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Jamouss KT, Damanakis AI, Cornwell AC, Jongepier M, Trujillo MA, Pflüger MJ, Kawalerski R, Maalouf A, Hirose K, Datta S, Sipes A, Pedro BA, Gudmundsson E, Assarzadegan N, Engle L, Scharpf RB, Kawamoto S, Thompson ED, Wood LD. Tumor immune microenvironment alterations associated with progression in human intraductal papillary mucinous neoplasms. J Pathol 2025; 266:40-50. [PMID: 40001347 DOI: 10.1002/path.6402] [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: 12/05/2023] [Revised: 11/26/2024] [Accepted: 01/08/2025] [Indexed: 02/27/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to late-stage diagnoses. To improve patient outcomes, early intervention in precursor lesions such as intraductal papillary mucinous neoplasm (IPMN) is crucial. However, early intervention must be balanced against overtreatment of low-risk lesions that are unlikely to progress, underscoring the need to better understand molecular alterations in neoplastic cells and changes in the tumor microenvironment (TME) that drive the progression of IPMNs. In this study, we characterized alterations in the TME of IPMNs as they progressed to high-grade dysplasia, using immunohistochemistry to quantify immune cell density and activation status in more than 100 well-characterized human IPMN samples. Analyses revealed progression to a more immunosuppressive TME in high-grade IPMN compared with low-grade IPMN, characterized by elevated expression of immune checkpoint molecules (PD-L1, TIM3, VISTA), increased density of macrophages, and decreased density of cytotoxic T cells. Intriguingly, the alterations in macrophages were limited to focal regions of high-grade dysplasia, while T-cell alterations affected the entire IPMN. Additionally, elevated VISTA expression was associated with poorer clinical outcome after IPMN resection in an independent cohort. These findings provide important insights into the interplay between the immune microenvironment and IPMN progression, highlighting potential targets to modify the TME for cancer interception. © 2025 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Kevin T Jamouss
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexander Ioannis Damanakis
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Abigail C Cornwell
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Martine Jongepier
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maria A Trujillo
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael Johannes Pflüger
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Graduate School of Life Sciences, Utrecht University, Utrecht, The Netherlands
| | - Ryan Kawalerski
- Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexandre Maalouf
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Katsuya Hirose
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shalini Datta
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Abigail Sipes
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Brian A Pedro
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Emma Gudmundsson
- Department of Physiology, University of Maryland, Baltimore, MD, USA
| | - Naziheh Assarzadegan
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology, University of Florida, Gainesville, FL, USA
| | - Logan Engle
- Bloomberg Kimmel Institute, Tumor Microenvironment Technology Development Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert B Scharpf
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Satomi Kawamoto
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elizabeth D Thompson
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
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Matykiewicz J, Adamus-Białek W, Wawszczak-Kasza M, Molasy B, Kołomańska M, Oblap R, Madej Ł, Kozieł D, Głuszek S. The known genetic variants of BRCA1, BRCA2 and NOD2 in pancreatitis and pancreatic cancer risk assessment. Sci Rep 2025; 15:1791. [PMID: 39805914 PMCID: PMC11729861 DOI: 10.1038/s41598-025-86249-8] [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: 04/29/2024] [Accepted: 01/09/2025] [Indexed: 01/16/2025] Open
Abstract
The single nucleotide polymorphism in NOD2 (rs2066847) is associated with conditions that may predispose to the development of gastrointestinal disorders, as well as the known BRCA1 and BRCA2 variants classified as risk factors in many cancers. In our study, we analyzed these variants in a group of patients with pancreatitis and pancreatic cancer to clarify their role in pancreatic disease development. The DNA was isolated from whole blood samples of 553 patients with pancreatitis, 83 patients with pancreatic cancer, 44 cases of other pancreatic diseases, and 116 healthy volunteers. The NOD2 (rs2066847), BRCA1 (rs80357914) and BRCA2 (rs276174813) were genotyped. The statistically significant 3-fold increased risk of pancreatic cancer was detected among the patients with rs2066847 polymorphism (OR = 2.77, p-value = 0.019). We did not find the studied polymorphisms in BRCA1 (rs80357914) and BRCA2 (rs276174813). However, the adjacent polymorphisms have been detected only in patients with pancreatic diseases. The studied variant in NOD2 occurs more frequently in pancreatic patients and significantly increases the risk of pancreatic cancer. It can be considered as a genetic risk factor that predisposes to cancer development. The analyzed regions in BRCA1 and BRCA2 may be a potential target in further search for a genetic marker of pancreatic diseases.
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Affiliation(s)
- Jarosław Matykiewicz
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | | | | | - Bartosz Molasy
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Magdalena Kołomańska
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Rusłan Oblap
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Łukasz Madej
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Dorota Kozieł
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
| | - Stanisław Głuszek
- Institute of Medical Sciences, Jan Kochanowski University of Kielce, Kielce, Poland
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3
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Athanasiou A, Kureshi N, Wittig A, Sterner M, Huber R, Palma NA, King T, Schiess R. Biomarker Discovery for Early Detection of Pancreatic Ductal Adenocarcinoma (PDAC) Using Multiplex Proteomics Technology. J Proteome Res 2025; 24:315-322. [PMID: 39699878 PMCID: PMC11705213 DOI: 10.1021/acs.jproteome.4c00752] [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: 09/13/2024] [Revised: 11/27/2024] [Accepted: 12/13/2024] [Indexed: 12/20/2024]
Abstract
Early detection of pancreatic ductal adenocarcinoma (PDAC) can improve survival but is hampered by the absence of early disease symptoms. Imaging remains key for surveillance but is cumbersome and may lack sensitivity to detect small tumors. CA19-9, the only FDA-approved blood biomarker for PDAC, is insufficiently sensitive and specific to be recommended for surveillance. We aimed to discover a blood-based protein signature to improve PDAC detection in our main target population consisting of stage I or II PDAC patients (n = 75) and various controls including healthy controls (n = 50), individuals at high risk (genetic and familial) for PDAC (n = 47), or those under surveillance for an intraductal papillary mucinous neoplasm (n = 36). Roughly 3000 proteins were measured using Olink multiplex technology and conventional immunoassays. Machine learning combined biomarker candidates into 4- to 6-plex signatures. These signatures significantly (p < 0.001) outperformed CA19-9 with 84% sensitivity at 95% specificity, compared to CA19-9's sensitivity of 53% in the target population. Exploratory analysis was performed in new-onset diabetes (n = 81) and chronic pancreatitis (n = 50) patients. In conclusion, 41 promising biomarker candidates across multiple signatures were identified using proteomics technology and will be further tested in an independent cohort.
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Affiliation(s)
| | - Natasha Kureshi
- Immunovia
Inc., 26 Forest Street,
Suite 110, Marlborough, Massachusetts 01752, United States
| | - Anja Wittig
- Proteomedix
AG, Wagistrasse 23, CH-8952 Schlieren, Switzerland
| | - Maria Sterner
- Immunovia
AB, Medicon Village,
Scheelevägen 8, SE-223 63 Lund, Sweden
| | - Ramy Huber
- Proteomedix
AG, Wagistrasse 23, CH-8952 Schlieren, Switzerland
| | - Norma A. Palma
- Immunovia
Inc., 26 Forest Street,
Suite 110, Marlborough, Massachusetts 01752, United States
| | - Thomas King
- Immunovia
Inc., 26 Forest Street,
Suite 110, Marlborough, Massachusetts 01752, United States
| | - Ralph Schiess
- Proteomedix
AG, Wagistrasse 23, CH-8952 Schlieren, Switzerland
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Wen YR, Lin XW, Zhou YW, Xu L, Zhang JL, Chen CY, He J. N-glycan biosignatures as a potential diagnostic biomarker for early-stage pancreatic cancer. World J Gastrointest Oncol 2024; 16:659-669. [PMID: 38577461 PMCID: PMC10989390 DOI: 10.4251/wjgo.v16.i3.659] [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: 10/05/2023] [Revised: 12/21/2023] [Accepted: 01/18/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of less than 10%, owing to its late-stage diagnosis. Early detection of pancreatic cancer (PC) can significantly increase survival rates. AIM To identify the serum biomarker signatures associated with early-stage PDAC by serum N-glycan analysis. METHODS An extensive patient cohort was used to determine a biomarker signature, including patients with PDAC that was well-defined at an early stage (stages I and II). The biomarker signature was derived from a case-control study using a case-cohort design consisting of 29 patients with stage I, 22 with stage II, 4 with stage III, 16 with stage IV PDAC, and 88 controls. We used multiparametric analysis to identify early-stage PDAC N-glycan signatures and developed an N-glycan signature-based diagnosis model called the "Glyco-model". RESULTS The biomarker signature was created to discriminate samples derived from patients with PC from those of controls, with a receiver operating characteristic area under the curve of 0.86. In addition, the biomarker signature combined with cancer antigen 19-9 could discriminate patients with PDAC from controls, with a receiver operating characteristic area under the curve of 0.919. Glyco-model demonstrated favorable diagnostic performance in all stages of PC. The diagnostic sensitivity for stage I PDAC was 89.66%. CONCLUSION In a prospective validation study, this serum biomarker signature may offer a viable method for detecting early-stage PDAC.
