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Nassar M, Baraka B, Talal AH. Innovative approaches in predicting outcomes for rectal neuroendocrine tumors. World J Gastroenterol 2025; 31:100517. [PMID: 39958439 PMCID: PMC11752703 DOI: 10.3748/wjg.v31.i6.100517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/05/2024] [Accepted: 12/09/2024] [Indexed: 01/10/2025] Open
Abstract
Rectal neuroendocrine neoplasms pose significant challenges due to their varied presentations and prognoses. Traditional prognostic models, while useful, often fall short of accurately predicting clinical outcomes for these patients. This article discusses the development and implications of a novel prognostic tool, the GATIS score, which aims to enhance predictive accuracy and guide treatment strategies more effectively than current methods. Utilizing data from a large cohort and employing sophisticated statistical models, the GATIS score integrates clinical and pathological markers to provide a nuanced assessment of prognosis. We evaluate the potential of this score to transform clinical decision-making processes, its integration into current medical practices, and future directions for its development. The integration of genetic markers and other biomarkers could further refine its predictive power, highlighting the ongoing need for innovation in the management of rectal neuroendocrine neoplasms.
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Affiliation(s)
- Mahmoud Nassar
- Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, Buffalo, NY 14221, United States
- Department of Research, American Society for Inclusion, Diversity, and Equity in Healthcare, Lewes, DE 19958, United States
| | - Bahaaeldin Baraka
- Medical Oncologist, Oncology, Nottingham University Hospitals, City Hospital, Nottingham NG5 1PB, United Kingdom
| | - Andrew H Talal
- Department of Medicine, University at Buffalo, State University of New York, Buffalo, NY 14203, United States
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2
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Ciobanu OA, Herlea V, Milanesi E, Dobre M, Fica S. miRNA profile in pancreatic neuroendocrine tumors: Preliminary results. Sci Prog 2025; 108:368504251326864. [PMID: 40152231 PMCID: PMC11952036 DOI: 10.1177/00368504251326864] [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] [Indexed: 03/29/2025]
Abstract
OBJECTIVE Our understanding of the pathophysiology of pancreatic neuroendocrine tumors (PanNETs) remains incomplete, largely due to their historically underestimated incidence and the perception of these tumors as rare and slow-growing cancers. Additionally, conventional reliance on histological examination alone is gradually being supplemented by the exploration and introduction of molecular biomarkers, such as microRNAs (miRNAs). As miRNAs modulate the expression of multiple genes and pathways involved in the tumorigenesis of PanNETs, these biomarkers hold considerable promise for diagnosis and prognosis applications. In this study, we aimed to identify miRNAs as tissue markers associated with the diagnosis of PanNETs. METHODS We conducted a case-control study including: 7 PanNETs and 19 nontumoral pancreatic tissues obtained from Romanian patients. The samples underwent miRNA profiling via quantitative RT-PCR to assess the expression of 84 miRNAs. Our results were compared with those obtained by reanalyzing a public dataset. Furthermore, we structured our miRNA expression data according to their targeted mRNAs and their roles in signaling pathways. RESULTS Fourteen miRNAs (miR-1, miR-133a-3p, miR-210-3p, miR-7-5p, miR-10a-5p, miR-92b-3p, miR-132-3p, miR-221-3p, miR-29b-3p, miR-107, miR-103a-3p, let-7b-5p, miR-148a-3p, and miR-202-3p) were identified as differentially expressed by comparing PanNETs with pancreatic nontumoral tissues, with six miRNAs (miR-7-5p, miR-92b-3p, miR-29b-3p, miR-107, miR-103a-3p, and miR-148a-3p) also found in the public dataset analyzed. Bioinformatic analysis revealed that the 14 identified miRNAs target 17 genes. Reanalyzing two public gene expression datasets, five of these genes have been found differentially expressed in PanNET compared to controls. CONCLUSIONS Our preliminary results, albeit limited by a small sample size, highlighted a specific miRNA expression pattern able to distinguish tumoral from normal pancreatic tissue. The diagnostic performance of these miRNAs, matching with circulating miRNAs and validated in more homogeneous and large cohorts, could represent a starting point for improving the diagnostic accuracy of PanNETs.
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Affiliation(s)
- Oana A Ciobanu
- Department of Endocrinology and Diabetes, Elias Hospital, Bucharest, Romania
- Department of Endocrinology and Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Vlad Herlea
- Fundeni Clinical Institute, Bucharest, Romania
- Department of Pathological Anatomy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Elena Milanesi
- Victor Babes National Institute of Pathology, Bucharest, Romania
- Department of Cellular, Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Maria Dobre
- Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Simona Fica
- Department of Endocrinology and Diabetes, Elias Hospital, Bucharest, Romania
- Department of Endocrinology and Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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3
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Hoff CO, Manzi J, Ferreira R, Chauhan A, Housein P, Merchant N, Livingstone A, Vianna R, Abreu P. A neuroendocrine biomarker revolution from monoanalyte to multianalyte biomarkers in non-functioning gastro-entero-pancreatic neuroendocrine neoplasms. Crit Rev Oncol Hematol 2024; 203:104460. [PMID: 39153703 DOI: 10.1016/j.critrevonc.2024.104460] [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: 06/12/2023] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/19/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) arise from neuroendocrine cells in a wide variety of organs. One of the most affected disease sites is the gastrointestinal system, which originates the gastro-entero-pancreatic NENs (GEP-NENs), a heterogenous group of malignancies that are rapidly increasing in incidence. These tumors can be functioning, with secretory activity leading to identifiable clinical syndromes, or non-functioning, with no secretory activity but with local symptoms of tumor growth and metastasis. A limitation in biomarkers is a crucial unmet need in non-secretory NEN management, as clinical decision-making is made more difficult by obstacles in tumor classification, prognostic evaluation, assessment of treatment response and surveillance. The objective of this review is to present existing and novel biomarkers for NENs that can function as prognostic factors and monitor disease progression or regression longitudinally, with a special emphasis on innovative research into novel multianalyte biomarkers.
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Affiliation(s)
- Camilla O Hoff
- University of Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, Brazil; Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, USA
| | - Joao Manzi
- University of Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, Brazil
| | - Raphaella Ferreira
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, USA
| | - Aman Chauhan
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Peter Housein
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Nipun Merchant
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Alan Livingstone
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Rodrigo Vianna
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, USA
| | - Phillipe Abreu
- Division of Transplant Surgery, University of Colorado Anschutz Medical Campus, USA.
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4
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Tsoli M, Koumarianou A, Angelousi A, Kaltsas G. Established and novel circulating neuroendocrine tumor biomarkers for diagnostic, predictive and prognostic use. Best Pract Res Clin Endocrinol Metab 2023; 37:101785. [PMID: 37336711 DOI: 10.1016/j.beem.2023.101785] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/21/2023]
Abstract
The management of neuroendocrine tumors (NETs) represents a clinical challenge due to heterogeneity of their clinical behaviour, molecular biology and response to treatment. Over the years, several circulating biomarkers have been developed for the early diagnosis and follow-up of NETs. The specific secretory products of tumors associated with a secretory syndrome (functioning tumors) may be used as diagnostic and/or prognostic biomarkers while the most common non-specific circulating biomarkers, that may be increased in both functioning and non-functioning tumors, are chromogranin A and the neuron specific enolase. However, the diagnostic accuracy as well as the prognostic and predictive value of these biomarkers are limited and novel techniques of multianalyte analysis of regulators of tumor biology have been developed. The NETest has been most extensively studied and proved to be useful in NET diagnosis, early detection of post-operative recurrence and prediction of response to treatment but further investigation establishing higher level of evidence is required for implementation in clinical practice.
