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Lu X, Dai Y, Liu X, Jiang L, Zhang K, Wu J, Gao W, Jiang K, Dai C, Miao Y, Li M, Wei J. Differences in the Clinicopathologic and Radiological Characteristics of Patients With Microcystic and Macrocystic Serous Cystadenoma of the Pancreas. Pancreas 2025; 54:e317-e323. [PMID: 39999293 PMCID: PMC12017593 DOI: 10.1097/mpa.0000000000002436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 11/06/2024] [Indexed: 02/27/2025]
Abstract
OBJECTIVES The aims of the study were to elucidate the clinicopathological characteristics, imaging features, and surgical outcomes of patients with serous cystic neoplasms (SCNs) and to compare the features between microcystic (MiC) and macrocystic (MaC) SCNs. MATERIALS AND METHODS In this single-center retrospective study, information of patients with SCN between 2016 and 2022 at our institution was collected and analyzed. RESULTS A total of 105 patients with SCNs were identified, including 58 (55.2%) with MiC type and 47 (44.8%) with MaC type. Patient age and American Society of Anesthesiologists grade in the MiC group were significantly higher than those in the MaC group. The overall preoperative diagnostic accuracy was 7.6%, with no patients in the MaC group correctly diagnosed before surgery. In imaging examinations, almost all (97.1%) exhibited a lobulated pattern. Internal septation, honeycomb pattern, central scar, and calcification were common, with a significantly higher incidence in the MiC group. No in-hospital deaths occurred, and the incidence of major complications were comparable in both groups. CONCLUSIONS Although many patients presented with typical imaging features, accurate diagnosis of SCN remained difficult. Except for older age and higher American Society of Anesthesiologists grade in the MiC group, there were no significant differences in the clinicopathological characteristics between MiC and MaC SCN patients.
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Affiliation(s)
- Xiaozhi Lu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuran Dai
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinchun Liu
- Department of Gastrointestinal and Anal Surgery, Affiliated Hangzhou First People's Hospital, Hangzhou, China
- School of Medicine, Westlake University, Hangzhou, China
| | - Lei Jiang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kai Zhang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Junli Wu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wentao Gao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kuirong Jiang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Cuncai Dai
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mingna Li
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jishu Wei
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Li J, Macchia J, Elhossiny AM, Arya N, Kadiyala P, Branch G, Peterson N, Liu J, Kwon R, Machicado JD, Wamsteker EJ, Schulman A, Philips G, Menees S, Singhi AD, Sahai V, Fang JM, Frankel TL, Bednar F, Pasca di Magliano M, Shi J, Carpenter ES. Spatial analysis of IPMNs defines a paradoxical KRT17-positive, low-grade epithelial population harboring malignant features. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.18.643943. [PMID: 40166305 PMCID: PMC11957041 DOI: 10.1101/2025.03.18.643943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Background & Aims Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that represent one of the few radiologically identifiable precursors to pancreatic ductal adenocarcinoma (PDAC).Though the IPMN-bearing patient population represents a unique opportunity for early detection and interception, current guidelines provide insufficient accuracy in determining which patients should undergo resection versus surveillance, resulting in a sizable fraction of resected IPMNs only harboring low-grade dysplasia, suggesting that there may be overtreatment of this clinical entity. Methods To investigate the transcriptional changes that occur during IPMN progression, we performed spatial transcriptomics using the Nanostring GeoMx on patient samples containing the entire spectrum of IPMN disease including low-grade dysplasia, high-grade dysplasia, and IPMN-derived carcinoma. Single cell RNA sequencing was performed on side branch and main duct IPMN biospecimens. Results We identified a subpopulation of histologically low-grade IPMN epithelial cells that express malignant transcriptional features including KRT17 , S100A10 and CEACAM5 , markers that are enriched in PDAC. We validated and refined this high-risk gene signature by integrating our ST analysis with an external ST dataset containing a larger number of IPMN samples including non-tumor bearing IPMN (i.e. low-grade IPMN in isolation). We confirmed the presence of the KRT17+ population using immunofluorescence on a large cohort of patient tissues, revealing a widespread but patchy distribution of KRT17+ cells in histologically low-grade IPMN. Conclusions Our study demonstrates that KRT17 marks a distinct transcriptional signature in a subpopulation of epithelial cells within histologically low-grade IPMN. This population of cells likely represents a transitional state of histologically low-grade epithelial cells undergoing progression to a higher grade of dysplasia and thus may represent a higher risk of progression to carcinoma. Graphical abstract
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Hashimoto A, Hashimoto S. Plasticity and Tumor Microenvironment in Pancreatic Cancer: Genetic, Metabolic, and Immune Perspectives. Cancers (Basel) 2024; 16:4094. [PMID: 39682280 DOI: 10.3390/cancers16234094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 11/29/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
Cancer has long been believed to be a genetic disease caused by the accumulation of mutations in key genes involved in cellular processes. However, recent advances in sequencing technology have demonstrated that cells with cancer driver mutations are also present in normal tissues in response to aging, environmental damage, and chronic inflammation, suggesting that not only intrinsic factors within cancer cells, but also environmental alterations are important key factors in cancer development and progression. Pancreatic cancer tissue is mostly comprised of stromal cells and immune cells. The desmoplasmic microenvironment characteristic of pancreatic cancer is hypoxic and hypotrophic. Pancreatic cancer cells may adapt to this environment by rewiring their metabolism through epigenomic changes, enhancing intrinsic plasticity, creating an acidic and immunosuppressive tumor microenvironment, and inducing noncancerous cells to become tumor-promoting. In addition, pancreatic cancer has often metastasized to local and distant sites by the time of diagnosis, suggesting that a similar mechanism is operating from the precancerous stage. Here, we review key recent findings on how pancreatic cancers acquire plasticity, undergo metabolic reprogramming, and promote immunosuppressive microenvironment formation during their evolution. Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven by KRAS/TP53 mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.
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Affiliation(s)
- Ari Hashimoto
- Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Shigeru Hashimoto
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0818, Japan
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Li Z, Shi Y, Tang W, Chen C, Liu W, Zhuo Q, Ji S, Zhou C, Yu X, Xu X. Laparoscopic Duodenum and Spleen-Preserving Subtotal or Total Pancreatectomy: A Parenchyma-Sparing Strategy for Main Duct Intraductal Papillary Mucinous Neoplasms (with Video). Ann Surg Oncol 2024; 31:8734-8740. [PMID: 39312053 PMCID: PMC11549168 DOI: 10.1245/s10434-024-16244-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 09/10/2024] [Indexed: 11/10/2024]
Abstract
BACKGROUND For premalignant main duct intraductal papillary mucinous neoplasms (MD-IPMN), laparoscopic duodenum and spleen-preserving subtotal or total pancreatectomy (LDSP-STP/TP) seems to be a viable option for parenchyma-sparing pancreatectomy. PATIENTS AND METHODS On the basis of the imaging features, family history, genomic alterations, intraoperative ultrasound examination, and frozen section evaluation, we have proposed patient selection strategies for the LDSP-STP/TP technique for the first time. Additionally, a comprehensive step-by-step overview of this technique has been provided. To date, we have performed five LDSP-STP procedures and one LDSP-TP procedure. RESULTS We successfully performed selective resection of the affected pancreatic parenchyma while preserving the duodenum, common bile duct (CBD), spleen, and splenic artery and vein. The operation time ranged from 295 to 495 min, with blood loss ranging from 100 to 300 mL. Postoperative pathological results revealed low-grade dysplasia in the resected pancreatic samples and margins. The patients resumed eating within 3-5 days after surgery, and all postoperative complications were classified as grade I according to the Clavien-Dindo classification. At the 3-month follow-up, there were no cases of CBD ischemic stenosis, splenic ischemia, or pseudocyst formation observed. For patients who received LDSP-STP, the longitudinal diameter of the remaining pancreatic tail ranged from 2.2 to 4.6 cm, and they demonstrated satisfactory long-term blood glycemic control. CONCLUSIONS LDSP-STP/TP demonstrates technical feasibility and safety. It allows for the selective resection of the affected pancreatic parenchyma, thereby minimizing the impact of pancreatic functional impairment. However, it is crucial to validate this technique through long-term prospective observations.
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Affiliation(s)
- Zheng Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yihua Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wenjie Tang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Department of Nursing Administration, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Chen Chen
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wensheng Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Qifeng Zhuo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chenjie Zhou
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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Desai R, Huang L, Gonzalez RS, Muthuswamy SK. Oncogenic GNAS Uses PKA-Dependent and Independent Mechanisms to Induce Cell Proliferation in Human Pancreatic Ductal and Acinar Organoids. Mol Cancer Res 2024; 22:440-451. [PMID: 38319286 PMCID: PMC10906748 DOI: 10.1158/1541-7786.mcr-23-0199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 09/26/2023] [Accepted: 02/02/2024] [Indexed: 02/07/2024]
Abstract
IMPLICATIONS The study identifies an opportunity to discover a PKA-independent pathway downstream of oncogene GNAS for managing IPMN lesions and their progression to PDAC.
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Affiliation(s)
- Ridhdhi Desai
- Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Current Address: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Ling Huang
- Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Current Address: Department of Surgery, Henry Ford Pancreatic Cancer Center, Henry Ford Health, Detroit, Michigan
| | - Raul S. Gonzalez
- Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Senthil K. Muthuswamy
- Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, MA, 02215, USA
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Araki T, Miwa N. Selective epigenetic alterations in RNF43 in pancreatic exocrine cells from high-fat-diet-induced obese mice; implications for pancreatic cancer. BMC Res Notes 2024; 17:106. [PMID: 38622664 PMCID: PMC11020883 DOI: 10.1186/s13104-024-06757-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 03/26/2024] [Indexed: 04/17/2024] Open
Abstract
OBJECTIVE Pancreatic cancer (PC) originates and progresses with genetic mutations in various oncogenes and suppressor genes, notably KRAS, CDKN2A, TP53, and SMAD4, prevalent across diverse PC cells. In addition to genetic mutations/deletions, persistent exposure to high-risk factors, including obesity, induces whole-genome scale epigenetic alterations contributing to malignancy. However, the impact of obesity on DNA methylation in the presymptomatic stage, particularly in genes prone to PC mutation, remains uncharacterized. RESULTS We analyzed the methylation levels of 197 loci in six genes (KRAS, CDKN2A, TP53, SMAD4, GNAS and RNF43) using Illumina Mouse Methylation BeadChip array (280 K) data from pancreatic exocrine cells obtained from high-fat-diet (HFD) induced obese mice. Results revealed no significant differences in methylation levels in loci between HFD- and normal-fat-diet (NFD)-fed mice, except for RNF43, a negative regulator of Wnt signaling, which showed hypermethylation in three loci. These findings indicate that, in mouse pancreatic exocrine cells, high-fat dietary obesity induced aberrant DNA methylation in RNF43 but not in other frequently mutated PC-related genes.
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Affiliation(s)
- Tomoyuki Araki
- Department of Biochemistry, School of Medicine, Saitama Medical University, 38 Moro-hongo, Iruma-gun, 350-0495, Moroyama, Saitama, Japan.
| | - Naofumi Miwa
- Department of Physiology, School of Medicine, Saitama Medical University, 38 Moro-hongo, Iruma-gun, 350-0495, Moroyama, Saitama, Japan.
