, Guimera R, Garcia-Rico E, Alvarez-Puebla RA. Adaptive metabolic pattern biomarker for disease monitoring and staging of lung cancer with liquid biopsy. NPJ Precis Oncol 2018; 2:16. [PMID: 30109276 PMCID: PMC6082903 DOI: 10.1038/s41698-018-0059-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 06/19/2018] [Accepted: 06/21/2018] [Indexed: 12/17/2022] Open
Abstract
In this manuscript, we demonstrate the applicability of a metabolic liquid biopsy for the monitoring and staging of patients with lung cancer. This method provides an unbiased detection strategy to establish a more precise correlation between CTC quantification and the actual burden of disease, therefore improving the accuracy of staging based on current imaging techniques. Also, by applying statistical analysis techniques and probabilistic models to the metabolic status and distribution of peripheral blood mononuclear cell (PBMC) populations "perturbed" by the presence of CTCs, a new category of adaptive metabolic pattern biomarker (AMPB) is described and unambiguously correlated to the different clinical stages of the patients. In fact, this strategy allows for classification of different categories of disease within a single stage (stage IV) before computed tomography (CT) and positron emission tomography (PET) scans and with lower uncertainty.
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Affiliation(s)
- Manuel Garcia-Algar
- Department of Physical Chemistry, Universitat Rovira i Virgili, Marcel•lí Domingo 1, 43007 Tarragona, Spain
| | - Ana Fernandez-Carrascal
- Department of Physical Chemistry, Universitat Rovira i Virgili, Marcel•lí Domingo 1, 43007 Tarragona, Spain
| | - Ana Olano-Daza
- Department of Medical Oncology, Hospital Universitario HM Torrelodones, Castillo de Olivares s/n, 28250 Torrelodones Madrid, Spain
| | - Luca Guerrini
- Department of Physical Chemistry, Universitat Rovira i Virgili, Marcel•lí Domingo 1, 43007 Tarragona, Spain
| | - Neus Feliu
- Karolinska Institutet, Stockholm, Sweden
- Universität Hamburg, CHyN, Luruper Chaussee 149, 22607 Hamburg, Germany
| | - Wolfgang J. Parak
- Universität Hamburg, CHyN, Luruper Chaussee 149, 22607 Hamburg, Germany
| | - Roger Guimera
- Department of Chemical Engineering, Universitat Rovira i Virgili, Avinguda dels Països Catalans 26, 43007 Tarragona, Spain
- ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain
| | - Eduardo Garcia-Rico
- Department of Medical Oncology, Hospital Universitario HM Torrelodones, Castillo de Olivares s/n, 28250 Torrelodones Madrid, Spain
| | - Ramon A. Alvarez-Puebla
- Department of Physical Chemistry, Universitat Rovira i Virgili, Marcel•lí Domingo 1, 43007 Tarragona, Spain
- ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain
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Xiao B, Huang Z, Zhou R, Zhang J, Yu B. The Prognostic Value of Expression of the Long Noncoding RNA (lncRNA) Small Nucleolar RNA Host Gene 1 (SNHG1) in Patients with Solid Malignant Tumors: A Systematic Review and Meta-Analysis. Med Sci Monit 2018; 24:5462-5472. [PMID: 30080819 PMCID: PMC6091164 DOI: 10.12659/msm.911687] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2018] [Accepted: 07/16/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) is expressed in solid malignant tumors. The aim of this systematic review and meta-analysis was to determine whether expression of the lncRNA SNHG1 was associated with prognosis in patients with malignancy. MATERIAL AND METHODS A literature review from Jan 1970 to July 2018 identified publications in the English language. Databases searched included: PubMed, OVID, Web of Science, the Cochrane Database, Embase, EBSCO, Google Scholar. Systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Newcastle-Ottawa Scale (NOS) assessment tool for risk of bias was used. RESULTS Eight publications (570 patients) and eight solid tumors were identified, including osteosarcoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, esophageal cancer, ovarian cancer, glioma, and gastric cancer. Meta-analysis showed that expression of the lncRNA SNHG1 was significantly correlated with reduced overall survival (OS) (HR=1.917; 95% CI, 1.58-2.31) (P<0.001). Subgroup analysis showed that lncRNA SNHG1 expression was significantly correlated with TNM stage (OR=3.99; 95% CI, 2.48-6.43) and lymph node metastasis (OR=3.12; 95% CI, 1.95-4.98). There were no significant correlations between lncRNA SNHG1 expression and patient gender, tumor subtype, or tumor size. CONCLUSIONS Systematic literature review and meta-analysis identified eight publications that included 570 patients with eight types of solid malignant tumor, and showed that the expression of the lncRNA SNHG1 was significantly associated with worse clinical outcome.
