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Qiu Y, Xia J, Wang X. Tracking Acute Rejection in Heart Transplant Recipients by Using Donor-Derived Cell-Free DNA: A Promising Approach. EXP CLIN TRANSPLANT 2025; 23:241-246. [PMID: 40396703 DOI: 10.6002/ect.2024.0300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
Biomarkers play a crucial role in posttransplant monitoring as they enable early detection of graft dysfunction and rejection, thereby facilitating personalized therapeutic interventions. Although recent studies have demonstrated the potential of donor-derived cell-free DNA in monitoring acute rejection episodes in heart transplant recipients, further investigations are required to enhance its diagnostic accuracy and clinical applicability. Comprehensive clinical trials are warranted to establish standardized threshold values and evaluate the diagnostic utility of donor-derived cell-free DNA in identifying various patterns of allograft injury. A thorough investigation into the molecular mechanisms, clinical applications, and quantification methods of donor-derived cell-free DNA could substantially enhance posttransplant management and patient outcomes.
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Affiliation(s)
- Yan Qiu
- From the Department of Cardiovascular Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences/Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, China
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Götze J, Meißner K, Pereira-Veiga T, Belloum Y, Schneegans S, Kropidlowski J, Gorgulho J, Busch A, Honselmann KC, Schönrock M, Putscher A, Peine S, Nitschke C, Simon R, Spindler V, Izbicki JR, Hackert T, Bokemeyer C, Pantel K, Uzunoglu FG, Sinn M, Wikman H. Identification and characterization of tumor and stromal derived liquid biopsy analytes in pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res 2025; 44:14. [PMID: 39815324 PMCID: PMC11737273 DOI: 10.1186/s13046-024-03262-x] [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: 09/05/2024] [Accepted: 12/19/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND The lack of predictive biomarkers contributes notably to the poor outcomes of patients with pancreatic ductal adenocarcinoma (PDAC). Cancer-associated fibroblasts (CAFs) are the key components of the prominent PDAC stroma. Data on clinical relevance of CAFs entering the bloodstream, known as circulating CAFs (cCAFs) are scarce. Here, we developed a combined liquid biopsy assay to detect cCAFs and circulating tumor cells (CTCs) in metastatic PDAC (mPDAC) and other metastatic gastrointestinal malignancies (mGI). In addition, we evaluated plasma hyaluronan (HA) levels as a complementary surrogate biomarker of the stromal extent in patients with PDAC. METHODS A sequential liquid biopsy assay based on a two step-enrichment, combining marker dependent and independent cell enrichment, was established for cCAF and CTC detection and validated in mPDAC and mGI patients. The enriched cells were identified by multiplex immunofluorescence. HA measurement was performed by ELISA on blood samples from healthy blood donors (HD), localized and late-stage PDAC patients. RESULTS cCAFs (≥ 1cCAFs/7.5 mL blood) were detected in 95.4% of mPDAC and in 78.2% of mGI patients, with significantly higher numbers in mPDAC compared to mGI patients (mean number 22.7 vs. 11.0; P = 0.0318). mPDAC patients with ≥ 15 cCAFs/7.5 mL blood had a significant shorter median overall survival (mOS 3.2 months (95% confidence interval (CI) 0.801-5.855) vs. 14.2 months (95% CI 6.055-22.332); P = 0.013), whereby CTC levels were not associated with mOS. In mGI neither cCAFs nor CTCs had a significant impact on OS. HA plasma levels in mPDAC patients were significantly higher compared to HD (mean 123.0 ng/mL vs. 74.45 ng/mL, P = 0.015). High HA in localized and late-stage PDAC were associated with a significantly shorter mOS (mOSlocalized PDAC: 12.6 months vs. 23.5 months (P = 0.008); mOSmPDAC: 1.8 months vs. 5.3 months (P = 0.004)). CONCLUSIONS Our liquid biopsy assay provides robust detection of cCAFs in mPDAC and mGI patients. The measurement of both circulatory stromal parameters, cCAFs and HA, adds valuable clinical information as they are associated with an unfavorable outcome in PDAC. These results highlight that stromal characteristics unique to PDAC could be leveraged to fill the current gap in discovering predictive biomarkers.
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Affiliation(s)
- Julian Götze
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany.
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany.
| | - Kira Meißner
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Thais Pereira-Veiga
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Yassine Belloum
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Svenja Schneegans
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Jolanthe Kropidlowski
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Joao Gorgulho
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany
| | - Alina Busch
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany
| | - Kim Christin Honselmann
- Department of Surgery, University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
| | - Martin Schönrock
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany
| | - Arne Putscher
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Sven Peine
- Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Nitschke
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Mildred Scheel Cancer Career Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Volker Spindler
- Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob Robert Izbicki
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thilo Hackert
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Carsten Bokemeyer
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany
| | - Faik Güntaç Uzunoglu
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marianne Sinn
- Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, University Cancer Center Hamburg, Martinistr, 52, 20248, Hamburg, Germany.
| | - Harriet Wikman
- Department of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr, 52, 20248, Hamburg, Germany.
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Hussung S, Hess ME, Haghighi EB, Wittel UA, Boerries M, Fritsch RM. Integrated Analysis of Cell-Free DNA and Novel Protein Biomarkers for Stratification and Therapy Monitoring in Stage IV Pancreatic Cancer: A Preliminary Study. Diagnostics (Basel) 2024; 15:49. [PMID: 39795577 PMCID: PMC11720586 DOI: 10.3390/diagnostics15010049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 12/25/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025] Open
Abstract
Background: Given the poor prognosis of metastatic pancreatic adenocarcinoma (mPDAC), closer disease monitoring through liquid biopsy, most frequently based on serial measurements of cell-free mutated KRAS (KRASmut cfDNA), has become a highly active research focus, aimed at improving patients' long-term outcomes. However, most of the available data show only a limited predictive and prognostic value of single-parameter-based methods. We hypothesized that a combined longitudinal analysis of KRASmut cfDNA and novel protein biomarkers could improve risk stratification and molecular monitoring of patients with mPDAC. Methods: We prospectively collected 160 plasma samples from 47 patients with mPDAC at our institution. Highly sensitive single-target ddPCR assays were employed to detect and quantify KRASmut cfDNA. Additionally, analysis of ten protein biomarkers was performed through Enzyme-linked Immunosorbent Assay (ELISA), and Carbohydrate-Antigen 19-9 (CA 19-9) dynamics were registered. Results: KRASmut cfDNA was detectable in 37/47 (78.7%) patients throughout the course of study, and CA 19-9 levels were elevated in 40 out of 47 (85.1%) patients. KRASmut cfDNA increase at the time of the first follow-up could predict inferior progression-free survival (PFS) (Hazard ratio (HR) = 3.40, p = 0.0003) and overall survival (OS) (HR = 4.91, p < 0.0001). In contrast to CA 19-9 kinetics, which were not predictive of outcome, integrated analysis of KRASmut cfDNA combined with six evaluated circulating protein biomarkers allowed basal risk stratification at the time of the first follow-up (HR = 10.2, p = 0.0014). Conclusions: A combined longitudinal analysis of KRASmut cfDNA with selected protein biomarkers offers significantly improved prognostic value for patients with mPDAC compared to single-parameter methods. This innovative approach is a step forward in the molecular monitoring of mPDAC and should be validated in further prospective studies.
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Affiliation(s)
- Saskia Hussung
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, 79106 Freiburg, Germany;
- Department of Medical Oncology and Hematology, Zurich University Hospital, 8091 Zurich, Switzerland
| | - Maria E. Hess
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (M.E.H.); (E.B.H.); (M.B.)
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Elham Bavafaye Haghighi
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (M.E.H.); (E.B.H.); (M.B.)
| | - Uwe A. Wittel
- Department of Surgery, Freiburg University Medical Center, 79106 Freiburg, Germany;
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (M.E.H.); (E.B.H.); (M.B.)
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany
| | - Ralph M. Fritsch
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, 79106 Freiburg, Germany;
- Department of Medical Oncology and Hematology, Zurich University Hospital, 8091 Zurich, Switzerland
- Department of Surgery, Freiburg University Medical Center, 79106 Freiburg, Germany;
- German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Gu X, Wei S, Lv X. Circulating tumor cells: from new biological insights to clinical practice. Signal Transduct Target Ther 2024; 9:226. [PMID: 39218931 PMCID: PMC11366768 DOI: 10.1038/s41392-024-01938-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 05/31/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
The primary reason for high mortality rates among cancer patients is metastasis, where tumor cells migrate through the bloodstream from the original site to other parts of the body. Recent advancements in technology have significantly enhanced our comprehension of the mechanisms behind the bloodborne spread of circulating tumor cells (CTCs). One critical process, DNA methylation, regulates gene expression and chromosome stability, thus maintaining dynamic equilibrium in the body. Global hypomethylation and locus-specific hypermethylation are examples of changes in DNA methylation patterns that are pivotal to carcinogenesis. This comprehensive review first provides an overview of the various processes that contribute to the formation of CTCs, including epithelial-mesenchymal transition (EMT), immune surveillance, and colonization. We then conduct an in-depth analysis of how modifications in DNA methylation within CTCs impact each of these critical stages during CTC dissemination. Furthermore, we explored potential clinical implications of changes in DNA methylation in CTCs for patients with cancer. By understanding these epigenetic modifications, we can gain insights into the metastatic process and identify new biomarkers for early detection, prognosis, and targeted therapies. This review aims to bridge the gap between basic research and clinical application, highlighting the significance of DNA methylation in the context of cancer metastasis and offering new avenues for improving patient outcomes.
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Affiliation(s)
- Xuyu Gu
- Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shiyou Wei
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xin Lv
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
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Teja M, Ocanto A, Couñago F. Circulating tumor cells in pancreatic cancer: The prognostic impact in surgical patients. World J Clin Oncol 2024; 15:987-991. [PMID: 39193164 PMCID: PMC11346077 DOI: 10.5306/wjco.v15.i8.987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/27/2024] [Accepted: 07/03/2024] [Indexed: 08/16/2024] Open
Abstract
Pancreatic cancer is associated with a poor prognosis, even in the early stages, mainly due to metastatic progression. New diagnostic techniques that predict unfavorable outcomes are needed in order to improve treatment strategies. Circulating tumor cells (CTCs) are showing promising results as a predictive biomarker for various tumors. In this editorial we comment on the article by Zhang et al, who published the first systematic review and meta-analysis evaluating the prognostic value of CTCs as biomarkers in early-stage pancreatic cancer patients undergoing surgery. CTCs were detected in peripheral or central venous system blood, before or during surgery. Positive CTCs showed a correlation with decreased overall survival and decreased relapse-free, disease-free and progression-free survival in this meta-analysis. However, the heterogeneity was significant. The authors suggest that this result was related to the separation methods used between studies, but other differences such as the margin status or the neoadjuvant and adjuvant treatments used are also important to consider. CTCs may be a potential prognostic biomarker in pancreatic cancer patients, but it is necessary to compare and standardize the platforms used to isolate CTCs, to compare different biomarkers from liquid biopsy and to determine the impact on prognosis when therapeutic changes are made based on CTCs levels.
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Affiliation(s)
- Macarena Teja
- Department of Radiation Oncology, GenesisCare-San Francisco de Asís University Hospital, Madrid 28002, Spain
- Department of Radiation Oncology, GenesisCare-Vithas La Milagrosa University Hospital, Madrid 28010, Spain
| | - Abrahams Ocanto
- Department of Radiation Oncology, GenesisCare-San Francisco de Asís University Hospital, Madrid 28002, Spain
- Department of Radiation Oncology, GenesisCare-Vithas La Milagrosa University Hospital, Madrid 28010, Spain
| | - Felipe Couñago
- Department of Radiation Oncology, GenesisCare-San Francisco de Asís University Hospital, Madrid 28002, Spain
- Department of Radiation Oncology, GenesisCare-Vithas La Milagrosa University Hospital, Madrid 28010, Spain
- National Director, GenesisCare Spain, Madrid 28043, Spain
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Ntzifa A, Lianidou E. Epigenetics and CTCs: New biomarkers and impact on tumor biology. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 392:177-198. [PMID: 40287220 DOI: 10.1016/bs.ircmb.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
DNA methylation is one of the best-known epigenetic markers and plays a critical role in the control of gene activity and the architecture of the nucleus of the cell. Epigenetic alterations and especially DNA methylation have a high potential to provide valuable and innovative cancer biomarkers. Liquid biopsy is a unique minimally invasive tool for the management of cancer patients based on the extraction of information through detailed molecular analysis of circulating genetic material in peripheral blood and allows us to characterize the evolution of a solid tumor in real time. DNA methylation in combination with liquid biopsy is very powerful when it comes to providing circulating epigenetic biomarkers of clinical importance. Numerous DNA methylation markers are now being tested in liquid biopsies as potential biomarkers in various types of cancer. DNA methylation is mostly being studied in ctDNA but there are also a small number of studies up to now performed in gDNA isolated from CTCs. A highly important dimension of the combination of liquid biopsy/DNA methylation analysis is its high potential for early cancer detection since alterations in DNA methylation in plasma can be detected very early during cancer pathogenesis. Methylated DNA, modified nucleosomes and noncoding RNAs can be used as blood circulating epigenetic biomarkers for real-time and minimally-invasive cancer monitoring. DNA methylation is very promising and powerful in providing novel biomarkers for improving cancer diagnostics, while another important dimension in this field is the use of DNA methylation inhibitors in cancer treatment. In this chapter we present the current findings on epigenetic alterations detected in CTCs in various types of cancer, and further discuss their potential as novel liquid biopsy-based DNA methylation biomarkers.
