|
1
|
Rousta F, Esteki A, Shalbaf A, Sadeghi A, Moghadam PK, Voshagh A. Application of artificial intelligence in pancreas endoscopic ultrasound imaging- A systematic review. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2024; 250:108205. [PMID: 38703435 DOI: 10.1016/j.cmpb.2024.108205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 04/13/2024] [Accepted: 04/24/2024] [Indexed: 05/06/2024]
Abstract
The pancreas is a vital organ in digestive system which has significant health implications. It is imperative to evaluate and identify malignant pancreatic lesions promptly in light of the high mortality rate linked to such malignancies. Endoscopic Ultrasound (EUS) is a non-invasive precise technique to detect pancreas disorders, but it is highly operator dependent. Artificial intelligence (AI), including traditional machine learning (ML) and deep learning (DL) techniques can play a pivotal role to enhancing the performance of EUS regardless of operator. AI performs a critical function in the detection, classification, and segmentation of medical images. The utilization of AI-assisted systems has improved the accuracy and productivity of pancreatic analysis, including the detection of diverse pancreatic disorders (e.g., pancreatitis, masses, and cysts) as well as landmarks and parenchyma. This systematic review examines the rapidly developing domain of AI-assisted system in EUS of the pancreas. Its objective is to present a thorough study of the present research status and developments in this area. This paper explores the significant challenges of AI-assisted system in pancreas EUS imaging, highlights the potential of AI techniques in addressing these challenges, and suggests the scope for future research in domain of AI-assisted EUS systems.
Collapse
Affiliation(s)
- Fatemeh Rousta
- Department of Biomedical Engineering and Physics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Esteki
- Department of Biomedical Engineering and Physics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Shalbaf
- Department of Biomedical Engineering and Physics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Amir Sadeghi
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pardis Ketabi Moghadam
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardalan Voshagh
- Faculty of Electrical Engineering, Shahid Beheshti University, Tehran, Iran
| |
Collapse
|
|
2
|
Anwar MA, Keshteli AH, Yang H, Wang W, Li X, Messier HM, Cullis PR, Borchers CH, Fraser R, Wishart DS. Blood-Based Multiomics-Guided Detection of a Precancerous Pancreatic Tumor. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2024; 28:182-192. [PMID: 38634790 DOI: 10.1089/omi.2023.0278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/19/2024]
Abstract
Over a decade ago, longitudinal multiomics analysis was pioneered for early disease detection and individually tailored precision health interventions. However, high sample processing costs, expansive multiomics measurements along with complex data analysis have made this approach to precision/personalized medicine impractical. Here we describe in a case report, a more practical approach that uses fewer measurements, annual sampling, and faster decision making. We also show how this approach offers promise to detect an exceedingly rare and potentially fatal condition before it fully manifests. Specifically, we describe in the present case report how longitudinal multiomics monitoring (LMOM) helped detect a precancerous pancreatic tumor and led to a successful surgical intervention. The patient, enrolled in an annual blood-based LMOM since 2018, had dramatic changes in the June 2021 and 2022 annual metabolomics and proteomics results that prompted further clinical diagnostic testing for pancreatic cancer. Using abdominal magnetic resonance imaging, a 2.6 cm lesion in the tail of the patient's pancreas was detected. The tumor fluid from an aspiration biopsy had 10,000 times that of normal carcinoembryonic antigen levels. After the tumor was surgically resected, histopathological findings confirmed it was a precancerous pancreatic tumor. Postoperative omics testing indicated that most metabolite and protein levels returned to patient's 2018 levels. This case report illustrates the potentials of blood LMOM for precision/personalized medicine, and new ways of thinking medical innovation for a potentially life-saving early diagnosis of pancreatic cancer. Blood LMOM warrants future programmatic translational research with the goals of precision medicine, and individually tailored cancer diagnoses and treatments.
Collapse
Affiliation(s)
| | | | - Haiyan Yang
- Molecular You Corporation, Vancouver, British Columbia, Canada
| | - Windy Wang
- Molecular You Corporation, Vancouver, British Columbia, Canada
| | - Xukun Li
- Molecular You Corporation, Vancouver, British Columbia, Canada
| | - Helen M Messier
- Molecular You Corporation, Vancouver, British Columbia, Canada
- Fountain Life, Naples, Florida, USA
| | - Pieter R Cullis
- Molecular You Corporation, Vancouver, British Columbia, Canada
- Life Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christoph H Borchers
- Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
- Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
- Department of Pathology, McGill University, Montreal, Quebec, Canada
| | - Robert Fraser
- Molecular You Corporation, Vancouver, British Columbia, Canada
| | - David S Wishart
- Molecular You Corporation, Vancouver, British Columbia, Canada
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
- Department of Computing Science, University of Alberta, Edmonton, Alberta, Canada
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
3
|
Miao J, Zhang Z, Zhang X, Huang X, Zhang S, Zhan Z, Chen J, Chen L, Li L. Label-free assessment of pathological changes in pancreatic intraepithelial neoplasia by biomedical multiphoton microscopy. JOURNAL OF BIOPHOTONICS 2024; 17:e202300417. [PMID: 38221649 DOI: 10.1002/jbio.202300417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/26/2023] [Accepted: 12/21/2023] [Indexed: 01/16/2024]
Abstract
Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion that has the potential to progress to invasive pancreatic cancer, and early and rapid detection may offer patients a chance for treatment before the development of invasive carcinoma. Therefore, the identification of PanIN holds significant clinical importance. In this study, we first used multiphoton microscopy (MPM) combining two-photon excitation fluorescence and second-harmonic generation imaging to label-free detect PanIN and attempted to differentiate between normal pancreatic ducts and different grades of PanIN. Then, we also developed an automatic image processing strategy to extract eight morphological features of collagen fibers from MPM images to quantify the changes in collagen fibers surrounding the ducts. Experimental results demonstrate that the combination of MPM and quantitative information can accurately identify normal pancreatic ducts and different grades of PanIN. This study may contribute to the rapid diagnosis of pancreatic diseases and may lay the foundation for further clinical application of MPM.
Collapse
Affiliation(s)
- Jikui Miao
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China
| | - Zheng Zhang
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China
| | - Xiong Zhang
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China
| | - Xingxin Huang
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China
| | - Shichao Zhang
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China
| | - Zhenlin Zhan
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China
| | - Jianxin Chen
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China
| | - Linying Chen
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Lianhuang Li
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, China
| |
Collapse
|
|
4
|
Bararia A, Das A, Mitra S, Banerjee S, Chatterjee A, Sikdar N. Deoxyribonucleic acid methylation driven aberrations in pancreatic cancer-related pathways. World J Gastrointest Oncol 2023; 15:1505-1519. [PMID: 37746645 PMCID: PMC10514732 DOI: 10.4251/wjgo.v15.i9.1505] [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: 04/18/2023] [Revised: 05/29/2023] [Accepted: 08/01/2023] [Indexed: 09/13/2023] Open
Abstract
Pancreatic cancer (PanCa) presents a catastrophic disease with poor overall survival at advanced stages, with immediate requirement of new and effective treatment options. Besides genetic mutations, epigenetic dysregulation of signaling pathway-associated enriched genes are considered as novel therapeutic target. Mechanisms beneath the deoxyribonucleic acid methylation and its utility in developing of epi-drugs in PanCa are under trails. Combinations of epigenetic medicines with conventional cytotoxic treatments or targeted therapy are promising options to improving the dismal response and survival rate of PanCa patients. Recent studies have identified potentially valid pathways that support the prediction that future PanCa clinical trials will include vigorous testing of epigenomic therapies. Epigenetics thus promises to generate a significant amount of new knowledge of biological and medical importance. Our review could identify various components of epigenetic mechanisms known to be involved in the initiation and development of pancreatic ductal adenocarcinoma and related precancerous lesions, and novel pharmacological strategies that target these components could potentially lead to breakthroughs. We aim to highlight the possibilities that exist and the potential therapeutic interventions.
Collapse
Affiliation(s)
- Akash Bararia
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, India
| | - Amlan Das
- Department of Biochemistry, Royal Global University, Assam 781035, India
| | - Sangeeta Mitra
- Department of Biochemistry and Biophysics, University of Kalyani, West Bengal 741235, India
| | - Sudeep Banerjee
- Department of Gastrointestinal Surgery, Tata Medical Center, Kolkata 700160, India
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand
- School of Health Sciences and Technology, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Nilabja Sikdar
- Human Genetics Unit, Indian Statistical Institute, Kolkata 700108, India
| |
Collapse
|
|
5
|
Sarkar R, Xu Z, Perera CJ, Apte MV. Emerging role of pancreatic stellate cell-derived extracellular vesicles in pancreatic cancer. Semin Cancer Biol 2023; 93:114-122. [PMID: 37225047 DOI: 10.1016/j.semcancer.2023.05.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/17/2023] [Accepted: 05/19/2023] [Indexed: 05/26/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that is characterised by a prominent collagenous stromal reaction/desmoplasia surrounding tumour cells. Pancreatic stellate cells (PSCs) are responsible for the production of this stroma and have been shown to facilitate PDAC progression. Recently, extracellular vesicles (EVs), in particular, small extracellular vesicles (exosomes) have been a topic of interest in the field of cancer research for their emerging roles in cancer progression and diagnosis. EVs act as a form of intercellular communication by carrying their molecular cargo from one cell to another, regulating functions of the recipient cells. Although the knowledge of the bi-directional interactions between the PSCs and cancer cells that promote disease progression has advanced significantly over the past decade, studies on PSC-derived EVs in PDAC are currently rather limited. This review provides an overview of PDAC, pancreatic stellate cells and their interactions with cancer cells, as well as the currently known role of extracellular vesicles derived from PSCs in PDAC progression.
Collapse
Affiliation(s)
- Rohit Sarkar
- Pancreatic Research Group, South West Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; Ingham Institute of Applied Medical Research, Sydney 2170, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South West Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; Ingham Institute of Applied Medical Research, Sydney 2170, Australia
| | - Chamini J Perera
- Pancreatic Research Group, South West Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; Ingham Institute of Applied Medical Research, Sydney 2170, Australia.
| | - Minoti V Apte
- Pancreatic Research Group, South West Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; Ingham Institute of Applied Medical Research, Sydney 2170, Australia
| |
Collapse
|
|
6
|
Carpenter ES, Elhossiny AM, Kadiyala P, Li J, McGue J, Griffith BD, Zhang Y, Edwards J, Nelson S, Lima F, Donahue KL, Du W, Bischoff AC, Alomari D, Watkoske HR, Mattea M, The S, Espinoza CE, Barrett M, Sonnenday CJ, Olden N, Chen CT, Peterson N, Gunchick V, Sahai V, Rao A, Bednar F, Shi J, Frankel TL, Pasca di Magliano M. Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions. Cancer Discov 2023; 13:1324-1345. [PMID: 37021392 PMCID: PMC10236159 DOI: 10.1158/2159-8290.cd-23-0013] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/03/2023] [Accepted: 03/15/2023] [Indexed: 04/07/2023]
Abstract
UNLABELLED The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individuals irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. SIGNIFICANCE Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell-intrinsic factors that restrain or, conversely, promote malignant progression. See related commentary by Hoffman and Dougan, p. 1288. This article is highlighted in the In This Issue feature, p. 1275.