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Affiliation(s)
- Yan-Rong Wen
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Xia-Wen Lin
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
| | - Yu-Wen Zhou
- Department of Research and Development, Sysdiagno (Nanjing) Biotech Co., Ltd, Nanjing 210008, Jiangsu Province, China
| | - Lei Xu
- Department of Research and Development, Sysdiagno (Nanjing) Biotech Co., Ltd, Nanjing 210008, Jiangsu Province, China
| | - Jun-Li Zhang
- Department of Research and Development, Sysdiagno (Nanjing) Biotech Co., Ltd, Nanjing 210008, Jiangsu Province, China
| | - Cui-Ying Chen
- Department of Research and Development, Sysdiagno (Nanjing) Biotech Co., Ltd, Nanjing 210008, Jiangsu Province, China
| | - Jian He
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, Jiangsu Province, China
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Xin W, Tu S, Yi S, Xiong Y, Fang K, Sun G, Xiao W. Clinical significance of tumor suppressor genes methylation in circulating tumor DNA of patients with pancreatic cancer. Gene 2024; 897:148078. [PMID: 38097094 DOI: 10.1016/j.gene.2023.148078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 11/14/2023] [Accepted: 12/11/2023] [Indexed: 12/17/2023]
Abstract
BACKGROUND Circulating tumor DNA (ctDNA) has emerged as a potential diagnostic and prognostic biomarker in various tumors. However, the role of tumor suppressor genes (TSGs) methylation in ctDNA of patients with pancreatic cancer (PC) remains largely unclear. METHODS Patients with PC (n = 43), pancreatic benign diseases (n = 39), and healthy controls (n = 20) were enrolled in the study. Quantitative analysis of methylation pattern of five candidate TSGs including NPTX2, RASSF1A, EYA2, p16, and ppENK in ctDNA was performed by next generation sequencing (NGS). The diagnostic performances of these 5-TSGs methylation were assessed by the operating characteristic (ROC) curve and clinicopathological features correlation analysis. Meanwhile, the changes in methylation levels of these 5-TSGs on the 7th postoperative day were evaluated in 23 PC patients who underwent radical resection. RESULTS The methylation levels of RASSF1A, EYA2, ppENK and p16 genes in patients with PC were significantly higher than those in healthy controls. EYA2, p16 and ppENK genes showed significantly hypermethylation in PC than those in pancreatic benign diseases. NPTX2, RASSF1A, EYA2, p16 and ppENK genes showed significantly hypermethylation in pancreatic benign diseases than those in healthy controls (P < 0.05). The methylation levels of these 5 candidate TSGs were not correlated with the tumor size, nerve invasion, lymph node metastasis and TNM stage of PC. The AUC of these biomarkers for diagnosis of PC ranged from 0.65 to 0.96. The AUC values of these methylated genes and CpG sites for differentiating malignant and benign pancreatic diseases were ranging from 0.68 to 0.92. Combined the hypermethylated genes improved the detective ability of PC than single gene. The methylation levels of NPTX2, EYA2 and ppENK genes were significantly decreased after radical resection of PC. CONCLUSION Quantitative analysis of methylation pattern of NPTX2, RASSF1A, EYA2, p16 and ppENK in ctDNA by NGS could be a valuable non-invasive tool for detection and monitoring of PC.
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Affiliation(s)
- WanPeng Xin
- Department of General Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Shuju Tu
- Department of General Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Siqing Yi
- Department of General Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Yuanpeng Xiong
- Department of General Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Kang Fang
- Department of General Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Gen Sun
- Department of General Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Weidong Xiao
- Department of General Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China; Institute of Digestive Surgery, Nanchang University, Nanchang, Jiangxi, China.
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6
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Zhang CL, Shen Q, Liu FD, Yang F, Gao MQ, Jiang XC, Li Y, Zhang XY, En GE, Pan X, Pang B. SDC1 and ITGA2 as novel prognostic biomarkers for PDAC related to IPMN. Sci Rep 2023; 13:18727. [PMID: 37907515 PMCID: PMC10618477 DOI: 10.1038/s41598-023-44646-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 10/11/2023] [Indexed: 11/02/2023] Open
Abstract
The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC; therefore, identifying biomarkers from differentially expressed genes (DEGs) of PDAC and IPMN is a new and reliable strategy for predicting the prognosis of PDAC. In this study, four datasets were downloaded from the Gene Expression Omnibus database and standardized using the R package 'limma.' A total of 51 IPMN and 81 PDAC samples were analyzed, and 341 DEGs in PDAC and IPMN were identified; DEGs were involved in the extracellular matrix and tumor microenvironment. An acceptable survival prognosis was demonstrated by SDC1 and ITGA2, which were highly expressed during in vitro PDAC cell proliferation, apoptosis, and migration. SDC1high was enriched in interferon alpha (IFN-α) response and ITGA2high was primarily detected in epithelial-mesenchymal transition (EMT), which was verified using western blotting. We concluded that SDC1 and ITGA2 are potential prognostic biomarkers for PDAC associated with IPMN. Downregulation of SDC1 and ITGA2 expression in PDAC occurs via a mechanism involving possible regulation of IFN-α response, EMT, and immunity, which may act as new targets for PDAC therapy.
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Affiliation(s)
- Chuan-Long Zhang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Qian Shen
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Fu-Dong Liu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Fan Yang
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Meng-Qi Gao
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Xiao-Chen Jiang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Yi Li
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Xi-Yuan Zhang
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Ge-Er En
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xue Pan
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
- Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Bo Pang
- International Medical Department of Guang'anmen Hospital China Academy of Chinese Medical Sciences, Beijing, 100053, China.
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Punzi E, Carrubba C, Contegiacomo A, Posa A, Barbieri P, De Leoni D, Mazza G, Tanzilli A, Cina A, Natale L, Sala E, Iezzi R. Interventional Radiology in the Treatment of Pancreatic Adenocarcinoma: Present and Future Perspectives. Life (Basel) 2023; 13:life13030835. [PMID: 36983990 PMCID: PMC10059735 DOI: 10.3390/life13030835] [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: 02/12/2023] [Revised: 03/07/2023] [Accepted: 03/18/2023] [Indexed: 03/30/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease; patients' long-term survival is strictly linked to the surgical resection of the tumor but only a minority of patients (2-3%) have a resectable disease at diagnosis. In patients with surgically unresectable disease, interventional radiology is taking on an increasing role in treatment with the application of loco-regional percutaneous therapies. The primary purposes of this narrative review are to analyze the safety and efficacy of ablative techniques in the management of borderline resectable and locally advanced diseases and to underline the role of the interventional radiologist in the management of patients with distant metastases. The secondary purpose is to focus on the synergy between immunotherapy and ablative therapies.
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Affiliation(s)
- Ernesto Punzi
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
| | - Claudio Carrubba
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
| | - Andrea Contegiacomo
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
| | - Alessandro Posa
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
| | - Pierluigi Barbieri
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
| | - Davide De Leoni
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
| | - Giulia Mazza
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
| | - Alessandro Tanzilli
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
| | - Alessandro Cina
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
| | - Luigi Natale
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
- Istituto di Radiodiagnostica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Evis Sala
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
- Istituto di Radiodiagnostica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Roberto Iezzi
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia-Istituto di Radiologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, l.go A gemelli 8, 00168 Rome, Italy
- Istituto di Radiodiagnostica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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8
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Moon D, Kim H, Han Y, Byun Y, Choi Y, Kang J, Kwon W, Jang JY. Preoperative carbohydrate antigen 19-9 and standard uptake value of positron emission tomography-computed tomography as prognostic markers in patients with pancreatic ductal adenocarcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2022; 29:1133-1141. [PMID: 33063453 DOI: 10.1002/jhbp.845] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/30/2020] [Accepted: 09/20/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Among various prognostic factors of pancreatic cancer, preoperative clinical information is obtained by imaging modality. This study aimed to evaluate clinical usefulness of preoperative carbohydrate antigen and preoperative standard uptake value in 18F-fluorodeoxyglucose positron emission tomography as predictive biological markers for resectable pancreatic ductal adenocarcinoma. METHODS A total of 189 patients with PDAC who underwent preoperative PET-computed tomography were evaluated. Patients underwent neoadjuvant chemotherapy, and R2 resection was excluded. The correlation between SUVmax and clinicopathologic parameters was analyzed. The C-tree statistical method was used to estimate cutoff values of logCA19-9 and SUVmax for survival rate. A multivariate analysis was conducted to identify prognostic factors for overall survival. RESULTS The median duration of OS was 26 months, and the 5-year survival rate was 22.4%. The optimal cutoff values for CA19-9 level was 150 U/mL and SUVmax was 5.5. When subjects were divided into three groups according to the combination of CA19-9 level and SUVmax from C-tree (high-risk group, CA19-9 > 150 U/mL and SUVmax > 5.5; intermediate-risk group, CA19-9 ≤ 150 U/mL and SUVmax > 5.5 or CA19-9 > 150 U/mL and SUVmax ≤ 5.5; and low-risk group, CA19-9 ≤ 150 U/mL and SUVmax ≤ 5.5), there was a significant 5YSR difference (5.6%, 24.3%, and 36.5%, P < .001). The multivariate analysis revealed high SUVmax, high preoperative CA19-9 level, venous invasion, and adjuvant chemotherapy were prognostic factors of OS. CONCLUSIONS CA19-9 and SUVmax are strong prognostic biological factors in resectable PDAC. Moreover, patients with high CA19-9 level and SUVmax are not indicated for upfront surgery.
