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Colapietra F, Della Monica P, Di Napoli R, França Vieira e Silva F, Settembre G, Marino MM, Ballini A, Cantore S, Di Domenico M. Epigenetic Modifications as Novel Biomarkers for Diagnosis, Prognosis, and Therapeutic Targeting in Thyroid, Pancreas, and Lung Neuroendocrine Tumors. J Clin Med 2025; 14:2622. [PMID: 40283452 PMCID: PMC12027509 DOI: 10.3390/jcm14082622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 04/06/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
Neuroendocrine neoplasms (NENs) comprise a heterogeneous tumor group arising from neuroendocrine cells, commonly originating in the gastroenteropancreatic tract and bronchopulmonary system. Their incidence has risen significantly, owing to improved diagnostic techniques and increased clinical recognition. While previous reviews have explored the molecular and genetic basis of NENs, limited attention has been given to the role of epigenetic modifications, particularly DNA methylation, in tumorigenesis and disease progression. This review focuses on lung, pancreas, and thyroid well-differentiated neuroendocrine tumors (NETs), highlighting epigenetic mechanisms, particularly DNA methylation, as promising biomarkers for early diagnosis and risk stratification. Aberrant DNA methylation can silence key tumor suppressor genes, including RASSF1A and CDKN2A, thereby promoting tumorigenesis. Integrating DNA methylation profiles with conventional biomarkers such as chromogranin A (CgA) may enhance diagnostic accuracy and inform therapeutic strategies. Emerging epigenetic therapies offer potential avenues for personalized treatment based on molecular profiling. Unlike prior reviews that broadly cover genetic and epigenetic changes in NENs, this review uniquely emphasizes the translational potential of epigenetic biomarkers in clinical practice. By synthesizing recent findings and evaluating their clinical implications, we aim to bridge the gap between molecular research and practical applications in diagnosis, prognosis, and therapy.
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Affiliation(s)
- Federica Colapietra
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via Abramo Lincoln, 5, 81100 Caserta, Italy; (F.C.); (F.F.V.e.S.); (G.S.); (M.M.M.); (A.B.); (M.D.D.)
| | - Paola Della Monica
- Department of Advanced Medical and Surgical Science, University of Campania Luigi Vanvitelli, Via Abramo Lincoln, 5, 81100 Caserta, Italy;
| | - Raffaella Di Napoli
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Via Abramo Lincoln, 5, 81100 Caserta, Italy;
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, 80138 Naples, Italy
| | - Fábio França Vieira e Silva
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via Abramo Lincoln, 5, 81100 Caserta, Italy; (F.C.); (F.F.V.e.S.); (G.S.); (M.M.M.); (A.B.); (M.D.D.)
- Department of Pathology, Health Research Institute of Santiago de Compostela (FIDIS), Santiago de Compostela University Clinical Hospital, University of Santiago de Compostela, Choupana Street, s/n, 15706 Santiago de Compostela, Spain
| | - Giuliana Settembre
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via Abramo Lincoln, 5, 81100 Caserta, Italy; (F.C.); (F.F.V.e.S.); (G.S.); (M.M.M.); (A.B.); (M.D.D.)
| | - Maria Michela Marino
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via Abramo Lincoln, 5, 81100 Caserta, Italy; (F.C.); (F.F.V.e.S.); (G.S.); (M.M.M.); (A.B.); (M.D.D.)
| | - Andrea Ballini
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via Abramo Lincoln, 5, 81100 Caserta, Italy; (F.C.); (F.F.V.e.S.); (G.S.); (M.M.M.); (A.B.); (M.D.D.)
- Department of Clinical and Experimental Medicine, University of Foggia, Via Napoli, 20, 71122 Foggia, Italy
- Department of Life Science, Health and Health Professions, Link Campus University, 00165 Rome, Italy
| | - Stefania Cantore
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via Abramo Lincoln, 5, 81100 Caserta, Italy; (F.C.); (F.F.V.e.S.); (G.S.); (M.M.M.); (A.B.); (M.D.D.)
| | - Marina Di Domenico
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via Abramo Lincoln, 5, 81100 Caserta, Italy; (F.C.); (F.F.V.e.S.); (G.S.); (M.M.M.); (A.B.); (M.D.D.)