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Affiliation(s)
- Bufan Xiao
- The First Clinical Medical College, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Zhaohao Huang
- The First Clinical Medical College, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Ruihao Zhou
- The First Clinical Medical College, Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Jingtao Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
| | - Bentong Yu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P.R. China
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Phase Ib trial combining capecitabine, erlotinib and bevacizumab in pancreatic adenocarcinoma - REBECA trial. Invest New Drugs 2018; 37:127-138. [PMID: 29998365 DOI: 10.1007/s10637-018-0639-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 07/06/2018] [Indexed: 11/27/2022]
Abstract
Background Purpose of this phase Ib trial was to establish the maximum tolerable dose (MTD) of capecitabine and to escalate the dosages of erlotinib and bevacizumab to determine the recommended phase II dose (RP2D) in patients with advanced/metastatic pancreatic adenocarcinoma not pretreated for metastatic disease. Methods Starting doses were capecitabine 500 mg/m2 bid orally continuously, erlotinib 100 mg orally daily, and bevacizumab 5 mg/kg intravenously q 2 weeks. Dose escalation was performed according to a 3 + 3 design for capecitabine until MTD, for erlotinib and bevacizumab until the maximum doses registered by applying a substance-related, toxicity-based scheme accompanied by pharmacokinetic analysis. Circulating tumor cells (CTCs) were determined pretherapeutically by immunohistochemical identification after enrichment with immunomagnetic separation. Results Thirty patients were evaluable at six dose levels. 900 mg/m2 bid were determined as MTD for capecitabine based on dose-limiting toxicities: cutaneous in two patients and vascular in another. The most severe (Grade (G)3/4) drug-related treatment-emergent adverse events (toxicities) belonged to the categories gastrointestinal, vascular, cutaneous, cardiovascular, metabolic/nutritional or hematological. G3 toxicities occurred in 14 (47%), G3 + G4 in a single (3%) patient. 2 out of 28 patients (7%) exerted partial response, 17 (61%) stable disease. Pharmacokinetic evaluation revealed lack of drug-drug interaction between capecitabine and erlotinib and their metabolites. Presence of CTCs was associated with shorter progression-free survival (p = 0.009). Conclusions The study met the primary objective. RP2D was capecitabine 800 mg/m2 bid continuously, erlotinib 150 mg daily, and bevacizumab 10 mg/kg q 2 weeks. The regimen could be applied safely, but demonstrated limited efficacy.
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Armstrong EA, Beal EW, Chakedis J, Paredes AZ, Moris D, Pawlik TM, Schmidt CR, Dillhoff ME. Exosomes in Pancreatic Cancer: from Early Detection to Treatment. J Gastrointest Surg 2018; 22:737-750. [PMID: 29423813 DOI: 10.1007/s11605-018-3693-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/12/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Pancreatic cancer (PC) remains one of the most fatal forms of cancer worldwide with incidence nearly equal to mortality. This is often attributed to the fact that diagnosis is often not made until later disease stages when treatment proves difficult. Efforts have been made to reduce the mortality of PC through improvements in early screening techniques and treatments of late-stage disease. Exosomes, small extracellular vesicles involved in cellular communication, have shown promise in helping understand PC disease biology. METHODS In this review, we discuss current studies of the role of exosomes in PC physiology, and their potential use as diagnostic and treatment tools. RESULTS Exosomes have a role in diagnosing pancreatic cancer and in understanding tumor biology including migration, proliferation, chemoresistance, immunosuppression, cachexia and diabetes, and have a potential role in therapy for pancreatic cancer. CONCLUSIONS Exosomal analysis is beneficial in demonstrating mechanisms behind PC growth and metastasis, immunosuppression, drug resistance, and paraneoplastic conditions. Furthermore, the use of exosomes can be beneficial in detecting early-stage PC and exosomes have potential applications as therapeutic targets.