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Reshkin SJ, Cardone RA, Koltai T. Genetic Signature of Human Pancreatic Cancer and Personalized Targeting. Cells 2024; 13:602. [PMID: 38607041 PMCID: PMC11011857 DOI: 10.3390/cells13070602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/13/2024] Open
Abstract
Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.
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Affiliation(s)
- Stephan J. Reshkin
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Tomas Koltai
- Oncomed, Via Pier Capponi 6, 50132 Florence, Italy
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Tripathi S, Tabari A, Mansur A, Dabbara H, Bridge CP, Daye D. From Machine Learning to Patient Outcomes: A Comprehensive Review of AI in Pancreatic Cancer. Diagnostics (Basel) 2024; 14:174. [PMID: 38248051 PMCID: PMC10814554 DOI: 10.3390/diagnostics14020174] [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: 09/19/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Pancreatic cancer is a highly aggressive and difficult-to-detect cancer with a poor prognosis. Late diagnosis is common due to a lack of early symptoms, specific markers, and the challenging location of the pancreas. Imaging technologies have improved diagnosis, but there is still room for improvement in standardizing guidelines. Biopsies and histopathological analysis are challenging due to tumor heterogeneity. Artificial Intelligence (AI) revolutionizes healthcare by improving diagnosis, treatment, and patient care. AI algorithms can analyze medical images with precision, aiding in early disease detection. AI also plays a role in personalized medicine by analyzing patient data to tailor treatment plans. It streamlines administrative tasks, such as medical coding and documentation, and provides patient assistance through AI chatbots. However, challenges include data privacy, security, and ethical considerations. This review article focuses on the potential of AI in transforming pancreatic cancer care, offering improved diagnostics, personalized treatments, and operational efficiency, leading to better patient outcomes.
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Affiliation(s)
- Satvik Tripathi
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; (S.T.); (A.T.); (A.M.); (C.P.B.)
- Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA 02129, USA
- Harvard Medical School, Boston, MA 02115, USA
| | - Azadeh Tabari
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; (S.T.); (A.T.); (A.M.); (C.P.B.)
- Harvard Medical School, Boston, MA 02115, USA
| | - Arian Mansur
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; (S.T.); (A.T.); (A.M.); (C.P.B.)
- Harvard Medical School, Boston, MA 02115, USA
| | - Harika Dabbara
- Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA;
| | - Christopher P. Bridge
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; (S.T.); (A.T.); (A.M.); (C.P.B.)
- Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA 02129, USA
- Harvard Medical School, Boston, MA 02115, USA
| | - Dania Daye
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA; (S.T.); (A.T.); (A.M.); (C.P.B.)
- Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA 02129, USA
- Harvard Medical School, Boston, MA 02115, USA
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Koltai T. Earlier Diagnosis of Pancreatic Cancer: Is It Possible? Cancers (Basel) 2023; 15:4430. [PMID: 37760400 PMCID: PMC10526520 DOI: 10.3390/cancers15184430] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/31/2023] [Accepted: 08/06/2023] [Indexed: 09/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma has a very high mortality rate which has been only minimally improved in the last 30 years. This high mortality is closely related to late diagnosis, which is usually made when the tumor is large and has extensively infiltrated neighboring tissues or distant metastases are already present. This is a paradoxical situation for a tumor that requires nearly 15 years to develop since the first founding mutation. Response to chemotherapy under such late circumstances is poor, resistance is frequent, and prolongation of survival is almost negligible. Early surgery has been, and still is, the only approach with a slightly better outcome. Unfortunately, the relapse percentage after surgery is still very high. In fact, early surgery clearly requires early diagnosis. Despite all the advances in diagnostic methods, the available tools for improving these results are scarce. Serum tumor markers permit a late diagnosis, but their contribution to an improved therapeutic result is very limited. On the other hand, effective screening methods for high-risk populations have not been fully developed as yet. This paper discusses the difficulties of early diagnosis, evaluates whether the available diagnostic tools are adequate, and proposes some simple and not-so-simple measures to improve it.
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Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires C1094, Argentina
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Izdebska WM, Daniluk J, Niklinski J. Microbiome and MicroRNA or Long Non-Coding RNA-Two Modern Approaches to Understanding Pancreatic Ductal Adenocarcinoma. J Clin Med 2023; 12:5643. [PMID: 37685710 PMCID: PMC10488817 DOI: 10.3390/jcm12175643] [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: 07/21/2023] [Revised: 08/18/2023] [Accepted: 08/19/2023] [Indexed: 09/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of humans' most common and fatal neoplasms. Nowadays, a number of PDAC studies are being conducted in two different fields: non-coding RNA (especially microRNA and long non-coding RNA) and microbiota. It has been recently discovered that not only does miRNA affect particular bacteria in the gut microbiome that can promote carcinogenesis in the pancreas, but the microbiome also has a visible impact on the miRNA. This suggests that it is possible to use the combined impact of the microbiome and noncoding RNA to suppress the development of PDAC. Nevertheless, insufficient research has focused on bounding both approaches to the diagnosis, treatment, and prevention of pancreatic ductal adenocarcinoma. In this article, we summarize the recent literature on the molecular basis of carcinogenesis in the pancreas, the two-sided impact of particular types of non-coding RNA and the pancreatic cancer microbiome, and possible medical implications of the discovered phenomenon.
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Affiliation(s)
- Wiktoria Maria Izdebska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jaroslaw Daniluk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jacek Niklinski
- Department of Clinical Molecular Biology, Medical University of Bialystok, 15-089 Bialystok, Poland
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11
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Chaves J, Fernandez Y Viesca M, Arvanitakis M. Using Endoscopy in the Diagnosis of Pancreato-Biliary Cancers. Cancers (Basel) 2023; 15:3385. [PMID: 37444495 DOI: 10.3390/cancers15133385] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Pancreatic cancer and cholangiocarcinoma are life threatening oncological conditions with poor prognosis and outcome. Pancreatic cystic lesions are considered precursors of pancreatic cancer as some of them have the potential to progress to malignancy. Therefore, accurate identification and classification of these lesions is important to prevent the development of invasive cancer. In the biliary tract, the accurate characterization of biliary strictures is essential for providing appropriate management and avoiding unnecessary surgery. Techniques have been developed to improve the diagnosis, risk stratification, and management of pancreato-biliary lesions. Endoscopic ultrasound (EUS) and associated techniques, such as elastography, contrasted-enhanced EUS, and EUS-guided needle confocal laser endomicroscopy, may improve diagnostic accuracy. In addition, intraductal techniques applied during endoscopic retrograde cholangiopancreatography (ERCP), such as new generation cholangioscopy and in vivo cellular evaluation through probe-based confocal laser endomicroscopy, can increase the diagnostic yield in characterizing indeterminate biliary strictures. Both EUS-guided and intraductal approaches can provide the possibility for tissue sampling with new tools, such as needles, biopsies forceps, and brushes. At the molecular level, novel biomarkers have been explored that provide new insights into diagnosis, risk stratification, and management of these lesions.
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Affiliation(s)
- Julia Chaves
- Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Michael Fernandez Y Viesca
- Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Marianna Arvanitakis
- Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium
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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.
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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
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13
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Halbrook CJ, Lyssiotis CA, Pasca di Magliano M, Maitra A. Pancreatic cancer: Advances and challenges. Cell 2023; 186:1729-1754. [PMID: 37059070 PMCID: PMC10182830 DOI: 10.1016/j.cell.2023.02.014] [Citation(s) in RCA: 479] [Impact Index Per Article: 239.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/17/2023] [Accepted: 02/08/2023] [Indexed: 04/16/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant disease.
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Affiliation(s)
- Christopher J Halbrook
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA; Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 92868, USA.
| | - Costas A Lyssiotis
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Marina Pasca di Magliano
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Anirban Maitra
- Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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14
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Caiazza F, Conroy PC, Ivry SL, York T, Lin J, Hernandez S, Hoffmann TJ, Francis SS, Park WG, Yip-Schneider MT, Schmidt CM, Brand R, Craik CS, Kirkwood K. Accurate Identification of Mucinous Pancreatic Cystic Lesions Using Small-Volume Analytes. J Surg Res 2023; 284:322-331. [PMID: 36369049 DOI: 10.1016/j.jss.2022.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 07/26/2022] [Accepted: 08/19/2022] [Indexed: 11/11/2022]
Abstract
INTRODUCTION The accurate identification of mucinous pancreatic cystic lesions (PCLs) is paramount for cancer risk stratification. Cyst fluid carcinoembryonic antigen (CEA), the only routinely used test, requires high volumes and has low sensitivity. We aimed to compare the performance of two investigational small-volume biomarkers, glucose and the protease gastricsin, to CEA for PCL classification. METHODS We obtained cyst fluid samples from 81 patients with pathologically confirmed PCLs from four institutions between 2003 and 2016. Gastricsin activity was measured using an internally quenched fluorescent substrate. Glucose levels were measured with a standard glucometer. CEA levels were obtained from the medical record. Models using Classification and Regression Trees were created to predict mucinous status. Model performance was evaluated using nested cross-validation. RESULTS Gastricsin activity, CEA, and glucose levels from patients with mucinous (n = 50) and nonmucinous (n = 31) PCLs were analyzed. Area under the curve (AUC) was similar for individual classifiers (gastricsin volume normalized [GVN] 0.88; gastricsin protein concentration normalized [GPN] 0.95; glucose 0.83; CEA 0.84). The combination of two classifiers did not significantly improve AUC, with CEA + GVN (0.88) performing similarly to CEA + GPN (0.95), GVN + glucose (0.87), GPN + glucose (0.95), and CEA + glucose (0.84). The three-analyte combination performed similarly to single and dual classifiers (GPN + glucose + CEA AUC 0.95; GVN + glucose + CEA AUC 0.87). After multiple comparison corrections, there were no significant differences between the individual, dual, and triple classifiers. CONCLUSIONS Gastricsin and glucose performed similarly to CEA and required <5% of the volume required for CEA; these classifiers may be useful in patients with limited cyst fluid. Future multicenter prospective studies are needed to validate and compare these novel small-volume biomarkers.
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Affiliation(s)
- Francesco Caiazza
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California
| | - Patricia C Conroy
- Department of Surgery, University of California, San Francisco, San Francisco, California
| | - Sam L Ivry
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California
| | - Tyler York
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joseph Lin
- Department of Surgery, University of California, San Francisco, San Francisco, California
| | - Sophia Hernandez
- Department of Surgery, University of California, San Francisco, San Francisco, California
| | - Thomas J Hoffmann
- Department of Epidemiology & Biostatistics, and Institute for Human Genetics, University of California, San Francisco, San Francisco, California
| | - Stephen S Francis
- Department of Neurological Surgery, University of California, San Francisco, San Francisco, California
| | - Walter G Park
- Department of Medicine, Division of Gastroenterology & Hepatology, Stanford University, Stanford, California
| | | | - C Max Schmidt
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Randall Brand
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Charles S Craik
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California
| | - Kimberly Kirkwood
- Department of Surgery, University of California, San Francisco, San Francisco, California.