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Affiliation(s)
- Aliki Ntzifa
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece
| | - Evi Lianidou
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece.
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Miyahara S, Takahashi H, Akita H, Sasaki K, Mukai Y, Iwagami Y, Hasegawa S, Yamada D, Tomimaru Y, Noda T, Wada H, Kobayashi S, Doki Y, Eguchi H. Prognostic Significance of Biologic Factors in Patients with a Modest Radiologic Response to Neoadjuvant Treatment for Resectable and Borderline Resectable Pancreatic Cancers: Impact of the Combination Index of Sialyl-Lewis Antigen-Related Tumor Markers. Ann Surg Oncol 2024; 31:2932-2942. [PMID: 38368291 DOI: 10.1245/s10434-024-14945-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 01/04/2024] [Indexed: 02/19/2024]
Abstract
BACKGROUND Appropriate re-evaluation after neoadjuvant treatment (NAT) is important for optimal treatment selection. Nonetheless, determining the operative eligibility of patients with a modest radiologic response remains controversial. This study aimed to assess the prognostic significance of biologic factors for patients showing a modest radiologic response to NAT and investigate the tumor markers (TMs), CA19-9 alone, DUPAN-II alone, and their combination, to create an index that combines these sialyl-Lewis antigen-related TMs associated with treatment outcomes. METHODS This study enrolled patients deemed to have a "stable disease" by RECIST classification with slight progression (tumor size increase rate, ≤20%) as their radiologic response after NAT. A sialyl-Lewis-related index (sLe index), calculated by adding one fourth of the serum DUPAN-II value to the CA19-9 value, was created. The prognostic significances of CA19-9, DUPAN-II, and the sLe index were assessed in relation to postoperative outcomes. RESULTS An sLe index lower than the cutoff value (45.25) was significantly associated with favorable disease-free survival. Moreover, the post-NAT sLe index had a higher area under the curve value for recurrence within 24 months than the post-NAT levels of CA19-9 or DUPAN-II alone. Multivariable analysis showed that a post-NAT sLe index higher than 45.25 was the single independent predictive factor for recurrence within 24 months. CONCLUSIONS Additional evaluation of biologic factors can potentially enhance patient selection, particularly for patients showing a limited radiologic response to NAT. The authors' index is a simple indicator for the biologic evaluation of multiple combined sialyl-Lewis antigen-related TMs and may offer a better predictive significance.
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Affiliation(s)
- Satoru Miyahara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka City, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka City, Osaka, Japan.
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka City, Osaka, Japan
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yosuke Mukai
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka City, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shinichiro Hasegawa
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka City, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka City, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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Tharrun Daniel Paul L, Munuswamy-Ramanujam G, Kumar RCS, Ramachandran V, Gnanasampanthapandian D, Palaniyandi K. Recent advancement in molecular markers of pancreatic cancer. BIOMARKERS IN CANCER DETECTION AND MONITORING OF THERAPEUTICS 2024:121-149. [DOI: 10.1016/b978-0-323-95114-2.00025-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Gostomczyk K, Marsool MDM, Tayyab H, Pandey A, Borowczak J, Macome F, Chacon J, Dave T, Maniewski M, Szylberg Ł. Targeting circulating tumor cells to prevent metastases. Hum Cell 2024; 37:101-120. [PMID: 37874534 PMCID: PMC10764589 DOI: 10.1007/s13577-023-00992-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/03/2023] [Indexed: 10/25/2023]
Abstract
Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor, enter the bloodstream or body fluids, and spread to other body parts, leading to metastasis. Their presence and characteristics have been linked to cancer progression and poor prognosis in different types of cancer. Analyzing CTCs can offer valuable information about tumors' genetic and molecular diversity, which is crucial for personalized therapy. Epithelial-mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), play a significant role in generating and disseminating CTCs. Certain proteins, such as EpCAM, vimentin, CD44, and TGM2, are vital in regulating EMT and MET and could be potential targets for therapies to prevent metastasis and serve as detection markers. Several devices, methods, and protocols have been developed for detecting CTCs with various applications. CTCs interact with different components of the tumor microenvironment. The interactions between CTCs and tumor-associated macrophages promote local inflammation and allow the cancer cells to evade the immune system, facilitating their attachment and invasion of distant metastatic sites. Consequently, targeting and eliminating CTCs hold promise in preventing metastasis and improving patient outcomes. Various approaches are being explored to reduce the volume of CTCs. By investigating and discussing targeted therapies, new insights can be gained into their potential effectiveness in inhibiting the spread of CTCs and thereby reducing metastasis. The development of such treatments offers great potential for enhancing patient outcomes and halting disease progression.
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Affiliation(s)
- Karol Gostomczyk
- Department of Obstetrics, Gynaecology and Oncology, Chair of Pathomorphology and Clinical Placentology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland.
- University Hospital No. 2 Im. Dr Jan Biziel, Ujejskiego 75, 85-168, Bydgoszcz, Poland.
| | | | | | | | - Jędrzej Borowczak
- Department of Obstetrics, Gynaecology and Oncology, Chair of Pathomorphology and Clinical Placentology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland
| | - Facundo Macome
- Universidad del Norte Santo Tomás de Aquino, San Miquel de Tucuman, Argentina
| | - Jose Chacon
- American University of Integrative Sciences, Cole Bay, Saint Martin, Barbados
| | - Tirth Dave
- Bukovinian State Medical University, Chernivtsi, Ukraine
| | - Mateusz Maniewski
- Department of Obstetrics, Gynaecology and Oncology, Chair of Pathomorphology and Clinical Placentology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland
| | - Łukasz Szylberg
- Department of Obstetrics, Gynaecology and Oncology, Chair of Pathomorphology and Clinical Placentology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland
- Department of Tumor Pathology and Pathomorphology, Oncology Centre, Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
- Chair of Pathology, Dr Jan Biziel Memorial University Hospital No. 2, Bydgoszcz, Poland
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Zhang ZH, Bao YW, Zhao YJ, Wang JQ, Guo JT, Sun SY. Circulating tumor cells as potential prognostic biomarkers for early-stage pancreatic cancer: A systematic review and meta-analysis. World J Clin Oncol 2023; 14:504-517. [PMID: 38059182 PMCID: PMC10696218 DOI: 10.5306/wjco.v14.i11.504] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/14/2023] [Accepted: 10/26/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND Pancreatic cancer is difficult to be diagnosed early clinically, while often leads to poor prognosis. If optimal personalized treatment plan can be provided to pancreatic cancer patient at an earlier stage, this can greatly improve overall survival (OS). Circulating tumor cells (CTCs) are a collective term for various types of tumor cells present in the peripheral blood (PB), which are formed by detachment during the development of solid tumor lesions. Most CTCs undergo apoptosis or are phagocytosed after entering the PB, whereas a few can escape and anchor at distal sites to develop metastasis, increasing the risk of death for patients with malignant tumors. AIM To investigate the significance of CTCs in predicting the prognosis of early pancreatic cancer patients. METHODS The PubMed, EMBASE, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine, and ChinaInfo databases were searched for articles published through December 2022. Studies were considered qualified if they included patients with early pancreatic cancer, analyzed the prognostic value of CTCs, and were full papers reported in English or Chinese. Researches were selected and assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and the Newcastle-Ottawa Scale criteria. We used a funnel plot to assess publication bias. RESULTS From 1595 publications, we identified eight eligible studies that collectively enrolled 355 patients with pancreatic cancer. Among these original studies, two were carried out in China; three in the United States; and one each in Italy, Spain, and Norway. All eight studies analyzed the relevance between CTCs and the prognosis of patients with early-stage pancreatic cancer after surgery. A meta-analysis showed that the patients that were positive pre-treatment or post-treatment for CTCs were associated with decreased OS [hazard ratio (HR) = 1.93, 95% confidence interval (CI): 1.197-3.126, P = 0.007] and decreased relapse-free/disease-free/progression-free survival (HR = 1.27, 95%CI: 1.137-1.419, P < 0.001) in early-stage pancreatic cancer. Additionally, the results suggest no statistically noticeable publication bias for overall, disease-free, progression-free, and recurrence-free survival. CONCLUSION This pooled meta-analysis shows that CTCs, as biomarkers, can afford reliable prognostic information for patients with early-stage pancreatic cancer and help develop individualized treatment plans.
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Affiliation(s)
- Zi-Han Zhang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Yi-Wen Bao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Ya-Jun Zhao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Jian-Quan Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Jin-Tao Guo
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Si-Yu Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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11
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Ungkulpasvich U, Hatakeyama H, Hirotsu T, di Luccio E. Pancreatic Cancer and Detection Methods. Biomedicines 2023; 11:2557. [PMID: 37760999 PMCID: PMC10526344 DOI: 10.3390/biomedicines11092557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/05/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
The pancreas is a vital organ with exocrine and endocrine functions. Pancreatitis is an inflammation of the pancreas caused by alcohol consumption and gallstones. This condition can heighten the risk of pancreatic cancer (PC), a challenging disease with a high mortality rate. Genetic and epigenetic factors contribute significantly to PC development, along with other risk factors. Early detection is crucial for improving PC outcomes. Diagnostic methods, including imagining modalities and tissue biopsy, aid in the detection and analysis of PC. In contrast, liquid biopsy (LB) shows promise in early tumor detection by assessing biomarkers in bodily fluids. Understanding the function of the pancreas, associated diseases, risk factors, and available diagnostic methods is essential for effective management and early PC detection. The current clinical examination of PC is challenging due to its asymptomatic early stages and limitations of highly precise diagnostics. Screening is recommended for high-risk populations and individuals with potential benign tumors. Among various PC screening methods, the N-NOSE plus pancreas test stands out with its high AUC of 0.865. Compared to other commercial products, the N-NOSE plus pancreas test offers a cost-effective solution for early detection. However, additional diagnostic tests are required for confirmation. Further research, validation, and the development of non-invasive screening methods and standardized scoring systems are crucial to enhance PC detection and improve patient outcomes. This review outlines the context of pancreatic cancer and the challenges for early detection.
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Affiliation(s)
| | | | | | - Eric di Luccio
- Hirotsu Bioscience Inc., 22F The New Otani Garden Court, 4-1 Kioi-cho, Chiyoda-ku, Tokyo 102-0094, Japan; (U.U.); (H.H.); (T.H.)
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12
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Yaghoubi Naei V, Bordhan P, Mirakhorli F, Khorrami M, Shrestha J, Nazari H, Kulasinghe A, Ebrahimi Warkiani M. Advances in novel strategies for isolation, characterization, and analysis of CTCs and ctDNA. Ther Adv Med Oncol 2023; 15:17588359231192401. [PMID: 37692363 PMCID: PMC10486235 DOI: 10.1177/17588359231192401] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 07/19/2023] [Indexed: 09/12/2023] Open
Abstract
Over the past decade, the detection and analysis of liquid biopsy biomarkers such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have advanced significantly. They have received recognition for their clinical usefulness in detecting cancer at an early stage, monitoring disease, and evaluating treatment response. The emergence of liquid biopsy has been a helpful development, as it offers a minimally invasive, rapid, real-time monitoring, and possible alternative to traditional tissue biopsies. In resource-limited settings, the ideal platform for liquid biopsy should not only extract more CTCs or ctDNA from a minimal sample volume but also accurately represent the molecular heterogeneity of the patient's disease. This review covers novel strategies and advancements in CTC and ctDNA-based liquid biopsy platforms, including microfluidic applications and comprehensive analysis of molecular complexity. We discuss these systems' operational principles and performance efficiencies, as well as future opportunities and challenges for their implementation in clinical settings. In addition, we emphasize the importance of integrated platforms that incorporate machine learning and artificial intelligence in accurate liquid biopsy detection systems, which can greatly improve cancer management and enable precision diagnostics.
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Affiliation(s)
- Vahid Yaghoubi Naei
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
- Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Pritam Bordhan
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
- Faculty of Science, Institute for Biomedical Materials & Devices, University of Technology Sydney, Australia
| | - Fatemeh Mirakhorli
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
| | - Motahare Khorrami
- Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jesus Shrestha
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
| | - Hojjatollah Nazari
- School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
| | - Arutha Kulasinghe
- Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Majid Ebrahimi Warkiani
- School of Biomedical Engineering, University of Technology Sydney, 1, Broadway, Ultimo New South Wales 2007, Australia
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13
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Takagi T, Nagai M, Nishiwada S, Terai T, Yasuda S, Matsuo Y, Doi S, Kohara Y, Sho M. Importance of triple tumor markers as biomarkers in patients with pancreatic ductal adenocarcinoma. Ann Gastroenterol Surg 2023; 7:326-335. [PMID: 36998299 PMCID: PMC10043775 DOI: 10.1002/ags3.12629] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 09/25/2022] [Indexed: 04/01/2023] Open
Abstract
Aim There is an urgent need to establish biomarkers for the treatment of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the usefulness of the combined assessment of carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and duke pancreatic monoclonal antigen type 2 (DUPAN-2) in PDAC. Methods We retrospectively investigated the impact of three tumor markers on overall survival (OS) and recurrence-free survival (RFS). Patients were classified into two groups: upfront surgery (US) and neoadjuvant chemoradiation (NACRT) groups. Results In total, 310 patients were evaluated. In the US group, patients who had all three elevated markers showed a significantly worse prognosis than the others (median: 16.4 months, P = .005). In the NACRT group, patients who had elevated CA 19-9 and CEA levels after NACRT had significantly worse prognosis than the others (median: 26.2 months, P < .001). The elevated DUPAN-2 levels before NACRT were associated with significantly worse prognosis than normal levels (median: 44.0 vs 59.2 months, P = .030). Patients who had elevated DUPAN-2 levels before NACRT with elevated CA 19-9 and CEA levels after NACRT showed extremely poor RFS (median: 5.9 months). Multivariate analysis revealed that a modified triple-positive tumor marker indicating elevated DUPAN-2 levels before NACRT and elevated CA19-9 and CEA levels after NACRT was an independent prognostic factor of OS (hazard ratio: 2.49, P = .007) and RFS (hazard ration: 2.47, P = .007). Conclusions The combined evaluation of three tumor markers may provide useful information for the treatment of patients with PDAC.