Collapse
Affiliation(s)
- Eileen S. Carpenter
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Ahmed M. Elhossiny
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Padma Kadiyala
- Immunology Graduate Program, University of Michigan, Ann Arbor, Michigan
| | - Jay Li
- Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan
| | - Jake McGue
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | | | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Jacob Edwards
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Sarah Nelson
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Fatima Lima
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | | | - Wenting Du
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | | | - Danyah Alomari
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
| | | | - Michael Mattea
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Stephanie The
- Cancer Data Science Resource, University of Michigan, Ann Arbor, Michigan
| | | | - Meredith Barrett
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | | | | | - Chin-Tung Chen
- Colorectal Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nicole Peterson
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan
| | - Valerie Gunchick
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan
| | - Vaibhav Sahai
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan
| | - Arvind Rao
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
- Cancer Data Science Resource, University of Michigan, Ann Arbor, Michigan
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
| | - Filip Bednar
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Jiaqi Shi
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
- Department of Pathology, University of Michigan, Ann Arbor, Michigan
| | - Timothy L. Frankel
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
- Immunology Graduate Program, University of Michigan, Ann Arbor, Michigan
| | - Marina Pasca di Magliano
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| |
Collapse
|
|
7
|
Carpenter ES, Elhossiny AM, Kadiyala P, Li J, McGue J, Griffith B, Zhang Y, Edwards J, Nelson S, Lima F, Donahue KL, Du W, Bischoff AC, Alomari D, Watkoske H, Mattea M, The S, Espinoza C, Barrett M, Sonnenday CJ, Olden N, Peterson N, Gunchick V, Sahai V, Rao A, Bednar F, Shi J, Frankel TL, Di Magliano MP. Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.13.523300. [PMID: 36712058 PMCID: PMC9882230 DOI: 10.1101/2023.01.13.523300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Statement of significance The causes underlying the onset of pancreatic cancer remain largely unknown, hampering early detection and prevention strategies. Here, we show that PanIN are abundant in healthy individuals and present at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell intrinsic factors that restrain, or, conversely, promote, malignant progression.
Collapse
Affiliation(s)
- Eileen S Carpenter
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI
| | - Ahmed M Elhossiny
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI
| | - Padma Kadiyala
- Immunology Graduate Program, University of Michigan, Ann Arbor, MI
| | - Jay Li
- Medical Scientist Training Program, University of Michigan, Ann Arbor, MI
| | - Jake McGue
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Brian Griffith
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Jacob Edwards
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Sarah Nelson
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Fatima Lima
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | | | - Wenting Du
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | | | - Danyah Alomari
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Hannah Watkoske
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Michael Mattea
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Stephanie The
- Cancer Data Science Resource, University of Michigan, Ann Arbor, MI
| | - Carlos Espinoza
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | | | | | | | - Nicole Peterson
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI
| | - Valerie Gunchick
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI
| | - Vaibhav Sahai
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI
| | - Arvind Rao
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI
- Cancer Data Science Resource, University of Michigan, Ann Arbor, MI
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI
- Department of Biostatistics, University of Michigan, Ann Arbor, MI
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Jiaqi Shi
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI
- Department of Pathology, University of Michigan, Ann Arbor, MI
| | - Timothy L Frankel
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI
- Immunology Graduate Program, University of Michigan, Ann Arbor, MI
| | - Marina Pasca Di Magliano
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI
- Department of Surgery, University of Michigan, Ann Arbor, MI
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI
| |
Collapse
|
|
8
|
Lugo-Fagundo E, Weisberg EM, Fishman EK. Pancreatic cancer in patient with groove pancreatitis: Potential pitfalls in diagnosis. Radiol Case Rep 2022; 17:4632-4635. [PMID: 36204401 PMCID: PMC9530484 DOI: 10.1016/j.radcr.2022.09.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/02/2022] [Accepted: 09/07/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer is among the leading causes of cancer death in the United States of America. Early detection and intervention are critical as a large majority of patients have either local or distant metastatic disease at the time of diagnosis. However, groove pancreatitis, a rare form of chronic pancreatitis, presents as a challenge for adequate and efficient differential diagnosis of pancreatic cancer as a result of similar clinical symptoms and imaging features. Furthermore, intraductal papillary mucinous neoplasms and pancreatic intraepithelial neoplasia are 2 of the precursor lesions that have been identified with pancreatic ductal adenocarcinoma. Intraductal papillary mucinous neoplasms are cystic tumors of the pancreas characterized by excessive mucin production in either the main pancreatic duct or its branches. Conversely, pancreatic intraepithelial neoplasia are microscopic lesions in the smaller pancreatic ducts. In this article, we report the case of a 46-year-old male with a diagnosis of groove pancreatitis, main duct intraductal papillary mucinous neoplasm, and pancreatic intraepithelial neoplasia whose tumor was excised by means of a Whipple procedure. We focus on optimizing diagnosis and treatment through the application of radiological modalities.
Collapse
|
|
9
|
Badheeb M, Abdelrahim A, Esmail A, Umoru G, Abboud K, Al-Najjar E, Rasheed G, Alkhulaifawi M, Abudayyeh A, Abdelrahim M. Pancreatic Tumorigenesis: Precursors, Genetic Risk Factors and Screening. Curr Oncol 2022; 29:8693-8719. [PMID: 36421339 PMCID: PMC9689647 DOI: 10.3390/curroncol29110686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/09/2022] [Accepted: 11/14/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic cancer (PC) is a highly malignant and aggressive tumor. Despite medical advancement, the silent nature of PC results in only 20% of all cases considered resectable at the time of diagnosis. It is projected to become the second leading cause in 2030. Most pancreatic cancer cases are diagnosed in the advanced stages. Such cases are typically unresectable and are associated with a 5-year survival of less than 10%. Although there is no guideline consensus regarding recommendations for screening for pancreatic cancer, early detection has been associated with better outcomes. In addition to continued utilization of imaging and conventional tumor markers, clinicians should be aware of novel testing modalities that may be effective for early detection of pancreatic cancer in individuals with high-risk factors. The pathogenesis of PC is not well understood; however, various modifiable and non-modifiable factors have been implicated in pancreatic oncogenesis. PC detection in the earlier stages is associated with better outcomes; nevertheless, most oncological societies do not recommend universal screening as it may result in a high false-positive rate. Therefore, targeted screening for high-risk individuals represents a reasonable option. In this review, we aimed to summarize the pathogenesis, genetic risk factors, high-risk population, and screening modalities for PC.
Collapse
Affiliation(s)
- Mohamed Badheeb
- Internal Medicine Department, College of Medicine, Hadhramout University, Mukalla 50512, Yemen
| | | | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
- Correspondence: (A.E.); (M.A.)
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Karen Abboud
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ebtesam Al-Najjar
- Faculty of Medicine and Health Sciences, University of Science and Technology, Sana’a 15201, Yemen
| | - Ghaith Rasheed
- Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan
| | | | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
- Weill Cornell Medical College, New York, NY 14853, USA
- Cockrell Center for Advanced Therapeutic Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Correspondence: (A.E.); (M.A.)
| |
Collapse
|
|
10
|
Makler A, Narayanan R, Asghar W. An Exosomal miRNA Biomarker for the Detection of Pancreatic Ductal Adenocarcinoma. BIOSENSORS 2022; 12:831. [PMID: 36290970 PMCID: PMC9599289 DOI: 10.3390/bios12100831] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/25/2022] [Accepted: 09/29/2022] [Indexed: 06/16/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a difficult tumor to diagnose and treat. To date, PDAC lacks routine screening with no markers available for early detection. Exosomes are 40-150 nm-sized extracellular vesicles that contain DNA, RNA, and proteins. These exosomes are released by all cell types into circulation and thus can be harvested from patient body fluids, thereby facilitating a non-invasive method for PDAC detection. A bioinformatics analysis was conducted utilizing publicly available miRNA pancreatic cancer expression and genome databases. Through this analysis, we identified 18 miRNA with strong potential for PDAC detection. From this analysis, 10 (MIR31, MIR93, MIR133A1, MIR210, MIR330, MIR339, MIR425, MIR429, MIR1208, and MIR3620) were chosen due to high copy number variation as well as their potential to differentiate patients with chronic pancreatitis, neoplasms, and PDAC. These 10 were examined for their mature miRNA expression patterns, giving rise to 18 mature miRs for further analysis. Exosomal RNA from cell culture media was analyzed via RTqPCR and seven mature miRs exhibited statistical significance (miR-31-5p, miR-31-3p, miR-210-3p, miR-339-5p, miR-425-5p, miR-425-3p, and miR-429). These identified biomarkers can potentially be used for early detection of PDAC.
Collapse
Affiliation(s)
- Amy Makler
- Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL 33431, USA
- Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Ramaswamy Narayanan
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
- Department of Biology, University of North Florida, Jacksonville, FL 32224, USA
| | - Waseem Asghar
- Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL 33431, USA
- Department of Computer & Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL 33431, USA
| |
Collapse
|
|
11
|
Bell PD, Singhi AD. Integrating Molecular Analysis into the Pathologic Evaluation of Pancreatic Cysts. Surg Pathol Clin 2022; 15:455-468. [PMID: 36049828 DOI: 10.1016/j.path.2022.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
The development of cross-sectional imaging techniques has enhanced the detection of pancreatic cystic lesions (PCLs). PCLs are found in approximately 2% of the general population, often as incidentally detected lesions on computed tomography or MRI during the evaluation of other medical conditions. Broadly, PCLs are classified as mucinous or nonmucinous. Mucinous PCLs include mucinous cystic neoplasms and intraductal papillary mucinous neoplasms. Nonmucinous PCLs include pseudocysts, serous cystadenomas, solid pseudopapillary neoplasms, and cystic pancreatic neuroendocrine tumors, as well as cystic acinar cell carcinoma, cystic degeneration of pancreatic ductal adenocarcinoma, lymphoepithelial cyst, and others.
Collapse
Affiliation(s)
- Phoenix D Bell
- Department of Pathology, University of Pittsburgh Medical Center, 200 Lothrop St. Pittbsurgh, PA 15213, USA.