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Affiliation(s)
- Dokyoon Moon
- Departments of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hongbeom Kim
- Departments of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Youngmin Han
- Departments of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoonhyeong Byun
- Departments of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoojin Choi
- Departments of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jaeseung Kang
- Departments of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Wooil Kwon
- Departments of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jin-Young Jang
- Departments of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Ermiah E, Eddfair M, Abdulrahman O, Elfagieh M, Jebriel A, Al‑Sharif M, Assidi M, Buhmeida A. Prognostic value of serum CEA and CA19‑9 levels in pancreatic ductal adenocarcinoma. Mol Clin Oncol 2022; 17:126. [PMID: 35832472 PMCID: PMC9264325 DOI: 10.3892/mco.2022.2559] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/10/2022] [Indexed: 11/10/2022] Open
Abstract
The present study investigated the associations of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels with clinicopathological variables and survival outcomes in Libyan patients with pancreatic ductal adenocarcinoma (PDAC). The clinicopathological variables of 123 patients with PDAC registered at the National Cancer Institute in Misurata, Libya, between 2010 and 2018 were retrospectively analyzed. Blood samples from these patients were analyzed for serum CEA and CA19-9 levels before treatment by electrochemiluminescence immunoassay (double antibody sandwich ELISA) on a Roche cobas e 602 modules. The relationships between CA19-9 and CEA serum levels with clinicopathologic variables and survival outcomes were analyzed using the Kaplan-Meier method, log-rank test and Cox regression analyzes. Cut-off values for serum CEA and CA19-9 levels were 5 ng/ml and 400 U/ml, respectively. The median serum levels of all patients with PDAC for CEA and CA19-9 were 8 ng/ml (1.1-377 ng/ml) and 389 U/ml (1-10,050 U/ml), respectively. Tumors with higher serum CEA and CA19-9 levels were found in 63 and 48% of patients, respectively. Higher CEA and CA19-9 serum levels were significantly associated with more indicators of a malignant phenotype, including a surgically unresectable tumor, unevaluable lymph nodes, advanced stages and distant metastases. Regarding survival, patients with higher serum levels of the biomarkers CEA and CA19-9 had shorter overall survival rates (P<0.016 and (P<0.014, log-rank, respectively) and lower disease-free survival rates (P<0.002 and P<0.0001, log-rank, respectively). The present study demonstrated significant clinical and prognostic value of serum levels of biomarkers CEA and CA19-9 for Libyan patients with PDAC. Moreover, patients with PDAC with higher serum CEA and CA19-9 levels had more aggressive tumors, higher rates of disease recurrence and shorter overall survival rates and thus required more vigilant follow-up. Further multinational studies with larger PDAC cohorts are warranted to confirm these findings in terms of improved clinical decision making, more effective management and improved survival.
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Affiliation(s)
- Eramah Ermiah
- Medical Research Unit, National Cancer Institute, Misurata 051, Libya
| | - Mona Eddfair
- Department of Medical Oncology, National Cancer Institute, Misurata 051, Libya
| | - Othman Abdulrahman
- Department of Medical Oncology, National Cancer Institute, Misurata 051, Libya
| | - Mohamed Elfagieh
- Department of Surgery, National Cancer Institute, Misurata 051, Libya
| | - Abdalla Jebriel
- Department of Medical Oncology, National Cancer Institute, Misurata 051, Libya
| | - Mona Al‑Sharif
- Department of Biology College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
| | - Mourad Assidi
- Medical Laboratory Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Abdelbaset Buhmeida
- Centre of Excellence in Genomic Medicine Research, King Abdul‑Aziz University, Jeddah 21589, Saudi Arabia
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10
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Benke M, Farkas N, Hegyi P, Tinusz B, Sarlós P, Erőss B, Szemes K, Vörhendi N, Szakács Z, Szücs Á. Preoperative Serum Carbohydrate Antigen 19-9 Levels Cannot Predict the Surgical Resectability of Pancreatic Cancer: A Meta-Analysis. Pathol Oncol Res 2022; 28:1610266. [PMID: 35645620 PMCID: PMC9136945 DOI: 10.3389/pore.2022.1610266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 04/12/2022] [Indexed: 11/18/2022]
Abstract
Background and Aims: Pancreatic ductal adenocarcinoma has one of the worst prognosis of all malignancies. This investigated the relationship between the preoperative serum carbohydrate antigen 19-9 and surgical resectability. Methods: A systematic search was performed in three databases (MEDLINE, EMBASE, and Web of Science) to compare the surgical resectability of pancreatic ductal adenocarcinoma in patients with high and low preoperative serum carbohydrate antigen 19-9 values. The receiving operating characteristic curves were constructed and the weighted mean differences for preoperative serum carbohydrate antigen 19-9 levels of resectable and unresectable groups of patients were calculated. The PROSPERO registration number is CRD42019132522. Results: Results showed that there was a significant difference in resectability between the low and high carbohydrate antigen 19-9 groups. Six out of the eight studies utilised receiver operating characteristic curves in order to find the cut-off preoperative carbohydrate antigen 19-9 levels marking unresectability. The overall result from the pooled area under curve values from the receiver operating characteristic curves was 0.794 (CI: 0.694-0.893), showing that the preoperative carbohydrate antigen 19-9 level is a "fair" marker of resectability. The result of the pooled weighted mean differences was 964 U/ml (p < 0.001) showing that there is a significant carbohydrate antigen 19-9 difference between the resectable and unresectable groups. Based on the results of the I-squared test, the result was 87.4%, accounting for "considerable" heterogeneity within the population. Conclusion: Carbohydrate antigen 19-9 is not a reliable marker of unresectability, it should not be used on its own in surgical decision-making.
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Affiliation(s)
- Márton Benke
- First Department of Surgery, Semmelweis University, Budapest, Hungary
| | - Nelli Farkas
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Institute of Bioanalysis, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Benedek Tinusz
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Patrícia Sarlós
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
- Clinical Medicine Doctoral School, University of Szeged, Szeged, Hungary
| | - Bálint Erőss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Clinical Medicine Doctoral School, University of Szeged, Szeged, Hungary
| | - Kata Szemes
- Division of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Nóra Vörhendi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Zsolt Szakács
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Ákos Szücs
- First Department of Surgery, Semmelweis University, Budapest, Hungary
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
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11
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Brand RE, Persson J, Bratlie SO, Chung DC, Katona BW, Carrato A, Castillo M, Earl J, Kokkola A, Lucas AL, Moser AJ, DeCicco C, Mellby LD, King TC. Detection of Early-Stage Pancreatic Ductal Adenocarcinoma From Blood Samples: Results of a Multiplex Biomarker Signature Validation Study. Clin Transl Gastroenterol 2022; 13:e00468. [PMID: 35166713 PMCID: PMC8963856 DOI: 10.14309/ctg.0000000000000468] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 02/08/2022] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION The IMMray PanCan-d test combines an 8-plex biomarker signature with CA19-9 in a proprietary algorithm to detect pancreatic ductal adenocarcinoma (PDAC) in serum samples. This study aimed to validate the clinical performance of the IMMray PanCan-d test and to better understand test performance in Lewis-null (le/le) individuals who cannot express CA19-9. METHODS Serum samples from 586 individuals were analyzed with the IMMray PanCan-d biomarker signature and CA19-9 assay, including 167 PDAC samples, 203 individuals at high risk of familial/hereditary PDAC, and 216 healthy controls. Samples were collected at 11 sites in the United States and Europe. The study was performed by Immunovia, Inc (Marlborough, MA), and sample identity was blinded throughout the study. Test results were automatically generated using validated custom software with a locked algorithm and predefined decision value cutoffs for sample classification. RESULTS The IMMray PanCan-d test distinguished PDAC stages I and II (n = 56) vs high-risk individuals with 98% specificity and 85% sensitivity and distinguished PDAC stages I-IV vs high-risk individuals with 98% specificity and 87% sensitivity. We identified samples with a CA19-9 value of 2.5 U/mL or less as probable Lewis-null (le/le) individuals. Excluding these 55 samples from the analysis increased the IMMray PanCan-d test sensitivity to 92% for PDAC stages I-IV (n = 157) vs controls (n = 379) while maintaining specificity at 99%; test sensitivity for PDAC stages I and II increased from 85% to 89%. DISCUSSION These results demonstrate the IMMray PanCan-d blood test can detect PDAC with high specificity (99%) and sensitivity (92%).