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Budek M, Nuszkiewicz J, Czuczejko J, Maruszak-Parda M, Wróblewska J, Wojtasik J, Hołyńska-Iwan I, Pawłowska M, Woźniak A, Szewczyk-Golec K. Searching for New Biomarkers of Neuroendocrine Tumors: A Comparative Analysis of Chromogranin A and Inflammatory Cytokines in Patients with Neuroendocrine Tumors. Curr Oncol 2024; 31:6110-6132. [PMID: 39451760 PMCID: PMC11506232 DOI: 10.3390/curroncol31100456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 10/07/2024] [Accepted: 10/10/2024] [Indexed: 10/26/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) present a diagnostic challenge due to their heterogeneous nature and non-specific clinical manifestations. This study aimed to explore novel biomarkers for NENs. Serum chromogranin A (CgA) levels and a panel of 48 inflammatory cytokines were analyzed in a cohort of 84 NEN patients and 40 healthy controls using enzyme-linked immunosorbent assay (ELISA) and multiplex ELISA. Significant alterations in cytokine levels were observed in the NEN patients compared to the controls, including elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), and reduced levels of angiogenic factors like platelet-derived growth factor-BB (PDGF-BB) and tumor necrosis factor beta (TNF-β). Notably, cytokines such as growth-regulated alpha protein (GRO-α) and TNF-β demonstrated strong potential as diagnostic markers, with receiver operating characteristic (ROC) curve analyses showing high sensitivity and specificity. Additionally, a positive correlation was found between CgA levels and several inflammatory cytokines, suggesting their synergistic role in tumor progression. These findings highlight the limited reliability of CgA alone as a diagnostic marker and underscore the importance of a multi-marker approach in diagnosing and monitoring NENs. Further research on a larger cohort is necessary to validate these biomarkers and their potential clinical applications.
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Affiliation(s)
- Marlena Budek
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland; (M.B.); (J.N.); (J.W.); (M.P.); (A.W.)
| | - Jarosław Nuszkiewicz
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland; (M.B.); (J.N.); (J.W.); (M.P.); (A.W.)
| | - Jolanta Czuczejko
- Department of Psychiatry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland;
- Department of Nuclear Medicine, Oncology Centre Prof. Franciszek Łukaszczyk Memorial Hospital, 85-796 Bydgoszcz, Poland;
| | - Marta Maruszak-Parda
- Department of Nuclear Medicine, Oncology Centre Prof. Franciszek Łukaszczyk Memorial Hospital, 85-796 Bydgoszcz, Poland;
| | - Joanna Wróblewska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland; (M.B.); (J.N.); (J.W.); (M.P.); (A.W.)
| | - Jakub Wojtasik
- Centre for Statistical Analysis, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland;
| | - Iga Hołyńska-Iwan
- Department of Pathobiochemistry and Clinical Chemistry, Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland;
| | - Marta Pawłowska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland; (M.B.); (J.N.); (J.W.); (M.P.); (A.W.)
| | - Alina Woźniak
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland; (M.B.); (J.N.); (J.W.); (M.P.); (A.W.)
| | - Karolina Szewczyk-Golec
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland; (M.B.); (J.N.); (J.W.); (M.P.); (A.W.)
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Hadoux J, Lamarca A, Grande E, Deandreis D, Kaltsas G, Janson ET, Tombal B, Pavel M, Thariat J, van Velthuysen MF, Herman P, Dromain C, Baudin E, Berruti A. Neuroendocrine neoplasms of head and neck, genitourinary and gynaecological systems, unknown primaries, parathyroid carcinomas and intrathyroid thymic neoplasms: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. ESMO Open 2024; 9:103664. [PMID: 39461777 PMCID: PMC11549527 DOI: 10.1016/j.esmoop.2024.103664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/21/2024] [Accepted: 07/15/2024] [Indexed: 10/29/2024] Open
Abstract
•This Clinical Practice Guideline provides key recommendations for managing rare endocrine tumours. •Neuroendocrine neoplasms of different origins, parathyroid carcinoma and intrathyroid thymic neoplasms are included. •The guideline covers clinical imaging and pathological diagnosis, staging and risk assessment, treatment and follow-up. •The authors comprise a multidisciplinary group of experts from different institutions and countries in Europe. •Recommendations are based on available scientific data and the authors’ collective expert opinion.