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, 200 Lothrop St. Pittbsurgh, PA 15213, USA
| |
Collapse
|
|
12
|
Ardeshna DR, Rangwani S, Cao T, Pawlik TM, Stanich PP, Krishna SG. Intraductal Papillary Mucinous Neoplasms in Hereditary Cancer Syndromes. Biomedicines 2022; 10:1475. [PMID: 35884779 PMCID: PMC9313108 DOI: 10.3390/biomedicines10071475] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 11/16/2022] Open
Abstract
Hereditary pancreatic cancer, which includes patients with familial pancreatic cancer (FPC) and hereditary pancreatic cancer syndromes, accounts for about 10% of all pancreatic cancer diagnoses. The early detection of pre-cancerous pancreatic cysts has increasingly become a focus of interest in recent years as a potential avenue to lower pancreatic cancer incidence and mortality. Intraductal papillary mucinous cystic neoplasms (IPMNs) are recognized precursor lesions of pancreatic cancer. IPMNs have high prevalence in patients with hereditary pancreatic cancer and their relatives. While various somatic mutations have been identified in IPMNs, certain germline mutations associated with hereditary cancer syndromes have also been identified in IPMNs, suggesting a role in their formation. While the significance for the higher prevalence of IPMNs or similar germline mutations in these high-risk patients remain unclear, IPMNs do represent pre-malignant lesions that need close surveillance. This review summarizes the available literature on the incidence and prevalence of IPMNs in inherited genetic predisposition syndromes and FPC and speculates if IPMN and pancreatic cancer surveillance in these high-risk individuals needs to change.
Collapse
Affiliation(s)
- Devarshi R. Ardeshna
- Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (D.R.A.); (S.R.)
| | - Shiva Rangwani
- Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (D.R.A.); (S.R.)
| | - Troy Cao
- College of Medicine, Ohio State University, Columbus, OH 43210, USA;
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Peter P. Stanich
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| |
Collapse
|
|
13
|
Oh S, Kim YJ, Park YT, Kim KG. Automatic Pancreatic Cyst Lesion Segmentation on EUS Images Using a Deep-Learning Approach. SENSORS (BASEL, SWITZERLAND) 2021; 22:s22010245. [PMID: 35009788 PMCID: PMC8749636 DOI: 10.3390/s22010245] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/22/2021] [Accepted: 12/27/2021] [Indexed: 05/05/2023]
Abstract
The automatic segmentation of the pancreatic cyst lesion (PCL) is essential for the automated diagnosis of pancreatic cyst lesions on endoscopic ultrasonography (EUS) images. In this study, we proposed a deep-learning approach for PCL segmentation on EUS images. We employed the Attention U-Net model for automatic PCL segmentation. The Attention U-Net was compared with the Basic U-Net, Residual U-Net, and U-Net++ models. The Attention U-Net showed a better dice similarity coefficient (DSC) and intersection over union (IoU) scores than the other models on the internal test. Although the Basic U-Net showed a higher DSC and IoU scores on the external test than the Attention U-Net, there was no statistically significant difference. On the internal test of the cross-over study, the Attention U-Net showed the highest DSC and IoU scores. However, there was no significant difference between the Attention U-Net and Residual U-Net or between the Attention U-Net and U-Net++. On the external test of the cross-over study, all models showed no significant difference from each other. To the best of our knowledge, this is the first study implementing segmentation of PCL on EUS images using a deep-learning approach. Our experimental results show that a deep-learning approach can be applied successfully for PCL segmentation on EUS images.
Collapse
Affiliation(s)
- Seok Oh
- Gil Medical Center, Department of Biomedical Engineering, Gachon University College of Medicine, Incheon 21565, Korea; (S.O.); (Y.-J.K.)
| | - Young-Jae Kim
- Gil Medical Center, Department of Biomedical Engineering, Gachon University College of Medicine, Incheon 21565, Korea; (S.O.); (Y.-J.K.)
| | - Young-Taek Park
- HIRA Research Institute, Health Insurance Review & Assessment Service (HIRA), Wonju-si 26465, Korea;
| | - Kwang-Gi Kim
- Gil Medical Center, Department of Biomedical Engineering, Gachon University College of Medicine, Incheon 21565, Korea; (S.O.); (Y.-J.K.)
- Correspondence:
| |
Collapse
|
|
14
|
Opitz FV, Haeberle L, Daum A, Esposito I. Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia. Cancers (Basel) 2021; 13:cancers13246188. [PMID: 34944807 PMCID: PMC8699458 DOI: 10.3390/cancers13246188] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive neoplasm with a poor survival rate. This is mainly due to late detection, which substantially limits therapy options. A better understanding of the early phases of pancreatic carcinogenesis is fundamental for improving patient prognosis in the future. In this article, we focused on the tumor microenvironment (TME), which provides the biological niche for the development of PDAC from its most common precursor lesions, PanIN (pancreatic intraepithelial neoplasias). Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression.
Collapse
|
|
15
|
Khachfe HH, Habib JR, Nassour I, Al Harthi S, Jamali FR. Borderline Resectable and Locally Advanced Pancreatic Cancers: A Review of Definitions, Diagnostics, Strategies for Treatment, and Future Directions. Pancreas 2021; 50:1243-1249. [PMID: 34860806 DOI: 10.1097/mpa.0000000000001924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
ABSTRACT Locally advanced and borderline resectable pancreatic cancers are being increasingly recognized as a result of significant improvements in imaging modalities. The main tools used in diagnosis of these tumors include endoscopic ultrasound, computed tomography, magnetic resonance imaging, and diagnostic laparoscopy. The definition of what constitutes a locally advanced or borderline resectable tumor is still controversial to this day. Borderline resectable tumors have been treated with neoadjuvant therapy approaches that aim at reducing tumor size, thus improving the chances of an R0 resection. Both chemotherapy and radiotherapy (solo or in combination) have been used in this setting. The main chemotherapy agents that have shown to increase resectability and survival are FOLFORINOX (a combination of folinic acid, fluorouracil, irinotecan, and oxaliplatin) and gemcitabine-nab-paclitaxel. Surgery on these tumors remains a significantly challenging task for pancreatic surgeons. More studies are needed to determine the best agents to be used in the neoadjuvant and adjuvant settings, biologic markers for prognostic and operative predictions, and validation of previously published retrospective results.
Collapse
Affiliation(s)
| | - Joseph R Habib
- Division of General Surgery, University of Maryland, Baltimore, MD
| | | | - Salem Al Harthi
- Division of General Surgery, University of Maryland, Baltimore, MD
| | - Faek R Jamali
- Department of General Surgery, Sheikh Shakhbout Medical City, Abu Dhabi, UAE
| |
Collapse
|
|
16
|
Brandi G, Turroni S, McAllister F, Frega G. The Human Microbiomes in Pancreatic Cancer: Towards Evidence-Based Manipulation Strategies? Int J Mol Sci 2021; 22:9914. [PMID: 34576078 PMCID: PMC8471697 DOI: 10.3390/ijms22189914] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023] Open
Abstract
Recent pieces of evidence have emerged on the relevance of microorganisms in modulating responses to anticancer treatments and reshaping the tumor-immune microenvironment. On the one hand, many studies have addressed the role of the gut microbiota, providing interesting correlative findings with respect to etiopathogenesis and treatment responses. On the other hand, intra-tumoral bacteria are being recognized as intrinsic and essential components of the cancer microenvironment, able to promote a plethora of tumor-related aspects from cancer growth to resistance to chemotherapy. These elements will be probably more and more valuable in the coming years in early diagnosis and risk stratification. Furthermore, microbial-targeted intervention strategies may be used as adjuvants to current therapies to improve therapeutic responses and overall survival. This review focuses on new insights and therapeutic approaches that are dawning against pancreatic cancer: a neoplasm that arises in a central metabolic "hub" interfaced between the gut and the host.
Collapse
Affiliation(s)
- Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Silvia Turroni
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy;
| | - Florencia McAllister
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Giorgio Frega
- Department of Experimental, Diagnostic and Specialty Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| |
Collapse
|
|
17
|
Satoh T, Ishiwatari H, Kawaguchi S, Sato J, Kaneko J, Kanemoto H, Sugiura T, Sasaki K, Matsubayashi H, Uesaka K, Ono H. Can regular follow-up imaging contribute to the determination of appropriate timing of surgery in patients with undiagnosed mucinous cystic neoplasm? A multicenter retrospective study. Jpn J Clin Oncol 2021; 51:1423-1429. [PMID: 34212179 DOI: 10.1093/jjco/hyab103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/17/2021] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE Guidelines suggest that patients with undiagnosed pancreatic cystic lesions should be monitored despite a lack of evidence supporting surveillance for undiagnosed mucinous cystic neoplasms (MCNs). We aimed to investigate the pre- and post-operative clinical course of patients with MCN and the utility of follow-up for patients who were not diagnosed with MCN at initial examination. PATIENTS AND METHODS This multicenter retrospective study enrolled 28 patients with resected pathology-proven MCN; 12 and 16 patients underwent surgery within and after 6 months from the initial examination (Groups A and B, respectively). Outcome measures included changes in imaging findings until surgery in Group B, pathological findings between both groups and differences in pathological findings between patients with and without regular follow-up imaging in Group B. RESULTS In Group B, the median cyst size was 30 and 48 mm at the initial examination and immediately before surgery, respectively. The incidence of mural cysts, thickened walls and mural nodules were 25, 19 and 0%, respectively, at the initial examination and 69, 56 and 31%, respectively, immediately before surgery. There were no significant differences in the invasive carcinoma rates between Groups A and B (13 vs. 17%). Regular follow-up imaging was offered to Group B. Among these, invasive carcinoma was found in one patient exhibiting no recurrence. One patient without follow-up imaging had invasive carcinoma recurrence post-operatively. CONCLUSIONS MCNs increased in size, and typical imaging findings appeared over time. For undiagnosed MCN, regular follow-up examination contributed to the determination of the appropriate surgical timing.
Collapse
Affiliation(s)
- Tatsunori Satoh
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
| | | | - Shinya Kawaguchi
- Department of Gastroenterology, Shizuoka General Hospital, Shizuoka, Japan
| | - Junya Sato
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
| | - Junichi Kaneko
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hideyuki Kanemoto
- Department of Gastroenterological Surgery, Shizuoka General Hospital, Shizuoka, Japan
| | - Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Keiko Sasaki
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroyuki Matsubayashi
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan.,Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hiroyuki Ono
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
| |
Collapse
|
|
18
|
Ma G, Li G, Xiao Z, Gou A, Xu Y, Song S, Guo K, Liu Z. Narrative review of intraductal papillary mucinous neoplasms: pathogenesis, diagnosis, and treatment of a true precancerous lesion. Gland Surg 2021; 10:2313-2324. [PMID: 34422602 PMCID: PMC8340339 DOI: 10.21037/gs-21-450] [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: 05/25/2021] [Accepted: 07/14/2021] [Indexed: 12/09/2022]
Abstract
OBJECTIVE Although considerable progress has been made in our understanding of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, there are still some problems to be solved. BACKGROUND IPMN is one of the most important precancerous lesions of pancreatic cancer, but the relationship between IPMN and pancreatic cancer, and the specific mechanism of the development from IPMN to invasive carcinoma, remain to be explored in depth. With the development of imaging, the detection rate of IPMN has been greatly improved. However, the degree of malignancy of IPMN is difficult to assess, and its classification criteria and surgical treatment strategies are still controversial. Therefore, there is an urgent need for the best treatment plan for IPMN and research that can better predict IPMN recurrence and tumor malignancy. METHODS From the online database Web of Science (https://webofknowledge.com/) and PubMed (https://pubmed.ncbi.nlm.nih.gov/), we use specific retrieval strategies to retrieve relevant articles based on the topics we discussed, and we review and discuss them. CONCLUSIONS This paper discusses the related research and progress of IPMN in recent years to improve the understanding of the incidence, diagnosis, treatment, and prognosis of this disease. The follow-up and monitoring of IPMN is particularly important, but the specific strategy also remains controversial.