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Affiliation(s)
- Emily A Armstrong
- The Ohio State University College of Medicine, Columbus, OH, 43210, USA
| | - Eliza W Beal
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 320 W 10th Ave. M256 Starling Loving Hall, Columbus, OH, 43210, USA.
| | - Jeffery Chakedis
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 320 W 10th Ave. M256 Starling Loving Hall, Columbus, OH, 43210, USA
| | - Anghela Z Paredes
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 320 W 10th Ave. M256 Starling Loving Hall, Columbus, OH, 43210, USA
| | - Demetrios Moris
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 320 W 10th Ave. M256 Starling Loving Hall, Columbus, OH, 43210, USA
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 320 W 10th Ave. M256 Starling Loving Hall, Columbus, OH, 43210, USA
| | - Carl R Schmidt
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 320 W 10th Ave. M256 Starling Loving Hall, Columbus, OH, 43210, USA
| | - Mary E Dillhoff
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 320 W 10th Ave. M256 Starling Loving Hall, Columbus, OH, 43210, USA
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Recent advances and perspectives on capture and concentration of label-free rare cells for biomedical science and engineering research. J Taiwan Inst Chem Eng 2018. [DOI: 10.1016/j.jtice.2018.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Wu G, Zhu R, Li Y, Zhao Y, Dai M. Prognostic significance of circulating tumor microemboli in patients with pancreatic ductal adenocarcinoma. Oncol Lett 2018; 15:7376-7382. [PMID: 29725451 DOI: 10.3892/ol.2018.8264] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 02/28/2018] [Indexed: 01/05/2023] Open
Abstract
The significance of circulating tumor microemboli (CTMs) in patients with pancreatic ductal adenocarcinoma (PDAC) is still unknown. Thus, the present study used a epithelial cellular adhesion molecule independent subtraction and immunostaining-fluorescence in situ hybridization (SET-iFISH) platform to enumerate circulating tumor cells (CTCs) and CTMs in a total of 86 peripheral blood samples from 19 patients with PDAC. The associations between CTCs and CTMs with clinicopathologic factors and prognoses were analyzed. Prior to treatment, CTCs were detected in all 19 patients, and CTMs were detected in 4 patients with different tumor-node-metastasis (TNM) stages. A total of 85 of the 86 peripheral blood samples had cytokeratin 18-negative CTCs. The number of CTCs and CTMs were significantly associated with tumor size and vascular invasion. Patients with CTMs had poorer overall survival and disease-free survival when compared with those without CTMs (7.3 vs. 25.40 months, P=0.001; and 1.80 vs. 18.97 months, P=0.037). The presence of CTMs in the peripheral blood prior to surgery was predictive of poor prognosis in PDAC patients. CTMs could be detected in patients of different TNM stage (II, III and IV). Surgery did not benefit patients with CTMs, thus, surgeons should take greater consideration when assessing the requirements for surgery in patients with CTMs.
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Affiliation(s)
- Guangdong Wu
- Department of General Surgery, Peking Union Medical College Hospital, Beijing 100730, P.R. China
| | - Rongrong Zhu
- Department of General Surgery, Peking Union Medical College Hospital, Beijing 100730, P.R. China
| | - Yatong Li
- Department of General Surgery, Peking Union Medical College Hospital, Beijing 100730, P.R. China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Beijing 100730, P.R. China
| | - Menghua Dai
- Department of General Surgery, Peking Union Medical College Hospital, Beijing 100730, P.R. China
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Tesfaye AA, Kamgar M, Azmi A, Philip PA. The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities. Expert Rev Anticancer Ther 2018; 18:131-148. [PMID: 29254387 PMCID: PMC6121777 DOI: 10.1080/14737140.2018.1417844] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Accepted: 12/12/2017] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer related mortality in the United States in 2030, with a 5-year overall survival of less than 10% despite decades of extensive research. Pancreatic cancer is marked by the accumulation of complex molecular changes, complex tumor-stroma interaction, and an immunosuppressive tumor microenvironment. PDAC has proven to be resistant to many cytotoxic, targeted and immunologic treatment approaches. Areas covered: In this paper, we review the major areas of research in PDAC, with highlights on the challenges and areas of opportunity for personalized treatment approaches. Expert commentary: The focus of research in pancreatic cancer has moved away from developing conventional cytotoxic combinations. The marked advances in understanding the molecular biology of this disease especially in the areas of the microenvironment, metabolism, and DNA repair have opened new opportunities for developing novel treatment strategies. Improved understanding of molecular abnormalities allows the development of personalized treatment approaches.