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Affiliation(s)
- Randall E. Brand
- Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA;
| | - Jan Persson
- Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden;
| | - Svein Olav Bratlie
- Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden;
| | - Daniel C. Chung
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA;
| | - Bryson W. Katona
- Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA;
| | - Alfredo Carrato
- Molecular Epidemiology and Predictive Markers in Cancer Group, Ramon y Cajal University Hospital, Alcala University, IRYCIS, CIBERONC, Madrid, Spain, Pancreatic Cancer Europe Chairperson, Brussels, Belgium
| | - Marién Castillo
- Molecular Epidemiology and Predictive Markers in Cancer Group, Ramón y Cajal University Hospital, IRYCIS, CIBERONC, Madrid, Spain;
| | - Julie Earl
- Molecular Epidemiology and Predictive Markers in Cancer Group, Ramón y Cajal University Hospital, IRYCIS, CIBERONC, Madrid, Spain;
| | - Arto Kokkola
- Helsinki University Hospital, Helsinki, Finland;
| | - Aimee L. Lucas
- Division of Gastroenterology, Mt. Sinai Medical Center, New York, New York, USA;
| | - A. James Moser
- Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
| | - Corinne DeCicco
- Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA;
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12
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Yoo MY, Yoon YS, Suh MS, Cho JY, Han HS, Lee WW. Prognosis prediction of pancreatic cancer after curative intent surgery using imaging parameters derived from F-18 fluorodeoxyglucose positron emission tomography/computed tomography. Medicine (Baltimore) 2020; 99:e21829. [PMID: 32871906 PMCID: PMC7458160 DOI: 10.1097/md.0000000000021829] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 06/27/2020] [Accepted: 07/18/2020] [Indexed: 01/25/2023] Open
Abstract
Imaging parameters including metabolic or textural parameters during F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) are being used for evaluation of malignancy. However, their utility for prognosis prediction has not been thoroughly investigated. Here, we evaluated the prognosis prediction ability of imaging parameters from preoperative FDGPET/CT in operable pancreatic cancer patients.Sixty pancreatic cancer patients (male:female = 36:24, age = 67.2 ± 10.5 years) who had undergone FDGPET/CT before the curative intent surgery were enrolled. Clinico-pathologic parameters, metabolic parameters from FDGPET/CT; maximal standard uptake value (SUVmax), glucose-incorporated SUVmax (GI-SUVmax), metabolic tumor volume, total-lesion glycolysis, and 53 textural parameters derived from imaging analysis software (MaZda version 4.6) were compared with overall survival.All the patients underwent curative resection. Mean and standard deviation of overall follow-up duration was 16.12 ± 9.81months. Among them, 39 patients had died at 13.46 ± 8.82 months after operation, whereas 21 patients survived with the follow-up duration of 18.56 ± 9.97 months. In the univariate analysis, Tumor diameter ≥4 cm (P = .003), Preoperative Carbohydrate antigen 19-9 ≥37 U/mL (P = .034), number of metastatic lymph node (P = .048) and GI-SUVmax (P = .004) were significant parameters for decreased overall survival. Among the textural parameters, kurtosis3D (P = .052), and skewness3D (P = .064) were potentially significant predictors in the univariate analysis. However, in multivariate analysis only GI-SUVmax (P = .026) and combined operation (P = .001) were significant independent predictors of overall survival.The current research result indicates that metabolic parameter (GI-SUVmax) from FDGPET/CT, and combined operation could predict the overall survival of surgically resected pancreatic cancer patients. Other metabolic or textural imaging parameters were not significant predictors for overall survival of localized pancreatic cancer.
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Affiliation(s)
- Min Young Yoo
- Departments of Nuclear Medicine, Chungbuk National University Hospital, Cheongju
| | - Yoo-Seok Yoon
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam
| | - Min Seok Suh
- Department of Nuclear Medicine, Seoul National University Hospital, Seoul
| | - Jai Young Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam
| | - Ho-Seong Han
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam
| | - Won Woo Lee
- Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam
- Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Republic of Korea
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13
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Molecular and Functional Analysis of Choline Transporters and Antitumor Effects of Choline Transporter-Like Protein 1 Inhibitors in Human Pancreatic Cancer Cells. Int J Mol Sci 2020; 21:ijms21155190. [PMID: 32707889 PMCID: PMC7432747 DOI: 10.3390/ijms21155190] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/14/2020] [Accepted: 07/21/2020] [Indexed: 12/11/2022] Open
Abstract
Choline, an organic cation, is one of the biofactors that play an important role in the structure and the function of biological membranes, and it is essential for the synthesis of phospholipids. Choline positron emission tomography-computed tomography (PET/CT) provides useful information for the imaging diagnosis of cancers, and increased choline accumulation has been identified in a variety of tumors. However, the molecular mechanisms of choline uptake and choline transporters in pancreatic cancer have not been elucidated. Here, we examined molecular and functional analyses of choline transporters in human pancreatic-cancer cell line MIA PaCa-2 and the elucidation of the action mechanism behind the antitumor effect of novel choline-transporter-like protein 1 (CTL1) inhibitors, Amb4269951 and its derivative Amb4269675. CTL1 and CTL2 mRNAs were highly expressed in MIA PaCa-2 cells, and CTL1 and CTL2 proteins were localized in the plasma membrane and the intracellular compartments, respectively. Choline uptake was characterized by Na+-independence, a single-uptake mechanism, and inhibition by choline-uptake inhibitor HC-3, similar to the function of CTL1. These results suggest that the uptake of extracellular choline in MIA PaCa-2 cells is mediated by CTL1. Choline deficiency and HC-3 treatment inhibited cell viability and increased caspase 3/7 activity, suggesting that the inhibition of CTL1 function, which is responsible for choline transport, leads to apoptosis-induced cell death. Both Amb4269951 and Amb4269675 inhibited choline uptake and cell viability and increased caspase-3/7 activity. Ceramide, which is increased by inhibiting choline uptake, also inhibited cell survival and increased caspase-3/7 activity. Lastly, both Amb4269951 and Amb4269675 significantly inhibited tumor growth in a mouse-xenograft model without any adverse effects such as weight loss. CTL1 is a target molecule for the treatment of pancreatic cancer, and its inhibitors Amb4269951 and Amb4269675 are novel lead compounds.
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14
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Incerti E, Vanoli EG, Broggi S, Gumina C, Passoni P, Slim N, Fiorino C, Reni M, Mapelli P, Cattaneo M, Zanon S, Calandrino R, Gianolli L, Di Muzio N, Picchio M. Early variation of 18-fluorine-labelled fluorodeoxyglucose PET-derived parameters after chemoradiotherapy as predictors of survival in locally advanced pancreatic carcinoma patients. Nucl Med Commun 2019; 40:1072-1080. [PMID: 31365502 DOI: 10.1097/mnm.0000000000001065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
OBJECTIVE To investigate if early variation of PET-derived parameters after concomitant chemoradiotherapy (CRT) predicts overall survival (OS), local relapse free survival (LRFS), distant relapse free survival (DRFS) and progression free survival (PFS) in locally advanced pancreatic cancer (LAPC) patients. METHODS Fifty-two LAPC patients (median age: 61 years; range: 35-85) with available FDG PET/CT before and after RT (2-6 months, median: 2) were enrolled from May 2005 to June 2015. The predictive value of the percentage variation of mean/maximum standard uptake value (ΔSUVmean/max), metabolic tumour volume (ΔMTV) and total lesion glycolysis (ΔTLG), estimated considering different uptake thresholds (40-50-60%), was investigated between pre- and post-RT PET. The percentage difference between gastrointestinal cancer-associated antigen (ΔGICA) levels measured at the time of PET was also considered. Log-rank test and Cox regression analysis were performed to assess the prognostic value of considered PET-derived parameters on survival outcomes. RESULTS The median follow-up was 13 months (range: 4-130). At univariate analysis, ΔTLG50 showed borderline significance in predicting OS (P = 0.05) and was the most significant parameter correlated to LRFS and PFS (P = 0.001). Median LRFS was 4 and 33 months if ΔTLG50 was below or above 35% respectively (P = 0.0003); similarly, median PFS was 3 vs 6 months (P = 0.0009). No significant correlation was found between PET-derived parameters and DRFS, while the ΔGICA was the only borderline significant prognostic value for this endpoint (P = 0.05). CONCLUSION PET-derived parameters predict survival in LAPC patients; in particular, ΔTLG50 is the strongest predictor. The combination of these biochemical and imaging biomarkers is promising in identifying patients at higher risk of earlier relapse.
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Affiliation(s)
| | | | | | | | | | | | | | - Michele Reni
- Department of Oncology, IRCCS San Raffaele Scientific Institute
| | - Paola Mapelli
- Unit of Nuclear Medicine
- Vita-Salute San Raffaele University, Milan, Italy
| | | | - Silvia Zanon
- Department of Oncology, IRCCS San Raffaele Scientific Institute
| | | | | | | | - Maria Picchio
- Unit of Nuclear Medicine
- Vita-Salute San Raffaele University, Milan, Italy
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15
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Preoperative maximum standardized uptake value and carbohydrate antigen 19-9 were independent predictors of pathological stages and overall survival in Chinese patients with pancreatic duct adenocarcinoma. BMC Cancer 2019; 19:456. [PMID: 31092213 PMCID: PMC6521479 DOI: 10.1186/s12885-019-5691-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 05/08/2019] [Indexed: 02/07/2023] Open
Abstract
Background Purpose of this study was to analyze whether preoperative maximum standardized uptake value (SUVmax) and carbohydrate antigen 19–9 (CA19–9) levels might provide prognostic information in Chinese patients with pancreatic duct adenocarcinoma (PDAC) after pancreaticoduodenectomy (PD). Methods Standard PD was performed on 109 patients with PDAC by the same operative team, and all patients received preoperative positron emission tomography/computed tomography examination and blood test. Results Patients had a mean age of 59 ± 9.35 years. Females accounted for 38.5%. Mean levels of SUVmax, carcino-embryonic antigen (CEA) and CA19–9 were 5.70 ± 2.76, 3.95 ± 4.16ng/mL and 321.62 ± 780.71kU/L. In univariate Logistic regression analysis, preoperative SUVmax, CEA and CA19–9 levels (p < 0.05 for all) rather than other preoperative variables (p > 0.05 for all) were significantly related to AJCC stages. Multivariate Logistic regression analysis showed that preoperative SUVmax and CA19–9 levels (p < 0.05 for all) rather than other preoperative variables (p > 0.05 for all) were significantly associated with AJCC stages. Mean overall survival (OS) was 21 ± 14.50 months. In univariate Cox regression analysis, age, SUVmax, CEA and CA19–9 levels before operation (p < 0.05 for all) rather than other preoperative variables (p > 0.05 for all) were significantly related to OS. Multivariate Cox regression analysis showed that age, SUVmax and CA19–9 levels before operation (p < 0.05 for all) rather than other preoperative variables (p > 0.05 for all) were significantly associated with OS. Conclusions This study demonstrated that preoperative SUVmax and CA19–9 levels independently predicted pathological stages and OS of patients with PDAC after PD. These preoperative variables might have significant prognostic implication in patients with PDAC after PD. Patients with abnormal SUVmax and CA19–9 levels should be paid special attention to in operative strategy and perioperative management.