Collapse
Affiliation(s)
- Gang Ma
- Department of Pancreatic-Biliary Surgery, First Hospital of China Medical University, Shenyang, China
| | - Guichen Li
- Department of Pancreatic-Biliary Surgery, First Hospital of China Medical University, Shenyang, China
| | - Zhihuan Xiao
- Department of Pancreatic-Biliary Surgery, First Hospital of China Medical University, Shenyang, China
| | - Anjiang Gou
- Department of Pancreatic-Biliary Surgery, First Hospital of China Medical University, Shenyang, China
| | - Yuanhong Xu
- Department of Pancreatic-Biliary Surgery, First Hospital of China Medical University, Shenyang, China
| | - Shaowei Song
- Department of Pancreatic-Biliary Surgery, First Hospital of China Medical University, Shenyang, China
| | - Kejian Guo
- Department of Pancreatic-Biliary Surgery, First Hospital of China Medical University, Shenyang, China
| | - Zhe Liu
- Department of Pancreatic-Biliary Surgery, First Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
19
|
Mesoscopic 3D imaging of pancreatic cancer and Langerhans islets based on tissue autofluorescence. Sci Rep 2020; 10:18246. [PMID: 33106532 PMCID: PMC7588461 DOI: 10.1038/s41598-020-74616-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/05/2020] [Indexed: 12/16/2022] Open
Abstract
The possibility to assess pancreatic anatomy with microscopic resolution in three dimensions (3D) would significantly add to pathological analyses of disease processes. Pancreatic ductal adenocarcinoma (PDAC) has a bleak prognosis with over 90% of the patients dying within 5 years after diagnosis. Cure can be achieved by surgical resection, but the efficiency remains drearily low. Here we demonstrate a method that without prior immunohistochemical labelling provides insight into the 3D microenvironment and spread of PDAC and premalignant cysts in intact surgical biopsies. The method is based solely on the autofluorescent properties of the investigated tissues using optical projection tomography and/or light-sheet fluorescence microscopy. It does not interfere with subsequent histopathological analysis and may facilitate identification of tumor-free resection margins within hours. We further demonstrate how the developed approach can be used to assess individual volumes and numbers of the islets of Langerhans in unprecedently large biopsies of human pancreatic tissue, thus providing a new means by which remaining islet mass may be assessed in settings of diabetes. Generally, the method may provide a fast approach to provide new anatomical insight into pancreatic pathophysiology.
Collapse
|
|
20
|
Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2020; 75:153-168. [PMID: 33049362 DOI: 10.1016/j.semcancer.2020.10.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging as attractive candidates for biomarker development in various cancers, including PDAC. More specifically, the ncRNAs play a pivotal role in PDAC biology as they affect tumor growth, migration, and invasion by regulating cellular processes including cell cycle, apoptosis, and epithelial-mesenchymal transition. In this review, we focus on three types of well-established ncRNAs - microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - and discuss their potential as diagnostic, prognostic and predictive biomarkers in PDAC.
Collapse
|
|
21
|
Luchini C, Grillo F, Fassan M, Vanoli A, Capelli P, Paolino G, Ingravallo G, Renzulli G, Doglioni C, D’Amuri A, Mattiolo P, Pecori S, Parente P, Florena AM, Zamboni G, Scarpa A. Malignant epithelial/exocrine tumors of the pancreas. Pathologica 2020; 112:210-226. [PMID: 33179623 PMCID: PMC7931574 DOI: 10.32074/1591-951x-167] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 07/07/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.
Collapse
Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Federica Grillo
- Anatomic Pathology, San Martino IRCCS Hospital, Genova, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Italy
| | - Paola Capelli
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Gaetano Paolino
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Giuseppe Ingravallo
- Department of Emergency and Organ Transplantation, Section of Pathological Anatomy, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppina Renzulli
- Department of Emergency and Organ Transplantation, Section of Pathological Anatomy, University of Bari Aldo Moro, Bari, Italy
| | - Claudio Doglioni
- Vita e Salute University, Milan, Italy
- Pathology Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Sara Pecori
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
| | - Ada M. Florena
- Department of Sciences for Promotion of Health and Mother and Child Care, Anatomic Pathology, University of Palermo, Italy
| | - Giuseppe Zamboni
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- IRCSS Sacro Cuore Don Calabria Hospital, Negrar, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-NET Research Centre, University of Verona, Verona, Italy
| |
Collapse
|
|
22
|
RNF43 Mutations in IPMN Cases: A Potential Prognostic Factor. Gastroenterol Res Pract 2020; 2020:1457452. [PMID: 32934653 PMCID: PMC7479465 DOI: 10.1155/2020/1457452] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 06/29/2020] [Indexed: 12/15/2022] Open
Abstract
An intraductal papillary mucinous neoplasm (IPMN) is a common pancreatic precursor lesion, and it often harbors mutations in KRAS, GNAS, and RNF43. To clarify the molecular profiles of IPMNs, we conducted mutation analysis of KRAS, GNAS, and RNF43 in 61 IPMN formalin-fixed, paraffin-embedded (FFPE) specimens. The mutation rates of codons 12, 13, and 61 in KRAS and codon 201 in GNAS were detected by Sanger sequencing. Next-generation sequencing was performed on RNF43, and the results were further verified by Sanger sequencing. We identified KRAS and GNAS mutations in 35 (57%) and 40 (66%) IPMN cases, respectively. GNAS mutations were significantly correlated with the morphologic subtype (P < 0.001) and were more prevalent in the intestinal subtype (93%) than in the gastric (55%) and pancreatobiliary subtypes (44%) but were absent in the oncocytic subtype. RNF43 mutations were found in 5 cases (8%), all of which occurred in high-grade dysplasia and invasive lesions (2/5 and 3/5). All 5 cases harboring RNF43 mutations also exhibited GNAS mutations. RNF43 mutations were associated with a worse prognosis in invasive IPMN patients (P = 0.002), while KRAS and GNAS mutations did not affect the prognosis of patients.
Collapse
|
|
23
|
Abstract
Pancreatic cancer (PC) is a leading cause of cancer-related death in developed countries, and since most patients have incurable disease at the time of diagnosis, developing a screening method for early detection is of high priority. Due to its metabolic importance, alterations in pancreatic functions may affect the composition of the gut microbiota, potentially yielding biomarkers for PC. However, the usefulness of these biomarkers may be limited if they are specific for advanced stages of disease, which may involve comorbidities such as biliary obstruction or diabetes. In this study we analyzed the fecal microbiota of 30 patients with pancreatic adenocarcinoma, 6 patients with pre-cancerous lesions, 13 healthy subjects and 16 with non-alcoholic fatty liver disease, using amplicon sequencing of the bacterial 16S rRNA gene. Fourteen bacterial features discriminated between PC and controls, and several were shared with findings from a recent Chinese cohort. A Random Forest model based on the microbiota classified PC and control samples with an AUC of 82.5%. However, inter-subject variability was high, and only a small part of the PC-associated microbial signals were also observed in patients with pre-cancerous pancreatic lesions, implying that microbiome-based early detection of such lesions will be challenging.
Collapse
|
|
24
|
Dalal V, Carmicheal J, Dhaliwal A, Jain M, Kaur S, Batra SK. Radiomics in stratification of pancreatic cystic lesions: Machine learning in action. Cancer Lett 2019; 469:228-237. [PMID: 31629933 DOI: 10.1016/j.canlet.2019.10.023] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 10/03/2019] [Accepted: 10/15/2019] [Indexed: 12/15/2022]
Abstract
Pancreatic cystic lesions (PCLs) are well-known precursors of pancreatic cancer. Their diagnosis can be challenging as their behavior varies from benign to malignant disease. Precise and timely management of malignant pancreatic cysts might prevent transformation to pancreatic cancer. However, the current consensus guidelines, which rely on standard imaging features to predict cyst malignancy potential, are conflicting and unclear. This has led to an increased interest in radiomics, a high-throughput extraction of comprehensible data from standard of care images. Radiomics can be used as a diagnostic and prognostic tool in personalized medicine. It utilizes quantitative image analysis to extract features in conjunction with machine learning and artificial intelligence (AI) methods like support vector machines, random forest, and convolutional neural network for feature selection and classification. Selected features can then serve as imaging biomarkers to predict high-risk PCLs. Radiomics studies conducted heretofore on PCLs have shown promising results. This cost-effective approach would help us to differentiate benign PCLs from malignant ones and potentially guide clinical decision-making leading to better utilization of healthcare resources. In this review, we discuss the process of radiomics, its myriad applications such as diagnosis, prognosis, and prediction of therapy response. We also discuss the outcomes of studies involving radiomic analysis of PCLs and pancreatic cancer, and challenges associated with this novel field along with possible solutions. Although these studies highlight the potential benefit of radiomics in the prevention and optimal treatment of pancreatic cancer, further studies are warranted before incorporating radiomics into the clinical decision support system.