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Affiliation(s)
- Anteneh A Tesfaye
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI
- Barbara Ann Karmanos Cancer Institute, Detroit, MI
| | - Mandana Kamgar
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI
- Barbara Ann Karmanos Cancer Institute, Detroit, MI
| | - Asfar Azmi
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI
- Barbara Ann Karmanos Cancer Institute, Detroit, MI
| | - Philip A Philip
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI
- Barbara Ann Karmanos Cancer Institute, Detroit, MI
- Department of Pharmacology, Wayne State University, School of Medicine, Detroit, MI
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Nordgård O, Tjensvoll K, Gilje B, Søreide K. Circulating tumour cells and DNA as liquid biopsies in gastrointestinal cancer. Br J Surg 2018; 105:e110-e120. [DOI: 10.1002/bjs.10782] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 10/02/2017] [Accepted: 11/09/2017] [Indexed: 12/15/2022]
Abstract
Abstract
Background
Blood is the most extensively studied body fluid and, because it contains circulating tumour cells (CTCs) and circulating tumour-derived cell-free DNA (ctDNA), it may represent a liquid biopsy for cancer. Methods for enrichment and detection of CTCs and ctDNA, their clinical applications and future opportunities in gastrointestinal cancers were the focus of this review.
Methods
The PubMed database was searched for literature up to 24 June 2017, with a focus on the past 10 years. Identified articles were further scrutinized for relevant references. Articles were those in English relating to colorectal, gastric and pancreatic cancer.
Results
Both CTCs and ctDNA are in low abundance compared with other cellular components of blood, but effective enrichment and highly sensitive techniques are available for their detection. Potential clinical applications of these liquid biopsies include screening, prognostic stratification, therapy administration, monitoring of treatment effect or resistance, and surveillance. Liquid biopsies provide opportunities to reduce the need for invasive tissue sampling, especially in the context of intratumoral heterogeneity and the need for tumour genotyping.
Conclusion
Liquid biopsies have applications in gastrointestinal cancers to improve clinical decision-making.
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Affiliation(s)
- O Nordgård
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
- Department of Mathematics and Natural Science, University of Stavanger, Stavanger, Norway
| | - K Tjensvoll
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - B Gilje
- Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - K Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Clinical Surgery, Royal Infirmary of Edinburgh and University of Edinburgh, Edinburgh, UK
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Yamada M, Sugiura T, Okamura Y, Ito T, Yamamoto Y, Ashida R, Sasaki K, Nagino M, Uesaka K. Microscopic Venous Invasion in Pancreatic Cancer. Ann Surg Oncol 2018; 25:1043-1051. [PMID: 29302820 DOI: 10.1245/s10434-017-6324-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Microscopic venous invasion (MVI) and the subsequent peripheral blood circulation of cancer cells are considered to be the primary route for systemic dissemination of pancreatic cancer. METHODS Patients who underwent pancreatectomy for invasive ductal carcinoma of the pancreas between January 2007 and December 2015 were retrospectively reviewed. The prognostic significance of MVI was analyzed. RESULTS A total of 352 patients underwent pancreatectomy for invasive ductal carcinoma of the pancreas. A pathologic examination showed MVI in 228 (64.5%) of the patients. The median survival time (MST) was 21 months for the patients with MVI and 58 months for those without MVI (p < 0.001). A multivariate analysis showed the following to be significant prognostic factors: non-administration of adjuvant chemotherapy [hazard ratio (HR) 2.37; p < 0.001], lymph node metastasis (HR 2.95; p = 0.001), CA19-9 value of 300 U/ml or higher (HR 1.70; p = 0.018), and MVI (HR 1.84; p = 0.011). The overall survival was clearly stratified into three groups; favorable (MST not reached in stage 1 or 2A without MVI; p = 0.867), moderate (30 months in stage 2A with MVI and 30 months in stage 2B without MVI; p = 0.528), and poor (19 months in stage 2B with MVI and 17 months in stage 4; p = 0.322). The differences between these three groups all were significant. CONCLUSIONS Approximately two-thirds of patients with radiologically resectable pancreatic cancer had MVI and were considered to have potentially systemic disease. This study identified MVI as one of the significant factors for a poor prognosis and a valuable complement of tumor-node-metastasis staging.