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Affiliation(s)
| | - Minako Nagai
- Department of SurgeryNara Medical UniversityKashiharaJapan
| | | | - Taichi Terai
- Department of SurgeryNara Medical UniversityKashiharaJapan
| | - Satoshi Yasuda
- Department of SurgeryNara Medical UniversityKashiharaJapan
| | - Yasuko Matsuo
- Department of SurgeryNara Medical UniversityKashiharaJapan
| | - Shunsuke Doi
- Department of SurgeryNara Medical UniversityKashiharaJapan
| | | | - Masayuki Sho
- Department of SurgeryNara Medical UniversityKashiharaJapan
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14
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Szymoński K, Chmura Ł, Lipiec E, Adamek D. Vibrational spectroscopy – are we close to finding a solution for early pancreatic cancer diagnosis? World J Gastroenterol 2023; 29:96-109. [PMID: 36683712 PMCID: PMC9850953 DOI: 10.3748/wjg.v29.i1.96] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/03/2022] [Accepted: 10/31/2022] [Indexed: 01/04/2023] Open
Abstract
Pancreatic cancer (PC) is an aggressive and lethal neoplasm, ranking seventh in the world for cancer deaths, with an overall 5-year survival rate of below 10%. The knowledge about PC pathogenesis is rapidly expanding. New aspects of tumor biology, including its molecular and morphological heterogeneity, have been reported to explain the complicated “cross-talk” that occurs between the cancer cells and the tumor stroma or the nature of pancreatic ductal adenocarcinoma-associated neural remodeling. Nevertheless, currently, there are no specific and sensitive diagnosis options for PC. Vibrational spectroscopy (VS) shows a promising role in the development of early diagnosis technology. In this review, we summarize recent reports about improvements in spectroscopic methodologies, briefly explain and highlight the drawbacks of each of them, and discuss available solutions. The important aspects of spectroscopic data evaluation with multivariate analysis and a convolutional neural network methodology are depicted. We conclude by presenting a study design for systemic verification of the VS-based methods in the diagnosis of PC.
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Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Jagiellonian University Medical College, Cracow 33-332, Poland
- Department of Pathomorphology, University Hospital in Cracow, Cracow 31-501, Poland
| | - Łukasz Chmura
- Department of Pathomorphology, Jagiellonian University Medical College, Cracow 33-332, Poland
- Department of Pathomorphology, University Hospital in Cracow, Cracow 31-501, Poland
| | - Ewelina Lipiec
- M. Smoluchowski Institute of Physics, Jagiellonian University, Cracow 30-348, Poland
| | - Dariusz Adamek
- Department of Pathomorphology, University Hospital in Cracow, Cracow 31-501, Poland
- Department of Neuropathology, Jagiellonian University Medical College, Cracow 33-332, Poland
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15
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Blood-based DNA methylation signatures in cancer: A systematic review. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166583. [PMID: 36270476 DOI: 10.1016/j.bbadis.2022.166583] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/30/2022] [Accepted: 10/11/2022] [Indexed: 11/07/2022]
Abstract
DNA methylation profiles are in dynamic equilibrium via the initiation of methylation, maintenance of methylation and demethylation, which control gene expression and chromosome stability. Changes in DNA methylation patterns play important roles in carcinogenesis and primarily manifests as hypomethylation of the entire genome and the hypermethylation of individual loci. These changes may be reflected in blood-based DNA, which provides a non-invasive means for cancer monitoring. Previous blood-based DNA detection objects primarily included circulating tumor DNA/cell-free DNA (ctDNA/cfDNA), circulating tumor cells (CTCs) and exosomes. Researchers gradually found that methylation changes in peripheral blood mononuclear cells (PBMCs) also reflected the presence of tumors. Blood-based DNA methylation is widely used in early diagnosis, prognosis prediction, dynamic monitoring after treatment and other fields of clinical research on cancer. The reversible methylation of genes also makes them important therapeutic targets. The present paper summarizes the changes in DNA methylation in cancer based on existing research and focuses on the characteristics of the detection objects of blood-based DNA, including ctDNA/cfDNA, CTCs, exosomes and PBMCs, and their application in clinical research.
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16
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Dai S, Shao X, Wei Q, Du S, Hou C, Li H, Jin D. Association of circulating tumor cells and IMP3 expression with metastasis of osteosarcoma. Front Oncol 2023; 13:819357. [PMID: 36937398 PMCID: PMC10021108 DOI: 10.3389/fonc.2023.819357] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 01/16/2023] [Indexed: 02/25/2023] Open
Abstract
Background Circulating tumor cells (CTCs) have been identified as a prognostic biomarker of tumors such as breast cancer and nasopharyngeal carcinoma, because they are obtained through a simple and noninvasive blood draw or liquid biopsy, but its clinical significance in osteosarcoma is still unclear. In this study, we analyzed the relationship between CTCs and clinicopathological features and discussed whether CTCs could be used as a biomarker for metastasis in osteosarcoma. Methods We enrolled 50 osteosarcoma patients with Enneking Stage IIB and Stage III and detected CTCs in 5 ml of peripheral blood samples collected from patients using the Canpatrol® CTC detection platform. Subsequently, multiplex RNA in situ hybridization (RNA-ISH) based on various molecular markers was performed to identify and classify CTCs. The relationships between clinical pathological features and CTC counts, subtypes (epithelial type, E type; hybrid epithelial/mesenchymal type, H type; mesenchymal type, M type), and insulin-like growth factor mRNA-binding protein 3 (IMP3) expression in CTCs were analyzed. Results CTCs were detected in 86% (43/50) of the osteosarcoma patients. The CTC counts, especially the total CTCs and H-type CTCs, signifcantly differed between Enneking Stage IIB and Stage III patients (P < 0.05). No significant differences were observed between the CTC count or type and other clinicopathological features (P > 0.05). There were significant differences in the expression of IMP3 in different types of CTCs, and the IMP3 positive rates in E/H/M type CTCs were 38.4, 65.6, and 62.0%, respectively (P < 0.001). Receiver operating characteristic (ROC) curve analysis showed that IMP3-positive CTC count had the best performance for diagnostic metastasis, with the largest area under the curve of 0.873 and cutoff value of four cells/5ml blood (sensitivity = 87.5%; specificity = 82.4%). Serial CTC monitoring in one patient suggested that total CTCs and H-type CTCs were associated with disease progression. Conclusion This study demonstrates that the CTCs, especially the IMP3-positive CTCs and H/M-type CTCs, are related to the metastasis of osteosarcoma.
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Affiliation(s)
- Shuangwu Dai
- Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Xinxin Shao
- Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Qingzhu Wei
- Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Shaohua Du
- Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Changhe Hou
- Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Haomiao Li
- Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
- *Correspondence: Dadi Jin, ; Haomiao Li,
| | - Dadi Jin
- Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
- *Correspondence: Dadi Jin, ; Haomiao Li,
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17
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Lin J, Wu Y, Wang J, Yang R, Wu W, Li B, Chen X, Xue W, Liao Y. Gold island‐enhanced multiplex quantum dots fluorescent system for biomedical analysis of circulating tumor nucleic acids. NANO SELECT 2022. [DOI: 10.1002/nano.202200172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Jingyan Lin
- Department of Thoracic Surgery Shenzhen Third People's Hospital Shenzhen China
| | - Yunxia Wu
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development Department of Biomedical Engineering Jinan University Guangzhou China
- Department of Burn Surgery The First People's Hospital of Foshan Foshan China
| | - Jingru Wang
- Department of Burn Surgery The First People's Hospital of Foshan Foshan China
| | - Ronghua Yang
- Department of Burn and Plastic Surgery Guangzhou First People's Hospital, South China University of Technology Guangzhou China
| | - Wenjie Wu
- Molecular Diagnosis and Treatment Center for Infectious Diseases Dermatology Hospital of Southern Medical University Guangzhou China
| | - Bin Li
- Department of Burn Surgery The First People's Hospital of Foshan Foshan China
- Molecular Diagnosis and Treatment Center for Infectious Diseases Dermatology Hospital of Southern Medical University Guangzhou China
| | - Xiaodong Chen
- Department of Burn Surgery The First People's Hospital of Foshan Foshan China
| | - Wei Xue
- Key Laboratory of Biomaterials of Guangdong Higher Education Institutes Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development Department of Biomedical Engineering Jinan University Guangzhou China
| | - Yuhui Liao
- Molecular Diagnosis and Treatment Center for Infectious Diseases Dermatology Hospital of Southern Medical University Guangzhou China
- Department of Infectious Disease Fifth Affiliated Hospital of Sun Yat‐sen University Zhuhai China
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18
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Characterization of RARRES1 Expression on Circulating Tumor Cells as Unfavorable Prognostic Marker in Resected Pancreatic Ductal Adenocarcinoma Patients. Cancers (Basel) 2022; 14:cancers14184405. [PMID: 36139565 PMCID: PMC9497091 DOI: 10.3390/cancers14184405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/04/2022] [Accepted: 09/01/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Our explorative study used a microfluidic-based approach for circulating tumor cell (CTC) detection in 55 pancreatic ductal adenocarcinoma (PDAC) patients before treatment initiation (baseline) and during follow-up (FUP). For the first time, we assessed the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs. CTCs were detected in 25.5% of patients at baseline, while the detection rate during FUP was higher (45.5%). Especially high CTC counts during FUP in resected patients were associated with early tumor relapse (p = 0.02). Combining CTC detection and RARRES1 protein expression showed that RARRES1-positive patients with high CTCs counts after curative operation during FUP had a worse prognosis (p = 0.001). In conclusion, RARRES1 is a new marker of interest for further research investigations on subtypes of CTCs in PDAC. Abstract Background: In pancreatic ductal adenocarcinoma (PDAC), the characterization of circulating tumor cells (CTCs) opens new insights into cancer metastasis as the leading cause of cancer-related death. Here, we focused on the expression of retinoic acid receptor responder 1 (RARRES1) on CTCs as a novel marker for treatment failure and early relapse. Methods: The stable isotope labeling of amino acids in cell culture (SILAC)—approach was applied for identifying and quantifying new biomarker proteins in PDAC cell lines HPDE and its chemoresistant counterpart, L3.6pl-Res. Fifty-five baseline and 36 follow-up (FUP) peripheral blood samples were processed via a marker-independent microfluidic-based CTC detection approach using RARRES1 as an additional marker. Results: SILAC-based proteomics identified RARRES1 as an abundantly expressed protein in more aggressive chemoresistant PDAC cells. At baseline, CTCs were detected in 25.5% of all PDAC patients, while FUP analysis (median: 11 months FUP) showed CTC detection in 45.5% of the resected patients. CTC positivity (≥3 CTC) at FUP was significantly associated with short recurrence-free survival (p = 0.002). Furthermore, detection of RARRES1 positive CTCs was indicative of an even earlier relapse after surgery (p = 0.001). Conclusions: CTC detection in resected PDAC patients during FUP is associated with a worse prognosis, and RARRES1 expression might identify an aggressive subtype of CTCs that deserves further investigation.
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19
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Sheel A, Addison S, Nuguru SP, Manne A. Is Cell-Free DNA Testing in Pancreatic Ductal Adenocarcinoma Ready for Prime Time? Cancers (Basel) 2022; 14:3453. [PMID: 35884515 PMCID: PMC9322623 DOI: 10.3390/cancers14143453] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/03/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022] Open
Abstract
Cell-free DNA (cfDNA) testing currently does not have a significant role in PDA management: it is insufficient to diagnose PDA, and its use is primarily restricted to identifying targetable mutations (if tissue is insufficient or unavailable). cfDNA testing has the potential to address critical needs in PDA management, such as pre-operative risk stratification (POR), prognostication, and predicting (and monitoring) treatment response. Prior studies have focused primarily on somatic mutations, specifically KRAS variants, and have shown limited success in addressing prognosis and POR. Recent studies have demonstrated the importance of other less prevalent mutations (ERBB2 and TP53), but no studies have provided reliable mutation panels for clinical use. Methylation aberrations in cfDNA (epigenetic markers) in PDA have been relatively less explored. However, early evidence has suggested they offer diagnostic and, to some extent, prognostic value. The inclusion of epigenetic markers of cfDNA adds another dimension to genomic testing and may open new therapeutic avenues beyond addressing critical areas of need in PDA treatment. For cfDNA to substantially influence PDA management, concerted efforts are required to include less frequent mutations and epigenetic markers. Furthermore, relying on KRAS mutations for PDA management will always be inadequate.