Collapse
Affiliation(s)
- Vipin Dalal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Joseph Carmicheal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Amaninder Dhaliwal
- Department of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; The Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; The Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
| |
Collapse
|
|
25
|
Prignon A, Provost C, Alshoukr F, Wendum D, Couvelard A, Barbet J, Forgez P, Talbot JN, Gruaz-Guyon A. Preclinical Evaluation of 68Ga-DOTA-NT-20.3: A Promising PET Imaging Probe To Discriminate Human Pancreatic Ductal Adenocarcinoma from Pancreatitis. Mol Pharm 2019; 16:2776-2784. [PMID: 31013092 DOI: 10.1021/acs.molpharmaceut.9b00283] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Neurotensin receptor 1 (NTSR1) is overexpressed in human pancreatic ductal adenocarcinoma (PDAC). Specific noninvasive positron-emission tomography (PET) imaging probes may improve the diagnostic accuracy and the monitoring of therapy for patients with PDAC. Here, we report the use of the 68Ga-labeled neurotensin (NTS) analogue DOTA-NT-20.3 to image human PDAC in animal models and to discriminate tumors from pancreatitis. In addition to the preclinical study, two tissue microarray slides, constructed by small core biopsies (2-5) from standard paraffin-embedded tumor tissues, were used to confirm the high (78%) positivity rate of NTSR1 expression in human PDAC. PET imaging, biodistribution, blocking, and histology studies were performed in subcutaneous AsPC-1 pancreatic tumor-bearing mice. 68Ga-DOTA-NT-20.3 PET images showed rapid tumor uptake and high contrast between the tumor and background with a fast blood clearance and a moderate accumulation in the kidneys. Ex vivo biodistribution showed low uptake in normal pancreas (0.22% IA/g) and in the remaining organs at 1 h postinjection, kidney retention (5.38 ± 0.54% IA/g), and fast clearance from blood and confirmed high uptake in tumors (5.28 ± 0.93% IA/g), leading to a tumor-to-blood ratio value of 6 at 1 h postinjection. The significant decrease of tumor uptake in a blocking study demonstrated the specificity of 68Ga-DOTA-N-T20.3 to target NTSR1 in vivo. PET imaging was also conducted in an orthotopic xenograft model that allows tumors to grow in their native microenvironment and in an experimental pancreatitis model generated by caerulein injections. As opposed to 2-[18F]fluoro-deoxyglucose, 68Ga-DOTA-NT-20.3 distinguishes PDAC from pancreatitis. Thus, 68Ga-DOTA-NT-20.3 is a promising PET imaging probe for imaging PDAC in humans.
Collapse
Affiliation(s)
- Aurélie Prignon
- Sorbonne Université, UMS28 Phénotypage du Petit Animal, Laboratoire d'Imagerie Moléculaire Positonique (LIMP) , Paris 75020 , France
| | - Claire Provost
- Sorbonne Université, UMS28 Phénotypage du Petit Animal, Laboratoire d'Imagerie Moléculaire Positonique (LIMP) , Paris 75020 , France
| | - Faisal Alshoukr
- Nuclear Medicine Department , CHR de Metz-Thionville , Thionville 57100 , France
| | - Dominique Wendum
- Sorbonne Université, Pathology Department Saint-Antoine Hospital AP-HP , Paris 75012 , France
| | - Anne Couvelard
- University of Paris, Pathology Department Bichat Hospital AP-HP , Paris 75006 , France
| | | | - Patricia Forgez
- Inserm UMRS 1007, Paris Descartes University , Paris 75006 , France
| | - Jean-Noël Talbot
- Sorbonne Université, UMS28 Phénotypage du Petit Animal, Laboratoire d'Imagerie Moléculaire Positonique (LIMP) , Paris 75020 , France
- Sorbonne Université, Nuclear Medicine Department Tenon Hospital AP-HP , Paris 75020 , France
| | - Anne Gruaz-Guyon
- Sorbonne Université, UMS28 Phénotypage du Petit Animal, Laboratoire d'Imagerie Moléculaire Positonique (LIMP) , Paris 75020 , France
| |
Collapse
|
|
26
|
Characteristics and Clinical Outcomes of Individuals at High Risk for Pancreatic Cancer: A Descriptive Analysis from a Comprehensive Cancer Center. GASTROINTESTINAL DISORDERS 2019; 1:106-119. [PMID: 32601617 PMCID: PMC7324042 DOI: 10.3390/gidisord1010008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer (PC), a leading cause of cancer-related deaths in the United States, is typically diagnosed at an advanced stage. To improve survival, there is an unmet need to detect pre-malignant lesions and early invasive disease. Prime populations to study for early detection efforts include cohorts of high risk individuals (HRI): those with increased risk to develop pre-malignant pancreatic cysts and PC because of a familial or hereditary predisposition to the disease and those in the general population of sporadic cases who are incidentally found to harbor a pre-malignant pancreatic cyst. The objective of this study was to describe the characteristics and clinical outcomes of cohorts of HRI identified at Moffitt Cancer Center. We set out to determine the uptake of screening, the prevalence and characteristics of solid and cystic pancreatic lesions detected via screening or as incidental findings, and the age at which lesions were detected. Of a total of 329 HRI, roughly one-third were found to have pancreatic lesions, most of which constituted pre-malignant cysts known as intraductal papillary mucinous neoplasms. Individuals with the highest genetic risk for PC were found to have smaller cysts at a much earlier age than sporadic cases with incidental findings; however, many individuals at high genetic risk did not have abdominal imaging reports on file. We also identified a subset of HRI at moderate genetic risk for PC that were found to have cystic and solid pancreatic lesions as part of a diagnostic work-up rather than a screening protocol. These findings suggest the pancreatic research community should consider expanding criteria for who should be offered screening. We also emphasize the importance of continuity of care between cancer genetics and gastrointestinal oncology clinics so that HRI are made aware of the opportunities related to genetic counseling, genetic testing, and screening.
Collapse
|
|
27
|
McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS. Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol 2018; 24:4846-4861. [PMID: 30487695 PMCID: PMC6250924 DOI: 10.3748/wjg.v24.i43.4846] [Citation(s) in RCA: 1199] [Impact Index Per Article: 171.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 10/19/2018] [Accepted: 10/27/2018] [Indexed: 02/06/2023] Open
Abstract
This review aims to outline the most up-to-date knowledge of pancreatic adenocarcinoma risk, diagnostics, treatment and outcomes, while identifying gaps that aim to stimulate further research in this understudied malignancy. Pancreatic adenocarcinoma is a lethal condition with a rising incidence, predicted to become the second leading cause of cancer death in some regions. It often presents at an advanced stage, which contributes to poor five-year survival rates of 2%-9%, ranking firmly last amongst all cancer sites in terms of prognostic outcomes for patients. Better understanding of the risk factors and symptoms associated with this disease is essential to inform both health professionals and the general population of potential preventive and/or early detection measures. The identification of high-risk patients who could benefit from screening to detect pre-malignant conditions such as pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms and mucinous cystic neoplasms is urgently required, however an acceptable screening test has yet to be identified. The management of pancreatic adenocarcinoma is evolving, with the introduction of new surgical techniques and medical therapies such as laparoscopic techniques and neo-adjuvant chemoradiotherapy, however this has only led to modest improvements in outcomes. The identification of novel biomarkers is desirable to move towards a precision medicine era, where pancreatic cancer therapy can be tailored to the individual patient, while unnecessary treatments that have negative consequences on quality of life could be prevented for others. Research efforts must also focus on the development of new agents and delivery systems. Overall, considerable progress is required to reduce the burden associated with pancreatic cancer. Recent, renewed efforts to fund large consortia and research into pancreatic adenocarcinoma are welcomed, but further streams will be necessary to facilitate the momentum needed to bring breakthroughs seen for other cancer sites.
Collapse
Affiliation(s)
- Andrew McGuigan
- Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7AE, United Kingdom
| | - Paul Kelly
- Department of Pathology, Royal Victoria Hospital, Belfast BT12 6BA, United Kingdom
| | - Richard C Turkington
- Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast BT9 7AE, United Kingdom
| | - Claire Jones
- Department of Hepatobiliary Surgery, Mater Hospital, Belfast BT14 6AB, United Kingdom
| | - Helen G Coleman
- Centre for Public Health, Queen’s University Belfast, Belfast BT12 6BJ, United Kingdom
| | - R Stephen McCain
- Department of Hepatobiliary Surgery, Mater Hospital, Belfast BT14 6AB, United Kingdom
- Centre for Public Health, Queen’s University Belfast, Belfast BT12 6BJ, United Kingdom
| |
Collapse
|
|
28
|
Robinson C, Estrada A, Zaheer A, Singh VK, Wolfgang CL, Goggins MG, Hruban RH, Wood LD, Noë M, Montgomery EA, Guthrie LC, Lennon AM, Boyce AM, Collins MT. Clinical and Radiographic Gastrointestinal Abnormalities in McCune-Albright Syndrome. J Clin Endocrinol Metab 2018; 103:4293-4303. [PMID: 30124968 PMCID: PMC6194803 DOI: 10.1210/jc.2018-01022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022]
Abstract
Context McCune-Albright syndrome (MAS) is a rare disorder characterized by fibrous dysplasia of bone, café-au-lait macules, and hyperfunctioning endocrinopathies. It arises from somatic gain-of-function mutations in GNAS, which encodes the cAMP-regulating protein Gαs. Somatic GNAS mutations have been reported in intraductal papillary mucinous neoplasms (IPMNs) and various gastrointestinal (GI) tumors. The clinical spectrum and prevalence of MAS-associated GI disease is not well established. Objective Define the spectrum and prevalence of MAS-associated GI pathology in a large cohort of patients with MAS. Design Cross-sectional study. Setting National Institutes of Health Clinical Center and The Johns Hopkins Hospital. Methods Fifty-four consecutive subjects with MAS (28 males; age range, 7 to 67 years) were screened with magnetic resonance cholangiopancreatography (MRCP). Results Thirty of 54 subjects (56%) had radiographic GI abnormalities. Twenty-five (46%) of the screened subjects had IPMNs (mean age of 35.1 years). Fourteen of the 25 had IPMNs alone, and 11 had IPMNs and abnormal hepatobiliary imaging. The 30 patients with MAS-associated GI pathology had a higher prevalence of acute pancreatitis, diabetes mellitus, and skeletal disease burden of fibrous dysplasia than patients without GI disease. Conclusions A broad spectrum of GI pathology is associated with MAS. IPMNs are common and occur at a younger age than in the general population. Patients with MAS should be considered for screening with a focused GI history and baseline MRCP. Further determination of the natural history and malignant potential of IPMNs in MAS is needed.
Collapse
Affiliation(s)
- Cemre Robinson
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
- Program in Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
- Department of Pediatrics, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
| | - Andrea Estrada
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
- Division of Endocrinology and Diabetes, Children’s National Health System, Washington, DC
| | - Atif Zaheer
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Vikesh K Singh
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Christopher L Wolfgang
- Departments of Surgery, Radiology, and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michael G Goggins
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Laura D Wood
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Michaël Noë
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Elizabeth A Montgomery
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lori C Guthrie
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Anne Marie Lennon
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
- Departments of Surgery, Radiology, and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Alison M Boyce
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
- Division of Endocrinology and Diabetes, Children’s National Health System, Washington, DC
| | - Michael T Collins
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| |
Collapse
|
|
29
|
Unger K, Mehta KY, Kaur P, Wang Y, Menon SS, Jain SK, Moonjelly RA, Suman S, Datta K, Singh R, Fogel P, Cheema AK. Metabolomics based predictive classifier for early detection of pancreatic ductal adenocarcinoma. Oncotarget 2018; 9:23078-23090. [PMID: 29796173 PMCID: PMC5955422 DOI: 10.18632/oncotarget.25212] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 04/06/2018] [Indexed: 12/13/2022] Open
Abstract
The availability of robust classification algorithms for the identification of high risk individuals with resectable disease is critical to improving early detection strategies and ultimately increasing survival rates in PC. We leveraged high quality biospecimens with extensive clinical annotations from patients that received treatment at the Medstar-Georgetown University hospital. We used a high resolution mass spectrometry based global tissue profiling approach in conjunction with multivariate analysis for developing a classification algorithm that would predict early stage PC with high accuracy. The candidate biomarkers were annotated using tandem mass spectrometry. We delineated a six metabolite panel that could discriminate early stage PDAC from benign pancreatic disease with >95% accuracy of classification (Specificity = 0.85, Sensitivity = 0.9). Subsequently, we used multiple reaction monitoring mass spectrometry for evaluation of this panel in plasma samples obtained from the same patients. The pattern of expression of these metabolites in plasma was found to be discordant as compared to that in tissue. Taken together, our results show the value of using a metabolomics approach for developing highly predictive panels for classification of early stage PDAC. Future investigations will likely lead to the development of validated biomarker panels with potential for clinical translation in conjunction with CA-19-9 and/or other biomarkers.