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15
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Murugesan P, Begum H, Tangutur AD. Inhibitor of DNA binding/differentiation proteins as IDs for pancreatic cancer: Role in pancreatic cancer initiation, development and prognosis. Gene 2023; 853:147092. [PMID: 36464175 DOI: 10.1016/j.gene.2022.147092] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/11/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022]
Abstract
A family of inhibitors of cell differentiation or DNA-binding proteins, known as ID proteins (ID1-4), function as mighty transcription factors in various cellular processes, such as inhibiting differentiation, promoting cell-cycle progression, senescence, angiogenesis, tumorigenesis, and metastasis in cancer. Pancreatic cancer represents the deadliest cancer with the lowest survival rate of 10% due to the diagnosis at an advanced fatal stage and therapeutic resistance. Modestly, the only curative option for this lethal cancer is surgery but is done in less than 15-20% of patients because of the locally aggressive and early metastatic nature. Finding the earliest biomarkers and targeting the various hallmarks of pancreatic cancer can improve the treatment and survival of pancreatic cancer patients. Therefore, herein in this review, we explore in depth the potential roles of ID proteins function in hallmarks of pancreatic cancer, signaling pathways, and its oncogenic and tumor-suppressive effects. Hence, understanding the roles of dysregulated ID proteins would provide new insights into its function in pancreatic cancer tumorigenesis.
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Affiliation(s)
- Periyasamy Murugesan
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India
| | - Habeebunnisa Begum
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India
| | - Anjana Devi Tangutur
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India.
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16
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Desai R, Muthuswamy S. Oncogenic GNAS uses PKA-dependent and independent mechanisms to induce cell proliferation in human pancreatic ductal and acinar organoids. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.16.524220. [PMID: 36789419 PMCID: PMC9928035 DOI: 10.1101/2023.01.16.524220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Ductal and acinar pancreatic organoids generated from human pluripotent stem cells (hPSCs) are promising models to study pancreatic diseases, including precursor lesions of pancreatic cancer. Genome sequencing studies have revealed that mutations in a G-protein (GNASR201C) are exclusively observed in intraductal papillary mucinous neoplasms (IPMNs), one of the most common cystic pancreatic precancerous lesions. GNASR201C cooperates with oncogenic KRASG12V/D to produce IPMN lesions in mice; however, the biological mechanisms by which oncogenic GNAS affects the ductal and acinar exocrine pancreas are not understood. In this study, we use pancreatic ductal and acinar organoids generated from human embryonic stem cells to investigate mechanisms by which GNASR201C functions. As expected, GNASR201C-induced cell proliferation in acinar organoids was PKA-dependent. Surprisingly, GNASR201C-induced cell proliferation independent of the canonical PKA signaling in short-term and stable, long-term cultures of GNAS-expressing ductal organoids and in an immortalized ductal epithelial cell line, demonstrating that GNASR201C uses PKA-dependent and independent mechanisms to induce cell proliferation in the exocrine pancreas. Co-expression of oncogenic KRASG12V and GNASR201C induced cell proliferation in ductal and acini organoids in a PKA-independent and dependent manner, respectively. Thus, we identify cell lineage-specific roles for PKA signaling driving pre-cancerous lesions and report the development of a human pancreatic ductal organoid model system to investigate mechanisms regulating GNASR201C-induced IPMNs.
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Affiliation(s)
- Ridhdhi Desai
- Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Current Address: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Senthil Muthuswamy
- Cancer Research Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- Current Address: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, MD, MA, 02215, USsA
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17
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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.
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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
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18
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Henn J, Wyzlic PK, Esposito I, Semaan A, Branchi V, Klinger C, Buhr HJ, Wellner UF, Keck T, Lingohr P, Glowka TR, Manekeller S, Kalff JC, Matthaei H. Surgical treatment for pancreatic cystic lesions-implications from the multi-center and prospective German StuDoQ|Pancreas registry. Langenbecks Arch Surg 2023; 408:28. [PMID: 36640188 PMCID: PMC9840584 DOI: 10.1007/s00423-022-02740-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 10/20/2022] [Indexed: 01/15/2023]
Abstract
PURPOSE The detection of pancreatic cystic lesions (PCL) causes uncertainty for physicians and patients, and international guidelines are based on low evidence. The extent and perioperative risk of resections of PCL in Germany needs comparison with these guidelines to highlight controversies and derive recommendations. METHODS Clinical data of 1137 patients who underwent surgery for PCL between 2014 and 2019 were retrieved from the German StuDoQ|Pancreas registry. Relevant features for preoperative evaluation and predictive factors for adverse outcomes were statistically identified. RESULTS Patients with intraductal papillary mucinous neoplasms (IPMN) represented the largest PCL subgroup (N = 689; 60.6%) while other entities (mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), neuroendocrine tumors, pseudocysts) were less frequently resected. Symptoms of pancreatitis were associated with IPMN (OR, 1.8; P = 0.012) and pseudocysts (OR, 4.78; P < 0.001), but likewise lowered the likelihood of MCN (OR, 0.49; P = 0.046) and SCN (OR, 0.15, P = 0.002). A total of 639 (57.2%) patients received endoscopic ultrasound before resection, as recommended by guidelines. Malignancy was histologically confirmed in 137 patients (12.0%), while jaundice (OR, 5.1; P < 0.001) and weight loss (OR, 2.0; P = 0.002) were independent predictors. Most resections were performed by open surgery (N = 847, 74.5%), while distal lesions were in majority treated using minimally invasive approaches (P < 0.001). Severe morbidity was 28.4% (N = 323) and 30d mortality was 2.6% (N = 29). Increased age (P = 0.004), higher BMI (P = 0.002), liver cirrhosis (P < 0.001), and esophageal varices (P = 0.002) were independent risk factors for 30d mortality. CONCLUSION With respect to unclear findings frequently present in PCL, diagnostic means recommended in guidelines should always be considered in the preoperative phase. The therapy of PCL should be decided upon in the light of patient-specific factors, and the surgical strategy needs to be adapted accordingly.
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Affiliation(s)
- Jonas Henn
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Patricia K Wyzlic
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Irene Esposito
- Institute of Pathology, Heinrich-Heine University, Düsseldorf, Germany
| | - Alexander Semaan
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Vittorio Branchi
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Carsten Klinger
- German Society of General and Visceral Surgery (DGAV), Berlin, Germany
| | - Heinz J Buhr
- German Society of General and Visceral Surgery (DGAV), Berlin, Germany
| | | | - Tobias Keck
- Department of Surgery, UKSH Campus Lübeck, Lübeck, Germany
| | - Philipp Lingohr
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Tim R Glowka
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Steffen Manekeller
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Jörg C Kalff
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Hanno Matthaei
- Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany.
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19
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Raut P, Nimmakayala RK, Batra SK, Ponnusamy MP. Clinical and Molecular Attributes and Evaluation of Pancreatic Cystic Neoplasm. Biochim Biophys Acta Rev Cancer 2023; 1878:188851. [PMID: 36535512 PMCID: PMC9898173 DOI: 10.1016/j.bbcan.2022.188851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/08/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are all considered "Pancreatic cystic neoplasms (PCNs)" and show a varying risk of developing into pancreatic ductal adenocarcinoma (PDAC). These lesions display different molecular characteristics, mutations, and clinical manifestations. A lack of detailed understanding of PCN subtype characteristics and their molecular mechanisms limits the development of efficient diagnostic tools and therapeutic strategies for these lesions. Proper in vivo mouse models that mimic human PCNs are also needed to study the molecular mechanisms and for therapeutic testing. A comprehensive understanding of the current status of PCN biology, mechanisms, current diagnostic methods, and therapies will help in the early detection and proper management of patients with these lesions and PDAC. This review aims to describe all these aspects of PCNs, specifically IPMNs, by describing the future perspectives.
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Affiliation(s)
- Pratima Raut
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Rama Krishna Nimmakayala
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
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20
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Tan M, Chang Y, Liu X, Li H, Tang Z, Nyati MK, Sun Y. The Sag-Shoc2 axis regulates conversion of mPanINs to cystic lesions in Kras pancreatic tumor model. Cell Rep 2022; 41:111837. [PMID: 36543126 DOI: 10.1016/j.celrep.2022.111837] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/15/2022] [Accepted: 11/24/2022] [Indexed: 12/24/2022] Open
Abstract
SAG/RBX2 is an E3 ligase, whereas SHOC2 is a RAS-RAF positive regulator. In this study, we address how Sag-Shoc2 crosstalk regulates pancreatic tumorigenesis induced by KrasG12D. Sag deletion increases the size of pancreas and causes the conversion of murine pancreatic intraepithelial neoplasms (mPanINs) to neoplastic cystic lesions with a mechanism involving Shoc2 accumulation, suggesting that Sag determines the pathological process via targeting Shoc2. Shoc2 deletion significantly inhibits pancreas growth, mPanIN formation, and acinar cell transdifferentiation, indicating that Shoc2 is essential for KrasG12D-induced pancreatic tumorigenesis. Likewise, in a primary acinar 3D culture, Sag deletion inhibits acinar-to-ductal transdifferentiation, while Shoc2 deletion significantly reduces the duct-like structures. Mechanistically, SAG is an E3 ligase that targets SHOC2 for degradation to affect both Mapk and mTorc1 pathways. Shoc2 deletion completely rescues the phenotype of neoplastic cystic lesions induced by Sag deletion, indicating physiological relevance of the Sag-Shoc2 crosstalk. Thus, the Sag-Shoc2 axis specifies the pancreatic tumor types induced by KrasG12D.
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Affiliation(s)
- Mingjia Tan
- Department of Radiation Oncology, NCRC, Building 520, University of Michigan, Ann Arbor, MI 48105, USA
| | - Yu Chang
- Department of Radiation Oncology, NCRC, Building 520, University of Michigan, Ann Arbor, MI 48105, USA
| | - Xiaoqiang Liu
- Department of Radiation Oncology, NCRC, Building 520, University of Michigan, Ann Arbor, MI 48105, USA
| | - Hua Li
- Department of Radiation Oncology, NCRC, Building 520, University of Michigan, Ann Arbor, MI 48105, USA
| | - Zaiming Tang
- Cancer Institute, The Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
| | - Mukesh K Nyati
- Department of Radiation Oncology, NCRC, Building 520, University of Michigan, Ann Arbor, MI 48105, USA
| | - Yi Sun
- Cancer Institute, The Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; Zhejiang University Cancer Center, Hangzhou 310029, China; Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang 310053, China.