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Affiliation(s)
- Ankur Sheel
- Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH 432120, USA;
| | - Sarah Addison
- School of Medicine, The Ohio State University, Columbus, OH 432120, USA;
| | - Surya Pratik Nuguru
- Department of Internal Medicine, Kamineni Academy of Medical Sciences and Research Center, Hyderabad 500012, India;
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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20
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Mullen M, Wen Tan WL, Rhee JW, Wu JC. Modeling Susceptibility to Cardiotoxicity in Cancer Therapy Using Human iPSC-Derived Cardiac Cells and Systems Biology. Heart Fail Clin 2022; 18:335-347. [PMID: 35718410 PMCID: PMC12001829 DOI: 10.1016/j.hfc.2022.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The development of human-induced pluripotent stem cell-derived cardiac cell types has created a new paradigm in assessing drug-induced cardiotoxicity. Advances in genomics and epigenomics have also implicated several genomic loci and biological pathways that may contribute to susceptibility to cancer therapies. In this review, we first provide a brief overview of the cardiotoxicity associated with chemotherapy. We then provide a detailed summary of systems biology approaches being applied to elucidate potential molecular mechanisms involved in cardiotoxicity. Finally, we discuss combining systems biology approaches with iPSC technology to help discover molecular mechanisms associated with cardiotoxicity.
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Affiliation(s)
- McKay Mullen
- Stanford Cardiovascular Institute, Stanford University, 265 Campus Drive G1120B, Stanford, CA 94304, USA
| | - Wilson Lek Wen Tan
- Stanford Cardiovascular Institute, Stanford University, 265 Campus Drive G1120B, Stanford, CA 94304, USA
| | - June-Wha Rhee
- Department of Medicine, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA 91010, USA.
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University, 265 Campus Drive G1120B, Stanford, CA 94304, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University; Department of Radiology, Stanford University, 265 Campus Drive G1120B, Stanford, CA 94304, USA.
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21
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Götze J, Nitschke C, Uzunoglu FG, Pantel K, Sinn M, Wikman H. Tumor-Stroma Interaction in PDAC as a New Approach for Liquid Biopsy and its Potential Clinical Implications. Front Cell Dev Biol 2022; 10:918795. [PMID: 35712663 PMCID: PMC9197075 DOI: 10.3389/fcell.2022.918795] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/05/2022] [Indexed: 12/29/2022] Open
Abstract
The extremely poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) has remained unchanged for decades. As a hallmark of PDAC histology, the distinct desmoplastic response in the tumor microenvironment is considered a key factor exerting pro- and antitumor effects. Increasing emphasis has been placed on cancer-associated fibroblasts (CAFs), whose heterogeneity and functional diversity is reflected in the numerous subtypes. The myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs) and antigen presenting CAFs (apCAFs) are functionally divergent CAF subtypes with tumor promoting as well as repressing effects. Precise knowledge of the underlying interactions is the basis for a variety of treatment approaches, which are subsumed under the term antistromal therapy. Clinical implementation is still pending due to the lack of benefit-as well as paradoxical preclinical findings. While the prominent significance of CAFs in the immediate environment of the tumor is becoming clear, less is known about the circulating (c)CAFs. cCAFs are of particular interest as they seem not only to be potential new liquid biopsy biomarkers but also to support the survival of circulating tumor cells (CTC) in the bloodstream. In PDAC, CTCs correlate with an unfavorable outcome and can also be employed to monitor treatment response, but the current clinical relevance is limited. In this review, we discuss CTCs, cCAFs, secretomes that include EVs or fragments of collagen turnover as liquid biopsy biomarkers, and clinical approaches to target tumor stroma in PDAC.
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Affiliation(s)
- Julian Götze
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, Hamburg, Germany.,Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christine Nitschke
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Faik G Uzunoglu
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marianne Sinn
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, Hamburg, Germany
| | - Harriet Wikman
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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22
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Szymoński K, Milian-Ciesielska K, Lipiec E, Adamek D. Current Pathology Model of Pancreatic Cancer. Cancers (Basel) 2022; 14:2321. [PMID: 35565450 PMCID: PMC9105915 DOI: 10.3390/cancers14092321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive and lethal malignant neoplasms, ranking in seventh place in the world in terms of the incidence of death, with overall 5-year survival rates still below 10%. The knowledge about PC pathomechanisms is rapidly expanding. Daily reports reveal new aspects of tumor biology, including its molecular and morphological heterogeneity, explain complicated "cross-talk" that happens between the cancer cells and tumor stroma, or the nature of the PC-associated neural remodeling (PANR). Staying up-to-date is hard and crucial at the same time. In this review, we are focusing on a comprehensive summary of PC aspects that are important in pathologic reporting, impact patients' outcomes, and bring meaningful information for clinicians. Finally, we show promising new trends in diagnostic technologies that might bring a difference in PC early diagnosis.
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Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
- Department of Pathomorphology, University Hospital, 30-688 Cracow, Poland;
| | | | - Ewelina Lipiec
- M. Smoluchowski Institute of Physics, Jagiellonian University, 30-348 Cracow, Poland;
| | - Dariusz Adamek
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
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23
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Correlation between RASSF1A Methylation in Cell-Free DNA and the Prognosis of Cancer Patients: A Systematic Review and Meta-Analysis. JOURNAL OF ONCOLOGY 2022; 2022:3458420. [PMID: 35528240 PMCID: PMC9071870 DOI: 10.1155/2022/3458420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/18/2022] [Accepted: 04/07/2022] [Indexed: 11/17/2022]
Abstract
Background Although the effects of methylation of the Ras association domain-containing protein 1 isoform A (RASSF1A) gene in cell-free DNA on the outcomes of patients with different types of cancer have been reported, the results are inconsistent. Objective : To explore the relationships between RASSF1A methylation in cell-free DNA and the outcomes of cancer patients. Methods The PubMed, Embase, and Web of Science databases were searched for papers related to this topic on December 8, 2021. The retrieved articles were screened by two independent researchers, following which the methodological quality of the selected studies was evaluated using the Newcastle-Ottawa Scale. Additionally, hazard ratios were calculated, and publication bias of the studies was determined using Egger's test. Results Nine relevant publications involving a combined total of 1254 patients with different types of cancer were included in this study. The combined results of the random effects models yielded a hazard ratio of 1.73 (95% confidence interval: 1.31, 2.29; P < 0.001), which suggested there was a significant association between RASSF1A methylation and overall survival, and patients with an RASSF1A methylation status had a significantly increased risk of total death. Moreover, the Egger test result suggested there was no significant publication bias among the included studies. Conclusions The methylation of RASSF1A in cell-free DNA in cancer patients was observably associated with an increased risk of poor overall survival.
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24
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Connor AA, Gallinger S. Pancreatic cancer evolution and heterogeneity: integrating omics and clinical data. Nat Rev Cancer 2022; 22:131-142. [PMID: 34789870 DOI: 10.1038/s41568-021-00418-1] [Citation(s) in RCA: 173] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/18/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), already among the deadliest epithelial malignancies, is rising in both incidence and contribution to overall cancer deaths. Decades of research have improved our understanding of PDAC carcinogenesis, including characterizing germline predisposition, the cell of origin, precursor lesions, the sequence of genetic alterations, including simple and structural alterations, transcriptional changes and subtypes, tumour heterogeneity, metastatic progression and the tumour microenvironment. These fundamental advances inform contemporary translational efforts in primary prevention, screening and early detection, multidisciplinary management and survivorship, as prospective clinical trials begin to adopt molecular-based selection criteria to guide targeted therapies. Genomic and transcriptomic data on PDAC were also included in the international pan-cancer analysis of approximately 2,600 cancers, a milestone in cancer research that allows further insight through comparison with other tumour types. Thus, this is an ideal time to review our current knowledge of PDAC evolution and heterogeneity, gained from the study of preclinical models and patient biospecimens, and to propose a model of PDAC evolution that takes into consideration findings from varied sources, with a particular focus on the genomics of human PDAC.
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Affiliation(s)
- Ashton A Connor
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - Steven Gallinger
- Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada.
- PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada.
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, ON, Canada.
- Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, ON, Canada.
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25
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Edwards RL, Menteer J, Lestz RM, Baxter-Lowe LA. Cell-free DNA as a solid-organ transplant biomarker: technologies and approaches. Biomark Med 2022; 16:401-415. [PMID: 35195028 DOI: 10.2217/bmm-2021-0968] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
High-quality biomarkers that detect emergent graft damage and/or rejection after solid-organ transplantation offer new opportunities to improve post-transplant monitoring, allow early therapeutic intervention and facilitate personalized patient management. Donor-derived cell-free DNA (DD-cfDNA) is a particularly exciting minimally invasive biomarker because it has the potential to be quantitative, time-sensitive and cost-effective. Increased DD-cfDNA has been associated with graft damage and rejection episodes. Efforts are underway to further improve sensitivity and specificity. This review summarizes the procedures used to process and detect DD-cfDNA, measurement of DD-cfDNA in clinical transplantation, approaches for improving sensitivity and specificity and long-term prospects as a transplant biomarker to supplement traditional organ monitoring and invasive biopsies.
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Affiliation(s)
- Rebecca L Edwards
- Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Jondavid Menteer
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.,Division of Cardiology, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Rachel M Lestz
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.,Division of Nephrology, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Lee Ann Baxter-Lowe
- Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
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26
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Botrus G, Uson Junior PLS, Raman P, Kaufman AE, Kosiorek H, Yin J, Fu Y, Majeed U, Sonbol MB, Ahn DH, Chang IW, Drusbosky LM, Dada H, Starr J, Borad M, Mody K, Bekaii-Saab TS. Circulating Cell-Free Tumor DNA in Advanced Pancreatic Adenocarcinoma Identifies Patients With Worse Overall Survival. Front Oncol 2022; 11:794009. [PMID: 35083150 PMCID: PMC8784799 DOI: 10.3389/fonc.2021.794009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Background Plasma-based circulating cell-free tumor DNA (ctDNA) genomic profiling by next-generation sequencing (NGS)is an emerging diagnostic tool for pancreatic cancer (PC). The impact of detected genomic alterations and variant allele fraction (VAF) in tumor response to systemic treatments and outcomes is under investigation. Methods Patients with advanced PC who had ctDNA profiled at time of initial diagnosis were retrospectively evaluated. We considered the somatic alteration with the highest VAF as the dominant clone allele frequency (DCAF). ctDNA NGS results were related to clinical demographics, progression-free survival (PFS) and overall survival (OS). Results A total of 104 patients were evaluated. Somatic alterations were detected in 84.6% of the patients. Patients with ≥ 2 detectable genomic alterations had worse median PFS (p < 0.001) and worse median OS (p = 0.001). KRAS was associated with disease progression to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (p < 0.001) and worse median OS (p = 0.002). TP53 was associated with worse median PFS (p = 0.02) and worse median OS (p = 0.001). The median DCAF was 0.45% (range 0-55%). DCAF >0.45% was associated with worse median PFS (p<0.0001) and median OS (p=0.0003). Patients that achieved clearance of KRAS had better PFS (p=0.047), while patients that achieved clearance of TP53 had better PFS (p=0.0056) and OS (p=0.037). Conclusions Initial detection of ctDNA in advanced PC can identify somatic alterations that may help predict clinical outcomes. The dynamics of ctDNA are prognostic of outcomes and should be evaluated in prospective studies.
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Affiliation(s)
- Gehan Botrus
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Pedro Luiz Serrano Uson Junior
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States.,Center for Personalized Medicine, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Puneet Raman
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Adrienne E Kaufman
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Heidi Kosiorek
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Jun Yin
- Division of Oncology, Mayo Clinic, Jacksonville, FL, United States
| | - Yu Fu
- Guardant Health, Inc., Redwood City, CA, United States
| | - Umair Majeed
- Division of Oncology, Mayo Clinic, Jacksonville, FL, United States
| | - Mohamad Bassam Sonbol
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Daniel H Ahn
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Isabela W Chang
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | | | - Hiba Dada
- Guardant Health, Inc., Redwood City, CA, United States
| | - Jason Starr
- Division of Oncology, Mayo Clinic, Jacksonville, FL, United States
| | - Mitesh Borad
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States.,Center of individualized Medicine, Mayo Clinic, Rochester, MN, United States.,Mayo Clinic Cancer Center, Phoenix, AZ, United States
| | - Kabir Mody
- Division of Oncology, Mayo Clinic, Jacksonville, FL, United States
| | - Tanios S Bekaii-Saab
- Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, United States
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27
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Schreyer D, Neoptolemos JP, Barry ST, Bailey P. Deconstructing Pancreatic Cancer Using Next Generation-Omic Technologies-From Discovery to Knowledge-Guided Platforms for Better Patient Management. Front Cell Dev Biol 2022; 9:795735. [PMID: 35096825 PMCID: PMC8793685 DOI: 10.3389/fcell.2021.795735] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Comprehensive molecular landscaping studies reveal a potentially brighter future for pancreatic ductal adenocarcinoma (PDAC) patients. Blood-borne biomarkers obtained from minimally invasive "liquid biopsies" are now being trialled for early disease detection and to track responses to therapy. Integrated genomic and transcriptomic studies using resectable tumour material have defined intrinsic patient subtypes and actionable genomic segments that promise a shift towards genome-guided patient management. Multimodal mapping of PDAC using spatially resolved single cell transcriptomics and imaging techniques has identified new potentially therapeutically actionable cellular targets and is providing new insights into PDAC tumour heterogeneity. Despite these rapid advances, defining biomarkers for patient selection remain limited. This review examines the current PDAC cancer biomarker ecosystem (identified in tumour and blood) and explores how advances in single cell sequencing and spatially resolved imaging modalities are being used to uncover new targets for therapeutic intervention and are transforming our understanding of this difficult to treat disease.