Collapse
Affiliation(s)
- Keith Unger
- MedStar Georgetown University Hospital, Washington, DC, United States of America
| | - Khyati Y Mehta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Prabhjit Kaur
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Yiwen Wang
- Department of Biostatistics and Biomathematics, Georgetown University Medical Center, Washington, DC, United States of America
| | - Smrithi S Menon
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Shreyans K Jain
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Rose A Moonjelly
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Shubhankar Suman
- Departments of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, United States of America
| | - Kamal Datta
- Departments of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, United States of America
| | - Rajbir Singh
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America
| | - Paul Fogel
- Unité MéDIAN, UMR CNRS 6237 MEDYC, Université de Reims, Reims, France
| | - Amrita K Cheema
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America.,Departments of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, United States of America
| |
Collapse
|
|
30
|
Ilies M, Sappa PK, Iuga CA, Loghin F, Gesell Salazar M, Weiss FU, Beyer G, Lerch MM, Völker U, Mayerle J, Hammer E. Plasma protein profiling of patients with intraductal papillary mucinous neoplasm of the pancreas as potential precursor lesions of pancreatic cancer. Clin Chim Acta 2018; 477:127-134. [DOI: 10.1016/j.cca.2017.12.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 11/17/2017] [Accepted: 12/05/2017] [Indexed: 02/07/2023]
|
|
31
|
Choi SH, Park SH, Kim KW, Lee JY, Lee SS. Progression of Unresected Intraductal Papillary Mucinous Neoplasms of the Pancreas to Cancer: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2017; 15:1509-1520.e4. [PMID: 28342950 DOI: 10.1016/j.cgh.2017.03.020] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/26/2017] [Accepted: 03/05/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is not clear how best to manage patients with low-risk intraductal papillary mucinous neoplasms (IPMNs) of the pancreas because little is known about IPMN progression to cancer. We sought to determine the cumulative incidence of development of pancreatic cancer in persons with unresected IPMNs (particularly low-risk IPMNs). METHODS We performed a systematic search of the MEDLINE and Embase databases through November 30, 2016 for studies reporting the cumulative incidence of pancreatic cancer in patients with unresected IPMNs or studies that provided data in sufficient detail for us to calculate cumulative incidence values. We categorized patient series as studies on low-risk IPMNs (lesions without main pancreatic duct involvement or mural nodules) or non-low-risk IPMNs. We calculated meta-analytic cumulative incidence values for pancreatic cancer at 1, 3, 5, and 10 years of follow-up by using the inverse variance method and random-effects model. RESULTS Among 1514 articles screened, we identified 10 studies of low-risk IPMNs (n = 2411) and 9 studies of non-low-risk IPMNs (n = 825). In studies of low-risk IPMNs, the meta-analytic cumulative incidence values for pancreatic cancer were 0.02% at 1 year (95% confidence interval [CI], 0.0%-0.23%; I2= 0.0%), 1.40% at 3 years (95% CI, 0.58%-2.48%; I2 = 58.5%), 3.12% at 5 years (95% CI, 1.12%-5.90%; I2 = 88.0%), and 7.77% at 10 years (95% CI, 4.09%-12.39%; I2 = 79.8%). These values were much higher in studies of non-low-risk IPMNs; cumulative incidence values for pancreatic cancer were 1.95% at 1 year (95% CI, 0.0%-5.99%; I2 = 84.2%), 5.69% at 3 years (95% CI, 1.10%-12.77%; I2 = 89.9%), 9.77% at 5 years (95% CI, 3.04%-19.27%; I2 = 92.0%), and 24.68% at 10 years (95% CI, 14.87%-35.90%; I2 = 74.3%). The pooled cumulative incidence steadily increased linearly as the follow-up duration increased. CONCLUSIONS In a systematic review and meta-analysis, we found that low-risk IPMNs have almost 8% chance of progressing to pancreatic cancer within 10 years, and higher-risk IPMNs have almost 25% chance of progressing to cancer in 10 years; incidence values increase linearly with time. Continued long-term surveillance is therefore vital for patients with low-risk IPMNs.
Collapse
Affiliation(s)
- Sang Hyun Choi
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Seong Ho Park
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
| | - Kyung Won Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Ja Youn Lee
- National Evidence-based Healthcare Collaborating Agency, Seoul, South Korea
| | - Sang Soo Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| |
Collapse
|
|
32
|
Abstract
Pancreatic cystic neoplasms are discovered with increasing frequency. Accurate knowledge of the natural history of cystic neoplasms is crucial to develop useful and cost-effective strategies for surveillance and surgical resection. To date, the natural history of cystic neoplasms is still incomplete due to lack of adequate diagnostic accuracy in the absence of surgical pathology. Nevertheless, current evidence points to risk factors for malignant transformation to help clinical management. New biomarkers that accurately distinguish cyst neoplasms and those most likely to progress to cancer would help clarify the natural history of cystic neoplasms.
Collapse
Affiliation(s)
- Alexander Larson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Richard S Kwon
- Division of Gastroenterology and Hepatology, University of Michigan, 1500 E. Medical Center Drive, Taubman 3912, Ann Arbor, MI, 48109-5362, USA.
| |
Collapse
|
|
33
|
Kawanishi A, Hirabayashi K, Kono H, Takanashi Y, Hadano A, Kawashima Y, Ogawa M, Kawaguchi Y, Yamada M, Nakagohri T, Nakamura N, Mine T. A Serous Cystic Neoplasm of the Pancreas Coexisting with High-Grade Pancreatic Intraepithelial Neoplasia Mimicking an Intraepithelial Papillary Mucinous Neoplasm: A Case Report. Case Rep Oncol 2017; 10:143-150. [PMID: 28413390 PMCID: PMC5346927 DOI: 10.1159/000456611] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 01/17/2017] [Indexed: 01/29/2023] Open
Abstract
Serous cystic neoplasms of the pancreas are rare exocrine pancreatic neoplasms, most of which are benign and do not communicate with the pancreatic duct. Pancreatic intraepithelial neoplasm (PanIN) is considered a precursor of ductal adenocarcinoma that is microscopically recognized in pancreatic ducts. A 67-year-old Japanese woman presented with a 10-mm multilocular cystic lesion at the pancreatic body. Magnetic resonance pancreatography showed stenosis of the main pancreatic duct at the pancreatic body and dilatation of the distal side of the main pancreatic duct. Furthermore, communication between the cystic lesion and the main pancreatic duct was suspected based on magnetic resonance pancreatography findings. Distal pancreatectomy was performed under the preoperative diagnosis of intraductal papillary mucinous neoplasm. Histologically, the cystic lesion was lined with a non-atypical cuboidal or flat epithelium with clear cytoplasm and was thus diagnosed as a serous cystic neoplasm. High-grade PanIN lesions with stromal fibrosis were observed at the main and branch pancreatic ducts. Histological examination revealed no communication between the serous cystic neoplasm and the pancreatic ducts. Immunohistochemically, the epithelium of the serous cystic neoplasm showed positive anti-von Hippel-Lindau antibody staining, whereas the epithelium of the PanIN showed negative staining. A serous cystic neoplasm coexisting with another pancreatic neoplasm is rare. When dilatation of the main or branch pancreatic ducts coexists with a serous cystic neoplasm, as in this case, the lesion clinically mimics an intraductal papillary mucinous neoplasm.
Collapse
Affiliation(s)
- Aya Kawanishi
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Kenichi Hirabayashi
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Hirotaka Kono
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Yumi Takanashi
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Atsuko Hadano
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Yohei Kawashima
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Masami Ogawa
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Yoshiaki Kawaguchi
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Misuzu Yamada
- Department of Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Toshio Nakagohri
- Department of Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Tetsuya Mine
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| |
Collapse
|
|
34
|
Luo H, England CG, Goel S, Graves SA, Ai F, Liu B, Theuer CP, Wong HC, Nickles RJ, Cai W. ImmunoPET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer with a Dual-Labeled Bispecific Antibody Fragment. Mol Pharm 2017; 14:1646-1655. [PMID: 28292180 DOI: 10.1021/acs.molpharmaceut.6b01123] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Dual-targeted imaging agents have shown improved targeting efficiencies in comparison to single-targeted entities. The purpose of this study was to quantitatively assess the tumor accumulation of a dual-labeled heterobifunctional imaging agent, targeting two overexpressed biomarkers in pancreatic cancer, using positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging modalities. A bispecific immunoconjugate (heterodimer) of CD105 and tissue factor (TF) Fab' antibody fragments was developed using click chemistry. The heterodimer was dual-labeled with a radionuclide (64Cu) and fluorescent dye. PET/NIRF imaging and biodistribution studies were performed in four-to-five week old nude athymic mice bearing BxPC-3 (CD105/TF+/+) or PANC-1 (CD105/TF-/-) tumor xenografts. A blocking study was conducted to investigate the specificity of the tracer. Ex vivo tissue staining was performed to compare TF/CD105 expression in tissues with PET tracer uptake to validate in vivo results. PET imaging of 64Cu-NOTA-heterodimer-ZW800 in BxPC-3 tumor xenografts revealed enhanced tumor uptake (21.0 ± 3.4%ID/g; n = 4) compared to the homodimer of TRC-105 (9.6 ± 2.0%ID/g; n = 4; p < 0.01) and ALT-836 (7.6 ± 3.7%ID/g; n = 4; p < 0.01) at 24 h postinjection. Blocking studies revealed that tracer uptake in BxPC-3 tumors could be decreased by 4-fold with TF blocking and 2-fold with CD105 blocking. In the negative model (PANC-1), heterodimer uptake was significantly lower than that found in the BxPC-3 model (3.5 ± 1.1%ID/g; n = 4; p < 0.01). The specificity was confirmed by the successful blocking of CD105 or TF, which demonstrated that the dual targeting with 64Cu-NOTA-heterodimer-ZW800 provided an improvement in overall tumor accumulation. Also, fluorescence imaging validated the PET imaging, allowing for clear delineation of the xenograft tumors. Dual-labeled heterodimeric imaging agents, like 64Cu-NOTA-heterodimer-ZW800, may increase the overall tumor accumulation in comparison to single-targeted homodimers, leading to improved imaging of cancer and other related diseases.