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16
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Baugh KA, Villafane N, Farinas C, Dhingra S, Silberfein EJ, Massarweh NN, Cao HT, Fisher WE, Van Buren G. Pancreatic Incidentalomas: A Management Algorithm for Identifying Ectopic Spleens. J Surg Res 2019; 236:144-152. [DOI: 10.1016/j.jss.2018.11.032] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 10/01/2018] [Accepted: 11/19/2018] [Indexed: 12/21/2022]
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17
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Mellby LD, Nyberg AP, Johansen JS, Wingren C, Nordestgaard BG, Bojesen SE, Mitchell BL, Sheppard BC, Sears RC, Borrebaeck CAK. Serum Biomarker Signature-Based Liquid Biopsy for Diagnosis of Early-Stage Pancreatic Cancer. J Clin Oncol 2018; 36:2887-2894. [PMID: 30106639 DOI: 10.1200/jco.2017.77.6658] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival of < 10% because of diffuse symptoms leading to late-stage diagnosis. That survival could increase significantly if localized tumors could be detected early. Therefore, we used multiparametric analysis of blood samples to obtain a novel biomarker signature of early-stage PDAC. The signature was derived from a large patient cohort, including patients with well-defined early-stage (I and II) PDAC. This biomarker signature was validated subsequently in an independent patient cohort. PATIENTS AND METHODS The biomarker signature was derived from a case-control study, using a Scandinavian cohort, consisting of 16 patients with stage I, 132 patients with stage II, 65 patients with stage III, and 230 patients with stage IV PDAC, and 888 controls. This signature was validated subsequently in an independent case-control cohort in the United States with 15 patients with stage I, 75 patients with stage II, 15 patients with stage III, and 38 patients with stage IV PDAC, and 219 controls. An antibody microarray platform was used to identify the serum biomarker signature associated with early-stage PDAC. RESULTS Using the Scandinavian case-control study, a biomarker signature was created, discriminating samples derived from patients with stage I and II from those from controls with a receiver operating characteristic area under the curve value of 0.96. This signature, consisting of 29 biomarkers, was then validated in an independent case-control study in the United States. The biomarker signature could discriminate patients with stage I and II PDAC from controls in this independent patient cohort with a receiver operating characteristic area under the curve value of 0.96. CONCLUSION This serum biomarker signature might represent a tenable approach to detecting early-stage, localized PDAC if these findings are supported by a prospective validation study.
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Affiliation(s)
- Linda D Mellby
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Andreas P Nyberg
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Julia S Johansen
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Christer Wingren
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Børge G Nordestgaard
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Stig E Bojesen
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Breeana L Mitchell
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Brett C Sheppard
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Rosalie C Sears
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
| | - Carl A K Borrebaeck
- Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR
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Yoshikawa T, Abe T, Amano H, Hanada K, Minami T, Kobayashi T, Yonehara S, Nakahara M, Ohdan H, Noriyuki T. Metachronous triple cancer associated with Peutz-Jeghers syndrome treated with curative surgery: a case report. Surg Case Rep 2018; 4:84. [PMID: 30069736 PMCID: PMC6070452 DOI: 10.1186/s40792-018-0492-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 07/23/2018] [Indexed: 12/17/2022] Open
Abstract
Background Peutz–Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by mucocutaneous pigmentation and hamartomatous gastrointestinal polyposis. It is well known that individuals with PJS are at an increased risk of cancer in a variety of organs. Case presentation Here, we present a patient with PJS who achieved long-term survival by undergoing repeat curative surgery for metachronous triple cancer. Her medical history included hilar cholangiocarcinoma and cervical carcinoma; curative surgery was performed for both conditions. On annual follow-up, the level of carcinoembryonic antigen was elevated at 6.9 ng/ml. Enhanced computed tomography revealed a cystic tumor consisting of mural nodules at the pancreatic head; the maximal diameter was 15 mm. Magnetic resonance imaging clearly demonstrated the tumor with low intensity on T1-weighted images and high intensity on T2-weighted images. Endoscopic ultrasound sonography showed a high echoic tumor at the pancreatic head, which was confirmed as adenocarcinoma by fine-needle aspiration biopsy. The preoperative diagnosis was intraductal papillary mucinous carcinoma (IPMC; T1N0M0, stage IA). Subtotal stomach-preserving pancreaticoduodenectomy was performed and the final diagnosis was IPMC, stage 0 (TisN0M0). Conclusions Aggressive surgery for metachronous triple cancer resulted in good long-term prognosis. Continuous and systematic follow-up would allow the detection of malignancy at an early stage and make treatment with curative surgery possible.
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Affiliation(s)
- Toru Yoshikawa
- Department of Surgery, Onomichi General Hospital, 1-10-23, Onomichi, Hiroshima, 722-8508, Japan
| | - Tomoyuki Abe
- Department of Surgery, Onomichi General Hospital, 1-10-23, Onomichi, Hiroshima, 722-8508, Japan.
| | - Hironobu Amano
- Department of Surgery, Onomichi General Hospital, 1-10-23, Onomichi, Hiroshima, 722-8508, Japan.,Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keiji Hanada
- Department of Gastroenterology, Onomichi General Hospital, Onomichi, Hiroshima, Japan
| | - Tomoyuki Minami
- Department of Gastroenterology, Onomichi General Hospital, Onomichi, Hiroshima, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shuji Yonehara
- Department of Pathology, Onomichi General Hospital, Onomichi, Hiroshima, Japan
| | - Masahiro Nakahara
- Department of Surgery, Onomichi General Hospital, 1-10-23, Onomichi, Hiroshima, 722-8508, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Toshio Noriyuki
- Department of Surgery, Onomichi General Hospital, 1-10-23, Onomichi, Hiroshima, 722-8508, Japan.,Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Zhou Y, Shan T, Ding W, Hua Z, Shen Y, Lu Z, Chen B, Dai T. Study on mechanism about long noncoding RNA MALAT1 affecting pancreatic cancer by regulating Hippo-YAP signaling. J Cell Physiol 2018; 233:5805-5814. [PMID: 29215734 DOI: 10.1002/jcp.26357] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 11/30/2017] [Indexed: 12/19/2022]
Abstract
By investigating the migration and invasion ability in pancreatic cancer, this study probed into the lncRNA MALAT1 molecular mechanism on Hippo-YAP signaling. The expression of lncRNA MALAT1 in PC tissues and cells was detected by qRT-PCR and Western blot. The effect of si-MALAT1 on proliferation was determined by CCK-8 assay. Cell apoptosis, migration, and invasion were respectively detected by flow cytometry assay, wound healing assay, and transwell assay. Western blot and immunohistochemistry were successively used for detecting LATS1 and YAP1 expression in pancreatic cancer tissues. The microarray analysis determined that lncRNA MALAT1 in pancreatic cancer was highly expressed. LncRNA MALAT1 presented an extremely high expression level in pancreatic cancer tissues and cells. After transfected with si-MALAT1, the proliferation of AsPC-1 cells decreased, induce apoptosis of AsPC-1 cells, and migration and invasion ability were reduced. The tendency of LATS1 expression level was down-regulated and YAP1 show the opposite trend in the Hippo-YAP signaling. The in vivo assay was found that the tumor to be small in size and volume, and the expression of Ki-67 was decreased. High expression of lncRNA MALAT1 in PC disorder the proliferation, apoptosis, and migration and invasion ability via influence Hippo-YAP signaling pathway.
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Affiliation(s)
- Yongping Zhou
- Department of Hepatobiliary, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Ting Shan
- Department of General Surgery, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Wenzhou Ding
- Department of Hepatobiliary, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Zhiyuan Hua
- Department of Hepatobiliary, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Yijun Shen
- Department of Hepatobiliary, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Zhihua Lu
- Department of Hepatobiliary, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Bo Chen
- Department of Hepatobiliary, East Hospital Affiliated to Tongji University, Shanghai, China
| | - Tu Dai
- Department of Hepatobiliary, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
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Abstract
PURPOSE This article reviews the current evidence surrounding pancreatic cancer screening. The current targets of screening include identification of early pancreatic cancer, as well as the two most important precursor lesions; intraductal papillary mucinous neoplasm and high grade pancreatic intraepithelial neoplasia. Given the relatively low incidence of pancreatic adenocarcinoma in the general population, patients with elevated risk based on family history or an underlying genetic syndrome are felt to be the most appropriate patients to undergo screening. METHODS An extensive review of the literature was performed and the major findings of the available literature regarding pancreatic screening are reviewed in detail. RESULTS Several prospective trials have evaluated pancreatic cancer screening in high-risk groups. The results of those trials are summarized in this article. Current consensus guidelines and recommendations from the International Cancer of the Pancreas Screening Consortium Summit are also discussed. CONCLUSIONS The exact benefit of pancreatic cancer screening remains unclear at this time, but emerging evidence suggests that there is a window of opportunity to detect precursor lesions and early pancreatic adenocarcinomas in high-risk patient populations. Better understanding of the pathway of carcinogenesis will hopefully improve our ability to detect early, resectable pancreatic carcinomas, and provide a mortality benefit to patients at significantly elevated risk of pancreatic adenocarcinoma.