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Affiliation(s)
- Marina Tsoli
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Greece.
| | - Anna Koumarianou
- Haematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon Hospital, National and Kapodistrian University of Athens, 12462, Greece
| | - Anna Angelousi
- Unit of Endocrinology, First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Greece
| | - Gregory Kaltsas
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Greece
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Bevere M, Masetto F, Carazzolo ME, Bettega A, Gkountakos A, Scarpa A, Simbolo M. An Overview of Circulating Biomarkers in Neuroendocrine Neoplasms: A Clinical Guide. Diagnostics (Basel) 2023; 13:2820. [PMID: 37685358 PMCID: PMC10486716 DOI: 10.3390/diagnostics13172820] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/14/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of diseases that are characterized by different behavior and clinical manifestations. The diagnosis and management of this group of tumors are challenging due to tumor complexity and lack of precise and widely validated biomarkers. Indeed, the current circulating mono-analyte biomarkers (such as chromogranin A) are ineffective in describing such complex tumors due to their poor sensitivity and specificity. In contrast, multi-analytical circulating biomarkers (including NETest) are emerging as more effective tools to determine the real-time profile of the disease, both in terms of accurate diagnosis and effective treatment. In this review, we will analyze the capabilities and limitations of different circulating biomarkers focusing on three relevant questions: (1) accurate and early diagnosis; (2) monitoring of disease progression and response to therapy; and (3) detection of early relapse.
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Affiliation(s)
- Michele Bevere
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
| | - Francesca Masetto
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
| | - Maria Elena Carazzolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
| | - Alice Bettega
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
| | - Anastasios Gkountakos
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
| | - Aldo Scarpa
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
| | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
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Escobar KM, Vicente-Villardon JL, Villacís Gonzalez RE, Castillo Cordova PH, Sánchez Rodríguez JM, De la Cruz-Velez M, Siteneski A. Neuroendocrine Tumors: An Analysis of Prevalence, Incidence, and Survival in a Hospital-Based Study in Ecuador. Healthcare (Basel) 2022; 10:1569. [PMID: 36011226 PMCID: PMC9408119 DOI: 10.3390/healthcare10081569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/05/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
Neuroendocrine tumors (NETs) represent a heterogeneous malignancy group of neoplasms, with a limited amount of data from Latin America. Thus, this observational study aimed to provide data about the prevalence, incidence, and survival rates for NET in Ecuadorian hospitals. The study was conducted using data from the Society for the Fight Against Cancer (SOLCA). We evaluated patients with NETs (2000−2020) using the HJ-Biplot method and Cox proportional hazards. Annual age-adjusted incidence and limited-duration prevalence in multivariable analyses as well as hazard ratios (HRs) for mortality and survival were obtained. In the years 2000−2020, the age-adjusted incidence rate increased by 9-fold in the stomach and by 7-fold in the breast. The incidence rates were 1.38 per 100,000 persons in the lung and at 1.79 per 100,000 persons in gastroenteropancreatic sites (rectum, stomach, and pancreas). The prevalence increased from 0.0027% in 2000 to 0.0736% in 2019 and 0.0245% in 2020. Overall survival was worse for metastatic NETs (HR, 4.061; 95% CI, 1.932−8.540; p < 0.001) and advanced local NETs (HR, 2.348; 95% CI, 1.007−5.475 p < 0.048) than for localized NETs. In conclusion, the NET incidence increased in the last 20 years and survival decreased over time, especially for metastatic tumors in the pancreas and the nostril.
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Affiliation(s)
- Karime Montes Escobar
- Department of Mathematics and Statistics, Institute of Basic Sciences, Universidad Técnica de Manabí, Portoviejo 130105, Ecuador
- Statistics Department, University of Salamanca, 37007 Salamanca, Spain
| | | | | | | | - Johanna Mabel Sánchez Rodríguez
- Facultad de Medicina, Universidad Laica Eloi Alfaro de Manabí, Manta 130203, Ecuador
- Facultad de Ciencias de la Salud, Universidad Estatal del Sur de Manabi, Jipijapa 130650, Ecuador
| | - Melina De la Cruz-Velez
- Faculty of Health Sciences, Medicine Career, Universidad Técnica de Manabí, Portoviejo 130105, Ecuador
| | - Aline Siteneski
- Research Institute, Universidad Técnica de Manabí, Portoviejo 130105, Ecuador
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7
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Lee L, Ramos-Alvarez I, Jensen RT. Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies. Cancers (Basel) 2022; 14:1250. [PMID: 35267558 PMCID: PMC8909561 DOI: 10.3390/cancers14051250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/08/2022] [Accepted: 02/23/2022] [Indexed: 12/14/2022] Open
Abstract
Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- National Kyushu Cancer Center, Department of Hepato-Biliary-Pancreatology, Fukuoka 811-1395, Japan
| | - Irene Ramos-Alvarez
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
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8
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MicroRNA Profile Alterations in Parathyroid Carcinoma: Latest Updates and Perspectives. Cancers (Basel) 2022; 14:cancers14040876. [PMID: 35205624 PMCID: PMC8869975 DOI: 10.3390/cancers14040876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/02/2022] [Accepted: 02/08/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Despite the considerable development of diagnostic tools, distinguishing between benign and malignant parathyroid tumors poses a significant diagnostic challenge. Epigenetic regulations, including noncoding microRNAs (miRNAs), have recently emerged as a new and promising source of biomarkers. MiRNAs are post-transcriptional regulators of gene expression. These tissue-specific molecules are known to be deregulated between cancer and normal cells. This review delineates changes in miRNA expression in parathyroid carcinoma (PC), advancing our understanding of PC tumorigenesis and emphasizing, at the same time, that miRNAs can be further exploited for diagnostic and therapeutic purposes. Abstract Parathyroid tumors are a genetically heterogenous group with a significant variability in clinical features. Due to a lack of specific signs and symptoms and uncertain histopathological criteria, parathyroid carcinomas (PCs) are challenging to diagnose, both before and after surgery. There is a great interest in searching for accurate molecular biomarkers for early detection, disease monitoring, and clinical management. Due to improvements in molecular pathology, the latest studies have reported that PC tumorigenesis is strongly linked to the epigenetic regulation of gene expression. MicroRNA (miRNA) profiling may serve as a helpful adjunct in distinguishing parathyroid adenoma (PAd) from PC and provide further insight into regulatory pathways involved in PTH release and parathyroid tumorigenesis. So far, only a few studies have attempted to show the miRNA signature for PC, and very few overlaps could be found between these relatively similar studies. A global miRNA downregulation was detected in PC compared with normal glands among differentially expressed miRNAs. This review summarizes changes in miRNA expression in PC and discusses the future research directions in this area.
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Prisciandaro M, Antista M, Raimondi A, Corti F, Morano F, Centonze G, Sabella G, Mangogna A, Randon G, Pagani F, Prinzi N, Niger M, Corallo S, Castiglioni di Caronno E, Massafra M, Bartolomeo MD, de Braud F, Milione M, Pusceddu S. Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective. Front Oncol 2022; 12:780716. [PMID: 35186729 PMCID: PMC8856722 DOI: 10.3389/fonc.2022.780716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 01/10/2022] [Indexed: 11/26/2022] Open
Abstract
Neuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2–G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical–pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.