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21
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Okasha HH, Abdellatef A, Elkholy S, Mogawer MS, Yosry A, Elserafy M, Medhat E, Khalaf H, Fouad M, Elbaz T, Ramadan A, Behiry ME, Y William K, Habib G, Kaddah M, Abdel-Hamid H, Abou-Elmagd A, Galal A, Abbas WA, Altonbary AY, El-Ansary M, Abdou AE, Haggag H, Abdellah TA, Elfeki MA, Faheem HA, Khattab HM, El-Ansary M, Beshir S, El-Nady M. Role of endoscopic ultrasound and cyst fluid tumor markers in diagnosis of pancreatic cystic lesions. World J Gastrointest Endosc 2022; 14:402-415. [PMID: 35978716 PMCID: PMC9265252 DOI: 10.4253/wjge.v14.i6.402] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/28/2021] [Accepted: 05/05/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic cystic lesions (PCLs) are common in clinical practice. The accurate classification and diagnosis of these lesions are crucial to avoid unnecessary treatment of benign lesions and missed opportunities for early treatment of potentially malignant lesions. AIM To evaluate the role of cyst fluid analysis of different tumor markers such as cancer antigens [e.g., cancer antigen (CA)19-9, CA72-4], carcinoembryonic antigen (CEA), serine protease inhibitor Kazal-type 1 (SPINK1), interleukin 1 beta (IL1-β), vascular endothelial growth factor A (VEGF-A), and prostaglandin E2 (PGE2)], amylase, and mucin stain in diagnosing pancreatic cysts and differentiating malignant from benign lesions. METHODS This study included 76 patients diagnosed with PCLs using different imaging modalities. All patients underwent endoscopic ultrasound (EUS) and EUS-fine needle aspiration (EUS-FNA) for characterization and sampling of different PCLs. RESULTS The mean age of studied patients was 47.4 ± 11.4 years, with a slight female predominance (59.2%). Mucin stain showed high statistical significance in predicting malignancy with a sensitivity of 87.1% and specificity of 95.56%. It also showed a positive predictive value and negative predictive value of 93.1% and 91.49%, respectively (P < 0.001). We found that positive mucin stain, cyst fluid glucose, SPINK1, amylase, and CEA levels had high statistical significance (P < 0.0001). In contrast, IL-1β, CA 72-4, VEGF-A, VEGFR2, and PGE2 did not show any statistical significance. Univariate regression analysis for prediction of malignancy in PCLs showed a statistically significant positive correlation with mural nodules, lymph nodes, cyst diameter, mucin stain, and cyst fluid CEA. Meanwhile, logistic multivariable regression analysis proved that mural nodules, mucin stain, and SPINK1 were independent predictors of malignancy in cystic pancreatic lesions. CONCLUSION EUS examination of cyst morphology with cytopathological analysis and cyst fluid analysis could improve the differentiation between malignant and benign pancreatic cysts. Also, CEA, glucose, and SPINK1 could be used as promising markers to predict malignant pancreatic cysts.
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Affiliation(s)
- Hussein Hassan Okasha
- Department of Internal Medicine and Hepatogastroenterology, Kasr Al-Aini Hospitals, Cairo University, Kasr Al-Aini Hospitals, Cairo University, Cairo 11451, Egypt
| | - Abeer Abdellatef
- Department of Internal Medicine and Hepatogastroenterology, Kasr Al-Aini Hospitals, Cairo University, Kasr Al-Aini Hospitals, Cairo University, Cairo 11451, Egypt
| | - Shaimaa Elkholy
- Department of Internal Medicine and Hepatogastroenterology, Kasr Al-Aini Hospitals, Cairo University, Kasr Al-Aini Hospitals, Cairo University, Cairo 11451, Egypt
| | - Mohamad-Sherif Mogawer
- Department of Internal Medicine and Hepatogastroenterology, Kasr Al-Aini Hospitals, Cairo University, Kasr Al-Aini Hospitals, Cairo University, Cairo 11451, Egypt
| | - Ayman Yosry
- Department of Endemic Diseases, Cairo University, Cairo 11451, Egypt
| | - Magdy Elserafy
- Department of Endemic Diseases, Cairo University, Cairo 11451, Egypt
| | - Eman Medhat
- Department of Endemic Diseases, Cairo University, Cairo 11451, Egypt
| | - Hanaa Khalaf
- Department of Tropical Medicine and Gastroenterology, Minia University, Minia 61511, Egypt
| | - Magdy Fouad
- Department of Tropical Medicine and Gastroenterology, Minia University, Minia 61511, Egypt
| | - Tamer Elbaz
- Department of Endemic Diseases, Cairo University, Cairo 11451, Egypt
| | - Ahmed Ramadan
- Department of Endemic Diseases, Cairo University, Cairo 11451, Egypt
| | - Mervat E Behiry
- Department of Internal Medicine, Kasr Al-Aini Hospitals, Cairo University, Cairo 11562, Egypt
| | - Kerolis Y William
- Department of Internal Medicine and Hepatogastroenterology, Kasr Al-Aini Hospitals, Cairo University, Kasr Al-Aini Hospitals, Cairo University, Cairo 11451, Egypt
| | - Ghada Habib
- Department of Endemic Diseases, Cairo University, Cairo 11451, Egypt
| | - Mona Kaddah
- Department of Endemic Diseases, Cairo University, Cairo 11451, Egypt
| | - Haitham Abdel-Hamid
- Department of Tropical Medicine and Gastroenterology, Minia University, Minia 61511, Egypt
| | - Amr Abou-Elmagd
- Department of Gastroenterology, Armed forces College of Medicine, Cairo 11451, Egypt
| | - Ahmed Galal
- Endoscopy and Internal Medicine Consultant at Dr/Ahmed Galal Endoscopy Center, Alexandria 35516, Egypt
| | - Wael A Abbas
- Department of Internal Medicine, Faculty of Medicine, Assuit University, Assuit 71111, Egypt
| | | | - Mahmoud El-Ansary
- Department of Gastroenterology and Hepatology, Theodor Bilharz Research Institute, Cairo 11451, Egypt
| | - Aml E Abdou
- Department of Microbiology and Immunology, Faculty of Medicine for girls Al-Azhar University, Cairo 11451, Egypt
| | - Hani Haggag
- Department of Internal Medicine and Hepatogastroenterology, Kasr Al-Aini Hospitals, Cairo University, Kasr Al-Aini Hospitals, Cairo University, Cairo 11451, Egypt
| | - Tarek Ali Abdellah
- Department of Internal Medicine, Faculty of Medicine, Ain shams University, Cairo 11451, Egypt
| | - Mohamed A Elfeki
- Department of Internal Medicine, Bani-suef University, Bani-suef, Bani-suef 62511, Egypt
| | - Heba Ahmed Faheem
- Department of Internal Medicine, Faculty of Medicine, Ain shams University, Cairo 11451, Egypt
| | - Hani M Khattab
- Department of Pathology, Faculty of Medicine, Cairo University, Cairo 11451, Egypt
| | - Mervat El-Ansary
- Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo 11451, Egypt
| | - Safia Beshir
- Department of Environmental Medicine & Clinical Pathology, National Research Centre, Cairo 11451, Egypt
| | - Mohamed El-Nady
- Department of Internal Medicine and Hepatogastroenterology, Kasr Al-Aini Hospitals, Cairo University, Kasr Al-Aini Hospitals, Cairo University, Cairo 11451, Egypt
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22
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Hernandez S, Parra ER, Uraoka N, Tang X, Shen Y, Qiao W, Jiang M, Zhang S, Mino B, Lu W, Pandurengan R, Haymaker C, Affolter K, Scaife CL, Yip-Schneider M, Schmidt CM, Firpo MA, Mulvihill SJ, Koay EJ, Wang H, Wistuba II, Maitra A, Solis LM, Sen S. Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception. Clin Cancer Res 2022; 28:1938-1947. [PMID: 35491652 PMCID: PMC9069801 DOI: 10.1158/1078-0432.ccr-21-2585] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/02/2021] [Accepted: 02/21/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses. EXPERIMENTAL DESIGN Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology-related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set. RESULTS Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression. CONCLUSIONS Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.
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Affiliation(s)
- Sharia Hernandez
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Edwin Roger Parra
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Naohiro Uraoka
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ximing Tang
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yu Shen
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei Qiao
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mei Jiang
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shanyu Zhang
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Barbara Mino
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei Lu
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Renganayaki Pandurengan
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cara Haymaker
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kajsa Affolter
- Department of Pathology, University of Utah, Salt Lake City, Utah
| | | | | | - C. Max Schmidt
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | | | | | - Eugene J. Koay
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Huamin Wang
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ignacio I. Wistuba
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anirban Maitra
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Luisa M. Solis
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Subrata Sen
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
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23
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Kato H, Tateishi K, Fujiwara H, Nakatsuka T, Yamamoto K, Kudo Y, Hayakawa Y, Nakagawa H, Tanaka Y, Ijichi H, Otsuka M, Iwadate D, Oyama H, Kanai S, Noguchi K, Suzuki T, Sato T, Hakuta R, Ishigaki K, Saito K, Saito T, Takahara N, Kishikawa T, Hamada T, Takahashi R, Miyabayashi K, Mizuno S, Kogure H, Nakai Y, Hirata Y, Toyoda A, Ichikawa K, Qu W, Morishita S, Arita J, Tanaka M, Ushiku T, Hasegawa K, Fujishiro M, Koike K. MNX1-HNF1B Axis Is Indispensable for Intraductal Papillary Mucinous Neoplasm Lineages. Gastroenterology 2022; 162:1272-1287.e16. [PMID: 34953915 DOI: 10.1053/j.gastro.2021.12.254] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 11/16/2021] [Accepted: 12/16/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Chromatin architecture governs cell lineages by regulating the specific gene expression; however, its role in the diversity of cancer development remains unknown. Among pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMN) with an associated invasive carcinoma (IPMNinv) arise from 2 distinct precursors, and their fundamental differences remain obscure. Here, we aimed to assess the difference of chromatin architecture regulating the transcriptional signatures or biological features in pancreatic cancers. METHODS We established 28 human organoids from distinct subtypes of pancreatic tumors, including IPMN, IPMNinv, and PDAC. We performed exome sequencing (seq), RNA-seq, assay for transposase-accessible chromatin-seq, chromatin immunoprecipitation-seq, high-throughput chromosome conformation capture, and phenotypic analyses with short hairpin RNA or clustered regularly interspaced short palindromic repeats interference. RESULTS Established organoids successfully reproduced the histology of primary tumors. IPMN and IPMNinv organoids harbored GNAS, RNF43, or KLF4 mutations and showed the distinct expression profiles compared with PDAC. Chromatin accessibility profiles revealed the gain of stomach-specific open regions in IPMN and the pattern of diverse gastrointestinal tissues in IPMNinv. In contrast, PDAC presented an impressive loss of accessible regions compared with normal pancreatic ducts. Transcription factor footprint analysis and functional assays identified that MNX1 and HNF1B were biologically indispensable for IPMN lineages. The upregulation of MNX1 was specifically marked in the human IPMN lineage tissues. The MNX1-HNF1B axis governed a set of genes, including MYC, SOX9, and OLFM4, which are known to be essential for gastrointestinal stem cells. High-throughput chromosome conformation capture analysis suggested the HNF1B target genes to be 3-dimensionally connected in the genome of IPMNinv. CONCLUSIONS Our organoid analyses identified the MNX1-HNF1B axis to be biologically significant in IPMN lineages.