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Affiliation(s)
- Daniel Schreyer
- Institute of Cancer Sciences, University of Glasgow, Scotland, United Kingdom
| | - John P. Neoptolemos
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Simon T. Barry
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Peter Bailey
- Institute of Cancer Sciences, University of Glasgow, Scotland, United Kingdom
- Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Section Surgical Research, University Clinic Heidelberg, Heidelberg, Germany
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28
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Faleiro I, Roberto VP, Demirkol Canli S, Fraunhoffer NA, Iovanna J, Gure AO, Link W, Castelo-Branco P. DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study. Cancers (Basel) 2021; 13:cancers13246354. [PMID: 34944974 PMCID: PMC8699150 DOI: 10.3390/cancers13246354] [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: 11/17/2021] [Revised: 12/02/2021] [Accepted: 12/07/2021] [Indexed: 11/19/2022] Open
Abstract
Simple Summary Pancreatic cancer is a highly lethal malignancy. Dysregulation of epigenetic mechanisms leads to abnormal patterns of gene expression contributing to the development and progression of cancer. We explored the ability of DNA methylation of PI3K-related genes to differentiate between malignant and healthy pancreatic tissue using distinct pancreatic cancer cohorts, and found that the methylation levels of the ITGA4, SFN, ITGA2, and PIK3R1 genes are altered in tumour samples since the early stages of malignant transformation and could serve as new diagnostic tools. We also demonstrate that these alterations correlate with overall survival and recurrence-free survival of the patients suggesting that its assessment can serve as independent prognostic indicators of patients’ survival with higher sensitivity and specificity than the currently implemented biomarkers. Therefore, the methylation profile of genes involved in this pathway may be an alternative method for predicting cell malignancy and help doctors’ decisions on patient care. Abstract Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.
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Affiliation(s)
- Inês Faleiro
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal;
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
- Instituto de Medicina Molecular João Lobo Antunes (IMM), Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal
| | - Vânia Palma Roberto
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal;
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisbon, Portugal
- Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139 Faro, Portugal
- Correspondence: (V.P.R.); (P.C.-B.)
| | - Secil Demirkol Canli
- Molecular Pathology Application and Research Center, Hacettepe University, 06100 Ankara, Turkey;
| | - Nicolas A. Fraunhoffer
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, 13288 Marseille, France; (N.A.F.); (J.I.)
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, 13288 Marseille, France; (N.A.F.); (J.I.)
| | - Ali Osmay Gure
- Department of Medical Biology, Acibadem University, 34684 Istanbul, Turkey;
| | - Wolfgang Link
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain;
| | - Pedro Castelo-Branco
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal;
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisbon, Portugal
- Correspondence: (V.P.R.); (P.C.-B.)
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29
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Lin D, Shen L, Luo M, Zhang K, Li J, Yang Q, Zhu F, Zhou D, Zheng S, Chen Y, Zhou J. Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther 2021; 6:404. [PMID: 34803167 PMCID: PMC8606574 DOI: 10.1038/s41392-021-00817-8] [Citation(s) in RCA: 466] [Impact Index Per Article: 116.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/06/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.
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Affiliation(s)
- Danfeng Lin
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Department of Breast Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lesang Shen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Meng Luo
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kun Zhang
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinfan Li
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qi Yang
- Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fangfang Zhu
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dan Zhou
- Department of Surgery, Traditional Chinese Medical Hospital of Zhuji, Shaoxing, China
| | - Shu Zheng
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiding Chen
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jiaojiao Zhou
- Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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30
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Perales S, Torres C, Jimenez-Luna C, Prados J, Martinez-Galan J, Sanchez-Manas JM, Caba O. Liquid biopsy approach to pancreatic cancer. World J Gastrointest Oncol 2021; 13:1263-1287. [PMID: 34721766 PMCID: PMC8529923 DOI: 10.4251/wjgo.v13.i10.1263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/18/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to pose a major clinical challenge. There has been little improvement in patient survival over the past few decades, and it is projected to become the second leading cause of cancer mortality by 2030. The dismal 5-year survival rate of less than 10% after the diagnosis is attributable to the lack of early symptoms, the absence of specific biomarkers for an early diagnosis, and the inadequacy of available chemotherapies. Most patients are diagnosed when the disease has already metastasized and cannot be treated. Cancer interception is vital, actively intervening in the malignization process before the development of a full-blown advanced tumor. An early diagnosis of PC has a dramatic impact on the survival of patients, and improved techniques are urgently needed to detect and evaluate this disease at an early stage. It is difficult to obtain tissue biopsies from the pancreas due to its anatomical position; however, liquid biopsies are readily available and can provide useful information for the diagnosis, prognosis, stratification, and follow-up of patients with PC and for the design of individually tailored treatments. The aim of this review was to provide an update of the latest advances in knowledge on the application of carbohydrates, proteins, cell-free nucleic acids, circulating tumor cells, metabolome compounds, exosomes, and platelets in blood as potential biomarkers for PC, focusing on their clinical relevance and potential for improving patient outcomes.
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Affiliation(s)
- Sonia Perales
- Department of Biochemistry and Molecular Biology I, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Carolina Torres
- Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Sciences, University of Granada, Granada 18071, Spain
| | - Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Jose Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
| | - Joaquina Martinez-Galan
- Department of Medical Oncology, Hospital Universitario Virgen de las Nieves, Granada 18011, Spain
| | | | - Octavio Caba
- Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada 18100, Spain
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31
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Szkukalek J, Dóczi R, Dirner A, Boldizsár Á, Varga Á, Déri J, Lakatos D, Tihanyi D, Vodicska B, Schwáb R, Pajkos G, Várkondi E, Vályi-Nagy I, Valtinyi D, Nagy Z, Peták I. Personalized First-Line Treatment of Metastatic Pancreatic Neuroendocrine Carcinoma Facilitated by Liquid Biopsy and Computational Decision Support. Diagnostics (Basel) 2021; 11:1850. [PMID: 34679548 PMCID: PMC8534772 DOI: 10.3390/diagnostics11101850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/28/2021] [Accepted: 09/28/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND We present the case of a 50-year-old female whose metastatic pancreatic neuroendocrine tumor (pNET) diagnosis was delayed by the COVID-19 pandemic. The patient was in critical condition at the time of diagnosis due to the extensive tumor burden and failing liver functions. The clinical dilemma was to choose between two registered first-line molecularly-targeted agents (MTAs), sunitinib or everolimus, or to use chemotherapy to quickly reduce tumor burden. METHODS Cell-free DNA (cfDNA) from liquid biopsy was analyzed by next generation sequencing (NGS) using a comprehensive 591-gene panel. Next, a computational method, digital drug-assignment (DDA) was deployed for rapid clinical decision support. RESULTS NGS analysis identified 38 genetic alterations. DDA identified 6 potential drivers, 24 targets, and 79 MTAs. Everolimus was chosen for first-line therapy based on supporting molecular evidence and the highest DDA ranking among therapies registered in this tumor type. The patient's general condition and liver functions rapidly improved, and CT control revealed partial response in the lymph nodes and stable disease elsewhere. CONCLUSION Deployment of precision oncology using liquid biopsy, comprehensive molecular profiling, and DDA make personalized first-line therapy of advanced pNET feasible in clinical settings.
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Affiliation(s)
- Judita Szkukalek
- Department of Clinical Oncology, St. Imre Hospital, 1115 Budapest, Hungary; (J.S.); (D.V.); (Z.N.)
| | - Róbert Dóczi
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Anna Dirner
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Ákos Boldizsár
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Ágnes Varga
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Júlia Déri
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Dóra Lakatos
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Dóra Tihanyi
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Barbara Vodicska
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Richárd Schwáb
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Gábor Pajkos
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - Edit Várkondi
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
| | - István Vályi-Nagy
- Centrum Hospital of Southern Pest, National Hematology and Infectology Institute, 1097 Budapest, Hungary;
| | - Dorottya Valtinyi
- Department of Clinical Oncology, St. Imre Hospital, 1115 Budapest, Hungary; (J.S.); (D.V.); (Z.N.)
| | - Zsuzsanna Nagy
- Department of Clinical Oncology, St. Imre Hospital, 1115 Budapest, Hungary; (J.S.); (D.V.); (Z.N.)
| | - István Peták
- Oncompass Medicine Hungary Ltd., 1024 Budapest, Hungary; (R.D.); (A.D.); (Á.B.); (Á.V.); (J.D.); (D.L.); (D.T.); (B.V.); (R.S.); (G.P.); (E.V.)
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary
- Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
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Cardiomyocyte-Specific Circulating Cell-Free Methylated DNA in Esophageal Cancer Patients Treated with Chemoradiation. GASTROINTESTINAL DISORDERS 2021; 3:100-112. [PMID: 35531260 PMCID: PMC9074856 DOI: 10.3390/gidisord3030011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Thoracic high-dose radiation therapy (RT) for cancer has been associated with early and late cardiac toxicity. To assess altered rates of cardiomyocyte cell death due to RT we monitored changes in cardiomyocyte-specific, cell-free methylated DNA (cfDNA) shed into the circulation. Eleven patients with distal esophageal cancer treated with neoadjuvant chemoradiation to 50.4 Gy (RT) and concurrent carboplatin and paclitaxel were enrolled. Subjects underwent fasting blood draws prior to the initiation and after completion of RT as well as 4–6 months following RT. An island of six unmethylated CpGs in the FAM101A locus was used to identify cardiomyocyte-specific cfDNA in serum. After bisulfite treatment this specific cfDNA was quantified by amplicon sequencing at a depth of >35,000 reads/molecule. Cardiomyocyte-specific cfDNA was detectable before RT in the majority of patient samples and showed some distinct changes during the course of treatment and recovery. We propose that patient-specific cardiac damages in response to the treatment are indicated by these changes although co-morbidities may obscure treatment-specific events.
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Diab HMH, Smith HG, Jensen KK, Jørgensen LN. The current role of blood-based biomarkers in surgical decision-making in patients with localised pancreatic cancer: A systematic review. Eur J Cancer 2021; 154:73-81. [PMID: 34243080 DOI: 10.1016/j.ejca.2021.05.033] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/20/2021] [Accepted: 05/23/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The role of blood-based biomarkers in surgical decision-making in patients with localised pancreatic cancer remains unclear. This review aimed to report the utility of blood-based biomarkers focusing on prediction of response to neoadjuvant therapy, prediction of surgical resectability and early relapse after surgery. MATERIALS AND METHODS MEDLINE/PubMed, Embase and Web of Science were searched till October 2019. Studies published between January 2000 and September 2019 with a minimum of 20 patients with pancreatic adenocarcinoma, reporting the utility of at least one blood-based biomarker in predicting response to neoadjuvant therapy and predicting surgical resectability or early relapse after surgery were included. RESULTS A total of 2604 studies were identified, of which 24 comprising of 3367 patients and 12 blood-based biomarkers were included. All included studies were observational. Levels of carbohydrate antigen (CA)19-9 were reported in the majority of the studies. Levels of CA19-9 predicted the response to neoadjuvant therapy and early relapse in 10 studies. CA125 levels above 35 U/ml were predictive of surgical irresectability in two studies. However, marked variation in both timing of sampling and cut-off values was noted between studies. CONCLUSION Despite some evidence of potential benefit, the utility of currently available blood-based biomarkers in aiding surgical decision-making in patients undergoing potentially curative treatment for pancreatic cancer is limited by methodological heterogeneity. Standardisation of future studies may allow a more comprehensive analysis of the biomarkers described in this review.