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Affiliation(s)
- Michele Prisciandaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- *Correspondence: Michele Prisciandaro,
| | - Maria Antista
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandra Raimondi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Corti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Morano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanni Centonze
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giovanna Sabella
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy
| | - Giovanni Randon
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pagani
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Natalie Prinzi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Niger
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Corallo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | - Marco Massafra
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Massimo Milione
- First Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Pusceddu
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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10
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Role of Somatostatin Signalling in Neuroendocrine Tumours. Int J Mol Sci 2022; 23:ijms23031447. [PMID: 35163374 PMCID: PMC8836266 DOI: 10.3390/ijms23031447] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.
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11
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Havasi A, Sur D, Cainap SS, Lungulescu CV, Gavrilas LI, Cainap C, Vlad C, Balacescu O. Current and New Challenges in the Management of Pancreatic Neuroendocrine Tumors: The Role of miRNA-Based Approaches as New Reliable Biomarkers. Int J Mol Sci 2022; 23:1109. [PMID: 35163032 PMCID: PMC8834851 DOI: 10.3390/ijms23031109] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/10/2022] [Accepted: 01/18/2022] [Indexed: 12/17/2022] Open
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are rare tumors; however, their incidence greatly increases with age, and they occur more frequently among the elderly. They represent 5% of all pancreatic tumors, and despite the fact that low-grade tumors often have an indolent evolution, they portend a poor prognosis in an advanced stages and undifferentiated tumors. Additionally, functional pancreatic neuroendocrine tumors greatly impact quality of life due to the various clinical syndromes that result from abnormal hormonal secretion. With limited therapeutic and diagnostic options, patient stratification and selection of optimal therapeutic strategies should be the main focus. Modest improvements in the management of pancreatic neuroendocrine tumors have been achieved in the last years. Therefore, it is imperative to find new biomarkers and therapeutic strategies to improve patient survival and quality of life, limiting the disease burden. MicroRNAs (miRNAs) are small endogenous molecules that modulate the expression of thousands of genes and control numerous critical processes involved in tumor development and progression. New data also suggest the implication of miRNAs in treatment resistance and their potential as prognostic or diagnostic biomarkers and therapeutic targets. In this review, we discusses the current and new challenges in the management of PanNETs, including genetic and epigenetic approaches. Furthermore, we summarize the available data on miRNAs as potential prognostic, predictive, or diagnostic biomarkers and discuss their function as future therapeutic targets.
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Affiliation(s)
- Andrei Havasi
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.C.)
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
- MedEuropa Radiotherapy Center, 410191 Oradea, Romania
| | - Daniel Sur
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.C.)
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
| | - Simona Sorana Cainap
- Department of Mother and Child, Pediatric Cardiology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
| | | | - Laura-Ioana Gavrilas
- Department of Bromatology, Hygiene, Nutrition, University of Medicine and Pharmacy “Iuliu Hatieganu”, 23 Marinescu Street, 400337 Cluj-Napoca, Romania;
| | - Calin Cainap
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania; (A.H.); (C.C.)
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
| | - Catalin Vlad
- Department of Surgery, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34–36, Republicii Street, 400015 Cluj-Napoca, Romania;
- Department of Oncology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8, Victor Babes Street, 400012 Cluj-Napoca, Romania
| | - Ovidiu Balacescu
- 11th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 400015 Cluj-Napoca, Romania;
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta’’, 400015 Cluj-Napoca, Romania
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12
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Ciobanu OA, Martin S, Fica S. Perspectives on the diagnostic, predictive and prognostic markers of neuroendocrine neoplasms (Review). Exp Ther Med 2021; 22:1479. [PMID: 34765020 PMCID: PMC8576627 DOI: 10.3892/etm.2021.10914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors with different types of physiology and prognosis. Therefore, prognostic information, including morphological differentiation, grade, tumor stage and primary location, are invaluable and contribute to the formulation of treatment decisions. Biomarkers that are currently used, including chromogranin A (CgA), serotonin and neuron-specific enolase, are singular parameters that cannot be used to accurately predict variables associated with tumor growth, including proliferation, metabolic rate and metastatic potential. In addition, site-specific biomarkers, such as insulin and gastrin, cannot be applied to all types of NENs. The clinical application of broad-spectrum markers, as it is the case for CgA, remains controversial despite being widely used. Due to limitations of the currently available mono-analyte biomarkers, recent studies were conducted to explore novel parameters for NEN diagnosis, prognosis, therapy stratification and evaluation of treatment response. Identification of prognostic factors for predicting NEN outcome is a critical requirement for the planning of adequate clinical management. Advances in ‘liquid’ biopsies and genomic analysis techniques, including microRNA, circulating tumor DNA or circulating tumor cells and sophisticated biomathematical analysis techniques, such as NETest or molecular image-based biomarkers, are currently under investigation as potentially novel tools for the management of NENs in the future. Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors.
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Affiliation(s)
- Oana Alexandra Ciobanu
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Sorina Martin
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Simona Fica
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
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13
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The Role of miRNA in the Pathophysiology of Neuroendocrine Tumors. Int J Mol Sci 2021; 22:ijms22168569. [PMID: 34445276 PMCID: PMC8395312 DOI: 10.3390/ijms22168569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/16/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022] Open
Abstract
Neuroendocrine tumors (NETs) represent a tumor group that is both rare and heterogeneous. Prognosis is largely determined by the tumor grading and the site of the primary tumor and metastases. Despite intensive research efforts, only modest advances in diagnostic and therapeutic approaches have been achieved in recent years. For patients with non-respectable tumor stages, prognosis is poor. In this context, the development of novel diagnostic tools for early detection of NETs and prediction of tumor response to therapy as well as estimation of the overall prognosis would greatly improve the clinical management of NETs. However, identification of novel diagnostic molecules is hampered by an inadequate understanding of the pathophysiology of neuroendocrine malignancies. It has recently been demonstrated that microRNA (miRNA), a family of small RNA molecules with an established role in the pathophysiology of quite different cancer entities, may also play a role as a biomarker. Here, we summarize the available knowledge on the role of miRNAs in the development of NET and highlight their potential use as serum-based biomarkers in the context of this disease. We discuss important challenges currently preventing their use in clinical routine and give an outlook on future directions of miRNA research in NET.
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14
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MiRNA Expression in Neuroendocrine Neoplasms of Frequent Localizations. Noncoding RNA 2021; 7:ncrna7030038. [PMID: 34202122 PMCID: PMC8293323 DOI: 10.3390/ncrna7030038] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine neoplasms (NEN) are infrequent malignant tumors of a neuroendocrine nature that arise in various organs. They occur most frequently in the lungs, intestines, stomach and pancreas. Molecular diagnostics and prognosis of NEN development are highly relevant. The role of clinical biomarkers can be played by microRNAs (miRNAs). This work is devoted to the analysis of data on miRNA expression in NENs. For the first time, a search for specificity or a community of their functional characteristics in different types of NEN was carried out. Their properties as biomarkers were also analyzed. To date, more than 100 miRNAs have been characterized as differentially expressed and significant for the development of NEN tumors. Only about 10% of the studied miRNAs are expressed in several types of NEN; differential expression of the remaining 90% was found only in tumors of specific localizations. A significant number of miRNAs have been identified as potential biomarkers. However, only a few miRNAs have values that characterized their quality as markers. The analysis demonstrates the predominant specific expression of miRNA in each studied type of NEN. This indicates that miRNA’s functional features are predominantly influenced by the tissue in which they are formed.