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Affiliation(s)
- Chris M Lindquist
- Department of Radiology, Faculty of Medicine, St. Boniface General Hospital, University of Manitoba, 409 Tache Ave, Winnipeg, MB, R2H 2A6, Canada.
| | - Frank H Miller
- Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St. Suite 800, Chicago, IL, 60611, USA
| | - Nancy A Hammond
- Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St. Suite 800, Chicago, IL, 60611, USA
| | - Paul Nikolaidis
- Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, 676 N. St. Clair St. Suite 800, Chicago, IL, 60611, USA
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21
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Pavlidis ET, Pavlidis TE. Current Molecular and Genetic Aspects of Pancreatic Cancer, the Role of Metastasis Associated Proteins (MTA): A Review. J INVEST SURG 2018; 31:54-66. [PMID: 28060554 DOI: 10.1080/08941939.2016.1269854] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
UNLABELLED Purpose/aim: To focus on current molecular and genetic aspects and MTA proteins, since pancreatic cancer is a lethal malignant with poor prognosis. Early diagnosis is essential step, contributing to potential curative resection. MATERIALS AND METHODS A PubMed search of relevant articles published up to August 2016 was performed to identify current information about pancreatic cancer regarding molecular biomarkers, with emphasis on carcinogenesis, novel therapeutic targets, and MTA proteins. RESULTS Understanding the mechanisms involved in the process of carcinogenesis at the molecular level and the recognition of various oncogenes has opened new horizons for both diagnosis and targeted therapy. Metastasis associated (MTA) proteins (MTA1, MTA2, MTA3) comprise a well-established family of biomarkers. The oncogene MTA1 and its expression product MTA1 protein are the most important and adequately studied in the current research. It defines the growth, local invasiveness, lymphatic spread, and metastatic capacity of various malignancies such as colorectal or gastric cancer including also pancreatic cancer. This protein is associated with malignant potential and biological behavior. Consequently, it could contribute to cancer detection since the first stages of carcinogenesis, as well as in prediction of its malignant differentiation grade. The pre-operative information of the possibility of lymph node involvement may also affect the attempt and the extent of curative resection and lymphadenectomy. CONCLUSIONS Carcinogenesis and implicated oncogenes, either activators or repressors, concentrate much research interest, as well as being useful as biomarkers and for targeted therapy. MTA proteins could become useful diagnostic and prognostic biomarkers in current management of pancreatic cancer.
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Affiliation(s)
- Efstathios T Pavlidis
- a Aristotle University of Thessaloniki, Medical School , Second Surgical Propedeutic Department, Hippocration Hospital , Konstantinoupoleos 49, 546 42 Thessaloniki , Greece
| | - Theodoros E Pavlidis
- a Aristotle University of Thessaloniki, Medical School , Second Surgical Propedeutic Department, Hippocration Hospital , Konstantinoupoleos 49, 546 42 Thessaloniki , Greece
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Tanaka M, Ishikawa S, Ushiku T, Morikawa T, Isagawa T, Yamagishi M, Yamamoto H, Katoh H, Takeshita K, Arita J, Sakamoto Y, Hasegawa K, Kokudo N, Fukayama M. EVI1 modulates oncogenic role of GPC1 in pancreatic carcinogenesis. Oncotarget 2017; 8:99552-99566. [PMID: 29245923 PMCID: PMC5725114 DOI: 10.18632/oncotarget.20601] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 07/11/2017] [Indexed: 12/22/2022] Open
Abstract
Glypican-1 (GPC1) protein in exosomes was recently identified as a biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analyses and in vitro assays were conducted to assess the usefulness of GPC1 as a PDAC biomarker, to reveal the biological role of GPC1 in pancreatic carcinogenesis, and to ascertain the regulation mechanism of GPC1. An aberrant overexpression of GPC1 protein which is usually absent in normal pancreatic duct, was a widespread marker across the full spectrum of human PDAC precursors, PDAC, and pancreatic cancerous stroma. In intraductal papillary-mucinous neoplasms (IPMNs), GPC1 tended to be positive in gastric-type IPMN. KRAS mutations were found in all GPC1-positive IPMN cases and in one-third of GPC1-negative IPMN cases. In pancreatic cell lines, GPC1 depletion caused remarkable inhibition of cell growth and migration, suggesting its oncogenic roles. GPC1 depletion upregulated the molecules associated with cell cycle arrest in pancreatic cell lines. Furthermore, KRAS and ecotropic viral integration site 1 (EVI1) oncoprotein upregulated GPC1 expression. In a clinical cohort, GPC1 overexpression was not correlated with pancreatic cancer prognosis. Taken together, these findings suggest the necessity of establishing a threshold of GPC1 value for detecting pancreatic malignancy because GPC1 is overexpressed even in low-grade PDAC precursors which do not always become malignant. Our study also reveals a new aspect of pancreatic carcinogenesis: KRAS and EVI1, two important molecules in early phases of pancreatic carcinogenesis, positively regulate GPC1 expression and likely promote pancreatic carcinogenesis.
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Affiliation(s)
- Mariko Tanaka
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shumpei Ishikawa
- Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Teppei Morikawa
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takayuki Isagawa
- Department of Cardiovascular Medicine, Nagasaki University Hospital, Nagasaki, Japan
| | - Makoto Yamagishi
- Graduate School of Frontier Sciences, Department of Computational Biology and Medical Sciences, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Yamamoto
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroto Katoh
- Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kimiko Takeshita
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junichi Arita
- Department of Hepatobiliary-pancreatic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshihiro Sakamoto
- Department of Hepatobiliary-pancreatic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Department of Hepatobiliary-pancreatic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Frič P, Šedo A, Škrha J, Bušek P, Laclav M, Škrha P, Zavoral M. Early detection of sporadic pancreatic cancer: time for change. Eur J Gastroenterol Hepatol 2017; 29:885-891. [PMID: 28471824 DOI: 10.1097/meg.0000000000000904] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Sporadic pancreatic cancer amounts to ∼90% of all pancreatic cancers. It is a gloomy depressive disease and the most recalcitrant malignancy, with a very low 5-year survival (3-6%). At present, diagnostic methods are commonly applied, as used half a century ago, after the appearance of local and systemic symptoms (abdominal and back pain, cholestasis, painless jaundice, fatigue, anorexia, weight loss, anemia, peripheral phlebitis, and cachexia). Unfortunately, these symptoms are harbingers of an advanced disease. The subsequent imaging methods may offer additional information on the location, size, and morphology of the lesion, but they do not influence the prognosis. Radical surgery may be offered to 15-20% of patients. The relapses after surgery are frequent and chemotherapy may be palliative. Preventive programs represent the only possibility of improvement. We propose the first multistep and multidisciplinary preventive program for early detection of sporadic pancreatic cancer for the differential identification of average-risk patients who probably have the disease from those who do not.
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Affiliation(s)
- Přemysl Frič
- aDepartment of Medicine/Gastroenterology, Military University Hospital bInstitute of Biochemistry and Experimental Oncology cLaboratory of Endocrinology and Metabolism, General University Hospital, First Faculty of Medicine dSecond Department of Medicine, University Hospital, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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Zhu D, Wang L, Zhang H, Chen J, Wang Y, Byanju S, Liao M. Prognostic value of 18F-FDG-PET/CT parameters in patients with pancreatic carcinoma: A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96:e7813. [PMID: 28816978 PMCID: PMC5571715 DOI: 10.1097/md.0000000000007813] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 07/13/2017] [Accepted: 07/31/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The identification of pancreatic carcinoma (PC) patients with poor prognosis is a priority in clinical oncology because of their high 5-year mortality. However, the prognostic value of pretreatment F-fluorodeoxyglucose (F-FDG)- positron emission tomography (PET)/computed tomography (CT) parameters in PC patients is controversial and no consensus exists as to its predictive capability. This meta-analysis was performed to comprehensively explore the prognostic significance of F-FDG-PET/CT parameters in patients with pancreatic carcinoma. METHODS Extensive literature searches of the PubMed, Embase, Web of Science, and Cochrane Library databases were conducted to identify literature published until March 5, 2017. Comparative analyses of the pooled hazard ratios (HRs) for event-free survival (EFS) and overall survival (OS) were performed to assess their correlations with pretreatment maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Either the fixed- or the random-effects model was adopted, depending on the heterogeneity observed across studies. Subgroup and sensitivity analyses were performed to assess the robustness of the results. RESULTS Sixteen studies including 1146 patients were identified. The pooled HRs for the probability of EFS were 1.90 (95% confidential interval (CI): 1.48-2.45) for SUVmax, 1.76 (95% CI: 1.20-2.58) for MTV, and 1.81 (95% CI: 1.27-2.58) for TLG. The pooled HRs for the probability of OS were 1.21 (95% CI: 1.12-1.31) for SUVmax, 1.56 (95% CI: 1.13-2.16) for MTV, and 1.70 (95% CI: 1.25-2.30) for TLG. A slight publication bias was detected using Begg test. After adjustment using the trim and fill procedure, the corrected HRs were not significantly different. The results of the subgroup analyses by SUVmax, MTV, and TLG showed that these factors may have similar prognostic significance. CONCLUSION F-FDG-PET/CT parameters, such as SUVmax, MTV, and TLG, may be significant prognostic factors in patients with pancreatic carcinoma. F-FDG-PET/CT imaging could be a promising tool to provide prognostic information for these patients.