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Affiliation(s)
- Hadi M H Diab
- Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Denmark.
| | - Henry G Smith
- Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Denmark
| | - Kristian K Jensen
- Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Denmark
| | - Lars N Jørgensen
- Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Denmark
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Milin-Lazovic J, Madzarevic P, Rajovic N, Djordjevic V, Milic N, Pavlovic S, Veljkovic N, Milic NM, Radenkovic D. Meta-Analysis of Circulating Cell-Free DNA's Role in the Prognosis of Pancreatic Cancer. Cancers (Basel) 2021; 13:3378. [PMID: 34298594 PMCID: PMC8303288 DOI: 10.3390/cancers13143378] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/13/2021] [Accepted: 06/23/2021] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION The analysis of cell-free DNA (cfDNA) for genetic abnormalities is a promising new approach for the diagnosis and prognosis of pancreatic cancer patients. Insights into the molecular characteristics of pancreatic cancer may provide valuable information, leading to its earlier detection and the development of targeted therapies. MATERIAL AND METHODS We conducted a systematic review and a meta-analysis of studies that reported cfDNA in pancreatic ductal adenocarcinoma (PDAC). The studies were considered eligible if they included patients with PDAC, if they had blood tests for cfDNA/ctDNA, and if they analyzed the prognostic value of cfDNA/ctDNA for patients' survival. The studies published before 22 October 2020 were identified through the PubMED, EMBASE, Web of Science and Cochrane Library databases. The assessed outcomes were the overall (OS) and progression-free survival (PFS), expressed as the log hazard ratio (HR) and standard error (SE). The summary of the HR effect size was estimated by pooling the individual trial results using the Review Manager, version 5.3, Cochrane Collaboration. The heterogeneity was assessed using the Cochran Q test and I2 statistic. RESULTS In total, 48 studies were included in the qualitative review, while 44 were assessed in the quantitative synthesis, with the total number of patients included being 3524. Overall negative impacts of cfDNA and KRAS mutations on OS and PFS in PDAC (HR = 2.42, 95% CI: 1.95-2.99 and HR = 2.46, 95% CI: 2.01-3.00, respectively) were found. The subgroup analysis of the locally advanced and metastatic disease presented similar results (HR = 2.51, 95% CI: 1.90-3.31). In the studies assessing the pre-treatment presence of KRAS, there was a moderate to high degree of heterogeneity (I2 = 87% and I2 = 48%, for OS and PFS, respectively), which was remarkably decreased in the analysis of the studies measuring post-treatment KRAS (I2 = 24% and I2 = 0%, for OS and PFS, respectively). The patients who were KRAS positive before but KRAS negative after treatment had a better prognosis than the persistently KRAS-positive patients (HR = 5.30, 95% CI: 1.02-27.63). CONCLUSION The assessment of KRAS mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients.
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Affiliation(s)
- Jelena Milin-Lazovic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.M.-L.); (P.M.); (N.R.); (N.M.M.)
| | - Petar Madzarevic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.M.-L.); (P.M.); (N.R.); (N.M.M.)
| | - Nina Rajovic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.M.-L.); (P.M.); (N.R.); (N.M.M.)
| | - Vladimir Djordjevic
- Department of Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Nikola Milic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Sonja Pavlovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11000 Belgrade, Serbia;
| | - Nevena Veljkovic
- Vinca Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia;
- Heliant Ltd., 11000 Belgrade, Serbia
| | - Natasa M. Milic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (J.M.-L.); (P.M.); (N.R.); (N.M.M.)
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902, USA
| | - Dejan Radenkovic
- Department of Surgery, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
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Henriksen SD, Stubbe BE, Madsen PH, Johansen JS, Jensen BV, Hansen CP, Johansen MN, Pedersen IS, Krarup H, Thorlacius-Ussing O. Cell-free DNA promoter hypermethylation as a diagnostic marker for pancreatic ductal adenocarcinoma - An external validation study. Pancreatology 2021; 21:S1424-3903(21)00154-X. [PMID: 33994313 DOI: 10.1016/j.pan.2021.05.003] [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: 01/05/2021] [Revised: 04/27/2021] [Accepted: 05/04/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND We recently identified a diagnostic prediction model based on promoter hypermethylation of eight selected genes in plasma cell-free (cf) DNA, which showed promising results as a diagnostic biomarker for pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to validate this biomarker profile in an external patient cohort and examine any additional effect of serum CA 19-9. METHODS Patients with PDAC (n = 346, stage I-IV) and chronic pancreatitis (n = 25) were included. Methylation-specific PCR of a 28-gene panel was performed on serum cfDNA samples. The previously developed diagnostic prediction model (age>65 years, BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2) was validated alone and in combination with serum CA 19-9 in this external patient cohort. RESULTS Patients with PDAC had a higher number of hypermethylated genes (mean 8.11, 95% CI 7.70-8.52) than patients with chronic pancreatitis (mean 5.60, 95% CI 4.42-6.78, p = 0.011). Validation of the diagnostic prediction model yielded an AUC of 0.77 (95% CI 0.69-0.84). The combination of serum CA 19-9 and our test had an AUC of 0.93 (95% CI 0.89-0.96) in the primary study and 0.85 (95% CI 0.79-0.91) in the validation study. CONCLUSION In this validation study, PDAC was associated with a higher number of hypermethylated genes in serum cfDNA than chronic pancreatitis. Our diagnostic test was superior to the predictive value of serum CA 19-9 alone in both the primary and the validation study. The combination of our test with CA 19-9 may serve as a clinically useful diagnostic biomarker for PDAC.
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Affiliation(s)
- Stine D Henriksen
- Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark; Department of Clinical Medicine, Aalborg University, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Denmark.
| | - Benjamin E Stubbe
- Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark
| | - Poul H Madsen
- Department of Molecular Diagnostics, Aalborg University Hospital, Denmark
| | - Julia S Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Benny V Jensen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
| | - Carsten P Hansen
- Department of Surgery, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Martin N Johansen
- Unit of Clinical Biostatistics, Aalborg University Hospital, Denmark
| | - Inge S Pedersen
- Department of Clinical Medicine, Aalborg University, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Denmark; Department of Molecular Diagnostics, Aalborg University Hospital, Denmark
| | - Henrik Krarup
- Clinical Cancer Research Center, Aalborg University Hospital, Denmark; Department of Molecular Diagnostics, Aalborg University Hospital, Denmark
| | - Ole Thorlacius-Ussing
- Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark; Department of Clinical Medicine, Aalborg University, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Denmark
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Al-Shaheri FN, Alhamdani MSS, Bauer AS, Giese N, Büchler MW, Hackert T, Hoheisel JD. Blood biomarkers for differential diagnosis and early detection of pancreatic cancer. Cancer Treat Rev 2021; 96:102193. [PMID: 33865174 DOI: 10.1016/j.ctrv.2021.102193] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer is currently the most lethal tumor entity and case numbers are rising. It will soon be the second most frequent cause of cancer-related death in the Western world. Mortality is close to incidence and patient survival after diagnosis stands at about five months. Blood-based diagnostics could be one crucial factor for improving this dismal situation and is at a stage that could make this possible. Here, we are reviewing the current state of affairs with its problems and promises, looking at various molecule types. Reported results are evaluated in the overall context. Also, we are proposing steps toward clinical utility that should advance the development toward clinical application by improving biomarker quality but also by defining distinct clinical objectives and the respective diagnostic accuracies required to achieve them. Many of the discussed points and conclusions are highly relevant to other solid tumors, too.
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Affiliation(s)
- Fawaz N Al-Shaheri
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany.
| | - Mohamed S S Alhamdani
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Andrea S Bauer
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
| | - Nathalia Giese
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Markus W Büchler
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Thilo Hackert
- Department of General Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Jörg D Hoheisel
- Division of Functional Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
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Giannis D, Moris D, Barbas AS. Diagnostic, Predictive and Prognostic Molecular Biomarkers in Pancreatic Cancer: An Overview for Clinicians. Cancers (Basel) 2021; 13:1071. [PMID: 33802340 PMCID: PMC7959127 DOI: 10.3390/cancers13051071] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/13/2021] [Accepted: 02/27/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy and is associated with aggressive tumor behavior and poor prognosis. Most patients with PDAC present with an advanced disease stage and treatment-resistant tumors. The lack of noninvasive tests for PDAC diagnosis and survival prediction mandates the identification of novel biomarkers. The early identification of high-risk patients and patients with PDAC is of utmost importance. In addition, the identification of molecules that are associated with tumor biology, aggressiveness, and metastatic potential is crucial to predict survival and to provide patients with personalized treatment regimens. In this review, we summarize the current literature and focus on newer biomarkers, which are continuously added to the armamentarium of PDAC screening, predictive tools, and prognostic tools.
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Affiliation(s)
- Dimitrios Giannis
- Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA;
| | - Dimitrios Moris
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA;
| | - Andrew S. Barbas
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA;
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Elmore LW, Greer SF, Daniels EC, Saxe CC, Melner MH, Krawiec GM, Cance WG, Phelps WC. Blueprint for cancer research: Critical gaps and opportunities. CA Cancer J Clin 2021; 71:107-139. [PMID: 33326126 DOI: 10.3322/caac.21652] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 10/15/2020] [Accepted: 10/15/2020] [Indexed: 12/12/2022] Open
Abstract
We are experiencing a revolution in cancer. Advances in screening, targeted and immune therapies, big data, computational methodologies, and significant new knowledge of cancer biology are transforming the ways in which we prevent, detect, diagnose, treat, and survive cancer. These advances are enabling durable progress in the goal to achieve personalized cancer care. Despite these gains, more work is needed to develop better tools and strategies to limit cancer as a major health concern. One persistent gap is the inconsistent coordination among researchers and caregivers to implement evidence-based programs that rely on a fuller understanding of the molecular, cellular, and systems biology mechanisms underpinning different types of cancer. Here, the authors integrate conversations with over 90 leading cancer experts to highlight current challenges, encourage a robust and diverse national research portfolio, and capture timely opportunities to advance evidence-based approaches for all patients with cancer and for all communities.
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Affiliation(s)
- Lynne W Elmore
- Office of the Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia
| | - Susanna F Greer
- Office of the Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia
| | - Elvan C Daniels
- Office of the Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia
| | - Charles C Saxe
- Office of the Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia
| | - Michael H Melner
- Office of the Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia
| | - Ginger M Krawiec
- Office of the Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia
| | - William G Cance
- Office of the Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia
| | - William C Phelps
- Office of the Chief Medical and Scientific Officer, American Cancer Society, Atlanta, Georgia
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Satoh K. Molecular Approaches Using Body Fluid for the Early Detection of Pancreatic Cancer. Diagnostics (Basel) 2021; 11:375. [PMID: 33671729 PMCID: PMC7926932 DOI: 10.3390/diagnostics11020375] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/12/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most malignant form of gastrointestinal tumor and is the fourth leading cause of deaths due to cancer in Japan. This cancer shows a poor outcome due to the difficulty of its early diagnosis and its rapid growth. Once this disease becomes clinically evident, it is frequently accompanied by distant metastasis at the time of diagnosis. A recent multicenter study in Japan revealed that patients with the early stage of this disease (stage 0 and I) showed favorable prognosis after surgical resection, indicating the importance of early detection for improvement of PDAC prognosis. PDAC develops through a stepwise progression from the precursor lesion, and over the last few decades molecular analyses have shown the detailed genetic alterations that occur in this process. Since advances in molecular technologies have enabled the detection of genetic changes from a very small quantity of samples, a large number of non-invasive molecular approaches have been utilized in an attempt to find precursor or non-invasive carcinoma lesions. In this review, the current efforts in terms of the molecular approaches applied for the early detection of PDAC-especially using body fluids such as pancreatic juice, blood, and saliva-are summarized.
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Affiliation(s)
- Kennichi Satoh
- Division of Gastroenterology, Tohoku Medical and Pharmaceutical University, 1-15-1 Fukumuro, Miyaginoku, Sendai, Miyagi 983-8536, Japan
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Wang SE, Shyr BU, Shyr BS, Chen SC, Chang SC, Shyr YM. Circulating Cell-Free DNA in Pancreatic Head Adenocarcinoma Undergoing Pancreaticoduodenectomy. Pancreas 2021; 50:214-218. [PMID: 33565798 DOI: 10.1097/mpa.0000000000001730] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Circulating cell-free DNA (cfDNA) analysis is recently reported as a promising prognostic biomarker in various types of cancer. This study aimed to evaluate the role of cfDNA in pancreatic head adenocarcinoma. METHODS Data for pancreatic head adenocarcinoma undergoing pancreaticoduodenectomy were studied for cfDNA. Prognostic factors were determined, and their correlation with cfDNA level was evaluated. RESULTS The median of cfDNA for 97 cases was 7724 copies/mL, with a mean of 10,467, and ranging from 1856 to 44,203. Cell-free DNA was significantly higher in positive lymph node involvement and advanced stage III. Poor prognostic factors included high cfDNA level (>7724 copies/mL), abnormal carbohydrate antigen 19-9, abnormal carcinoembryonic antigen, and advanced stage. The 1- and 5-year survivals for those with high cfDNA were poorer, 70.2% and 21.2%, respectively, as compared with 93.4% and 23.7% for those with low cfDNA level. Only cfDNA level and stage were independent prognostic factors after multivariate analysis. CONCLUSIONS The level of cfDNA was correlated with tumor burden. Therefore, it could be an emerging survival predictor for resectable pancreatic head adenocarcinoma, and its detection might be a promising liquid biopsy to monitor both tumor progression and treatment response.