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Affiliation(s)
- Hiroyuki Kato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Keisuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hiroaki Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Division of Gastroenterology, The Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Takuma Nakatsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Keisuke Yamamoto
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yotaro Kudo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yasuo Tanaka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hideaki Ijichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Dosuke Iwadate
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroki Oyama
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Sachiko Kanai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kensaku Noguchi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsunori Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsuya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryunosuke Hakuta
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazunaga Ishigaki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kei Saito
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomotaka Saito
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naminatsu Takahara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tsuyoshi Hamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Takahashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Koji Miyabayashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hirofumi Kogure
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Endoscopy and Endoscopic Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Yoshihiro Hirata
- Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Atsushi Toyoda
- Comparative Genomics Laboratory, National Institute of Genetics, Shizuoka, Japan
| | - Kazuki Ichikawa
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Wei Qu
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Shinichi Morishita
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mariko Tanaka
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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24
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Shields MA, Spaulding C, Metropulos AE, Khalafalla MG, Pham TND, Munshi HG. Gα13 loss in Kras/Tp53 mouse model of pancreatic tumorigenesis promotes tumors susceptible to rapamycin. Cell Rep 2022; 38:110441. [PMID: 35235808 PMCID: PMC8989626 DOI: 10.1016/j.celrep.2022.110441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 09/22/2021] [Accepted: 02/04/2022] [Indexed: 11/20/2022] Open
Abstract
Gα13 transduces signals from G-protein-coupled receptors. While Gα13 functions as a tumor suppressor in lymphomas, it is not known whether Gα13 is pro-tumorigenic or tumor suppressive in genetically engineered mouse (GEM) models of epithelial cancers. Here, we show that loss of Gα13 in the Kras/Tp53 (KPC) GEM model promotes well-differentiated tumors and reduces survival. Mechanistically, tumors developing in KPC mice with Gα13 loss exhibit increased E-cadherin expression and mTOR signaling. Importantly, human pancreatic ductal adenocarcinoma (PDAC) tumors with low Gα13 expression also exhibit increased E-cadherin expression and mTOR signaling. Treatment with the mTOR inhibitor rapamycin decreases the growth of syngeneic KPC tumors with Gα13 loss by promoting cell death. This work establishes a tumor-suppressive role of Gα13 in pancreatic tumorigenesis in the KPC GEM model and suggests targeting mTOR in human PDAC tumors with Gα13 loss.
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Affiliation(s)
- Mario A Shields
- Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA; The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA.
| | - Christina Spaulding
- Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA; Jesse Brown VA Medical Center, Chicago, IL, USA
| | - Anastasia E Metropulos
- Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA
| | - Mahmoud G Khalafalla
- Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA
| | - Thao N D Pham
- Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA
| | - Hidayatullah G Munshi
- Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Superior Avenue, Lurie 3-220 or Lurie 3-117, Chicago, IL 60611, USA; The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA.
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25
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The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy. Cancers (Basel) 2022; 14:cancers14010217. [PMID: 35008381 PMCID: PMC8750069 DOI: 10.3390/cancers14010217] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma is a leading cause of cancer death worldwide. Due to the frequently late diagnosis, early metastasis and high therapy resistance curation is rare and prognosis remains poor overall. To provide early diagnostic and therapeutic predictors, various molecules from blood, tissue and other origin e.g., saliva, urine and stool, have been identified as biomarkers. This review summarizes current trends in biomarkers for diagnosis and therapy of pancreatic ductal adenocarcinoma. Abstract Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer.
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26
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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.
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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
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27
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Tonini V, Zanni M. Pancreatic cancer in 2021: What you need to know to win. World J Gastroenterol 2021; 27:5851-5889. [PMID: 34629806 PMCID: PMC8475010 DOI: 10.3748/wjg.v27.i35.5851] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/14/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the solid tumors with the worst prognosis. Five-year survival rate is less than 10%. Surgical resection is the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage of the disease and surgery could be performed in a very limited number of patients. Moreover, surgery is still associated with high post-operative morbidity, while other therapies still offer very disappointing results. This article reviews every aspect of pancreatic cancer, focusing on the elements that can improve prognosis. It was written with the aim of describing everything you need to know in 2021 in order to face this difficult challenge.
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Affiliation(s)
- Valeria Tonini
- Department of Medical Sciences and Surgery, University of Bologna- Emergency Surgery Unit, IRCCS Sant’Orsola Hospital, Bologna 40121, Italy
| | - Manuel Zanni
- University of Bologna, Emergency Surgery Unit, IRCCS Sant'Orsola Hospital, Bologna 40121, Italy
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Oka A, Ishimura N, Ishihara S. A New Dawn for the Use of Artificial Intelligence in Gastroenterology, Hepatology and Pancreatology. Diagnostics (Basel) 2021; 11:1719. [PMID: 34574060 PMCID: PMC8468082 DOI: 10.3390/diagnostics11091719] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/17/2021] [Accepted: 09/17/2021] [Indexed: 12/15/2022] Open
Abstract
Artificial intelligence (AI) is rapidly becoming an essential tool in the medical field as well as in daily life. Recent developments in deep learning, a subfield of AI, have brought remarkable advances in image recognition, which facilitates improvement in the early detection of cancer by endoscopy, ultrasonography, and computed tomography. In addition, AI-assisted big data analysis represents a great step forward for precision medicine. This review provides an overview of AI technology, particularly for gastroenterology, hepatology, and pancreatology, to help clinicians utilize AI in the near future.
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Affiliation(s)
- Akihiko Oka
- Department of Internal Medicine II, Faculty of Medicine, Shimane University, Izumo 693-8501, Shimane, Japan; (N.I.); (S.I.)
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Abstract
For several decades, cytotoxic chemotherapy was the mainstay of treatment for pancreatic ductal adenocarcinoma (PDAC). Advances in molecular profiling have identified predictive genomic alterations in PDAC-the germline and somatic genome are now routinely interrogated in patients with PDAC because of their therapeutic relevance. The composite role of the epithelial cell compartment and the tumor microenvironment in defining PDAC biology needs further elucidation to deconvolute the spatiotemporal heterogeneity appreciated in this disease. Novel clinical trial approaches leveraging signal seeking, adaptive statistical designs, and master protocols using several candidate drugs that target relevant therapeutic targets are are essential to unlocking the potential of precision medicine in PDAC.
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Affiliation(s)
- Ben George
- Division of Hematology and Oncology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA.
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30
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Pan S, Brand RE, Lai LA, Dawson DW, Donahue TR, Kim S, Khalaf NI, Othman MO, Fisher WE, Bronner MP, Simeone DM, Brentnall TA, Chen R. Proteome heterogeneity and malignancy detection in pancreatic cyst fluids. Clin Transl Med 2021; 11:e506. [PMID: 34459141 PMCID: PMC8382978 DOI: 10.1002/ctm2.506] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 01/12/2023] Open
Affiliation(s)
- Sheng Pan
- The Brown Foundation Institute of Molecular MedicineUniversity of Texas Health Science Center at HoustonHoustonTexasUSA,Department of Integrative Biology and PharmacologyMcGovern Medical SchoolUniversity of Texas Health Science Center at HoustonHoustonTexasUSA
| | - Randall E. Brand
- Department of MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Lisa A. Lai
- Division of GastroenterologyDepartment of Medicinethe University of WashingtonSeattleWashingtonUSA
| | - David W. Dawson
- Department of Pathology and Laboratory MedicineDavid Geffen School of Medicine, UCLALos AngelesCaliforniaUSA,Jonsson Comprehensive Cancer CenterDavid Geffen School of Medicine, UCLALos AngelesCaliforniaUSA
| | - Timothy R. Donahue
- Jonsson Comprehensive Cancer CenterDavid Geffen School of Medicine, UCLALos AngelesCaliforniaUSA,Department of SurgeryDavid Geffen School of Medicine, UCLALos AngelesCaliforniaUSA
| | - Stephen Kim
- Division of Digestive DiseasesDavid Geffen School of Medicine, UCLALos AngelesCaliforniaUSA
| | - Natalia I. Khalaf
- Section of Gastroenterology and HepatologyDepartment of MedicineBaylor College of MedicineHoustonTexasUSA
| | - Mohamed O. Othman
- Section of Gastroenterology and HepatologyDepartment of MedicineBaylor College of MedicineHoustonTexasUSA
| | | | - Mary P. Bronner
- Department of PathologyUniversity of UtahSalt Lake CityUtahUSA
| | - Diane M. Simeone
- Department of SurgeryNew York UniversityNew YorkNew YorkUSA,Perlmutter Cancer CenterNew York UniversityNew YorkNew YorkUSA
| | - Teresa A. Brentnall
- Division of GastroenterologyDepartment of Medicinethe University of WashingtonSeattleWashingtonUSA
| | - Ru Chen
- Section of Gastroenterology and HepatologyDepartment of MedicineBaylor College of MedicineHoustonTexasUSA
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31
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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.
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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
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Abstract
Pancreatic cancer is a genetic disease, and the recurrent genetic alterations characteristic of pancreatic cancer indicate the cellular processes that are targeted for malignant transformation. In addition to somatic alterations in the most common driver genes (KRAS, CDKN2A, TP53 and SMAD4), large-scale studies have revealed major roles for genetic alterations of the SWI/SNF and COMPASS complexes, copy number alterations in GATA6 and MYC that partially define phenotypes of pancreatic cancer, and the role(s) of polyploidy and chromothripsis as factors contributing to pancreatic cancer biology and progression. Germline variants that increase the risk of pancreatic cancer continue to be discovered along with a greater appreciation of the features of pancreatic cancers with mismatch repair deficiencies and homologous recombination deficiencies that confer sensitivity to therapeutic targeting. Wild-type KRAS pancreatic cancers, some of which are driven by alternative oncogenic events affecting NRG1 or NTRK1 - for which targeted therapies exist - further underscore that pancreatic cancer is formally entering the era of precision medicine. Given the vast developments within this field, here we review the wide-ranging and most current information related to pancreatic cancer genomics with the goal of integrating this information into a unifying description of the life history of pancreatic cancer.
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33
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Milan M, Diaferia GR, Natoli G. Tumor cell heterogeneity and its transcriptional bases in pancreatic cancer: a tale of two cell types and their many variants. EMBO J 2021; 40:e107206. [PMID: 33844319 PMCID: PMC8246061 DOI: 10.15252/embj.2020107206] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), one of the most highly lethal tumors, is characterized by complex histology, with a massive fibrotic stroma in which both pseudo-glandular structures and compact nests of abnormally differentiated tumor cells are embedded, in different proportions and with different mutual relationships in space. This complexity and the heterogeneity of the tumor component have hindered the development of a broadly accepted, clinically actionable classification of PDACs, either on a morphological or a molecular basis. Here, we discuss evidence suggesting that such heterogeneity can to a large extent, albeit not exclusively, be traced back to two main classes of PDAC cells that commonly coexist in the same tumor: cells that maintained their ability to differentiate toward endodermal, mucin-producing epithelia and epithelial cells unable to form glandular structures and instead characterized by various levels of squamous differentiation and the expression of mesenchymal lineage genes. The underlying gene regulatory networks and how they are controlled by distinct transcription factors, as well as the practical implications of these two different populations of tumor cells, are discussed.