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Affiliation(s)
| | - Lisha Wang
- Department of Neurology, ZhongNan Hospital of WuHan University, Wuhan City, People's Republic of China
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25
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Abstract
Pancreatic cancer (PC) behaves very differently in comparison with other malignancies. Its incidence has been increasing continuously; mortality has not decreased, the diagnosis is frequently late, radical surgery is performed only in 15-20% of patients, and chemotherapy is only palliative. PC occurs in three different forms. Sporadic PC accounts for 90% of all PCs. Its most frequent form is the pancreatic ductal adenocarcinoma. The remaining 10% constitute two minority groups: familial PC (7%) and PC as a manifestation of a genetic cancer syndrome (3%). PCs are preceded by a precancerous lesion (precursor). At present, six different precursors are known. They have different histomorphological characteristics and malignant potential. The recognition and correct interpretation of individual precursors influences adequate clinical decision-making. The publication surveys the present knowledge of individual precursors and their role in the early pancreatic carcinogenesis.
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Rezaei M, Hosseini A, Nikeghbalian S, Ghaderi A. Establishment and characterization of a new human acinar cell carcinoma cell line, Faraz-ICR, from pancreas. Pancreatology 2017; 17:303-309. [PMID: 28215484 DOI: 10.1016/j.pan.2017.02.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 01/25/2017] [Accepted: 02/06/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Basic research in the field of acinar cell carcinoma (ACC) as a rare neoplasm of the pancreas is dependent on the availability of pragmatic model such as new pancreatic cancer cell lines. Thus, establishment and characterization of new pancreatic cancer cell lines from ACC origin are deemed important. METHODS Faraz-ICR cell line was derived from a 58-years old woman with pancreatic acinar cell carcinoma by the collagenase digestion protocol. We characterized the cell line by examining its morphology and cytostructural and functional profile. RESULTS Faraz-ICR has a doubling time of 35 hours and grows in soft agar with a colony-forming efficiency of 25%. The cell had nearly normal pattern of chromosomes in karyotype analysis and Comparative Genomic Hybridization (CGH) array analysis. Evaluation of cells by flowcytometry showed that Faraz-ICR is negative for EpCAM and mesenchymal markers in different passages, and has epithelial nature. Immunofluorescence staining revealed that cells were strongly positive for vimentin, desmin, ezrin, S100, nestin and they were negative for pan-cytokeratins, chromogranin and alpha smooth muscle actin. CONCLUSIONS We were able to establish a new pancreatic carcinoma cell line with partial aspects of Epithelial-mesenchymal transition and aggressiveness. This cell line might be suitable for studying various anticancer drugs and protein profile aiming to see any possible tumor associated marker for ACC.
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Affiliation(s)
- Marzieh Rezaei
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Hosseini
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Nikeghbalian
- Department of Surgery, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Ghaderi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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18F-FDG PET/CT Metabolic Tumor Volume and Intratumoral Heterogeneity in Pancreatic Adenocarcinomas: Impact of Dual-Time Point and Segmentation Methods. Clin Nucl Med 2017; 42:e16-e21. [PMID: 27819858 DOI: 10.1097/rlu.0000000000001446] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVES We aimed to determine the consistency of quantitative PET measurements of metabolic tumor volume (MTV) and intratumoral heterogeneity index for primary untreated pancreatic adenocarcinomas, when using dual-time point F-FDG PET/CT imaging. METHODS This is an institutional review board-approved, retrospective study including 71 patients with pancreatic adenocarcinoma, who underwent dual-time point F-FDG PET/CT imaging, at approximately 1 hour (early) and 2 hours (delayed), after injection. Automated gradient-based and 50% SUVmax-threshold segmentation methods were used to assess the primary tumor MTV and metabolic intratumoral heterogeneity index, calculated as the area under cumulative SUV-volume histograms (AUC-CSH), with lower AUC-CHS indexes corresponding to higher degrees of tumor heterogeneity. We defined that more than a ±10% change in MTV or AUC-CSH, compared with baseline, as clinically significant. RESULTS Seventy-one FDG-avid pancreatic tumors were identified, with an average tumor diameter of 3.4 ± 0.9 cm (range, 1.5-6.4 cm). Metabolic tumor volume values remained consistent between early and delayed imaging when using the gradient PET segmentation method (P = 0.086), whereas statistically significant change was seen when using 50% SUVmax-threshold segmentation (P < 0.001). A decrease in more than 10% change in MTV (% ΔMTV) was observed in 70.4% (50/71) tumors, and 7.0% (5/71) of the tumors showed an increase more than 10 % ΔMTV, when using the 50% SUVmax-threshold segmentation. AUC-CSH indexes showed statistically significant differences between early and delayed time points (P < 0.001), when using the gradient segmentation. AUC-CSH index decreased by 10% or greater in 40.8% (29/71) of the tumors. AUC-CSH index remained stable between early and delayed when using the 50% SUVmax-threshold segmentation (P = 0.148) with percentage of change of less than 10% for all tumors. CONCLUSIONS Metabolic tumor volume was relatively stable between early and delayed time points when PET gradient segmentation was used but changed greater than 10% in 77.4% of the tumors at delayed time point when threshold segmentation was used. The tumor heterogeneity index (AUC-CSH) changed greater than 10% in 40.8% of tumors at delayed imaging, when gradient segmentation was used but remained stable when threshold segmentation was used. It is important to standardize uptake time and segmentation methods to use FDG PET MTV and heterogeneity index as imaging biomarkers.
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Early detection of pancreatic cancer: impact of high-resolution imaging methods and biomarkers. Eur J Gastroenterol Hepatol 2016; 28:e33-e43. [PMID: 27769077 DOI: 10.1097/meg.0000000000000727] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
High-resolution imaging methods (HRIMs) and biomarkers present the second step of pancreatic cancer (PC) diagnostics in at-risk individuals. These include patients with positive risk factors, early symptoms, nonresponders to the initial antidiabetic therapy, patients older than 50 years of age with new-onset unstable diabetes requiring insulin as well as patients with long-term insulin-non-dependent diabetes and recent (up to 6 months) failure of antidiabetic therapy. The procedures should be started without delay and the co-operation between the primary and tertiary medical centers is highly desirable. An early indication of HRIMs and biomarkers is a prerequisite for the diagnosis of a resectable PC. This publication reviews the recent contribution of HRIMs and biomarkers toward an early diagnosis of PC.
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Gao Y, Zhu Y, Yuan Z. Circulating Tumor Cells and Circulating Tumor DNA Provide New Insights into Pancreatic Cancer. Int J Med Sci 2016; 13:902-913. [PMID: 27994495 PMCID: PMC5165683 DOI: 10.7150/ijms.16734] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 09/13/2016] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer has a rather dismal prognosis mainly due to high malignance of tumor biology. Up to now, the relevant researches on pancreatic cancer lag behind seriously partly due to the obstacles for tissue biopsy, which handicaps the understanding of molecular and genetic features of pancreatic cancer. In the last two decades, liquid biopsy, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), is promising to provide new insights into the biological and clinical characteristics of malignant tumors. Both CTCs and ctDNA provide an opportunity for studying tumor heterogeneity, drug resistance, and metastatic mechanism for pancreatic cancer. Furthermore, they can also play important roles in detecting early-stage tumors, providing prognostic information, monitoring tumor progression and guiding treatment regimens. In this review, we will introduce the latest findings on biological features and clinical applications of both CTCs and ctDNA in pancreatic cancer. In a word, CTCs and ctDNA are promising to promote precision medicine in pancreatic cancer.
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Affiliation(s)
| | | | - Zhou Yuan
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
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Heiler S, Wang Z, Zöller M. Pancreatic cancer stem cell markers and exosomes - the incentive push. World J Gastroenterol 2016; 22:5971-6007. [PMID: 27468191 PMCID: PMC4948278 DOI: 10.3748/wjg.v22.i26.5971] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 06/03/2016] [Accepted: 06/28/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC (Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, EpCAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outside-in signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as miRNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows Pa-CSC exosomes (TEX) to reprogram neighboring non-CSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC-TEX.
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Guo X, Lv X, Fang C, Lv X, Wang F, Wang D, Zhao J, Ma Y, Xue Y, Bai Q, Yao X, Chen Y. Dysbindin as a novel biomarker for pancreatic ductal adenocarcinoma identified by proteomic profiling. Int J Cancer 2016; 139:1821-9. [PMID: 27281120 DOI: 10.1002/ijc.30227] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 04/27/2016] [Accepted: 05/30/2016] [Indexed: 12/20/2022]
Abstract
Pancreatic adenocarcinoma (PDAC) is known to have a poor prognosis partly because of lack of effective biomarkers. In the test set, we investigated dysbindin (DTNBP1) as a potential biomarker for PDAC by comparing preoperative and postoperative serum mass spectrometry (MS) proteomic profilings. Of the included 50 PDAC patients, 42 (positivity of 84.0%) detected a lower MS peak in postoperative serums than preoperative ones which was then identified as dysbindin. In the verification set, receiver operating characteristics (ROC) were used to assess diagnostic efficiency. 550 participants were included in the verification set [250 with PDAC, 80 with benign biliary obstruction (BBO), 70 with chronic pancreatitis (CP) and 150 healthy donors (HD)]. Dysbindin was increased in PDAC patient sera than in all controls. ROC curves revealed the optimum diagnostic cutoff for dysbindin was 699.16 pg/ml [area under curve (AUC) 0.849 (95% CI 0.812-0.885), sensitivity 81.9% and specificity 84.7%]. Raised concentration of dysbindin in sera could differentiate PDAC from BBO, CP and HD. Moreover, dysbindin maintained its diagnostic accuracy for PDAC patients who were CA19-9 negative [AUC 0.875 (95% CI 0.804-0.945), sensitivity 83.0%, specificity 89.0%] and for patients with benign biliary obstruction [AUC 0.849 (95% CI 0.803-0.894), sensitivity 82.3%, specificity 84.0%].Our discovery of dysbindin may complement measurement of CA19-9 in the diagnosis of PDAC and help to discriminate PDAC from other pancreatic diseases or begin biliary obstruction.