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Affiliation(s)
- Shin-E Wang
- From the Department of Surgery, Taipei Veterans General Hospital, National Yang Ming University, Taipei, Taiwan
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Hussung S, Akhoundova D, Hipp J, Follo M, Klar RFU, Philipp U, Scherer F, von Bubnoff N, Duyster J, Boerries M, Wittel U, Fritsch RM. Longitudinal analysis of cell-free mutated KRAS and CA 19-9 predicts survival following curative resection of pancreatic cancer. BMC Cancer 2021; 21:49. [PMID: 33430810 PMCID: PMC7802224 DOI: 10.1186/s12885-020-07736-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 12/15/2020] [Indexed: 02/06/2023] Open
Abstract
Background Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that the combined longitudinal analysis of mutated cell-free plasma KRAS (cfKRASmut) and CA 19–9 during adjuvant treatment and follow-up might more accurately predict disease course than hitherto available parameters. Methods Between 07/2015 and 10/2018, we collected 134 plasma samples from 25 patients after R0/R1-resection of PDAC during adjuvant chemotherapy and post-treatment surveillance at our institution. Highly sensitive discriminatory multi-target ddPCR assays were employed to screen plasma samples for cfKRASmut. cfKRASmut and CA 19–9 dynamics were correlated with recurrence-free survival (RFS) and overall survival (OS). Patients were followed-up until 01/2020. Results Out of 25 enrolled patients, 76% had undergone R0 resection and 48% of resected PDACs were pN0. 17/25 (68%) of patients underwent adjuvant chemotherapy. Median follow-up was 22.0 months, with 19 out of 25 (76%) patients relapsing during study period. Median RFS was 10.0 months, median OS was 22.0 months. Out of clinicopathologic variables, only postoperative CA 19–9 levels and administration of adjuvant chemotherapy correlated with survival endpoints. cfKRASmut. was detected in 12/25 (48%) of patients, and detection of high levels inversely correlated with survival endpoint. Integration of cfKRASmut and CA 19–9 levels outperformed either individual marker. cfKRASmut outperformed CA 19–9 as dynamic marker since increase during adjuvant chemotherapy and follow-up was highly predictive of early relapse and poor OS. Conclusions Integrated analysis of cfKRASmut and CA 19–9 levels is a promising approach for molecular monitoring of patients following resection of PDAC. Larger prospective studies are needed to further develop this approach and dissect each marker’s specific potential. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07736-x.
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Affiliation(s)
- Saskia Hussung
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany.,Department of Medical Oncology and Hematology, Zurich University Hospital, Raemistrasse 100, 8091, Zürich, Switzerland
| | - Dilara Akhoundova
- Department of Medical Oncology and Hematology, Zurich University Hospital, Raemistrasse 100, 8091, Zürich, Switzerland
| | - Julian Hipp
- Department of Surgery, Freiburg University Medical Center, Freiburg, Germany
| | - Marie Follo
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Rhena F U Klar
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Ulrike Philipp
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Florian Scherer
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Nikolas von Bubnoff
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Justus Duyster
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany.,German Cancer Consortium (DKTK), partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Melanie Boerries
- German Cancer Consortium (DKTK), partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Institute of Medical Bioinformatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Uwe Wittel
- Department of Surgery, Freiburg University Medical Center, Freiburg, Germany
| | - Ralph M Fritsch
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany. .,Department of Medical Oncology and Hematology, Zurich University Hospital, Raemistrasse 100, 8091, Zürich, Switzerland. .,Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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Martuszewski A, Paluszkiewicz P, Król M, Banasik M, Kepinska M. Donor-Derived Cell-Free DNA in Kidney Transplantation as a Potential Rejection Biomarker: A Systematic Literature Review. J Clin Med 2021; 10:jcm10020193. [PMID: 33430458 PMCID: PMC7827757 DOI: 10.3390/jcm10020193] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/02/2021] [Accepted: 01/05/2021] [Indexed: 12/12/2022] Open
Abstract
Kidney transplantation (KTx) is the best treatment method for end-stage kidney disease. KTx improves the patient's quality of life and prolongs their survival time; however, not all patients benefit fully from the transplantation procedure. For some patients, a problem is the premature loss of graft function due to immunological or non-immunological factors. Circulating cell-free DNA (cfDNA) is degraded deoxyribonucleic acid fragments that are released into the blood and other body fluids. Donor-derived cell-free DNA (dd-cfDNA) is cfDNA that is exogenous to the patient and comes from a transplanted organ. As opposed to an invasive biopsy, dd-cfDNA can be detected by a non-invasive analysis of a sample. The increase in dd-cfDNA concentration occurs even before the creatinine level starts rising, which may enable early diagnosis of transplant injury and adequate treatment to avoid premature graft loss. In this paper, we summarise the latest promising results related to cfDNA in transplant patients.
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Affiliation(s)
- Adrian Martuszewski
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (A.M.); (P.P.); (M.B.)
| | - Patrycja Paluszkiewicz
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (A.M.); (P.P.); (M.B.)
| | - Magdalena Król
- Students Scientific Association, Department of Biomedical and Environmental Analysis, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (A.M.); (P.P.); (M.B.)
| | - Marta Kepinska
- Department of Biomedical and Environmental Analyses, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland
- Correspondence: ; Tel.: +48-71-784-0171
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Keller M, Agbor-Enoh S. Donor-Derived Cell-Free DNA for Acute Rejection Monitoring in Heart and Lung Transplantation. CURRENT TRANSPLANTATION REPORTS 2021; 8:351-358. [PMID: 34754720 PMCID: PMC8570240 DOI: 10.1007/s40472-021-00349-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2021] [Indexed: 01/03/2023]
Abstract
PURPOSE OF REVIEW Acute allograft rejection is a common cause of morbidity and mortality in heart and lung transplantation. Unfortunately, the current monitoring gold standard-biopsy plus histopathology-has several limitations. Plasma donor-derived cell-free DNA (dd-cfDNA) has emerged as a potentially valuable biomarker for rejection that addresses some of the limitations of biopsy. This review covers the current state of the evidence and future directions for the use of dd-cfDNA in the monitoring of acute rejection. RECENT FINDINGS The results of several observational cohort studies demonstrate that levels of dd-cfDNA increase in the setting of acute cellular rejection and antibody-mediated rejection in both heart and lung transplant recipients. dd-cfDNA demonstrates acceptable performance characteristics, but low specificity for the detection of underlying injury from rejection or infection. In particular, the high negative predictive value of the test in both heart and lung transplant patients provides the potential for its use as a screening tool for the monitoring of allograft health rather than tissue biopsy alone. SUMMARY Existing evidence shows that dd-cfDNA is a safe, convenient, and reliable method of acute rejection monitoring in heart and lung transplant recipients. Further studies are required to validate threshold values for clinical use and determine its role in the diagnosis of alternative forms of allograft injury.
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Affiliation(s)
- Michael Keller
- grid.94365.3d0000 0001 2297 5165Laborarory of Applied Precision Omics (APO) and Genomic Research Alliance for Transplantation (GRAfT), National Institute of Health, Bethesda, MD USA ,grid.94365.3d0000 0001 2297 5165Department of Critical Care Medicine, National Institute of Health, Bethesda, MD USA ,grid.411935.b0000 0001 2192 2723Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, MD USA
| | - Sean Agbor-Enoh
- grid.94365.3d0000 0001 2297 5165Laborarory of Applied Precision Omics (APO) and Genomic Research Alliance for Transplantation (GRAfT), National Institute of Health, Bethesda, MD USA ,grid.411935.b0000 0001 2192 2723Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, MD USA ,grid.279885.90000 0001 2293 4638Lasker Clinical Research Tenure Track, Laboratory of Applied Precision Omics, Division of Intramural Research, NHLBI, 10 Center Dr, Rm 7D5, Baltimore, USA
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Konno N, Suzuki R, Takagi T, Sugimoto M, Asama H, Sato Y, Irie H, Hikichi T, Ohira H. Clinical utility of a newly developed microfluidic device for detecting circulating tumor cells in the blood of patients with pancreatico-biliary malignancies. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:115-124. [PMID: 33090657 DOI: 10.1002/jhbp.850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The development of an optimal screening method is required to improve the prognosis of pancreatico-biliary (PB) cancers. A recently developed microfluidic device achieved a high diagnostic yield by detecting circulating tumor cells (CTCs) in the blood of cancer patients. We conducted this study to investigate the clinical utility of measuring CTCs in peripheral venous blood to diagnose PB cancer. METHODS Sixty-three subjects were enrolled in this study (29 with pancreatic cancer [PC], 19 with biliary cancer [BC] and 16 non-tumor controls). Using a microfluidic chip device and image analyzer, circulating blood cells were selected based on their size and immunocytochemistry staining pattern. The primary endpoint was the diagnostic accuracy of CTCs with regard to distinguishing between PB cancer patients and controls. We divided all cases into the training set (n = 32) and validation set (n = 31). The diagnostic accuracy of CTCs, carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9) were analyzed. RESULTS In both the training set and validation set, CTCs showed the highest diagnostic accuracy (training set: CTCs 90.6%, CA19-9 90.6%, CEA 65.6%, validation set: CTCs 87.5%, CA19-9 78.1%, CEA 81.2). Regarding non-metastatic PC (cStage I-III, n = 11), CTCs also had the highest diagnostic accuracy among the three markers tested (CTCs: 84.6%, CA19-9:80.7%, CEA 73.0%). CONCLUSIONS A newly developed microfluidic device could diagnose PB cancers by detecting CTCs. This trial was registered with the UMIN Clinical Trials Registry, no. UMIN000029808.
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Affiliation(s)
- Naoki Konno
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Rei Suzuki
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tadayuki Takagi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Mitsuru Sugimoto
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroyuki Asama
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yuki Sato
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroki Irie
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Takuto Hikichi
- Department of Endoscopy, Fukushima Medical University Hospital, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
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Mantini G, Meijer LL, Glogovitis I, In ‘t Veld SGJG, Paleckyte R, Capula M, Le Large TYS, Morelli L, Pham TV, Piersma SR, Frampton AE, Jimenez CR, Kazemier G, Koppers-Lalic D, Wurdinger T, Giovannetti E. Omics Analysis of Educated Platelets in Cancer and Benign Disease of the Pancreas. Cancers (Basel) 2020; 13:66. [PMID: 33383671 PMCID: PMC7795159 DOI: 10.3390/cancers13010066] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is traditionally associated with thrombocytosis/hypercoagulation and novel insights on platelet-PDAC "dangerous liaisons" are warranted. Here we performed an integrative omics study investigating the biological processes of mRNAs and expressed miRNAs, as well as proteins in PDAC blood platelets, using benign disease as a reference for inflammatory noise. Gene ontology mining revealed enrichment of RNA splicing, mRNA processing and translation initiation in miRNAs and proteins but depletion in RNA transcripts. Remarkably, correlation analyses revealed a negative regulation on SPARC transcription by isomiRs involved in cancer signaling, suggesting a specific "education" in PDAC platelets. Platelets of benign patients were enriched for non-templated additions of G nucleotides (#ntaG) miRNAs, while PDAC presented length variation on 3' (lv3p) as the most frequent modification on miRNAs. Additionally, we provided an actionable repertoire of PDAC and benign platelet-ome to be exploited for future studies. In conclusion, our data show that platelets change their biological repertoire in patients with PDAC, through dysregulation of miRNAs and splicing factors, supporting the presence of de novo protein machinery that can "educate" the platelet. These novel findings could be further exploited for innovative liquid biopsies platforms as well as possible therapeutic targets.
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Affiliation(s)
- Giulia Mantini
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (G.M.); (L.L.M.); (R.P.); (T.Y.S.L.L.); (T.V.P.); (S.R.P.); (C.R.J.)
- Fondazione Pisana per la Scienza, 56017 Pisa, Italy;
| | - Laura L. Meijer
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (G.M.); (L.L.M.); (R.P.); (T.Y.S.L.L.); (T.V.P.); (S.R.P.); (C.R.J.)
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands;
| | - Ilias Glogovitis
- Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (I.G.); (S.G.J.G.I.V.); (D.K.-L.)
- Department of Plant Physiology and Molecular Biology, University of Plovdiv, 4002 Plovdiv, Bulgaria
| | - Sjors G. J. G. In ‘t Veld
- Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (I.G.); (S.G.J.G.I.V.); (D.K.-L.)
| | - Rosita Paleckyte
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (G.M.); (L.L.M.); (R.P.); (T.Y.S.L.L.); (T.V.P.); (S.R.P.); (C.R.J.)
| | - Mjriam Capula
- Fondazione Pisana per la Scienza, 56017 Pisa, Italy;
- Institute of Life Sciences, Sant’Anna School of Advanced Studies, 56127 Pisa, Italy
| | - Tessa Y. S. Le Large
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (G.M.); (L.L.M.); (R.P.); (T.Y.S.L.L.); (T.V.P.); (S.R.P.); (C.R.J.)
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands;
| | - Luca Morelli
- General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy;
| | - Thang V. Pham
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (G.M.); (L.L.M.); (R.P.); (T.Y.S.L.L.); (T.V.P.); (S.R.P.); (C.R.J.)
| | - Sander R. Piersma
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (G.M.); (L.L.M.); (R.P.); (T.Y.S.L.L.); (T.V.P.); (S.R.P.); (C.R.J.)
| | - Adam E. Frampton
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, The Leggett Building, University of Surrey, Guildford GU2 7WG, UK;
- Faculty of Health and Medical Sciences, The Leggett Building, University of Surrey, Guildford GU2 7XH, UK
| | - Connie R. Jimenez
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (G.M.); (L.L.M.); (R.P.); (T.Y.S.L.L.); (T.V.P.); (S.R.P.); (C.R.J.)
| | - Geert Kazemier
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands;
| | - Danijela Koppers-Lalic
- Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (I.G.); (S.G.J.G.I.V.); (D.K.-L.)
| | - Thomas Wurdinger
- Department of Neurosurgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (I.G.); (S.G.J.G.I.V.); (D.K.-L.)
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands; (G.M.); (L.L.M.); (R.P.); (T.Y.S.L.L.); (T.V.P.); (S.R.P.); (C.R.J.)