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Affiliation(s)
- J Hadoux
- Département d'Imagerie, Service d'Oncologie Endocrinienne, Gustave Roussy, Villejuif, France
| | - A Lamarca
- Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester; Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - E Grande
- Department of Medical Oncology, MD Anderson Cancer Center Madrid, Madrid, Spain
| | - D Deandreis
- Département d'Imagerie, Service d'Oncologie Endocrinienne, Gustave Roussy, Villejuif, France; Nuclear Medicine Service, Gustave Roussy, Villejuif, France
| | - G Kaltsas
- First Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - E T Janson
- Department of Medical Sciences, Endocrine Oncology Unit, Uppsala University, Uppsala, Sweden
| | - B Tombal
- Institut de Recherche Clinique, Cliniques Universitaires Saint-Luc (UCLouvain Saint-Luc), Woluwe-Saint-Lambert, Belgium
| | - M Pavel
- Department of Medicine 1, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuernberg, Erlangen, Germany
| | - J Thariat
- Department of Radiation Oncology, Baclesse Cancer Center, Caen, France
| | - M F van Velthuysen
- Department of Pathology, Erasmus Medical Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - P Herman
- Department of Otorhinolaryngology, Head and Neck Surgery, Hôpital Lariboisière AP-HP, Paris, France
| | - C Dromain
- Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - E Baudin
- Département d'Imagerie, Service d'Oncologie Endocrinienne, Gustave Roussy, Villejuif, France
| | - A Berruti
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
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Padmanabhan Nair Sobha R, Jensen CT, Waters R, Calimano-Ramirez LF, Virarkar MK. Appendiceal Neuroendocrine Neoplasms: A Comprehensive Review. J Comput Assist Tomogr 2024; 48:545-562. [PMID: 37574653 DOI: 10.1097/rct.0000000000001528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
ABSTRACT Appendiceal neuroendocrine neoplasm (NEN) is the most common adult appendiceal malignant tumor, constituting 16% of gastrointestinal NENs. They are versatile tumors with varying morphology, immunohistochemistry, secretory properties, and cancer genomics. They are slow growing and clinically silent, to begin with, or present with features of nonspecific vague abdominal pain. Most acute presentations are attributed clinically to appendicitis, with most cases detected incidentally on pathology after an appendectomy. Approximately 40% of them present clinically with features of hormonal excess, which is likened to the functional secretory nature of their parent cell of origin. The symptoms of carcinoid syndrome render their presence clinically evident. However, slow growing and symptomatically silent in its initial stages, high-grade neuroendocrine tumors and neuroendocrine carcinomas of the appendix are aggressive and usually have hepatic and lymph node metastasis at presentation. This review article focuses on imaging characteristics, World Health Organization histopathological classification and grading, American Joint Committee on Cancer/Union or International Cancer Control, European Neuroendocrine Tumor Society staging, European Neuroendocrine Tumor Society standardized guidelines for reporting, data interpretation, early-stage management protocols, and advanced-stage appendiceal NENs. Guidelines are also set for the follow-up and reassessment. The role of targeted radiotherapy, chemotherapy, and high-dose somatostatin analogs in treating advanced disease are discussed, along with types of ablative therapies and liver transplantation for tumor recurrence. The search for newer location-specific biomarkers in NEN is also summarized. Regarding the varying aggressiveness of the tumor, there is a scope for research in the field, with plenty of data yet to be discovered.