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15
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Tarquini M, Ambrosio MR, Albertelli M, de Souza PB, Gafà R, Gagliardi I, Carnevale A, Franceschetti P, Zatelli MC. A tool to predict survival in stage IV entero-pancreatic NEN. J Endocrinol Invest 2021; 44:1185-1192. [PMID: 32892316 PMCID: PMC8124053 DOI: 10.1007/s40618-020-01404-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 08/22/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Well-differentiated stage IV neuroendocrine neoplasms (NEN) have an extremely heterogeneous, unpredictable clinical behavior. Survival prognostic markers, such as the recently proposed NEP-Score, would be very useful for better defining therapeutic strategies. We aim to verify NEP-Score applicability in an independent cohort of stage IV well-differentiated (WD) gastroentero-pancreatic (GEP) NEN, and identify a derivate prognostic marker taking into account clinical and pathological characteristics at diagnosis. METHODS Age, site of primary tumor, primary tumor surgery, symptoms, Ki67, timing of metastases of 27 patients (10 females; mean age at diagnosis 60.2 ± 2.9 years) with stage IV WD GEP NEN were evaluated to calculate the NEP-Score at the end of follow-up (NEP-T). We calculated the NEP-Score at diagnosis (NEP-D), which does not consider the appearance of new metastases during follow-up. Patients were subdivided according to whether they were alive or not at the end of follow-up (EOF) and an NEP-Score threshold was investigated to predict survival. RESULTS Mean NEP-T and mean NEP-D were significantly lower in 15 live patients as compared to 12 deceased patients (p < 0.01) at EOF. We identified an NEP-D = 116 as the cutoff that significantly predicts survival. No gender differences were identified. CONCLUSIONS In our series, we confirmed NEP-Score applicability. In addition, we propose NEP-D as a simple, quick and cheap prognostic score that can help clinicians in decision making. NEP-D threshold can predict NEN aggressiveness and may be used to define the best personalized therapeutic strategy.
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Affiliation(s)
- M Tarquini
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Via Ariosto 35, 44100, Ferrara, Italy
| | - M R Ambrosio
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Via Ariosto 35, 44100, Ferrara, Italy
- Endocrine Unit, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, Cona, 44124, Ferrara, Italy
| | - M Albertelli
- Endocrinology, Department of Internal Medicine DiMI, University of Genova, Genoa, Italy
| | - P B de Souza
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Via Ariosto 35, 44100, Ferrara, Italy
| | - R Gafà
- Pathology Unit, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - I Gagliardi
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Via Ariosto 35, 44100, Ferrara, Italy
| | - A Carnevale
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - P Franceschetti
- Endocrine Unit, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, Cona, 44124, Ferrara, Italy
| | - M C Zatelli
- Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Via Ariosto 35, 44100, Ferrara, Italy.
- Endocrine Unit, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, Cona, 44124, Ferrara, Italy.
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16
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Essential Role of the 14q32 Encoded miRNAs in Endocrine Tumors. Genes (Basel) 2021; 12:genes12050698. [PMID: 34066712 PMCID: PMC8151414 DOI: 10.3390/genes12050698] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The 14q32 cluster is among the largest polycistronic miRNA clusters. miRNAs encoded here have been implicated in tumorigenesis of multiple organs including endocrine glands. METHODS Critical review of miRNA studies performed in endocrine tumors have been performed. The potential relevance of 14q32 miRNAs through investigating their targets, and integrating the knowledge provided by literature data and bioinformatics predictions have been indicated. RESULTS Pituitary adenoma, papillary thyroid cancer and a particular subset of pheochromocytoma and adrenocortical cancer are characterized by the downregulation of miRNAs encoded by the 14q32 cluster. Pancreas neuroendocrine tumors, most of the adrenocortical cancer and medullary thyroid cancer are particularly distinct, as 14q32 miRNAs were overexpressed. In pheochromocytoma and growth-hormone producing pituitary adenoma, however, both increased and decreased expression of 14q32 miRNAs cluster members were observed. In the background of this phenomenon methodological, technical and biological factors are hypothesized and discussed. The functions of 14q32 miRNAs were also revealed by bioinformatics and literature data mining. CONCLUSIONS 14q32 miRNAs have a significant role in the tumorigenesis of endocrine organs. Regarding their stable expression in the circulation of healthy individuals, further investigation of 14q32 miRNAs could provide a potential for use as biomarkers (diagnostic or prognostic) in endocrine neoplasms.
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17
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Rindi G, Wiedenmann B. Neuroendocrine neoplasia of the gastrointestinal tract revisited: towards precision medicine. Nat Rev Endocrinol 2020; 16:590-607. [PMID: 32839579 DOI: 10.1038/s41574-020-0391-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2020] [Indexed: 02/06/2023]
Abstract
Over the past 5 years, a number of notable research advances have been made in the field of neuroendocrine cancer, specifically with regard to neuroendocrine cancer of the gastrointestinal tract. The aim of this Review is to provide an update on current knowledge that has proven effective for the clinical management of patients with these tumours. For example, for the first time in the tubular gastrointestinal tract, well-differentiated high-grade (grade 3) tumours and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are defined in the WHO classification. This novel classification enables efficient identification of the most aggressive well-differentiated neuroendocrine tumours and helps in defining the degree of aggressiveness of MiNENs. The Review also discusses updates to epidemiology, cell biology (including vesicle-specific components) and the as-yet-unresolved complex genetic background that varies according to site and differentiation status. The Review summarizes novel diagnostic instruments, including molecules associated with the secretory machinery, novel radiological approaches (including pattern recognition techniques), novel PET tracers and liquid biopsy combined with DNA or RNA assays. Surgery remains the treatment mainstay; however, peptide receptor radionuclide therapy with novel radioligands and new emerging medical therapies (including vaccination and immunotherapy) are evolving and being tested in clinical trials, which are summarized and critically reviewed here.
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Affiliation(s)
- Guido Rindi
- Università Cattolica del Sacro Cuore, Rome, Italy.
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
| | - Bertram Wiedenmann
- Charité, Campus Virchow Klinikum and Charité Mitte, University Medicine Berlin, Berlin, Germany
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18
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Kövesdi A, Kurucz PA, Nyírő G, Darvasi O, Patócs A, Butz H. Circulating miRNA Increases the Diagnostic Accuracy of Chromogranin A in Metastatic Pancreatic Neuroendocrine Tumors. Cancers (Basel) 2020; 12:cancers12092488. [PMID: 32887459 PMCID: PMC7565801 DOI: 10.3390/cancers12092488] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/24/2020] [Accepted: 08/27/2020] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Despite its varying sensitivity and decreased specificity, chromogranin A (CgA) is the most widely used biomarker for neuroendocrine tumors. The most common factor affecting its diagnostic accuracy is the use of proton pump inhibitors (PPIs). Our aim was to investigate circulating miRNA expression profiles in pancreatic neuroendocrine tumors (pNET) and pheochromocytomas/paragangliomas (PPGL) to find miRNAs which could be used as biomarkers along with CgA in these patients. MiRNA expression profiles were determined with next generation sequencing and validated by quantitative real time PCR in 74 samples obtained from patients and healthy volunteers treated with PPI. We observed a global downregulation of miRNAs in NET compared to controls. A set of miRNAs in combination with CgA resulted in the best discrimination of pNET irrespective of PPI treatment and a combination of miRNAs increased the diagnostic utility of CgA even in pNET patients with low CgA. Abstract Chromogranin A (CgA) is the most widely accepted biomarker for neuroendocrine tumors (NET) but its diagnostic accuracy is dependent on tumor type and the use of proton-pump inhibitors (PPI). We investigated the diagnostic value of circulating miRNAs along with CgA in pancreatic neuroendocrine tumors (pNET). 74 serum samples from patients with pNET (n = 25, nonfunctioning), pheochromocytoma/paraganglioma (PPGL, n = 20), healthy individuals with normal CgA (n = 29) including 10 samples from 5 healthy individuals with and without current PPI treatment were collected. MiRNA expression profiles were determined using next-generation sequencing, followed by validation with individual TaqMan assays. A global downregulation of miRNAs was observed in patients with NET compared to controls. MiRNA expression of 33 miRNAs was able to discriminate tumor samples from controls. No miRNA alone could be considered as an applicable biomarker for pNET or PPGL. However, using a logistic model, the combination of a set of miRNAs increased the discriminatory role of CgA irrespective of PPI treatment. In pNET patients with normal CgA level our regression model yielded high (89.4%) diagnostic accuracy (AUC: 0.904, sensitivity: 66.6%, specificity: 96.5%). A set of miRNAs increased the diagnostic utility of CgA in pNET even in patients with low CgA.