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Affiliation(s)
- Mihoko Yamada
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.,Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.
| | - Yukiyasu Okamura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Takaaki Ito
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yusuke Yamamoto
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Ryo Ashida
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Keiko Sasaki
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Masato Nagino
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
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Integrated Bioinformatics Analysis of Potential Biomarkers for Prostate Cancer. Pathol Oncol Res 2017; 25:455-460. [PMID: 29260398 DOI: 10.1007/s12253-017-0346-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/20/2017] [Indexed: 12/18/2022]
Abstract
The aim was to expound the pathogenesis of prostate cancer and to identify the potentially biomarkers for prostate cancer (PC). DNA methylation microarray data GSE38240 containing 8 prostate cancer metastases and 4 normal prostate samples as well as gene expression profile data GSE26910 containing 6 prostate primary tumors and 6 normal samples were used. Differentially expressed genes (DEGs) and differently methylated sites of PC were screened and the regulatory network was constructed with DEGs-related transcription factors (TFs). The obtained hub genes were subjected to protein-protein interaction network analysis. Enrichment analysis of down-regulated DEGs were performed. Total 351 DEGs including 190 down-regulated and 161 up-regulated genes and 3234 differently methylated sites were identified. In total 69 DEGs-related TFs were found. Regulatory network contained 1301 nodes and 2527 connection pairs and that FOXA1 (forkhead box A1), BZRAP1-AS1 (benzodiazapine receptor associated protein 1 antisense RNA 1) and KRT8 (keratin 8) were the top three nodes of it. The enriched GO terms were mainly biological activity of the blood and cells-related. Total 29 DEGs (such as AGTR1, angiotensin II receptor, type 1) and 57 none-DEGs involved in the PPI network. Biological functions in blood circulation and the involved AGTR1 may play important roles in PC by gene-methylation. Besides, BZRAP1-AS1 may be novel biomarker related with PC.
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Yang L, Dong H, Li Z, Pan Y, Qu L, Tan Z. Correlation between circulating tumor cells and D-D and platelet in patients with pulmonary malignancies. Oncol Lett 2017; 15:2169-2172. [PMID: 29434921 PMCID: PMC5776933 DOI: 10.3892/ol.2017.7595] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 11/20/2017] [Indexed: 12/18/2022] Open
Abstract
The aim of the present study was to investigate the correlation between circulating tumor cells (CTC) and D-dimer (D-D) and platelet (PLT) in patients with pulmonary malignancies. A total of 98 patients with lung cancer admitted to West China Hospital, Sichuan University, from June 2016 to February 2017 were enrolled in the present study. D-D and PLT levels were measured in the fasting elbow vein of the patients. The expression of CTC in peripheral blood was detected by negative separation using immunomagnetic beads and immunocytochemical staining. The correlation between CTC and D-D and PLT in patients with lung cancer was analyzed. The mean level of D-D in the peripheral blood of 98 patients was 1.80±1.63 µg/l, and the level of D-D was correlated with distant metastasis (P<0.05). The mean level of PLT in peripheral blood was 305.53±141.22×109/l in 98 patients, and the level of PLT was correlated with patient age, clinical stage and distant metastasis (P<0.05). The levels of D-D, PLT and distant metastasis were significantly higher in CTC-positive than in CTC-negative patients (P<0.05). Therefore, CTC can predict the distant metastasis of lung cancer, and the incidence of distant metastasis is high in patients with hypercoagulable state.