- Fondazione Pisana per la Scienza, 56017 Pisa, Italy;
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Chapman CG, Ayoub F, Swei E, Llano EM, Li B, Siddiqui UD, Waxman I. Endoscopic ultrasound acquired portal venous circulating tumor cells predict progression free survival and overall survival in patients with pancreaticobiliary cancers. Pancreatology 2020; 20:1747-1754. [PMID: 33082106 DOI: 10.1016/j.pan.2020.10.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/26/2020] [Accepted: 10/08/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Despite recent advances, patients with pancreaticobiliary cancers have a poor prognosis. We previously demonstrated the efficacy of endoscopic ultrasound (EUS) guided acquisition of portal vein (PV) blood for enumeration of circulating tumor cells (CTCs). The aim of this study was to assess PV-CTCs as potential biomarkers for the assessment of progression-free (PFS) and overall survival (OS) in patients with pancreaticobiliary cancers. METHODS 17 patients with biopsy-proven pancreaticobiliary malignancy were enrolled. CTCs were enumerated from both peripheral and PV blood. All patients were followed until death. PFS and OS were evaluated with the log-rank test and summarized with the use of Kaplan-Meier methods. Unadjusted and adjusted Cox-proportional hazards models were fitted to study the relationship between PV-CTCs and PFS and OS. RESULTS After 3.5 years of follow-up, all patients had expired. PV-CTCs were detected in all patients (median PV-CTCs 62.0/7.5 mL (interquartile range [IQR] 17-132). The mean PFS in patients with PV-CTCs <185/7.5 mL was significantly longer than patients with PV-CTCs ≥185/7.5 mL (43.3 weeks vs. 12.8 weeks, log-rank p = 0.002). The mean OS in patients with PV-CTCs <185/7.5 mL was significantly longer than patients with PV-CTCs ≥185/7.5 mL (75.8 weeks vs. 29.5 weeks, log-rank p = 0.021). In an adjusted Cox-proportional hazards model, PV-CTCs were significant predictors of both PFS and OS (HR 1.004, p = 0.037; HR 1.004, p = 0.044 respectively). CONCLUSION In this pilot and feasibility study, EUS-acquired PV-CTCs predicted PFS and OS. Our findings suggest that PV-CTCs can help provide important prognostic data for both providers and patients.
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Affiliation(s)
- Christopher G Chapman
- Center for Endoscopic Research and Therapeutics (CERT), The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Fares Ayoub
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Eric Swei
- Section of General Internal Medicine, Department of Medicine, The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Ernesto M Llano
- Section of General Internal Medicine, Department of Medicine, The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Betty Li
- Section of General Internal Medicine, Department of Medicine, The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Uzma D Siddiqui
- Center for Endoscopic Research and Therapeutics (CERT), The University of Chicago Medicine, Chicago, IL, 60637, USA
| | - Irving Waxman
- Center for Endoscopic Research and Therapeutics (CERT), The University of Chicago Medicine, Chicago, IL, 60637, USA.
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Matsubayashi H, Ishiwatari H, Sasaki K, Uesaka K, Ono H. Detecting Early Pancreatic Cancer: Current Problems and Future Prospects. Gut Liver 2020; 14:30-36. [PMID: 31009958 PMCID: PMC6974337 DOI: 10.5009/gnl18491] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/05/2019] [Accepted: 01/25/2019] [Indexed: 12/13/2022] Open
Abstract
The number of patients with pancreatic cancer (PC) is currently increasing in both Korea and Japan. The 5-year survival rate of patients with PC 13.0%; however, resection with minimal invasion (tumor size: ≤10 mm) increases the 5-year survival rate to 80%. For this reason, early detection is essential, but most patients with early-stage PC are asymptomatic. Early detection of PC has been reported to require screening of high-risk individuals (HRIs), such as those with a family history of PC, inherited cancer syndromes, intraductal papillary mucinous neoplasm, or chronic pancreatitis. Studies on screening of these HRIs have confirmed a significantly better prognosis among patients with PC who were screened than for patients with PC who were not screened. However, to date in Japan, most patients with early-stage PC diagnosed in routine clinics were not diagnosed during annual health checks or by surveillance; rather, PC was detected in these patients by incidental findings during examinations for other diseases. We need to increase the precision of the PC screening and diagnostic processes by introducing new technologies, and we need to pay greater attention to incidental clinical findings.
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Affiliation(s)
- Hiroyuki Matsubayashi
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan.,Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan
| | | | - Keiko Sasaki
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroyuki Ono
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
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Toledano-Fonseca M, Cano MT, Inga E, Rodríguez-Alonso R, Gómez-España MA, Guil-Luna S, Mena-Osuna R, de la Haba-Rodríguez JR, Rodríguez-Ariza A, Aranda E. Circulating Cell-Free DNA-Based Liquid Biopsy Markers for the Non-Invasive Prognosis and Monitoring of Metastatic Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12071754. [PMID: 32630266 PMCID: PMC7409337 DOI: 10.3390/cancers12071754] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/26/2020] [Accepted: 06/29/2020] [Indexed: 12/20/2022] Open
Abstract
Liquid biopsy may assist in the management of cancer patients, which can be particularly applicable in pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the utility of circulating cell-free DNA (cfDNA)-based markers as prognostic tools in metastatic PDAC. Plasma was obtained from 61 metastatic PDAC patients, and cfDNA levels and fragmentation were determined. BEAMing technique was used for quantitative determination of RAS mutation allele fraction (MAF) in cfDNA. We found that the prognosis was more accurately predicted by RAS mutation detection in plasma than in tissue. RAS mutation status in plasma was a strong independent prognostic factor for both overall survival (OS) and progression-free survival (PFS). Moreover, RAS MAF in cfDNA was also an independent risk factor for poor OS, and was strongly associated with primary tumours in the body/tail of the pancreas and liver metastases. Higher cfDNA levels and fragmentation were also associated with poorer OS and shorter PFS, body/tail tumors, and hepatic metastases, whereas cfDNA fragmentation positively correlated with RAS MAF. Remarkably, the combination of CA19-9 with MAF, cfDNA levels and fragmentation improved the prognostic stratification of patients. Furthermore, dynamics of RAS MAF better correlated with patients’ outcome than standard CA19-9 marker. In conclusion, our study supports the use of cfDNA-based liquid biopsy markers as clinical tools for the non-invasive prognosis and monitoring of metastatic PDAC patients.
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Affiliation(s)
- Marta Toledano-Fonseca
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
| | - M. Teresa Cano
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - Elizabeth Inga
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - Rosa Rodríguez-Alonso
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - M. Auxiliadora Gómez-España
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - Silvia Guil-Luna
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
| | - Rafael Mena-Osuna
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
| | - Juan R. de la Haba-Rodríguez
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - Antonio Rodríguez-Ariza
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
- Correspondence:
| | - Enrique Aranda
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
- Department of Medicine, Faculty of Medicine, University of Córdoba, E14004 Córdoba, Spain
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Takahashi H, Yamada D, Asukai K, Wada H, Hasegawa S, Hara H, Shinno N, Ushigome H, Haraguchi N, Sugimura K, Yamamoto K, Nishimura J, Yasui M, Omori T, Miyata H, Ohue M, Yano M, Sakon M, Ishikawa O. Clinical implications of the serum CA19-9 level in "biological borderline resectability" and "biological downstaging" in the setting of preoperative chemoradiation therapy for pancreatic cancer. Pancreatology 2020; 20:919-928. [PMID: 32563596 DOI: 10.1016/j.pan.2020.05.020] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 05/18/2020] [Accepted: 05/27/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Biological factors are emphasized in borderline resectable pancreatic cancer (BRPC), and CA19-9 is an important factor for biological borderline resectability (b-BR). The aim of this study was to investigate the cut-off value of CA19-9 for biological borderline resectability and "biological downstaging" in chemoradiation therapy (CRT) for pancreatic cancer (PC). METHODS A total of 407 patients with anatomically resectable PC (a-R) and BRPC (a-BR) received preoperative gemcitabine-based CRT. The b-BR was determined, according to the CA19-9 value prior to preoperative CRT (pre-CA19-9), as the subgroup of a-R cases in which the survival was comparable with that in a-BR cases. "Biological downstaging" was determined based on prognostic analyses regarding the CA19-9 value after preoperative CRT (post-CA19-9) in association with the survival of R cases (a-R cases without the b-BR factor). RESULTS The 5-year survival of a-R patients with pre-CA19-9 > 120 U/mL was comparable with that of a-BR patients (44% vs 34%, p = 0.082). The survival of b-BR patients with post-CRT CA19-9 ≤ 37 U/mL (normalized) was comparably favorable with that of R patients (56% vs 65%, p = 0.369). The incidence of distant recurrence was higher in b-BR patients without post-CA19-9 normalization than in those with post-CA19-9 normalization (70% vs 50%, p = 0.003), while the incidence of local recurrence was comparable between these two groups (12% vs 13%, p = 0.986). CONCLUSIONS Biological BRPC was determined to be an anatomically resectable disease with pre-CA19-9 > 120 U/mL, and post-CA19-9 normalization indicated "biological downstaging" in b-BR in the preoperative CRT strategy.
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Affiliation(s)
| | - Daisaku Yamada
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Kei Asukai
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Hiroshi Wada
- Department of Surgery, Osaka International Cancer Institute, Japan
| | | | - Hisashi Hara
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Naoki Shinno
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Hajime Ushigome
- Department of Surgery, Osaka International Cancer Institute, Japan
| | | | - Keijiro Sugimura
- Department of Surgery, Osaka International Cancer Institute, Japan
| | | | | | - Masayoshi Yasui
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Takeshi Omori
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Hiroshi Miyata
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Masayuki Ohue
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Masahiko Yano
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Masato Sakon
- Department of Surgery, Osaka International Cancer Institute, Japan
| | - Osamu Ishikawa
- Department of Surgery, Osaka International Cancer Institute, Japan
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Saha G, Singh R, Mandal A, Das S, Chattopadhyay E, Panja P, Roy P, DeSarkar N, Gulati S, Ghatak S, Ghosh S, Banerjee S, Roy B, Ghosh S, Chaudhuri D, Arora N, Biswas NK, Sikdar N. A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients. Mol Med 2020; 26:59. [PMID: 32552660 PMCID: PMC7302128 DOI: 10.1186/s10020-020-00183-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 06/03/2020] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Pancreatic Ductal Adenocarcinoma (PDAC) is a cancer of the exocrine pancreas and 5-year survival rates remain constant at 7%. Along with PDAC, Periampullary Adenocarcinoma (PAC) accounts for 0.5-2% of all gastrointestinal malignancies. Genomic observations were well concluded for PDAC and PACs in western countries but no reports are available from India till now. METHODS Targeted Next Generation Sequencing were performed in 8 (5 PDAC and 3 PAC) tumour normal pairs, using a panel of 412 cancer related genes. Primary findings were replicated in 85 tumour samples (31 PDAC and 54 PAC) using the Sanger sequencing. Mutations were also validated by ASPCR, RFLP, and Ion Torrent sequencing. IHC along with molecular dynamics and docking studies were performed for the p.A138V mutant of TP53. Key polymorphisms at TP53 and its associated genes were genotyped by PCR-RFLP method and association with somatic mutations were evaluated. All survival analysis was done using the Kaplan-Meier survival method which revealed that the survival rates varied significantly depending on the somatic mutations the patients harboured. RESULTS Among the total 114 detected somatic mutations, TP53 was the most frequently mutated (41%) gene, followed by KRAS, SMAD4, CTNNB1, and ERBB3. We identified a novel hotspot TP53 mutation (p.A138V, in 17% of all patients). Low frequency of KRAS mutation (33%) was detected in these samples compared to patients from Western counties. Molecular Dynamics (MD) simulation and DNA-protein docking analysis predicted p.A138V to have oncogenic characteristics. Patients with p.A138V mutation showed poorer overall survival (p = 0.01). So, our finding highlights elevated prevalence of the p53p.A138V somatic mutation in PDAC and pancreatobiliary PAC patients. CONCLUSION Detection of p.A138V somatic variant in TP53 might serve as a prognostic marker to classify patients. It might also have a role in determining treatment regimes. In addition, low frequency of KRAS hotspot mutation mostly in Indian PDAC patient cohort indicates presence of other early drivers in malignant transformation.
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Affiliation(s)
- Gourab Saha
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Richa Singh
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Argha Mandal
- Department of Biotechnology, Heritage Institute of Technology, Kolkata, India
| | - Subrata Das
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India
| | - Esita Chattopadhyay
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Prasun Panja
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Paromita Roy
- Department of Pathology & Department of Gastrointestinal Surgery, Tata Medical Center, Rajarhat, Kolkata, India
| | - Navonil DeSarkar
- Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, USA
| | - Sumit Gulati
- Department of Surgical Gastroenterology, Calcutta Medical Research Institute, Kolkata, India
| | - Supriyo Ghatak
- Department of Surgical Gastroenterology, Calcutta Medical Research Institute, Kolkata, India
| | - Shibajyoti Ghosh
- Department of General Surgery, Medical College and Hospital, Kolkata, India
| | - Sudeep Banerjee
- Department of Pathology & Department of Gastrointestinal Surgery, Tata Medical Center, Rajarhat, Kolkata, India
| | - Bidyut Roy
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Saurabh Ghosh
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Dipankar Chaudhuri
- Department of Biotechnology, Heritage Institute of Technology, Kolkata, India
| | - Neeraj Arora
- Department of Pathology & Department of Gastrointestinal Surgery, Tata Medical Center, Rajarhat, Kolkata, India
| | - Nidhan K Biswas
- National Institute of Biomedical Genomics, Kalyani, West Bengal, India
| | - Nilabja Sikdar
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India.
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