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Affiliation(s)
- Annamária Kövesdi
- 2nd Department of Internal Medicine, Semmelweis University, 1088 Budapest, Hungary;
| | - Petra Anna Kurucz
- Department of Laboratory Medicine, Semmelweis University, 1089 Budapest, Hungary; (P.A.K.); (H.B.)
| | - Gábor Nyírő
- Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, 1088 Budapest, Hungary;
| | - Ottó Darvasi
- Hereditary Tumours Research Group, Hungarian Academy of Sciences and Semmelweis University, 1089 Budapest, Hungary;
| | - Attila Patócs
- Department of Laboratory Medicine, Semmelweis University, 1089 Budapest, Hungary; (P.A.K.); (H.B.)
- Hereditary Tumours Research Group, Hungarian Academy of Sciences and Semmelweis University, 1089 Budapest, Hungary;
- Department of Molecular Genetics, National Institute of Oncology, 1122 Budapest, Hungary
- Correspondence:
| | - Henriett Butz
- Department of Laboratory Medicine, Semmelweis University, 1089 Budapest, Hungary; (P.A.K.); (H.B.)
- Hereditary Tumours Research Group, Hungarian Academy of Sciences and Semmelweis University, 1089 Budapest, Hungary;
- Department of Molecular Genetics, National Institute of Oncology, 1122 Budapest, Hungary
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[Gastroenteropancreatic neuroendocrine neoplasms-Heterogeneity, management and perspectives of treatment and research]. Internist (Berl) 2020; 61:875-890. [PMID: 32676723 DOI: 10.1007/s00108-020-00832-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The term neuroendocrine neoplasms (NEN) encompasses a molecularly and biologically very heterogeneous group of tumors, which have in common their origin in neuroendocrine cells. The also very heterogeneous subgroup of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is the best classified and investigated group. This article provides a systematic review of the current classification, diagnostics and treatment options of GEP-NEN. In order to achieve a better overview, it was consciously decided not to use an approach based on the primary localization. Instead, a thematic organization according to classification, clinical phenotype, diagnostics and treatment was chosen.
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20
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Survival in Patients with Neuroendocrine Tumours of the Small Intestine: Nomogram Validation and Predictors of Survival. J Clin Med 2020; 9:jcm9082502. [PMID: 32756529 PMCID: PMC7464451 DOI: 10.3390/jcm9082502] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/24/2020] [Accepted: 07/29/2020] [Indexed: 02/07/2023] Open
Abstract
Neuroendocrine tumours of the small intestine (SI-NETs) are rare and heterogeneous. There is an unmet need for prognostication of disease course and to aid treatment strategies. A previously developed nomogram based on clinical and tumour characteristics aims to predict disease-specific survival (DSS) in patients with a SI-NET. We aimed to validate the nomogram and identify predictors of survival. Four hundred patients with a grade 1 or 2 SI-NET were included, between January 2000 and June 2016. Predicted 5- and 10-year survival was compared to actual DSS. Multivariable analysis identified predictors for actual DSS. We found that in low-, medium- and high-risk groups 5-year nomogram DSS vs. actual DSS was 0.86 vs. 0.82 (p < 0.001), 0.52 vs. 0.71 (p < 0.001) and 0.26 vs. 0.53 (p < 0.001), respectively. Ten-year nomogram DSS vs. actual DSS was 0.68 vs. 0.69 (p < 0.001), 0.40 vs. 0.50 (p < 0.001) and 0.20 vs. 0.35 (p < 0.001), respectively. Age, WHO-performance score of 2, Ki-67 index ≥10, unknown primary tumour, CgA > 6x ULN and elevated liver tests were identified as independent predictors for a worse DSS. This shows that the nomogram was able to differentiate, but underestimated DSS for patients with a SI-NET. Improvement of prognostication incorporating new emerging biomarkers is necessary to adequately estimate survival.
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Bocchini M, Nicolini F, Severi S, Bongiovanni A, Ibrahim T, Simonetti G, Grassi I, Mazza M. Biomarkers for Pancreatic Neuroendocrine Neoplasms (PanNENs) Management-An Updated Review. Front Oncol 2020; 10:831. [PMID: 32537434 PMCID: PMC7267066 DOI: 10.3389/fonc.2020.00831] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 04/28/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic neuroendocrine tumors (PanNENs) are rare sporadic cancers or develop as part of hereditary syndromes. PanNENs can be both functioning and non-functioning based on whether they produce bioactive peptides. Some PanNENs are well differentiated while others-poorly. Symptoms, thus, depend on both oncological and hormonal causes. PanNEN diagnosis and treatment benefit from and in some instances are guided by biomarker monitoring. However, plasmatic monoanalytes are only suggestive of PanNEN pathological status and their positivity is typically followed by deepen diagnostic analyses through imaging techniques. There is a strong need for new biomarkers and follow-up modalities aimed to improve the outcome of PanNEN patients. Liquid biopsy follow-up, i.e., sequential analysis on tumor biomarkers in body fluids offers a great potential, that need to be substantiated by additional studies focusing on the specific markers and the timing of the analyses. This review provides the most updated panorama on PanNEN biomarkers.
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Affiliation(s)
- Martine Bocchini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Fabio Nicolini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Stefano Severi
- Nuclear Medicine and Radiometabolic Units, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alberto Bongiovanni
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giorgia Simonetti
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Ilaria Grassi
- Nuclear Medicine and Radiometabolic Units, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Massimiliano Mazza
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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22
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Bone Metabolism and Vitamin D Implication in Gastroenteropancreatic Neuroendocrine Tumors. Nutrients 2020; 12:nu12041021. [PMID: 32276412 PMCID: PMC7230756 DOI: 10.3390/nu12041021] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/30/2020] [Accepted: 04/03/2020] [Indexed: 12/11/2022] Open
Abstract
Patients affected by gastroenteropancreatic–neuroendocrine tumors (GEP–NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP–NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP–NET, focusing on vitamin D and its role in GEP–NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis.