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Affiliation(s)
- Lijun Yang
- School of Medicine, Tibet University, Lhasa, Tibet 850000, P.R. China
| | - Hai Dong
- School of Medicine, Tibet University, Lhasa, Tibet 850000, P.R. China
| | - Zixuan Li
- School of Medicine, Tibet University, Lhasa, Tibet 850000, P.R. China
| | - Yongyue Pan
- School of Medicine, Tibet University, Lhasa, Tibet 850000, P.R. China
| | - La Qu
- School of Medicine, Tibet University, Lhasa, Tibet 850000, P.R. China
| | - Zhiwen Tan
- School of Medicine, Tibet University, Lhasa, Tibet 850000, P.R. China
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Del Re M, Vivaldi C, Rofi E, Vasile E, Miccoli M, Caparello C, d'Arienzo PD, Fornaro L, Falcone A, Danesi R. Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer. Sci Rep 2017; 7:7931. [PMID: 28801547 PMCID: PMC5554237 DOI: 10.1038/s41598-017-08297-z] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 07/06/2017] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PDAC) is still lacking of reliable markers to monitor tumor response. CA 19-9 is the only biomarker approved, despite it has several limitations in sensitivity and specificity. Since mutations of KRAS occur in more than 90% of tumors, its detection in circulating free tumor DNA (cftDNA) could represent a biomarker to monitor chemotherapy response. Twenty-seven advanced PDAC patients given first-line 5-fluorouracil, irinotecan and oxaliplatin or gemcitabine and nab-paclitaxel were enrolled. Three ml of plasma were collected: 1) before starting chemotherapy (baseline); 2) at day 15 of treatment; and 3) at each clinical follow-up. cftDNA was extracted and analysed for KRAS mutations (mutKRAS) by digital droplet PCR. Nineteen patients displayed a mutKRAS in baseline plasma samples. There was a statistically significant difference in progression-free survival (PFS) and overall survival (OS) in patients with increase vs. stability/reduction of cftDNA in the sample collected at day 15 (median PFS 2.5 vs 7.5 months, p = 0.03; median OS 6.5 vs 11.5 months, p = 0.009). The results of this study demonstrate that cftDNA mutKRAS changes are associated with tumor response to chemotherapy and support the evidence that mutKRAS in plasma may be used as a new marker for monitoring treatment outcome and disease progression in PDAC.
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Affiliation(s)
- Marzia Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Caterina Vivaldi
- Medical Oncology Unit, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Eleonora Rofi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Enrico Vasile
- Medical Oncology Unit, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Mario Miccoli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Chiara Caparello
- Medical Oncology Unit, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Paolo Davide d'Arienzo
- Medical Oncology Unit, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.,Sant'Anna School of Advanced Studies, Department of Medical Sciences, Pisa, Italy
| | - Lorenzo Fornaro
- Medical Oncology Unit, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Alfredo Falcone
- Medical Oncology Unit, Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Romano Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Circulating and disseminated tumor cells in pancreatic cancer and their role in patient prognosis: a systematic review and meta-analysis. Oncotarget 2017; 8:107223-107236. [PMID: 29291024 PMCID: PMC5739809 DOI: 10.18632/oncotarget.19928] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 07/25/2017] [Indexed: 12/22/2022] Open
Abstract
Background Disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) have been postulated to seed metastases and contribute to poorer patient outcomes in many types of solid cancer. To date, no systematic reviews have examined the role of both DTCs and CTCs in pancreatic cancer. We aimed to determine the prognostic value of DTCs/CTCs in pancreatic cancer using a systematic review and meta-analysis. Materials and Methods A comprehensive literature search identified studies examining DTCs and CTCs in the bone marrow and blood of pancreatic cancer patients at diagnosis with follow-up to determine disease-free/progression-free survival (DFS/PFS) and overall survival (OS). Statistical analyses were performed to determine the hazard ratio (HR) of DTCs/CTCs on DFS/PFS and OS. Results The literature search identified 16 articles meeting the inclusion criteria. The meta-analysis demonstrated statistically significant HR differences in DFS/PFS (HR = 1.93, 95% CI 1.19–3.11, P = 0.007) and OS (HR = 1.84, 95% CI 1.37–2.45, P =< 0.0001), indicating patients with detectable DTCs/CTCs at diagnosis have worse prognoses. Subgroup analyses suggested CTCs in the peripheral blood (HR =2.03) were more indicative of poor OS prognosis than DTCs in the bone marrow (HR = 1.91), although the difference between these was not statistically significant. Positivity of the CellSearch detection method for DTC/CTC had the highest correlation with decreased OS (HR = 2.79) while immunodetection (HR = 1.91) and RT-PCR (HR = 1.25) were less effective in determining prognosis. Conclusion The detection of DTCs/CTCs at diagnosis is associated with poorer DFS/PFS and OS in pancreatic cancer.