Collapse
Affiliation(s)
- Haiming Luo
- Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Christopher G England
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Shreya Goel
- Materials Science Program, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States
| | - Stephen A Graves
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Fanrong Ai
- Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Bai Liu
- Altor BioScience Corporation , Miramar, Florida 33025, United States
| | - Charles P Theuer
- TRACON Pharmaceuticals Incorporation , San Diego, California 92122, United States
| | - Hing C Wong
- Altor BioScience Corporation , Miramar, Florida 33025, United States
| | - Robert J Nickles
- Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States
| | - Weibo Cai
- Department of Radiology, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Department of Medical Physics, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.,Materials Science Program, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.,University of Wisconsin Carbone Cancer Center , Madison, Wisconsin 53705, United States
| |
Collapse
|
|
35
|
Flattet Y, Yamaguchi T, Andrejevic-Blant S, Halkic N. Pancreatic adenocarcinoma: the impact of preneoplastic lesion pattern on survival. Biosci Trends 2016; 9:402-6. [PMID: 26781798 DOI: 10.5582/bst.2015.01163] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Pancreatic adenocarcinoma is associated with a very poor prognosis, characterized with a 5-year survival rate of only 5%. Surgery is the only curative treatment for selected patients. Nevertheless, recurrence is very frequent. Identifying prognostic factors is thus warranted. Like numerous other tumors, adenocarcinomas are preceded by preneoplastic lesions. The role and the impact of these lesions remain unclear. This study aimed to assess the impact of the preneoplastic lesion pattern and histo-morphological features, on survival after pancreatic resection. Thirty-five patients who underwent pancreatic resection for pancreatic adenocarcinoma were identified from a prospective database of a single center, between 2003 and 2008. We considered demographics, tumor characteristics and type of treatment. The major outcome was survival. Analyzes were separated into two groups, according to the preneoplastic lesions: Pancreatic intraepithelial neoplasia (PanIN)-related carcinomas and intracanalar papillary mucinous neoplasia (IPMN)-related carcinomas. The former were more frequent, accounting for 63% (22/35). Moreover, they displayed more aggressive features, with a higher tumor stage (p = 0.01) and higher rate of positive lymph nodes (p = 0.019). Lymphatic (p = 0.009) and perinervous (p = 0.019) invasions were also more frequent. Survival was negatively influenced by PanIN preneoplastic lesions (p = 0.015), T3-4 tumor stage (p = 0.038), positive lymph nodes (p = 0.044), lymphatic (p = 0.019) and vascular (p = 0.029) invasions. Pancreatic adenocarcinoma displays different behavior according to its preneoplastic lesion. Indeed, PanIN-related adenocarcinoma showed more aggressive features and lower survival rate. Preneoplastic lesions may represent predictive factors for survival. Their role and predictive value should be investigated more thoroughly.
Collapse
Affiliation(s)
- Yves Flattet
- Department of Pathology, University Hospital CHUV
| | | | | | | |
Collapse
|
|
36
|
Honda K, Srivastava S. Potential usefulness of apolipoprotein A2 isoforms for screening and risk stratification of pancreatic cancer. Biomark Med 2016; 10:1197-1207. [PMID: 27673558 PMCID: PMC5493967 DOI: 10.2217/bmm-2016-0209] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Given the low incidence of pancreatic cancer in the general population, screening of pancreatic cancer in the general population using invasive modalities is not feasible. Combination of invasive screening with noninvasive biomarkers for pancreatic cancer and its precancerous lesions has the potential to reduce mortality due to pancreatic cancer. In this review, we focus on biomarkers found in the blood that can indicate early-stage pancreatic cancer, and we discuss current strategies for screening for pancreatic cancer. We recently identified a unique alteration in apolipoprotein A2 isoforms in pancreatic cancer and its precancerous lesions, and we describe its clinical usefulness as a potential biomarker for the early detection and risk stratification of pancreatic cancer.
Collapse
Affiliation(s)
- Kazufumi Honda
- Division of Chemotherapy & Clinical Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan.,Japan Agency for Medical Research & Development (AMED) CREST, Tokyo 100-0004, Japan
| | - Sudhir Srivastava
- Division of Cancer Prevention, National Cancer Institute, Rockville, MD 20852, USA
| |
Collapse
|
|
37
|
Nilsson LN, Keane MG, Shamali A, Millastre Bocos J, Marijinissen van Zanten M, Antila A, Verdejo Gil C, Del Chiaro M, Laukkarinen J. Nature and management of pancreatic mucinous cystic neoplasm (MCN): A systematic review of the literature. Pancreatology 2016; 16:1028-1036. [PMID: 27681503 DOI: 10.1016/j.pan.2016.09.011] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 09/17/2016] [Accepted: 09/20/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND The current management of pancreatic mucinous cystic neoplasms (MCN) is defined by the consensus European, International Association of Pancreatology and American College of Gastroenterology guidelines. However, the criterion for surgical resection remains uncertain and differs between these guidelines. Therefore through this systematic review of the existing literature we aimed to better define the natural history and prognosis of these lesions, in order to clarify recommendations for future management. METHODS A systematic literature search was performed (PubMed, EMBASE, Cochrane Library) for studies published in the English language between 1970 and 2015. RESULTS MCNs occur almost exclusively in women (female:male 20:1) and are mainly located in the pancreatic body or tail (93-95%). They are usually found incidentally at the age of 40-60 years. Cross-sectional imaging and endoscopic ultrasound are the most frequently used diagnostic tools, but often it is impossible to differentiate MCNs from branch duct intraductal papillary mucinous neoplasms (BD-IPMN) or oligocystic serous adenomas pre-operatively. In resected MCNs, 0-34% are malignant, but in those less than 4 cm only 0.03% were associated with invasive adenocarcinoma. No surgically resected benign MCNs were associated with a synchronous lesion or recurrence; therefore further follow-up is not required after resection. Five-year survival after surgical resection of a malignant MCN is approximately 60%. CONCLUSIONS Compared to other pancreatic tumors, MCNs have a low aggressive behavior, with exceptionally low rates of malignant transformation when less than 4 cm in size, are asymptomatic and lack worrisome features on pre-operative imaging. This differs significantly from the natural history of small BD-IPMNs, supporting the need to differentiate mucinous cyst subtypes pre-operatively, where possible. The findings support the recommendations from the recent European Consensus Guidelines, for the more conservative management of MCNs.
Collapse
Affiliation(s)
| | - Margaret G Keane
- Institute for Liver and Digestive Health, University College London, UK
| | | | | | | | - Anne Antila
- Tampere University Hospital, Tampere, Finland
| | | | | | | |
Collapse
|
|
38
|
Cheng RF, Wang J, Zhang JY, Sun L, Zhao YR, Qiu ZQ, Sun BC, Sun Y. MicroRNA-506 is up-regulated in the development of pancreatic ductal adenocarcinoma and is associated with attenuated disease progression. CHINESE JOURNAL OF CANCER 2016; 35:64. [PMID: 27371108 PMCID: PMC4930606 DOI: 10.1186/s40880-016-0128-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 06/22/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND MicroRNA-506 (miR-506) has been reported to function in several tumors as a tumor suppressor gene or oncogene. However, the expression and role of miR-506 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we aimed to evaluate the phenotype of miR-506 in PDAC. METHODS Using miRNA in situ hybridization, we examined the expression of miR-506 in 113 PDACs and 87 paired normal pancreatic tissues. We evaluated miR-506 expression in PDAC cells, normal pancreatic ducts, and acinus/islands, and we analyzed the associations between miR-506 expression and the clinicopathologic characteristics of PDAC patients. RESULTS miR-506 expression was higher in PDAC than in matched normal pancreatic ductal cells (P < 0.001). On the other hand, the combined group of well and moderately differentiated PDACs showed higher levels of miR-506 than the poorly differentiated ones (P = 0.023). Moreover, miR-506 expression was negatively associated with pathologic T category (P = 0.004) and lymph node metastasis (P = 0.033), suggesting that miR-506 might inhibit the progression of PDAC. CONCLUSIONS Our results suggest that miR-506 either plays a role as an oncogene in the tumorigenesis and a tumor suppressor in the progression or serves as a house-keeping, tumor-suppressing miRNA, whose expression can be activated by oncogenic signals in early development to hinder the progression of PDAC.
Collapse
Affiliation(s)
- Run-Fen Cheng
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China
| | - Jian Wang
- Department of Pancreatic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China
| | - Jing-Yi Zhang
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China
| | - Lin Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China
| | - Yan-Rui Zhao
- Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China
| | - Zhi-Qiang Qiu
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China
| | - Bao-Cun Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China.,Department of Pathology, Tianjin Medical University, Tianjin, 300070, P. R. China
| | - Yan Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P. R. China.
| |
Collapse
|
|
39
|
Luo H, England CG, Shi S, Graves SA, Hernandez R, Liu B, Theuer CP, Wong HC, Nickles RJ, Cai W. Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer. Clin Cancer Res 2016; 22:3821-30. [PMID: 27026197 DOI: 10.1158/1078-0432.ccr-15-2054] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 03/01/2016] [Indexed: 12/19/2022]
Abstract
PURPOSE Pancreatic adenocarcinoma is a highly aggressive cancer, currently treated with limited success and dismal outcomes. New diagnostic and treatment strategies offer the potential to reduce cancer mortality. Developing highly specific noninvasive imaging probes for pancreatic cancer is essential to improving diagnostic accuracy and monitoring therapeutic intervention. EXPERIMENTAL DESIGN A bispecific heterodimer was synthesized by conjugating an anti-tissue factor (TF) Fab with an anti-CD105 Fab, via the bio-orthogonal "click" reaction between tetrazine (Tz) and trans-cyclooctene (TCO). The heterodimer was labeled with (64)Cu for PET imaging of nude mice bearing BXPC-3 xenograft and orthotopic pancreatic tumors. RESULTS PET imaging of BXPC-3 (TF/CD105(+/+)) xenograft tumors with (64)Cu-labeled heterodimer displayed significantly enhanced tumor uptake (28.8 ± 3.2 %ID/g; n = 4; SD) at 30 hours postinjection, as compared with each of their monospecific Fab tracers (12.5 ± 1.4 and 7.1 ± 2.6 %ID/g; n = 3; SD). In addition, the activity-concentration ratio allowed for effective tumor visualization (tumor/muscle ratio 75.2 ± 9.4 at 30 hours postinjection.; n = 4; SD). Furthermore, (64)Cu-NOTA-heterodimer enabled sensitive detection of orthotopic pancreatic tumor lesions with an uptake of 17.1 ± 4.9 %ID/g at 30 hours postinjection and tumor/muscle ratio of 72.3 ± 46.7. CONCLUSIONS This study demonstrates that dual targeting of TF and CD105 provided synergistic improvements in binding affinity and tumor localization of the heterodimer. Dual-targeted imaging agents of pancreatic and other cancers may assist in diagnosing pancreatic malignancies as well as reliable monitoring of therapeutic response. Clin Cancer Res; 22(15); 3821-30. ©2016 AACR.