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23
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A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1. Cancers (Basel) 2020; 12:cancers12030691. [PMID: 32183367 PMCID: PMC7140066 DOI: 10.3390/cancers12030691] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/04/2020] [Accepted: 03/12/2020] [Indexed: 02/08/2023] Open
Abstract
Experimental models of neuroendocrine tumor disease are scarce, with only a few existing neuroendocrine tumor cell lines of pancreatic origin (panNET). Their molecular characterization has so far focused on the neuroendocrine phenotype and cancer-related mutations, while a transcription-based assessment of their developmental origin and malignant potential is lacking. In this study, we performed immunoblotting and qPCR analysis of neuroendocrine, epithelial, developmental endocrine-related genes as well as next-generation sequencing (NGS) analysis of microRNAs (miRs) on three panNET cell lines, BON-1, QGP-1, and NT-3. All three lines displayed a neuroendocrine and epithelial phenotype; however, while insulinoma-derived NT-3 cells preferentially expressed markers of mature functional pancreatic β-cells (i.e., INS, MAFA), both BON-1 and QGP-1 displayed high expression of genes associated with immature or non-functional β/δ-cells genes (i.e., NEUROG3), or pancreatic endocrine progenitors (i.e., FOXA2). NGS-based identification of miRs in BON-1 and QGP-1 cells revealed the presence of all six members of the miR-17–92 cluster, which have been implicated in β-cell function and differentiation, but also have roles in cancer being both oncogenic or tumor suppressive. Notably, both BON-1 and QGP-1 cells expressed several miRs known to be negatively associated with epithelial–mesenchymal transition, invasion or metastasis. Moreover, both cell lines failed to exhibit migratory activity in vitro. Taken together, NT-3 cells resemble mature functional β-cells, while both BON-1 and QGP-1 are more similar to immature/non-functional pancreatic β/δ-cells or pancreatic endocrine progenitors. Based on the recent identification of three transcriptional subtypes in panNETs, NT-3 cells resemble the “islet/insulinoma tumors” (IT) subtype, while BON-1 and QGP-1 cells were tentatively classified as “metastasis-like/primary” (MLP). Our results provide a comprehensive characterization of three panNET cell lines and demonstrate their relevance as neuroendocrine tumor models.
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Gagliardi I, Tarquini M, Ambrosio MR, Giannetta E, Borges de Souza P, Gafà R, Carnevale A, Franceschetti P, Zatelli MC. NEP-Score Thresholds Predict Survival of Patients With Bronchial Carcinoids. Front Endocrinol (Lausanne) 2020; 11:621557. [PMID: 33628200 PMCID: PMC7897663 DOI: 10.3389/fendo.2020.621557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/17/2020] [Indexed: 01/19/2023] Open
Abstract
Survival prognostic markers are extremely needed to better define therapeutic strategies in patients with bronchial carcinoids (BC). We aim to verify the applicability of the NEP-Score in a homogeneous BC cohort and identify a derivative prognostic marker, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up. Sixty-four patients (38 females, and 26 males, mean age at diagnosis 58.9 ± 1.7 years) with BC were retrospectively evaluated. NEP-Score was calculated at the end of follow-up (NEP-T). A derivative score, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up, was then assessed. Patients were subdivided according to their living status at the end of follow-up. A NEP-Score threshold was investigated to predict survival. Mean NEP-T and mean NEP-D were significantly lower in live patients at end of follow-up. A NEP-T cut-off >138 significantly predicts survival. Atypical BC relapsed more frequently than Typical BC. Male gender and previous malignancy were negative prognostic factors for survival. We confirmed NEP-Score applicability in BC and NEP-D utility, being the latter a simple, quick, and cheap prognostic score that can help clinicians in decision making. The identified NEP-D threshold can predict NEN aggressiveness and may be used to define the best personalized therapeutic strategy. In this context, a validation study is needed.
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Affiliation(s)
- Irene Gagliardi
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Mario Tarquini
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Maria Rosaria Ambrosio
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Endocrine Unit, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
| | - Elisa Giannetta
- Section of Medical Physiopathology, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Patricia Borges de Souza
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Roberta Gafà
- Pathology Unit, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Aldo Carnevale
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Paola Franceschetti
- Endocrine Unit, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
| | - Maria Chiara Zatelli
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- Endocrine Unit, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
- *Correspondence: Maria Chiara Zatelli,
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Lee L, Ito T, Jensen RT. Prognostic and predictive factors on overall survival and surgical outcomes in pancreatic neuroendocrine tumors: recent advances and controversies. Expert Rev Anticancer Ther 2019; 19:1029-1050. [PMID: 31738624 PMCID: PMC6923565 DOI: 10.1080/14737140.2019.1693893] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023]
Abstract
Introduction: Recent advances in diagnostic modalities and therapeutic agents have raised the importance of prognostic factors in predicting overall survival, as well as predictive factors for surgical outcomes, in tailoring therapeutic strategies of patients with pancreatic neuroendocrine neoplasms (panNENs).Areas covered: Numerous recent studies of panNEN patients report the prognostic values of a number of clinically related factors (clinical, laboratory, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors on long-term survival. In addition, an increasing number of studies showed the usefulness of various factors, specifically biomarkers and molecular makers, in predicting recurrence and mortality related to surgical treatment. Recent findings (from the last 3 years) in each of these areas, as well as recent controversies, are reviewed.Expert commentary: The clinical importance of prognostic and predictive factors for panNENs is markedly increased for both overall outcome and post resection, as a result of recent advances in all aspects of the diagnosis, management and treatment of panNENs. Despite the proven prognostic utility of routinely used tumor grading/classification and staging systems, further studies are required to establish these novel prognostic factors to support their routine clinical use.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD, 20892-1804, USA
- Department of Hepato-Biliary-Pancreatology, National Kyushu Cancer Center, Fukuoka, 811-1395, Japan
| | - Tetsuhide Ito
- Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital, International University of Health and Welfare, Fukuoka, 814-0001, Japan
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD, 20892-1804, USA
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Zhao X, Li Y, Zhou Y. MicroRNA-96-3p promotes metastasis of papillary thyroid cancer through targeting SDHB. Cancer Cell Int 2019; 19:287. [PMID: 31749660 PMCID: PMC6852711 DOI: 10.1186/s12935-019-1003-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 10/25/2019] [Indexed: 12/27/2022] Open
Abstract
Background MicroRNA (MiRNA) is a small non-coding RNA which is implicated in a cohort of biological function in cancer, including proliferation, metastasis, apoptosis and invasion. MiR-96 has been reported to be involved in many cancers, including papillary thyroid cancer. However, the role of miR-96-3p in papillary thyroid cancer metastasis is still unclear. Methods qRT-PCR is used to detect the level of miR-96-3p and mRNA of SDHB in PTC tissues and cell lines. Western blot assays are used to verify the protein expression of SDHB. The transwell assays are performed to identify the migration ability of PTC cell lines. Moreover, dual-luciferase 3'-UTR reporter assays are chosen to illuminate the direct target of miR-96-3p. Results The relative miR-96-3p upregulate in PTC tissues and three PTC cell lines (B-CPAP, K-1 and TPC-1 cells) while the relative SDHB is opposite. Our results revealed that the miR-96-3p promotes metastasis and invasion in PTC cell lines (K-1 and TPC-1 cells) by direct targeting SDHB and influence the downstream protein AKT. Conclusions Taken together, the miR-96-3p is involved in PTC metastasis and invasion by direct targeting SDHB and the downstream molecule AKT and mTOR.