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Moravec R, Divi R, Verma M. Detecting circulating tumor material and digital pathology imaging during pancreatic cancer progression. World J Gastrointest Oncol 2017; 9:235-250. [PMID: 28656074 PMCID: PMC5472554 DOI: 10.4251/wjgo.v9.i6.235] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 03/04/2017] [Accepted: 03/24/2017] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer (PC) is a leading cause of cancer-related death worldwide. Clinical symptoms typically present late when treatment options are limited and survival expectancy is very short. Metastatic mutations are heterogeneous and can accumulate up to twenty years before PC diagnosis. Given such genetic diversity, detecting and managing the complex states of disease progression may be limited to imaging modalities and markers present in circulation. Recent developments in digital pathology imaging show potential for early PC detection, making a differential diagnosis, and predicting treatment sensitivity leading to long-term survival in advanced stage patients. Despite large research efforts, the only serum marker currently approved for clinical use is CA 19-9. Utility of CA 19-9 has been shown to improve when it is used in combination with PC-specific markers. Efforts are being made to develop early-screening assays that can detect tumor-derived material, present in circulation, before metastasis takes a significant course. Detection of markers that identify circulating tumor cells and tumor-derived extracellular vesicles (EVs) in biofluid samples offers a promising non-invasive method for this purpose. Circulating tumor cells exhibit varying expression of epithelial and mesenchymal markers depending on the state of tumor differentiation. This offers a possibility for monitoring disease progression using minimally invasive procedures. EVs also offer the benefit of detecting molecular cargo of tumor origin and add the potential to detect circulating vesicle markers from tumors that lack invasive properties. This review integrates recent genetic insights of PC progression with developments in digital pathology and early detection of tumor-derived circulating material.
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Circulating Tumor Cell Phenotype Predicts Recurrence and Survival in Pancreatic Adenocarcinoma. Ann Surg 2017; 264:1073-1081. [PMID: 26756760 DOI: 10.1097/sla.0000000000001600] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE We assessed circulating tumor cells (CTCs) with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for patients with pancreatic adenocarcinoma (PDAC). BACKGROUND PDAC is the fourth leading cause of cancer death in the United States. There is an urgent need to develop biomarkers that predict patient prognosis and allow for better treatment stratification. METHODS Peripheral and portal blood samples were obtained from 50 patients with PDAC before surgical resection and filtered using the Isolation by Size of Epithelial Tumor cells method. CTCs were identified by immunofluorescence using commercially available antibodies to cytokeratin, vimentin, and CD45. RESULTS Thirty-nine patients (78%) had epithelial CTCs that expressed cytokeratin but not CD45. Twenty-six (67%) of the 39 patients had CTCs which also expressed vimentin, a mesenchymal marker. No patients had cytokeratin-negative and vimentin-positive CTCs. The presence of cytokeratin-positive CTCs (P < 0.01), but not mesenchymal-like CTCs (P = 0.39), was associated with poorer survival. The presence of cytokeratin-positive CTCs remained a significant independent predictor of survival by multivariable analysis after accounting for other prognostic factors (P < 0.01). The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01). Among patients with cancer recurrence, those with vimentin-positive and cytokeratin-expressing CTCs had decreased median time to recurrence compared with patients without CTCs (P = 0.02). CONCLUSIONS CTCs are an exciting potential strategy for understanding the biology of metastases, and provide prognostic utility for PDAC patients. CTCs exist as heterogeneous populations, and assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers.