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Affiliation(s)
- Marta Milan
- Department of Experimental OncologyEuropean Institute of Oncology (IEO) IRCCSMilanItaly
- Present address:
The Francis Crick InstituteLondonUK
| | - Giuseppe R Diaferia
- Department of Experimental OncologyEuropean Institute of Oncology (IEO) IRCCSMilanItaly
| | - Gioacchino Natoli
- Department of Experimental OncologyEuropean Institute of Oncology (IEO) IRCCSMilanItaly
- Humanitas UniversityMilanItaly
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34
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Lodestijn SC, van Neerven SM, Vermeulen L, Bijlsma MF. Stem Cells in the Exocrine Pancreas during Homeostasis, Injury, and Cancer. Cancers (Basel) 2021; 13:cancers13133295. [PMID: 34209288 PMCID: PMC8267661 DOI: 10.3390/cancers13133295] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/16/2021] [Accepted: 06/26/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Pancreatic cancer is one of the most lethal malignancies. Hence, improved therapies are urgently needed. Recent research indicates that pancreatic cancers depend on cancer stem cells (CSCs) for tumor expansion, metastasis, and therapy resistance. However, the exact functionality of pancreatic CSCs is still unclear. CSCs have much in common with normal pancreatic stem cells that have been better, albeit still incompletely, characterized. In this literature review, we address how pancreatic stem cells influence growth, homeostasis, regeneration, and cancer. Furthermore, we outline which intrinsic and extrinsic factors regulate stem cell functionality during these different processes to explore potential novel targets for treating pancreatic cancer. Abstract Cell generation and renewal are essential processes to develop, maintain, and regenerate tissues. New cells can be generated from immature cell types, such as stem-like cells, or originate from more differentiated pre-existing cells that self-renew or transdifferentiate. The adult pancreas is a dormant organ with limited regeneration capacity, which complicates studying these processes. As a result, there is still discussion about the existence of stem cells in the adult pancreas. Interestingly, in contrast to the classical stem cell concept, stem cell properties seem to be plastic, and, in circumstances of injury, differentiated cells can revert back to a more immature cellular state. Importantly, deregulation of the balance between cellular proliferation and differentiation can lead to disease initiation, in particular to cancer formation. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of only ~9%. Unfortunately, metastasis formation often occurs prior to diagnosis, and most tumors are resistant to current treatment strategies. It has been proposed that a specific subpopulation of cells, i.e., cancer stem cells (CSCs), are responsible for tumor expansion, metastasis formation, and therapy resistance. Understanding the underlying mechanisms of pancreatic stem cells during homeostasis and injury might lead to new insights to understand the role of CSCs in PDAC. Therefore, in this review, we present an overview of the current literature regarding the stem cell dynamics in the pancreas during health and disease. Furthermore, we highlight the influence of the tumor microenvironment on the growth behavior of PDAC.
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Affiliation(s)
- Sophie C. Lodestijn
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (S.C.L.); (S.M.v.N.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Sanne M. van Neerven
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (S.C.L.); (S.M.v.N.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (S.C.L.); (S.M.v.N.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Maarten F. Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (S.C.L.); (S.M.v.N.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Correspondence:
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35
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Kothari A, Flick MJ. Coagulation Signaling through PAR1 as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2021; 22:ijms22105138. [PMID: 34066284 PMCID: PMC8152032 DOI: 10.3390/ijms22105138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/05/2021] [Accepted: 05/10/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with a 5-year survival rate of less than 10% following diagnosis. The aggressive and invasive properties of pancreatic cancer tumors coupled with poor diagnostic options contribute to the high mortality rate since most patients present with late-stage disease. Accordingly, PDAC is linked to the highest rate of cancer-associated venous thromboembolic disease of all solid tumor malignancies. However, in addition to promoting clot formation, recent studies suggest that the coagulation system in PDAC mediates a reciprocal relationship, whereby coagulation proteases and receptors promote PDAC tumor progression and dissemination. Here, upregulation of tissue factor (TF) by tumor cells can drive local generation of the central coagulation protease thrombin that promotes cell signaling activity through protease-activated receptors (PARs) expressed by both tumor cells and multiple stromal cell subsets. Moreover, the TF-thrombin-PAR1 signaling axis appears to be a major mechanism of cancer progression in general and PDAC in particular. Here, we summarize the current literature regarding the role of PAR1 in PDAC and review possibilities for pharmacologically targeting PAR1 as a PDAC therapeutic approach.
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36
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Barnholtz-Sloan JS, Rollison DE, Basu A, Borowsky AD, Bui A, DiGiovanna J, Garcia-Closas M, Genkinger JM, Gerke T, Induni M, Lacey JV, Mirel L, Permuth JB, Saltz J, Shenkman EA, Ulrich CM, Zheng WJ, Nadaf S, Kibbe WA. Cancer Informatics for Cancer Centers (CI4CC): Building a Community Focused on Sharing Ideas and Best Practices to Improve Cancer Care and Patient Outcomes. JCO Clin Cancer Inform 2021; 4:108-116. [PMID: 32078367 PMCID: PMC7186581 DOI: 10.1200/cci.19.00166] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Cancer Informatics for Cancer Centers (CI4CC) is a grassroots, nonprofit 501c3 organization intended to provide a focused national forum for engagement of senior cancer informatics leaders, primarily aimed at academic cancer centers anywhere in the world but with a special emphasis on the 70 National Cancer Institute-funded cancer centers. Although each of the participating cancer centers is structured differently, and leaders' titles vary, we know firsthand there are similarities in both the issues we face and the solutions we achieve. As a consortium, we have initiated a dedicated listserv, an open-initiatives program, and targeted biannual face-to-face meetings. These meetings are a place to review our priorities and initiatives, providing a forum for discussion of the strategic and pragmatic issues we, as informatics leaders, individually face at our respective institutions and cancer centers. Here we provide a brief history of the CI4CC organization and meeting highlights from the latest CI4CC meeting that took place in Napa, California from October 14-16, 2019. The focus of this meeting was "intersections between informatics, data science, and population science." We conclude with a discussion on "hot topics" on the horizon for cancer informatics.
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Affiliation(s)
- Jill S Barnholtz-Sloan
- Department of Population and Quantitative Health Science and Cleveland Center for Health Outcomes Research, Case Western Reserve University School of Medicine, and Case Comprehensive Cancer Center, Cleveland, OH
| | - Dana E Rollison
- Division of Quantitative Science, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Amrita Basu
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | - Alexander D Borowsky
- Department of Pathology and Laboratory Medicine, Comprehensive Cancer Center, and Center for Comparative Medicine, University of California Davis, Sacramento, CA
| | - Alex Bui
- Medical and Imaging Informatics, Department of Radiological Sciences, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
| | | | | | - Jeanine M Genkinger
- Department of Epidemiology, Mailman School of Public Health at Columbia University, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY
| | - Travis Gerke
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Marta Induni
- Cancer Registry of Greater California, Sacramento, CA
| | - James V Lacey
- Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA
| | - Lisa Mirel
- National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD
| | - Jennifer B Permuth
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.,Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Joel Saltz
- Department of Biomedical Informatics, Stony Brook Medicine, Stony Brook, NY
| | - Elizabeth A Shenkman
- Department of Health Outcomes and Biomedical Informatics, University of Florida, Gainesville, FL
| | - Cornelia M Ulrich
- Huntsman Cancer Institute and University of Utah, Salt Lake City, UT
| | - W Jim Zheng
- School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX
| | | | - Warren A Kibbe
- Duke University School of Medicine and Duke Comprehensive Cancer Center, Raleigh, NC
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Kane LE, Mellotte GS, Conlon KC, Ryan BM, Maher SG. Multi-Omic Biomarkers as Potential Tools for the Characterisation of Pancreatic Cystic Lesions and Cancer: Innovative Patient Data Integration. Cancers (Basel) 2021; 13:769. [PMID: 33673153 PMCID: PMC7918773 DOI: 10.3390/cancers13040769] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/27/2021] [Accepted: 02/09/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is regarded as one of the most lethal malignant diseases in the world, with GLOBOCAN 2020 estimates indicating that PC was responsible for almost half a million deaths worldwide in 2020. Pancreatic cystic lesions (PCLs) are fluid-filled structures found within or on the surface of the pancreas, which can either be pre-malignant or have no malignant potential. While some PCLs are found in symptomatic patients, nowadays many PCLs are found incidentally in patients undergoing cross-sectional imaging for other reasons-so called 'incidentalomas'. Current methods of characterising PCLs are imperfect and vary hugely between institutions and countries. As such, there is a profound need for improved diagnostic algorithms. This could facilitate more accurate risk stratification of those PCLs that have malignant potential and reduce unnecessary surveillance. As PC continues to have such a poor prognosis, earlier recognition and risk stratification of PCLs may lead to better treatment protocols. This review will focus on the importance of biomarkers in the context of PCLs and PCand outline how current 'omics'-related work could contribute to the identification of a novel integrated biomarker profile for the risk stratification of patients with PCLs and PC.
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Affiliation(s)
- Laura E. Kane
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin D08 W9RT, Ireland;
| | - Gregory S. Mellotte
- Department of Gastroenterology, Tallaght University Hospital, Dublin D24 NR0A, Ireland; (G.S.M.); (B.M.R.)
| | - Kevin C. Conlon
- Discipline of Surgery, School of Medicine, Trinity College Dublin, Dublin D02 PN40, Ireland;
| | - Barbara M. Ryan
- Department of Gastroenterology, Tallaght University Hospital, Dublin D24 NR0A, Ireland; (G.S.M.); (B.M.R.)
| | - Stephen G. Maher
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin D08 W9RT, Ireland;
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Activation of the RAS pathway through uncommon BRAF mutations in mucinous pancreatic cysts without KRAS mutation. Mod Pathol 2021; 34:438-444. [PMID: 32792597 DOI: 10.1038/s41379-020-00647-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023]
Abstract
Diagnostic testing of pancreatic cyst fluid obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has traditionally utilized elevated carcinoembryonic antigen (CEA) (≥192 ng/ml) and cytomorphologic examination to differentiate premalignant mucinous from benign pancreatic cystic lesions (PCLs). Molecular testing for KRAS/GNAS mutations has been shown to improve accuracy of detecting mucinous PCLs. Using a targeted next-generation sequencing (NGS) panel, we assess the status of PCL-associated mutations to improve understanding of the key diagnostic variables. Molecular analysis of cyst fluid was performed on 108 PCLs that had concurrent CEA and/or cytological analysis. A 48-gene NGS assay was utilized, which included genes commonly mutated in mucinous PCLs such as GNAS, KRAS, CDKN2A, and TP53. KRAS and/or GNAS mutations were seen in 59 of 68 (86.8%) cases with multimodality diagnosis of a mucinous PCL. Among 31 patients where surgical histopathology was available, the sensitivity, specificity, and diagnostic accuracy of NGS for the diagnosis of mucinous PCL was 88.5%, 100%, and 90.3%, respectively. Cytology with mucinous/atypical findings were found in only 29 of 62 cases (46.8%), with fluid CEA elevated in 33 of 58 cases (56.9%). Multiple KRAS mutations at different variant allele frequencies were seen in seven cases favoring multiclonal patterns, with six of them showing at least two separate PCLs by imaging. Among the 6 of 10 cases with GNAS + /KRAS- results, uncommon, non-V600E exon 11/15 hotspot BRAF mutations were identified. The expected high degree of accuracy of NGS detection of KRAS and/or GNAS mutations for mucinous-PCLs, as compared with CEA and cytological examination, was demonstrated. Multiple KRAS mutations correlated with multifocal cysts demonstrated by radiology. In IPMNs that lacked KRAS mutations, the concurring BRAF mutations with GNAS mutations supports an alternate mechanism of activation in the Ras pathway.