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Affiliation(s)
- Xupeng Zhao
- 1Department of Fourth General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032 China
| | - Yingjie Li
- 2Department of Sixth General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032 China
| | - Yong Zhou
- 1Department of Fourth General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032 China
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Jin KT, Chen XY, Lan HR, Wang SB, Ying XJ, Abdi SM, Wang W, Hu ZM, Mou XZ. Current progress in the clinical use of circulating tumor cells as prognostic biomarkers. Cancer Cytopathol 2019; 127:739-749. [PMID: 31589381 DOI: 10.1002/cncy.22189] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/11/2022]
Abstract
The process of metastasis is characterized by the shedding of tumor cells into the bloodstream, where they are transported to other parts of the body to seed new tumors. These cells, known as circulating tumor cells (CTCs), have the potential to reveal much about an individual cancer case, and theoretically can aid in the prediction of outcomes and design of precision treatments. Recent advances in technology now allow for the robust and reproducible characterization of CTCs from a simple blood draw. Both the number of circulating cells and important molecular characteristics correlated with clinical phenotypes such as drug resistance can be obtained and used for real-time prognostic analysis. Molecular characterization can provide a snapshot of the activity of the main tumor (serving as a "liquid biopsy") and early warnings concerning changes such as the development of resistance, and aid in predicting the efficacy of different therapeutic approaches for treatment optimization. Herein, the authors review the current clinical use of CTCs as prognostic biomarkers for several different cancers. The quantification of CTCs can lead to more accurate staging and decision making regarding options such as adjuvant chemotherapy.
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Affiliation(s)
- Ke-Tao Jin
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Xiao-Yi Chen
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Shi-Bing Wang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xiao-Jiang Ying
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Siyad Mohamed Abdi
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Wei Wang
- Department of Colorectal Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Zhi-Ming Hu
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Xiao-Zhou Mou
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
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Altieri B, Di Dato C, Martini C, Sciammarella C, Di Sarno A, Colao A, Faggiano A. Bone Metastases in Neuroendocrine Neoplasms: From Pathogenesis to Clinical Management. Cancers (Basel) 2019; 11:cancers11091332. [PMID: 31500357 PMCID: PMC6770134 DOI: 10.3390/cancers11091332] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/28/2019] [Accepted: 09/05/2019] [Indexed: 12/20/2022] Open
Abstract
Bone represents a common site of metastases for several solid tumors. However, the ability of neuroendocrine neoplasms (NENs) to localize to bone has always been considered a rare and late event. Thanks to the improvement of therapeutic options, which results in longer survival, and of imaging techniques, particularly after the introduction of positron emission tomography (PET) with gallium peptides, the diagnosis of bone metastases (BMs) in NENs is increasing. The onset of BMs can be associated with severe skeletal complications that impair the patient’s quality of life. Moreover, BMs negatively affect the prognosis of NEN patients, bringing out the lack of curative treatment options for advanced NENs. The current knowledge on BMs in gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) NENs is still scant and is derived from a few retrospective studies and case reports. This review aims to perform a critical analysis of the evidence regarding the role of BMs in GEP- and BP-NENs, focusing on the molecular mechanisms underlining the development of BMs, as well as clinical presentation, diagnosis, and treatment of BMs, in an attempt to provide suggestions that can be used in clinical practice.
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Affiliation(s)
- Barbara Altieri
- Department of Clinical Medicine and Surgery, Federico II University, 80131 Naples, Italy.
- Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Wuerzburg, 97080 Wuerzburg, Germany.
| | - Carla Di Dato
- Department of Clinical Medicine, Bufalini Hospital, 47521 Cesena, Italy.
| | - Chiara Martini
- Clinica Medica 3, Department of Medicine, DIMED, University of Padova, 35128 Padova, Italy.
| | - Concetta Sciammarella
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37126 Verona, Italy.
| | | | - Annamaria Colao
- Department of Clinical Medicine and Surgery, Federico II University, 80131 Naples, Italy.
| | - Antongiulio Faggiano
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
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Herrera-Martínez AD, Hofland LJ, Gálvez Moreno MA, Castaño JP, de Herder WW, Feelders RA. Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers. Endocr Relat Cancer 2019; 26:R157-R179. [PMID: 30615596 DOI: 10.1530/erc-18-0354] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 01/03/2019] [Indexed: 12/13/2022]
Abstract
Some biomarkers for functioning and non-functioning neuroendocrine neoplasms (NENs) are currently available. Despite their application in clinical practice, results should be interpreted cautiously. Considering the variable sensitivity and specificity of these parameters, there is an unmet need for novel biomarkers to improve diagnosis and predict patient outcome. Nowadays, several new biomarkers are being evaluated and may become future tools for the management of NENs. These biomarkers include (1) peptides and growth factors; (2) DNA and RNA markers based on genomics analysis, for example, the so-called NET test, which has been developed for analyzing gene transcripts in circulating blood; (3) circulating tumor/endothelial/progenitor cells or cell-free tumor DNA, which represent minimally invasive methods that would provide additional information for monitoring treatment response and (4) improved imaging techniques with novel radiolabeled somatostatin analogs or peptides. Below we summarize some future directions in the development of novel diagnostic and predictive/prognostic biomarkers in NENs. This review is focused on circulating and selected tissue markers.
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Affiliation(s)
- Aura D Herrera-Martínez
- Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC); Reina Sofia University Hospital, Córdoba, Spain
| | - Leo J Hofland
- Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - María A Gálvez Moreno
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC); Reina Sofia University Hospital, Córdoba, Spain
| | - Justo P Castaño
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC); Reina Sofia University Hospital, Córdoba, Spain
| | - Wouter W de Herder
- Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Richard A Feelders
- Division of Endocrinology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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Prognostic and predictive biomarkers for somatostatin analogs, peptide receptor radionuclide therapy and serotonin pathway targets in neuroendocrine tumours. Cancer Treat Rev 2018; 70:209-222. [PMID: 30292979 DOI: 10.1016/j.ctrv.2018.09.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/21/2018] [Accepted: 09/25/2018] [Indexed: 12/28/2022]
Abstract
Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms regarding their molecular biology, clinical behaviour, prognosis and response to therapy. Several attempts to establish robust predictive biomarkers have failed. Neither tissue markers nor blood borne ones have proven to be successful yet. Circulating tumour cells (CTCs) as "liquid biopsies" could provide prognostic information at the time a therapeutic decision needs to be made and could be an attractive tool for tumour monitoring throughout the treatment period. However, "liquid biopsies" are far from becoming the standard biomarker in NETs. Promising results have been presented over the last few years using a novel biomarker candidate, a multianalyte algorithm analysis PCR-based test (NETest). New technologies will open the field to different ways of approaching the biomarker conundrum in NETs. However, the complications derived from being a heterogeneous group of malignancies will remain with us forever. In summary, there is an unmet need to incorporate new biomarker candidates into clinical research trials to obtain a robust prospective validation under the most demanding scenario.