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Lapin M, Tjensvoll K, Oltedal S, Javle M, Smaaland R, Gilje B, Nordgård O. Single-cell mRNA profiling reveals transcriptional heterogeneity among pancreatic circulating tumour cells. BMC Cancer 2017; 17:390. [PMID: 28569190 PMCID: PMC5452374 DOI: 10.1186/s12885-017-3385-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 05/24/2017] [Indexed: 01/05/2023] Open
Abstract
Background Single-cell mRNA profiling of circulating tumour cells may contribute to a better understanding of the biology of these cells and their role in the metastatic process. In addition, such analyses may reveal new knowledge about the mechanisms underlying chemotherapy resistance and tumour progression in patients with cancer. Methods Single circulating tumour cells were isolated from patients with locally advanced or metastatic pancreatic cancer with immuno-magnetic depletion and immuno-fluorescence microscopy. mRNA expression was analysed with single-cell multiplex RT-qPCR. Hierarchical clustering and principal component analysis were performed to identify expression patterns. Results Circulating tumour cells were detected in 33 of 56 (59%) examined blood samples. Single-cell mRNA profiling of intact isolated circulating tumour cells revealed both epithelial-like and mesenchymal-like subpopulations, which were distinct from leucocytes. The profiled circulating tumour cells also expressed elevated levels of stem cell markers, and the extracellular matrix protein, SPARC. The expression of SPARC might correspond to an epithelial-mesenchymal transition in pancreatic circulating tumour cells. Conclusion The analysis of single pancreatic circulating tumour cells identified distinct subpopulations and revealed elevated expression of transcripts relevant to the dissemination of circulating tumour cells to distant organ sites. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3385-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Morten Lapin
- Department of Haematology and Oncology, Stavanger University Hospital, N-4068, Stavanger, Norway. .,Laboratory for Molecular Biology, Stavanger University Hospital, N-4068, Stavanger, Norway. .,Department of Mathematics and Natural Sciences, University of Stavanger, N-4036, Stavanger, Norway.
| | - Kjersti Tjensvoll
- Department of Haematology and Oncology, Stavanger University Hospital, N-4068, Stavanger, Norway.,Laboratory for Molecular Biology, Stavanger University Hospital, N-4068, Stavanger, Norway
| | - Satu Oltedal
- Department of Haematology and Oncology, Stavanger University Hospital, N-4068, Stavanger, Norway.,Laboratory for Molecular Biology, Stavanger University Hospital, N-4068, Stavanger, Norway
| | - Milind Javle
- Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA
| | - Rune Smaaland
- Department of Haematology and Oncology, Stavanger University Hospital, N-4068, Stavanger, Norway.,Laboratory for Molecular Biology, Stavanger University Hospital, N-4068, Stavanger, Norway
| | - Bjørnar Gilje
- Department of Haematology and Oncology, Stavanger University Hospital, N-4068, Stavanger, Norway.,Laboratory for Molecular Biology, Stavanger University Hospital, N-4068, Stavanger, Norway
| | - Oddmund Nordgård
- Department of Haematology and Oncology, Stavanger University Hospital, N-4068, Stavanger, Norway.,Laboratory for Molecular Biology, Stavanger University Hospital, N-4068, Stavanger, Norway
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50
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Detection of Circulating Tumor Cells Using Negative Enrichment Immunofluorescence and an In Situ Hybridization System in Pancreatic Cancer. Int J Mol Sci 2017; 18:ijms18040622. [PMID: 28333072 PMCID: PMC5412265 DOI: 10.3390/ijms18040622] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 03/05/2017] [Accepted: 03/07/2017] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is the most lethal type of gastrointestinal cancer, and early detection and monitoring is an urgent problem. Circulating tumor cells (CTCs) are emerging as a non-invasive biomarker for tumor detection. However, the low sensitivity is a main problem in the traditional CellSearch System for detecting CTCs, especially in patients with PC. In this study, we used negative enrichment (NE), immunofluorescence and in situ hybridization (FISH) of chromosome 8 (NE-iFISH) to capture and identify CTCs in PC patients. We showed that the NE-iFISH system exhibited a dramatically high detection rate of CTCs in PC patients (90%). The diagnostic rate of PC reached 97.5% when combining CTCs ≥ 2 and carbohydrate antigen 19-9 (CA19-9) > 37 µmol/L. The 1-year survival in the group of CTCs < 3 was significantly higher than that of CTCs ≥ 3 (p = 0.043). In addition, we analyzed the role of chromosomal instability in CTCs detection. The group of triploid (three hybridization signals of chromosome 8) CTCs ≥ 3 showed a shorter 1-year survival (p = 0.0279) and overall survival (p = 0.0188) than the group with triploid CTCs < 3. Importantly, the triploid CTC number but not the overall CTC counts could be a predictor of chemo-sensitivity. Moreover, circulating tumor microembolus (CTMs) were found in stage IV patients, and were positively related to the poor response to chemotherapy. In conclusion, the NE-iFISH system significantly improved the positive detection rate of CTCs and triploid CTC could be used to predict prognosis or the response to the chemotherapy of PC patients. CTM is a potential indicator of the chemotherapeutic effect in advanced PC patients.
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