Collapse
Affiliation(s)
- Haiming Luo
- Department of Radiology, University of Wisconsin-Madison, Wisconsin
| | | | - Sixiang Shi
- Materials Science Program, University of Wisconsin-Madison, Wisconsin
| | - Stephen A Graves
- Department of Medical Physics, University of Wisconsin-Madison, Wisconsin
| | - Reinier Hernandez
- Department of Medical Physics, University of Wisconsin-Madison, Wisconsin
| | - Bai Liu
- Altor BioSciences, Miramar, Florida
| | | | | | - Robert J Nickles
- Department of Medical Physics, University of Wisconsin-Madison, Wisconsin
| | - Weibo Cai
- Department of Radiology, University of Wisconsin-Madison, Wisconsin. Department of Medical Physics, University of Wisconsin-Madison, Wisconsin. Materials Science Program, University of Wisconsin-Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
| |
Collapse
|
|
40
|
Benzel J, Fendrich V. Molecular Characterization and Pathogenesis of Intraductal Papillary Mucinous Neoplasms of the Pancreas. Eur Surg Res 2015; 55:352-363. [PMID: 26505881 DOI: 10.1159/000441492] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 10/06/2015] [Indexed: 11/19/2022]
Abstract
Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are noninvasive neoplasms which occur in the main pancreatic duct or its major branches. IPMNs have an important meaning in the clinic and in research since they represent around 20% of all resected pancreatic neoplasms. Morphologically, branch duct, main duct and mixed-type IPMNs can be distinguished. Histologically, they can be divided into gastric, intestinal, pancreatobiliary and oncocytic type. There are different mutations in genes such as KRAS, GNAS, RNF43 and p53. The expression of miRNAs is specific to IPMNs; altogether, 14 miRNAs have been identified so far which are differently expressed in all IPMNs in contrast to normal pancreatic tissue. It has also been observed that methylation levels can be altered in IPMNs. This review summarizes the molecular characteristics of IPMNs of the pancreas and presents currently known markers.
Collapse
Affiliation(s)
- Julia Benzel
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | | |
Collapse
|
|
41
|
Clinicopathological Significance of CDKN2A Promoter Hypermethylation Frequency with Pancreatic Cancer. Sci Rep 2015; 5:13563. [PMID: 26338139 PMCID: PMC4642558 DOI: 10.1038/srep13563] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Accepted: 04/07/2015] [Indexed: 12/23/2022] Open
Abstract
The prognosis of pancreatic cancer patients is very poor, with a 5-year survival of less than 6%. Previous studies demonstrated that the loss of function of CDKN2A is mainly caused by the hypermethylation of CDKN2A gene promoter; however, whether or not it is associated with the incidence of pancreatic cancer still remains unclear. In this study, we systematically reviewed the association between CDKN2A promoter methylation and pancreatic cancer using meta-analysis methods. The pooled data were analyzed by Review Manager 5.2. Fourteen studies eligible studies, including 418 pancreatic cancer, 155 pancreatic intraepithelial neoplasia (PanINs) and 45 chronic pancreatitis (CP) patients were analyzed. We observed that the frequency of CDKN2A methylation was significantly higher in pancreatic cancer patients than in normal healthy controls, the pooled OR = 17.19, 95% CI = 8.72–33.86, P < 0.00001. The frequency of CDKN2A methylation was also significantly higher in PanINs patients than that in normal individual controls, OR = 12.35, 95% CI = 1.70–89.89, P = 0.01. In addition, CDKN2A methylation was associated with worse survival in pancreatic cancer, HR = 4.46, 95% CI = 1.37–14.53, P = 0.01. The results strongly suggest that CDKN2A methylation is correlated with an increased risk of pancreatic cancer. CDKN2A methylation plays a critical role in pancreatic carcinogenesis and may serve as a prognostic marker.
Collapse
|
|
42
|
Pancreatic mass leading to left-sided portal hypertension, causing bleeding from isolated gastric varices. Case Rep Gastrointest Med 2014; 2014:956490. [PMID: 25525530 PMCID: PMC4266757 DOI: 10.1155/2014/956490] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 11/12/2014] [Indexed: 01/04/2023] Open
Abstract
Mucinous cystic neoplasms (MCN) are an uncommon form of exocrine neoplasms of the pancreas. Symptoms are most often vague and this makes the diagnosis more difficult. The current case is one of three cases yet reported where the MCN caused left-sided portal hypertension leading to the formation of isolated gastric varices and subsequent bleeding from the varices. In the previously reported cases the main symptom was hematemesis. However in the current case the patient experienced no hematemesis, only isolated incidents of dark coloured diarrhea, but the main symptoms were those of iron-deficiency anemia. We present the case report of a 34-year-old woman who presented with dizziness and lethargy and was found to have 12 cm MCN in the pancreas.
Collapse
|
|
43
|
Esposito I, Konukiewitz B, Schlitter AM, Klöppel G. Pathology of pancreatic ductal adenocarcinoma: Facts, challenges and future developments. World J Gastroenterol 2014; 20:13833-13841. [PMID: 25320520 PMCID: PMC4194566 DOI: 10.3748/wjg.v20.i38.13833] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 01/02/2014] [Accepted: 05/14/2014] [Indexed: 02/06/2023] Open
Abstract
Despite major improvements concerning its diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology, as interface discipline between basic and clinical medicine, has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition, by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC, a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC. This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results. Finally, recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response. The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.
Collapse
|
|
44
|
Mohammed S, II GVB, Fisher WE. Pancreatic cancer: advances in treatment. World J Gastroenterol 2014; 20:9354-60. [PMID: 25071330 PMCID: PMC4110567 DOI: 10.3748/wjg.v20.i28.9354] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 01/20/2014] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing. While patients with pancreatic cancer have traditionally faced a dismal prognosis, over the past several years various advances in diagnosis and treatment have begun to positively impact this disease. Identification of effective combinations of existing chemotherapeutic agents, such as the FOLFIRINOX and the gemcitabine + nab-paclitaxel regimen, has improved survival for selected patients although concerns regarding their toxicity profiles remain. A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions, such as pancreatic intraepithelial neoplasias, intraductal papillary mucinous neoplasms, and cystic neoplasms. Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management. Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors, and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality. Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy. Furthermore, pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes. Lastly, a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents.
Collapse
|
|
45
|
Neureiter D, Jäger T, Ocker M, Kiesslich T. Epigenetics and pancreatic cancer: Pathophysiology and novel treatment aspects. World J Gastroenterol 2014; 20:7830-7848. [PMID: 24976721 PMCID: PMC4069312 DOI: 10.3748/wjg.v20.i24.7830] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 02/07/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16ink4a, are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.
Collapse
|
|
46
|
Han S, Jin G, Wang L, Li M, He C, Guo X, Zhu Q. The role of PAM4 in the management of pancreatic cancer: diagnosis, radioimmunodetection, and radioimmunotherapy. J Immunol Res 2014; 2014:268479. [PMID: 24818166 PMCID: PMC4003775 DOI: 10.1155/2014/268479] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 03/18/2014] [Indexed: 12/13/2022] Open
Abstract
PAM4, a new monoclonal antibody (MAb) known as clivatuzumab, is highly reactive with pancreatic cancer and precursor lesions. It is absent from the normal tissues and has limited reactivity with nonpancreatic cancer. The detailed characteristic of the PAM4 epitope is unknown but recent studies have shown that it is dependent on MUC1 glycosylation status. The limited PAM4 expression pattern makes it an attractive candidate for management of pancreatic adenocarcinoma. In addition, PAM4 is a serum biomarker for diagnosis of pancreatic cancer. Several different radiolabeled immunodiagnostic and immunotherapeutic agents of PAM4 have been developed and some are being evaluated in preclinical and/or clinical studies. The review will focus on PAM4 and its potential utility for the diagnosis, radioimmunodetection, and radioimmunotherapy of pancreatic cancer.
Collapse
Affiliation(s)
- Suxia Han
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University Medical Center, Xi'an, Shannxi 710061, China
| | - Guihua Jin
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University Medical Center, Xi'an, Shannxi 710061, China
| | - Lijuan Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University Medical Center, Xi'an, Shannxi 710061, China
| | - Meng Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University Medical Center, Xi'an, Shannxi 710061, China
| | - Chenchen He
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University Medical Center, Xi'an, Shannxi 710061, China
| | - Xijing Guo
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University Medical Center, Xi'an, Shannxi 710061, China
| | - Qing Zhu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University Medical Center, Xi'an, Shannxi 710061, China
| |
Collapse
|
|
47
|
Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. BIOMED RESEARCH INTERNATIONAL 2014; 2014:474905. [PMID: 24783207 PMCID: PMC3982269 DOI: 10.1155/2014/474905] [Citation(s) in RCA: 127] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 02/08/2014] [Accepted: 02/10/2014] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures.
Collapse
|
|
48
|
Fassan M, Baffa R, Kiss A. Advanced precancerous lesions within the GI tract: the molecular background. Best Pract Res Clin Gastroenterol 2013; 27:159-69. [PMID: 23809238 DOI: 10.1016/j.bpg.2013.03.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 02/14/2013] [Accepted: 03/08/2013] [Indexed: 01/31/2023]
Abstract
The mainstream carcinogenic processes involved within the gastrointestinal tract are characterized by phenotypic multistep progression cascades that eventually result in full-blown cancers. In this scenario, the understanding of the molecular dysregulations underlying the precancerous lesions is increasing but still remains incomplete. However, in recent years, the enthusiastic rise of innovative technologies (i.e., next-generation sequencing, high-throughput microarray analysis, mass spectrometry based proteomics) and the unexpected discovery of new classes of biomarkers (i.e., miRNA, long-noncoding RNAs) prompted new strength in the exploration of the accurate and comprehensive molecular characterization of premalignant and malignant neoplastic lesions. The challenge ahead lies in the reliable identification of disease progression-specific targets to enable molecular testing in the clinical management of the secondary prevention of gastrointestinal cancers.
Collapse
Affiliation(s)
- Matteo Fassan
- Department of Medicine DIMED, Surgical Pathology & Cytopathology Unit, University of Padua, 35121 Padua, Italy.
| | | | | |
Collapse
|