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39
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Tsuda M, Fukuda A, Kawai M, Araki O, Seno H. The role of the SWI/SNF chromatin remodeling complex in pancreatic ductal adenocarcinoma. Cancer Sci 2021; 112:490-497. [PMID: 33301642 PMCID: PMC7894000 DOI: 10.1111/cas.14768] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 12/22/2022] Open
Abstract
ATP-dependent chromatin remodeling complexes are a group of epigenetic regulators that can alter the assembly of nucleosomes and regulate the accessibility of transcription factors to DNA in order to modulate gene expression. One of these complexes, the SWI/SNF chromatin remodeling complex is mutated in more than 20% of human cancers. We have investigated the roles of the SWI/SNF complex in pancreatic ductal adenocarcinoma (PDA), which is the most lethal type of cancer. Here, we reviewed the recent literature regarding the role of the SWI/SNF complex in pancreatic tumorigenesis and current knowledge about therapeutic strategies targeting the SWI/SNF complex in PDA. The subunits of the SWI/SNF complex are mutated in 14% of human PDA. Recent studies have shown that they have context-dependent oncogenic or tumor-suppressive roles in pancreatic carcinogenesis. To target its tumor-suppressive properties, synthetic lethal strategies have recently been developed. In addition, their oncogenic properties could be novel therapeutic targets. The SWI/SNF subunits are potential therapeutic targets for PDA, and further understanding of the precise role of the SWI/SNF complex subunits in PDA is required for further development of novel strategies targeting SWI/SNF subunits against PDA.
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Affiliation(s)
- Motoyuki Tsuda
- Department of Gastroenterology and HepatologyKyoto University Graduate School of MedicineKyotoJapan
- Department of Gastroenterology and HepatologyKindai University Faculty of MedicineOsaka‐sayama CityJapan
| | - Akihisa Fukuda
- Department of Gastroenterology and HepatologyKyoto University Graduate School of MedicineKyotoJapan
| | - Munenori Kawai
- Department of Gastroenterology and HepatologyKyoto University Graduate School of MedicineKyotoJapan
| | - Osamu Araki
- Department of Gastroenterology and HepatologyKyoto University Graduate School of MedicineKyotoJapan
| | - Hiroshi Seno
- Department of Gastroenterology and HepatologyKyoto University Graduate School of MedicineKyotoJapan
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40
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Pergolini I, Jäger C, Safak O, Göß R, Novotny A, Ceyhan GO, Friess H, Demir IE. Diabetes and Weight Loss Are Associated With Malignancies in Patients With Intraductal Papillary Mucinous Neoplasms. Clin Gastroenterol Hepatol 2021; 19:171-179. [PMID: 32407968 DOI: 10.1016/j.cgh.2020.04.090] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 04/28/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The role of diabetes in intraductal papillary mucinous neoplasms (IPMNs) is not known. We investigated the prevalence of diabetes among patients with resected IPMNs and the association between diabetes, clinical and morphological features, and high-grade dysplasia or invasive cancer. METHODS We collected clinical, pathology, laboratory, and demographic data from 134 patients who underwent pancreatic resection for IPMN from a referral center in Germany. We identified 50 patients with diabetes (37%). RESULTS Higher proportions of patients with diabetes were male and older, but did not have increased body mass index, compared to patients without diabetes. Diabetes was significantly associated with main-duct involvement (odds ratio [OR], 2.827; 95% CI, 1.059-7.546; P = .038) and high-grade dysplasia or invasive carcinoma (OR, 2.692; 95% CI, 1.283-5.651; P = .009). Risk of high-grade dysplasia or invasive cancer was even higher in patients with new-onset or worsening diabetes (OR, 4.615; 95% CI, 1.423-14.698; P = .011). Fifty-eight percent of patients (18/31) with weight loss at diagnosis had diabetes vs 32% of patients (31/97) without weight loss (P = .009). However, when the analysis was restricted to IPMNs with low-grade dysplasia, weight loss and diabetes were no longer associated (42% [5/12] vs 21% [9/44]; P = .133). CONCLUSIONS In patients with IPMNs, diabetes is associated with increased risk of main duct involvement and high-grade dysplasia or invasive carcinoma. Studies are needed to determine the relationship between diabetes and progression of IPMNs, which might lead to strategies for early detection and prevention of invasive cancer. Findings from this study should be considered in the guidelines for management of IPMN.
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Affiliation(s)
- Ilaria Pergolini
- Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Carsten Jäger
- Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Okan Safak
- Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Rüdiger Göß
- Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Alexander Novotny
- Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Güralp O Ceyhan
- Department of General Surgery, HPB-Unit, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Helmut Friess
- Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Munich Germany; Collaborative Research Center (CRC) 1321 Modelling and Targeting Pancreatic Cancer, Munich Germany
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Department of General Surgery, HPB-Unit, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey; German Cancer Consortium (DKTK), Partner Site Munich, Munich Germany; Collaborative Research Center (CRC) 1321 Modelling and Targeting Pancreatic Cancer, Munich Germany.
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41
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Gao HL, Wang WQ, Yu XJ, Liu L. Molecular drivers and cells of origin in pancreatic ductal adenocarcinoma and pancreatic neuroendocrine carcinoma. Exp Hematol Oncol 2020; 9:28. [PMID: 33101770 PMCID: PMC7579802 DOI: 10.1186/s40164-020-00184-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 10/10/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is one of the most common causes of cancer-related deaths worldwide. The two major histological subtypes of pancreatic cancer are pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all cases, and pancreatic neuroendocrine neoplasm (PanNEN), which makes up 3-5% of all cases. PanNEN is classified into well-differentiated pancreatic neuroendocrine tumor and poorly-differentiated pancreatic neuroendocrine carcinoma (PanNEC). Although PDAC and PanNEN are commonly thought to be different diseases with distinct biology, cell of origin, and genomic abnormalities, the idea that PDAC and PanNEC share common cells of origin has been gaining support. This is substantiated by evidence that the molecular profiling of PanNEC is genetically and phenotypically related to PDAC. In the current review, we summarize published studies pointing to common potential cells of origin and speculate about how the distinct paths of differentiation are determined by the genomic patterns of each disease. We also discuss the overlap between PDAC and PanNEC, which has been noted in clinical observations.
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Affiliation(s)
- He-Li Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 20032 People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
- Shanghai Pancreatic Cancer Institute, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 20032 People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
- Shanghai Pancreatic Cancer Institute, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 20032 People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
- Shanghai Pancreatic Cancer Institute, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 20032 People’s Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
- Shanghai Pancreatic Cancer Institute, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
- Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai, 200032 People’s Republic of China
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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.
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Flick KF, Yip-Schneider MT, Sublette CM, Simpson RE, Colgate CL, Wu H, Soufi M, Dewitt JM, Mosley AL, Ceppa EP, Zhang J, Schmidt CM. A Quantitative Global Proteomics Approach Identifies Candidate Urinary Biomarkers That Correlate With Intraductal Papillary Mucinous Neoplasm Dysplasia. Pancreas 2020; 49:1044-1051. [PMID: 32769857 DOI: 10.1097/mpa.0000000000001628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES A proteomic discovery study was performed to determine if urine possesses a unique biosignature that could form the basis for a noninvasive test able to predict intraductal papillary mucinous neoplasm (IPMN) dysplasia. METHODS Urine was collected from patients undergoing surgery for IPMN (72 low/moderate, 27 high-grade/invasive). Quantitative mass spectrometry-based proteomics was performed. Proteins of interest were identified by differential expression analysis followed by principal component analysis. RESULTS Proteomics identified greater than 4800 urinary proteins. Low/moderate and high-grade/invasive IPMN were distinguished by 188 proteins (P < 0.05). Following principal component analysis and heatmap visualization, vitamin D binding protein (DBP), apolipoprotein A1 (APOA1), and alpha-1 antitrypsin (A1AT) were selected. The proteomic abundance of DBP (median [interquartile range]) was significantly higher for high-grade/invasive than for low/moderate IPMN (219,735 [128,882-269,943] vs. 112,295 [77,905-180,773] normalized reporter ion intensity units; P = 0.001). Similarly, APOA1 was more abundant in the high-grade/invasive than low/moderate groups (235,420 [144,933-371,247] vs 150,095 [103,419-236,591]; P = 0.0007) as was A1AT (567,514 [358,544-774,801] vs 358,393 [260,850-477,882]; P = 0.0006). CONCLUSIONS Urinary DBP, APOA1, and A1AT represent potential biomarker candidates that may provide a noninvasive means of predicting IPMN dysplastic grade.
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Affiliation(s)
| | | | | | | | | | | | | | - John M Dewitt
- Division of Gastroenterology, Department of Medicine
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Grossberg AJ, Chu LC, Deig CR, Fishman EK, Hwang WL, Maitra A, Marks DL, Mehta A, Nabavizadeh N, Simeone DM, Weekes CD, Thomas CR. Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. CA Cancer J Clin 2020; 70:375-403. [PMID: 32683683 PMCID: PMC7722002 DOI: 10.3322/caac.21626] [Citation(s) in RCA: 282] [Impact Index Per Article: 56.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/21/2020] [Accepted: 05/26/2020] [Indexed: 12/12/2022] Open
Abstract
Despite tremendous gains in the molecular understanding of exocrine pancreatic cancer, the prognosis for this disease remains very poor, largely because of delayed disease detection and limited effectiveness of systemic therapies. Both incidence rates and mortality rates for pancreatic cancer have increased during the past decade, in contrast to most other solid tumor types. Recent improvements in multimodality care have substantially improved overall survival, local control, and metastasis-free survival for patients who have localized tumors that are amenable to surgical resection. The widening gap in prognosis between patients with resectable and unresectable or metastatic disease reinforces the importance of detecting pancreatic cancer sooner to improve outcomes. Furthermore, the developing use of therapies that target tumor-specific molecular vulnerabilities may offer improved disease control for patients with advanced disease. Finally, the substantial morbidity associated with pancreatic cancer, including wasting, fatigue, and pain, remains an under-addressed component of this disease, which powerfully affects quality of life and limits tolerance to aggressive therapies. In this article, the authors review the current multidisciplinary standards of care in pancreatic cancer with a focus on emerging concepts in pancreatic cancer detection, precision therapy, and survivorship.