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Kyriakopoulos G, Mavroeidi V, Chatzellis E, Kaltsas GA, Alexandraki KI. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:252. [PMID: 30069454 DOI: 10.21037/atm.2018.06.27] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neuroendocrine neoplasms (NENs) arise from cells of the neuroendocrine system located in many sites amongst which most common are the gastrointestinal (GI) system and the lung. The efforts to assess the specific site of origin or predict the biological behavior of NENs is based upon a detailed study of neoplasm's architectural pattern, immunohistochemical, genetic and molecular profile. Immunohistochemistry is used to characterize the aggressivity of NENs, by assessing the proliferation index Ki-67, as well as the neuroendocrine differentiation by assessing chromogranin A (CgA) and CD56. Basal panels of immunohistochemical markers such as CDX-2, Isl-1, TTF-1, PAX6/8 are currently being used to allocate the neoplasms, while in dubious cases new markers are investigating. Unraveling the genetic and molecular mechanisms of NENs pathogenesis along with shedding light on the molecular heterogeneity of neoplasms and the individual patterns of molecular lesions, underlining these neoplasms may provide new tools in terms of diagnostics and therapeutics. Molecular targeted therapies (MTTs) such as everolimus and sunitinib have been the first example of druggable molecular targets implicated in NENs that have been approved for NEN treatment. New investigational drugs are developing along with genetic tests that may allow the identification of the specific subset of patients that will respond to each individual MTT. Multiparametrical molecular and genetic analysis such as the NETest and the MASTER are already in trials shedding light in a step-by-step management of NENs that allow not only the selection of an appropriate therapeutic option but also the identification of response to treatment or early relapse allowing an early amendment of the strategy. Summarizing the combination of histopathological, immunohistochemical, genetic and molecular profile of a NEN opens new horizons in the efficient management of NENs.
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Affiliation(s)
| | - Vasiliki Mavroeidi
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleftherios Chatzellis
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregory A Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Krystallenia I Alexandraki
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Auernhammer CJ, Spitzweg C, Angele MK, Boeck S, Grossman A, Nölting S, Ilhan H, Knösel T, Mayerle J, Reincke M, Bartenstein P. Advanced neuroendocrine tumours of the small intestine and pancreas: clinical developments, controversies, and future strategies. Lancet Diabetes Endocrinol 2018; 6:404-415. [PMID: 29229497 DOI: 10.1016/s2213-8587(17)30401-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 10/14/2017] [Accepted: 10/18/2017] [Indexed: 12/18/2022]
Abstract
In this Review, we discuss clinical developments and controversies in the treatment of neuroendocrine tumours (NETs) that are relevant for clinicians and clinical researchers. We describe advances in genetics, blood-based biomarkers, functional imaging, and systemic therapy of advanced NETs and discuss results of recent phase 3 studies, systemic treatment of advanced disease with peptide receptor radionuclide therapy, biotherapy, chemotherapy, and molecularly targeted therapy, and the potential role of immunotherapy in the treatment of NETs. Suggested treatment algorithms for NETs of ileal or jejunal origin and of pancreatic origin are presented.
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Affiliation(s)
- Christoph J Auernhammer
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 4, Ludwig-Maximilians-University of Munich, Munich, Germany.
| | - Christine Spitzweg
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 4, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Martin K Angele
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Stefan Boeck
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 3, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Ashley Grossman
- Neuroendocrine Tumour Centre, Royal Free Hospital, London, UK
| | - Svenja Nölting
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 4, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Harun Ilhan
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Thomas Knösel
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Institute of Pathology, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Julia Mayerle
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 2, Klinikum der Universitaet Muenchen, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Martin Reincke
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Internal Medicine 4, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Peter Bartenstein
- Interdisciplinary Center of Neuroendocrine Tumours of the GastroEnteroPancreatic System, Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
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Xue Y, Yin P, Li G, Zhong D. Genome-wide Integration Study of Circulating miRNAs and Peripheral Whole-Blood mRNAs of Male Acute Ischemic Stroke Patients. Neuroscience 2018; 380:27-37. [PMID: 29653195 DOI: 10.1016/j.neuroscience.2018.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 03/21/2018] [Accepted: 04/02/2018] [Indexed: 01/21/2023]
Abstract
Several circulating microRNAs (miRNAs) have been proved to serve as stable biomarkers in blood for acute ischemic stroke (AIS). However, the functions of these biomarkers remain elusive. By conducting the integration analysis of circulating miRNAs and peripheral whole-blood mRNAs using bioinformatics methods, we explored the biological role of these circulating markers in peripheral whole blood at the genome-wide level. Stroke-related circulating miRNA profile data (GSE86291) and peripheral whole-blood mRNA expression data (GSE16561) were collected from the Gene Expression Omnibus (GEO) datasets. We selected male patients to avoid any gender differences in stroke pathology. Male stroke-related miRNAs (M-miRNAs) and mRNAs (M-mRNAs) were detected using GEO2R. Nine M-miRNAs (five up- and four down-regulated) were applied to TargetScan to predict the possible target mRNAs. Next, we intersected these targets with the M-mRNAs (38 up- and three down-regulated) to obtain the male stroke-related overlapped mRNAs (Mo-mRNAs). Finally, we analyzed biological functions of Mo-mRNAs using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and constructed networks among the Mo-mRNAs, overlapped M-miRNAs (Mo-miRNAs), and their functions. The Mo-mRNAs were enriched in functions such as platelet degranulation, immune response, and pathways associated with phagosome biology and Staphylococcus aureus infection. This study provides an integrated view of interactions among circulating miRNAs and peripheral whole-blood mRNAs involved in the pathophysiological processes of male AIS.
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Affiliation(s)
- Yang Xue
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin 150001, Heilong Jiang Province, PR China
| | - Pengqi Yin
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin 150001, Heilong Jiang Province, PR China
| | - Guozhong Li
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin 150001, Heilong Jiang Province, PR China.
| | - Di Zhong
- Department of Neurology, The First Affiliated Hospital, Harbin Medical University, 23 You Zheng Street, Harbin 150001, Heilong Jiang Province, PR China.
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Li N, Yang M, Shi K, Li W. Long non-coding RNA HOXA11-AS in human cancer: A meta-analysis. Clin Chim Acta 2017; 474:165-170. [PMID: 28942241 DOI: 10.1016/j.cca.2017.09.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 09/17/2017] [Accepted: 09/20/2017] [Indexed: 12/27/2022]
Abstract
BACKGROUND Homeobox A11 antisense (HOXA11-AS), a newly identified lncRNA, is up-regulated in various carcinomas. We conducted the present meta-analysis to explore the potential of HOXA11-AS as a common predictive biomarker for metastasis and prognosis in malignant tumors. METHODS A systematic literature search on the online electronic databases of PubMed, Web of Science, and Embase was carried out to determine relevant studies (as of July 9, 2017). The pooled hazard ratios (HRs)/odds rates (ORs), and their 95% confidence intervals (CIs) were used to evaluate the relationship. RESULTS A total of 608 patients from seven studies were included in the current meta-analysis. The pooled results indicated that high HOXA11-AS expression was related to poor overall survival (OS) (HR=2.02, 95% CI: 1.48-2.75, P<0.001) and progression-free survival (PFS) (HR=1.91, 95% CI: 1.15-3.17, P=0.012). Further analyses reveal that patients with high HOXA11-AS expression are prone to develop distant metastasis (DM) (OR=6.05, 95% CI: 1.66-22.06, P=0.006). CONCLUSIONS This meta-analysis showed that increased expression of HOXA11-AS is a risk factor for poor clinical outcomes in numerous tumors and may act as a novel biomarker for poor prognosis and metastasis in cancers.
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Affiliation(s)
- Na Li
- Department of Pathology, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, Hunan Province, China
| | - Meilan Yang
- Department of Pathology, The First Affiliated Hospital of Hunan University of Medicine, Huaihua, Hunan Province, China
| | - Ke Shi
- Department of Geriatrics, Clinical Laboratory, Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Wei Li
- Department of Geriatrics, Clinical Laboratory, Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
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