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Affiliation(s)
- Xin Guo
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.,Department of Endoscopic Surgery, the people's Liberation Army 451st hospital, Xi'an, Shaanxi, People's Republic of China
| | - Xiaohui Lv
- Department of Endoscopic Surgery, the people's Liberation Army 451st hospital, Xi'an, Shaanxi, People's Republic of China
| | - Cheng Fang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Xing Lv
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Fengsong Wang
- Department ofgynecology and obstetrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.,Department of Biology, School of Life Science, Anhui Medical University, Hefei, Anhui, People's Republic of China
| | - Dongmei Wang
- Department of Hefei Laboratory for Physical Sciences at Microscale, School of Life Science, University of Science and Technology of China, Hefei, Anhui, People's Republic of China
| | - Jun Zhao
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Yueyun Ma
- Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
| | - Yu Xue
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Quan Bai
- Institute of Modern Separation Science, College of Chemistry & Materials Science, Northwest University, Xi'an, Shaanxi, People's Republic of China
| | - Xuebiao Yao
- Department of Hefei Laboratory for Physical Sciences at Microscale, School of Life Science, University of Science and Technology of China, Hefei, Anhui, People's Republic of China
| | - Yong Chen
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China
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Abstract
OBJECTIVE The chance to improve survival from pancreatic adenocarcinoma relies on early diagnosis through screening, but any screening program is subject to lead-time bias and no data are available in this regard. Aim of the present study was to evaluate the benefit obtainable from a screening program for early detection of pancreatic adenocarcinoma, considering screen-related biases. METHODS Monte Carlo simulation was performed using data from 1000 pancreatic cancer patients admitted in a tertiary referral hospital and from pertinent literature. Lead-time bias was assessed and subtracted from expected survival. RESULTS Mean expected life expectancy was 13.0 months. Assuming a 20%, 30%, or 50% stage III/IV reduction with screening, pancreatic resections would increase from 217 to 290 in front of a 20% stage III/IV reduction to 324 in front of a 30% reduction and to 385 in front of a 50% reduction. After lead-time adjustment, life expectancies were 14.0, 14.6, and 15.9 months, respectively. The number-needed-to-screen calculation suggests that screening can be harmful in a proportion of patients inversely dependent on the length of follow-up and a significant improvement of survival after diagnosis. CONCLUSIONS Pancreatic adenocarcinoma screening program would probably be successful in the presence of a considerable improvement of postdiagnostic survival; otherwise, it only increases surgical procedure amount.
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Majumder S, Chari ST, Ahlquist DA. Molecular detection of pancreatic neoplasia: Current status and future promise. World J Gastroenterol 2015; 21:11387-11395. [PMID: 26526068 PMCID: PMC4616215 DOI: 10.3748/wjg.v21.i40.11387] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 07/15/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is usually diagnosed at an advanced stage and curative resection is feasible in only a small minority of patients at the time of diagnosis. Diagnosis at an early stage is unequivocally associated with better long-term survival. Several candidate molecular markers for early detection are currently under investigation in different phases of discovery and validation. Recent advances in the technology for whole genome, methylome, ribonucleome, and proteome interrogation has enabled rapid advancements in the field of biomarker discovery. In this review we discuss the current status of molecular markers for detection of pancreatic cancer in blood, pancreatic cyst fluid, pancreatic juice and stool and briefly highlight some promising preliminary results of new approaches that have the potential of advancing this field in the near future.
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Liu B, Qi C, Liu XC, Zhao XD. AFAP-1L2 influences proliferation and apoptosis of pancreatic cancer cells via PI3K/Akt pathway. Shijie Huaren Xiaohua Zazhi 2015; 23:4490-4498. [DOI: 10.11569/wcjd.v23.i28.4490] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of actin filament-associated protein 1-like 2 (AFAP-1L2) in different pancreatic cancer cell lines, the effect of AFAP-1L2 on cell proliferation, cell cycle and apoptosis, and the possible mechanism.
METHODS: Western blot and real-time quantitative PCR (qRT-PCR) were used to detect the AFAP-1L2 protein and mRNA expression in PANC-1, MiaPaCa-2, Colo-357, BXPC-3, SW1990 and CFPAC-1 cell lines (having different differentiation degrees). siAFAP-1L2 plasmid was constructed and transfected into MiaPaCa-2 cell to downregulate the expression of AFAP-1L2. Proteins of the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway were detected by Western blot and qRT-PCR after siAFAP-1L2 transfection. Proliferation was detected by MTT assay. Cell cycle and apoptosis were detected by flow cytometry.
RESULTS: Western blot and qRT-PCR analyses showed that AFAP-1L2 was correlated with differentiation degree, and the expression was higher in cell lines with low differentiation than in those with moderate or high differentiation. PI3KCA protein expression in the siAFAP-1L2 group was lower than that in the MOCK and siRNA control groups (F = 20.16, P = 0.0022). α-Akt mRNA expression in the siAFAP-1L2 group was higher than that in the MOCK and siRNA control groups (F = 7.719, P = 0.0219); α-pAkt protein expression in the siAFAP-1L2 group was lower than that in MOCK and siRNA control groups (F = 5.507, P = 0.0439). PI3KCA mRNA expression in the siAFAP-1L2 group was lower than that in the AFAP-1L2 and siRNA control groups (F = 20.16, P = 0.0022). α-Akt mRNA expression in the siAFAP-1L2 group was higher than that in the MOCK and siRNA control groups (F = 6.068, P = 0.0362); α-pAkt mRNA expression in the siAFAP-1L2 group was lower than that in the MOCK and siRNA control groups (F = 10.33, P = 0.0114). MTT assay showed that the proliferation of MiaPaCa-2 cells at 48 h, 72 h, and 96 h was inhibited after siAFAP-1L2 transfection (F = 3.924, P < 0.05; F = 6.812, P < 0.01; F = 7.003, P < 0.01). Flow cytometry showed that cells in G1 phase were increased, but those in G2 and S phases were decreased (F = 4.87, 5.26, 4.94, P < 0.05 for all). The apoptosis rate of MiaPaCa-2 cell was increased after siAFAP-1L2 transfection (F = 7.231, P < 0.01).
CONCLUSION: AFAP-1L2 expression is associated with cell differentiation. AFAP-1L2 modulates cell proliferation, cell cycle and apoptosis via the PI3K/Akt pathway. AFAP-1L2 is a target candidate for pancreatic cancer therapy.
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Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523:177-82. [PMID: 26106858 PMCID: PMC4825698 DOI: 10.1038/nature14581] [Citation(s) in RCA: 2160] [Impact Index Per Article: 216.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 05/22/2015] [Indexed: 12/12/2022]
Abstract
Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1(+) circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1(+) crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1(+) crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1(+) crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1(+) crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.
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Affiliation(s)
- Sonia A. Melo
- Department of Cancer Biology, Metastasis Research Center, University
of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Linda B. Luecke
- Department of Cancer Biology, Metastasis Research Center, University
of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Christoph Kahlert
- Department of Cancer Biology, Metastasis Research Center, University
of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Agustin F. Fernandez
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias
(IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain
| | - Seth T. Gammon
- Department of Cancer Systems Imaging, The University of Texas M.D.
Anderson Cancer Center, Houston, TX 77054, USA
| | - Judith Kaye
- Department of Cancer Biology, Metastasis Research Center, University
of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Valerie S. LeBleu
- Department of Cancer Biology, Metastasis Research Center, University
of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Elizabeth A. Mittendorf
- Department of Surgical Oncology, The University of Texas MD Anderson
Cancer Center, Houston, TX 77030, USA
| | - Juergen Weitz
- Department of Gastrointestinal, Thoracic and Vascular Surgery,
Medizinische Fakultät Carl Gustav Carus, Technische Universität
Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Nuh Rahbari
- Department of Gastrointestinal, Thoracic and Vascular Surgery,
Medizinische Fakultät Carl Gustav Carus, Technische Universität
Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Christoph Reissfelder
- Department of Gastrointestinal, Thoracic and Vascular Surgery,
Medizinische Fakultät Carl Gustav Carus, Technische Universität
Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Christian Pilarsky
- Department of Gastrointestinal, Thoracic and Vascular Surgery,
Medizinische Fakultät Carl Gustav Carus, Technische Universität
Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Mario F. Fraga
- Cancer Epigenetics Laboratory, Institute of Oncology of Asturias
(IUOPA), HUCA, Universidad de Oviedo, Oviedo, Spain
- Department of Immunology and Oncology, National Center for
Biotechnology, CNB-CSIC, Cantoblanco, 28049 Madrid, Spain
| | - David Piwnica-Worms
- Department of Cancer Systems Imaging, The University of Texas M.D.
Anderson Cancer Center, Houston, TX 77054, USA
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University
of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
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Abstract
Cancer is caused by the accumulation of inherited and/or acquired alterations in specific genes. The recent decline in the cost of DNA sequencing has allowed tumor sequencing to be conducted on a large scale, which, in turn, has led to an unprecedented understanding of the genetic events that drive neoplasia. This understanding, when integrated with meticulous histologic analyses and with clinical findings, has direct clinical implications. The recent sequencing of all of the major types of cystic and noncystic neoplasms of the pancreas has revealed opportunities for molecular diagnoses and for personalized treatment. This review summarizes the results from these recent studies focusing on the clinical relevance of genomic data.
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