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Affiliation(s)
- Aaron J. Grossberg
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR
| | - Linda C. Chu
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Christopher R. Deig
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
| | - Eliot K. Fishman
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD
| | - William L. Hwang
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
- Broad Institute of Harvard and MIT, Cambridge, MA
| | - Anirban Maitra
- Departments of Pathology and Translational Molecular Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Daniel L. Marks
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR
- Department of Pediatrics and Pape Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR
| | - Arnav Mehta
- Broad Institute of Harvard and MIT, Cambridge, MA
- Dana Farber Cancer Institute, Boston, MA
| | - Nima Nabavizadeh
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
| | - Diane M. Simeone
- Departments of Surgery and Pathology, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Colin D. Weekes
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Charles R. Thomas
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
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Hu Y, Guo M. Synthetic lethality strategies: Beyond BRCA1/2 mutations in pancreatic cancer. Cancer Sci 2020; 111:3111-3121. [PMID: 32639661 PMCID: PMC7469842 DOI: 10.1111/cas.14565] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 06/15/2020] [Accepted: 07/02/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer cells are often characterized by abnormalities in DNA damage response including defects in cell cycle checkpoints and/or DNA repair. Synthetic lethality between DNA damage repair (DDR) pathways has provided a paradigm for cancer therapy by targeting DDR. The successful example is that cancer cells with BRCA1/2 mutations are sensitized to poly(adenosine diphosphate [ADP]-ribose)polymerase (PARP) inhibitors. Beyond the narrow scope of defects in the BRCA pathway, "BRCAness" provides more opportunities for synthetic lethality strategy. In human pancreatic cancer, frequent mutations were found in cell cycle and DDR genes, including P16, P73, APC, MLH1, ATM, PALB2, and MGMT. Combined DDR inhibitors and chemotherapeutic agents are under preclinical or clinical trials. Promoter region methylation was found frequently in cell cycle and DDR genes. Epigenetics joins the Knudson's "hit" theory and "BRCAness." Aberrant epigenetic changes in cell cycle or DDR regulators may serve as a new avenue for synthetic lethality strategy in pancreatic cancer.
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Affiliation(s)
- Yunlong Hu
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China.,Henan Key Laboratory for Esophageal Cancer Research, Zhengzhou University, Zhengzhou, China.,State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China
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Vicentini C, Calore F, Nigita G, Fadda P, Simbolo M, Sperandio N, Luchini C, Lawlor RT, Croce CM, Corbo V, Fassan M, Scarpa A. Exosomal miRNA signatures of pancreatic lesions. BMC Gastroenterol 2020; 20:137. [PMID: 32375666 PMCID: PMC7204029 DOI: 10.1186/s12876-020-01287-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 04/29/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Pancreatic and peri-pancreatic neoplasms encompass a variety of histotypes characterized by a heterogeneous prognostic impact. miRNAs are considered efficient candidate biomarkers due to their high stability in tissues and body fluids. We applied Nanostring profiling of circulating exosomal miRNAs to distinct pancreatic lesions in order to establish a source for biomarker development. METHODS A series of 140 plasma samples obtained from patients affected by pancreatic ductal adenocarcinoma (PDAC, n = 58), pancreatic neuroendocrine tumors (PanNET, n = 42), intraductal papillary mucinous neoplasms (IPMN, n = 20), and ampulla of Vater carcinomas (AVC, n = 20) were analyzed. Comprehensive miRNA profiling was performed on plasma-derived exosomes. Relevant miRNAs were validated by qRT-PCR and in situ hybridization (ISH). RESULTS Lesion specific miRNAs were identified through multiple disease comparisons. Selected miRNAs were validated in the plasma by qRT-PCR and at tissue level by ISH. We leveraged the presence of clinical subtypes with each disease cohort to identify miRNAs that are differentially enriched in aggressive phenotypes. CONCLUSIONS This study shows that pancreatic lesions are characterized by specific exosomal-miRNA signatures. We also provide the basis for further explorations in order to better understand the relevance of these signatures in pancreatic neoplasms.
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Affiliation(s)
| | - Federica Calore
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Giovanni Nigita
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Paolo Fadda
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | | | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Rita T Lawlor
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | - Carlo Maria Croce
- Department of Cancer Biology and Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
| | - Vincenzo Corbo
- ARC-NET Research Centre, University of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Matteo Fassan
- ARC-NET Research Centre, University of Verona, Verona, Italy.
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Via Aristide Gabelli 61, 35121, Padua, PD, Italy.
| | - Aldo Scarpa
- ARC-NET Research Centre, University of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
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De Jesus-Acosta A, Narang A, Mauro L, Herman J, Jaffee EM, Laheru DA. Carcinoma of the Pancreas. ABELOFF'S CLINICAL ONCOLOGY 2020:1342-1360.e7. [DOI: 10.1016/b978-0-323-47674-4.00078-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Park D, Shakya R, Koivisto C, Pitarresi JR, Szabolcs M, Kladney R, Hadjis A, Mace TA, Ludwig T. Murine models for familial pancreatic cancer: Histopathology, latency and drug sensitivity among cancers of Palb2, Brca1 and Brca2 mutant mouse strains. PLoS One 2019; 14:e0226714. [PMID: 31877165 PMCID: PMC6932818 DOI: 10.1371/journal.pone.0226714] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
Alterations of the PALB2 tumor suppressor gene have been identified in familial breast, ovarian and pancreatic cancer cases. PALB2 cooperates with BRCA1/2 proteins through physical interaction in initiation of homologous recombination, in maintenance of genome integrity following DNA double-strand breaks. To determine if the role of PALB2 as a linker between BRCA1 and BRCA2 is critical for BRCA1/2-mediated tumor suppression, we generated Palb2 mouse pancreatic cancer models and compared tumor latencies, phenotypes and drug responses with previously generated Brca1/2 pancreatic cancer models. For development of Palb2 pancreatic cancer, we crossed conditional Palb2 null mouse with mice carrying the KrasG12D; p53R270H; Pdx1-Cre (KPC) constructs, and these animals were observed for pancreatic tumor development. Individual deletion of Palb2, Brca1 or Brca2 genes in pancreas per se using Pdx1-Cre was insufficient to cause tumors, but it reduced pancreata size. Concurrent expression of mutant KrasG12D and p53R270H, with tumor suppressor inactivated strains in Palb2-KPC, Brca1-KPC or Brca2-KPC, accelerated pancreatic ductal adenocarcinoma (PDAC) development. Moreover, most Brca1-KPC and some Palb2-KPC animals developed mucinous cystic neoplasms with PDAC, while Brca2-KPC and KPC animals did not. 26% of Palb2-KPC mice developed MCNs in pancreata, which resemble closely the Brca1 deficient tumors. However, the remaining 74% of Palb2-KPC animals developed PDACs without any cysts like Brca2 deficient tumors. In addition, the number of ADM lesions and immune cells infiltrations (CD3+ and F/480+) were significantly increased in Brca1-KPC tumors, but not in Brca2-KPC tumors. Interestingly, the level of ADM lesions and infiltration of CD3+ or F/480+ cells in Palb2-KPC tumors were intermediate between Brca1-KPC and Brca2-KPC tumors. As expected, disruption of Palb2 and Brca1/2 sensitized tumor cells to DNA damaging agents in vitro and in vivo. Altogether, Palb2-KPC PDAC exhibited features observed in both Brca1-KPC and Brca2-KPC tumors, which could be due to its role, as a linker between Brca1 and Brca2.
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Affiliation(s)
- Dongju Park
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Reena Shakya
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Christopher Koivisto
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Jason R Pitarresi
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Matthias Szabolcs
- Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
| | - Raleigh Kladney
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Ashley Hadjis
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Thomas A Mace
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Thomas Ludwig
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
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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.
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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.
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50
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Springer S, Masica DL, Dal Molin M, Douville C, Thoburn CJ, Afsari B, Li L, Cohen JD, Thompson E, Allen PJ, Klimstra DS, Schattner MA, Schmidt CM, Yip-Schneider M, Simpson RE, Fernandez-Del Castillo C, Mino-Kenudson M, Brugge W, Brand RE, Singhi AD, Scarpa A, Lawlor R, Salvia R, Zamboni G, Hong SM, Hwang DW, Jang JY, Kwon W, Swan N, Geoghegan J, Falconi M, Crippa S, Doglioni C, Paulino J, Schulick RD, Edil BH, Park W, Yachida S, Hijioka S, van Hooft J, He J, Weiss MJ, Burkhart R, Makary M, Canto MI, Goggins MG, Ptak J, Dobbyn L, Schaefer J, Sillman N, Popoli M, Klein AP, Tomasetti C, Karchin R, Papadopoulos N, Kinzler KW, Vogelstein B, Wolfgang CL, Hruban RH, Lennon AM. A multimodality test to guide the management of patients with a pancreatic cyst. Sci Transl Med 2019; 11:eaav4772. [PMID: 31316009 PMCID: PMC7859881 DOI: 10.1126/scitranslmed.aav4772] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 01/07/2019] [Accepted: 06/24/2019] [Indexed: 12/12/2022]
Abstract
Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.
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Affiliation(s)
- Simeon Springer
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - David L Masica
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Biomedical Engineering, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD 21287, USA
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Marco Dal Molin
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Christopher Douville
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Biomedical Engineering, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD 21287, USA
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Christopher J Thoburn
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Bahman Afsari
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Lu Li
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Joshua D Cohen
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Biomedical Engineering, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Elizabeth Thompson
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Peter J Allen
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - David S Klimstra
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Mark A Schattner
- Department of Gastroenterology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - C Max Schmidt
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Michele Yip-Schneider
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Rachel E Simpson
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | | | - Mari Mino-Kenudson
- Department of Histopathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - William Brugge
- Department of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Randall E Brand
- Department of Medicine, University of Pittsburgh, Pittsburgh PA 15213, USA
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Aldo Scarpa
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona 37134, Italy
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Rita Lawlor
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona 37134, Italy
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Roberto Salvia
- General and Pancreatic Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Giuseppe Zamboni
- Department of Pathology, Ospedale Sacro Cuore-Don Calabria, Negrar 37024, Italy
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea
| | - Dae Wook Hwang
- Hepatobiliary and Pancreas Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, South Korea
| | - Jin-Young Jang
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Wooil Kwon
- Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Niall Swan
- Department of Histopathology, St. Vincent's University Hospital, Dublin D04 T6F4, Ireland
| | - Justin Geoghegan
- Department of Surgery, St. Vincent's University Hospital, Dublin D04 T6F4, Ireland
| | - Massimo Falconi
- Division of Pancreatic Surgery, Department of Surgery, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Stefano Crippa
- Division of Pancreatic Surgery, Department of Surgery, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Claudio Doglioni
- Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Jorge Paulino
- Department of Surgery, Centro Hepatobiliopancreático e Transplantação, Hospital Curry Cabral, Lisbon 1050-099, Portugal
| | | | - Barish H Edil
- Department of Surgery, University of Colorado, Aurora, CO 80045, USA
| | - Walter Park
- Department of Medicine, Stanford University Medical Center, Palo Alto, CA 94304, USA
| | - Shinichi Yachida
- Department of Hepatobiliary and Pancreatic Surgery, Pathology and Cancer Genomics, National Cancer Center Hospital and National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Susumu Hijioka
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Jeanin van Hooft
- Department of Gastroenterology and Hepatology, Amsterdam Medical Center, Amsterdam 1017 ZX, Netherlands
| | - Jin He
- Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Matthew J Weiss
- Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Richard Burkhart
- Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Martin Makary
- Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Marcia I Canto
- Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Michael G Goggins
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Janine Ptak
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Lisa Dobbyn
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Joy Schaefer
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Natalie Sillman
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Maria Popoli
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Alison P Klein
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Cristian Tomasetti
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA.
- Department of Biostatistics and Bioinformatics, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Rachel Karchin
- Department of Biomedical Engineering, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD 21287, USA
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA.
| | - Nickolas Papadopoulos
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Kenneth W Kinzler
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Bert Vogelstein
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Christopher L Wolfgang
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA.
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Ralph H Hruban
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
| | - Anne Marie Lennon
- Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
- Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA
- Department of Radiology, Johns Hopkins University, Baltimore, MD 21287, USA
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