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Affiliation(s)
| | - Corey T Jensen
- From the Department of Radiology, University of Texas MD Anderson Cancer Center
| | - Rebecca Waters
- Department of Pathology and Lab Medicine MD Anderson Cancer Center, Houston, TX
| | | | - Mayur K Virarkar
- Department of Radiology, University of Florida College of Medicine, Jacksonville, FL
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Johansen SU, Hansen T, Nordborg A, Meyer R, Goll R, Florholmen J, Jensen E. Plasma tryptophan pathway metabolites quantified by liquid chromatography-tandem mass spectrometry as biomarkers in neuroendocrine tumor patients. J Neuroendocrinol 2024; 36:e13372. [PMID: 38361341 DOI: 10.1111/jne.13372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/21/2023] [Accepted: 01/11/2024] [Indexed: 02/17/2024]
Abstract
A good and accessible biomarker is of great clinical value in neuroendocrine tumor (NET) patients, especially considering its frequently indolent nature and long-term follow-up. Plasma chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are currently used as biomarkers in NET, but their sensitivity and specificity are restricted. 5-HIAA is the main metabolite of serotonin, an important neurotransmitter of the tryptophan pathway. The aim of this study is to estabish a sensitive and accurate method for the quantification of tryptophan pathway metabolites in plasma. We further aimed to evaluate its utility as a clinical tool in NET disease. We obtained plasma samples from NET patients and healthy controls recruited from the University Hospital of North Norway, Tromsø. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and eight metabolites of the tryptophan pathway were quantified. We included 130 NET patients (72/130 small intestinal [SI] NET, 35/130 pancreatic NET, 23/130 other origin) and 20 healthy controls. In the SI-NET group, 26/72 patients presented with symptoms of carcinoid syndrome (CS). We found that combining tryptophan metabolites into a serotonin/kynurenine pathway ratio improved diagnostic sensitivity (92.3%) and specificity (100%) in detecting CS patients from healthy controls compared with plasma 5-HIAA alone (sensitivity 84.6%/specificity 100%). Further, a clinical marker based on the combination of plasma serotonin, 5-HIAA, and 5OH-tryptophan, increased diagnostic capacity identifying NET patients with metastasized disease from healthy controls compared with singular plasma 5-HIAA, serotonin, or CgA. In addition, this marker was positive in 61% of curatively operated SI-NET patients compared with only 10% of healthy controls (p < .001). Our results indicate that simultaneous quantification of several tryptophan metabolites in plasma, using LC-MS/MS, may represent a clinically useful diagnostic tool in NET disease.
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Affiliation(s)
- S U Johansen
- Department of Clinical Medicine, UiT the Arctic University of Norway, Tromsø, Norway
- Medical Gastroenterology, Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - T Hansen
- Department of Biotechnology and Nanomedicine, SINTEF Industry, Trondheim, Norway
- Department of Pharmacy, UiT the Arctic University of Norway, Tromsø, Norway
| | - A Nordborg
- Department of Biotechnology and Nanomedicine, SINTEF Industry, Trondheim, Norway
| | - R Meyer
- Medical Gastroenterology, Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - R Goll
- Department of Clinical Medicine, UiT the Arctic University of Norway, Tromsø, Norway
- Medical Gastroenterology, Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - J Florholmen
- Department of Clinical Medicine, UiT the Arctic University of Norway, Tromsø, Norway
- Medical Gastroenterology, Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - E Jensen
- Department of Pharmacy, UiT the Arctic University of Norway, Tromsø, Norway
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Gao C, Fan Z, Yang J, Shi M, Li Y, Zhan H. Diagnostic role and prognostic value of tumor markers in high-grade gastro-enteropancreatic neuroendocrine neoplasms. Pancreatology 2023; 23:204-212. [PMID: 36710224 DOI: 10.1016/j.pan.2023.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 01/09/2023] [Accepted: 01/16/2023] [Indexed: 01/31/2023]
Abstract
OBJECTIVES High-grade gastro-enteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of rare tumors of two different types: well differentiated neuroendocrine tumors grade 3 (NETs G3) and poorly differentiated neuroendocrine carcinomas (NECs). This study aimed to explore the value of eight common preoperative markers in differentiating NETs G3 from NECs and the prognosis prediction of high-grade GEP-NENs. METHODS Seventy-two patients diagnosed with high-grade GEP-NENs who underwent surgery at our institution were recruited for this study. Demographic and clinicopathological characteristics, preoperative serum tumor markers, and survival data were collected and analyzed. Kaplan-Meier methods were used to analyze survival rates, and a Cox regression model was used to perform multivariate analyses. RESULTS Serum carcinoembryonic antigen (CEA) was dramatically higher in NECs than in NETs G3 (P = 0.025). After follow-up, 57 of the 72 patients remained for survival analysis. Elevated serum carbohydrate antigen 19-9 (CA19-9), CEA, cancer antigen 125 and sialic acid (SA) levels indicated poorer survival of high-grade GEP-NEN patients. Only CA19-9 (HR: 6.901, 95% CI: 1.843 to 25.837, P = 0.004) was regarded as an independent risk factor for overall survival. Serum CA19-9 (HR: 4.689, 95% CI: 1.127 to 19.506, P = 0.034) was also regarded as an independent factor for overall survival in NECs. CONCLUSIONS Serum CEA levels can be used to distinguish NETs G3 from NECs. Preoperative CA19-9, CEA, cancer antigen 125 and SA levels have predictive value in the prognosis of high-grade GEP-NENs. Preoperative CA19-9, neuron-specific enolase, and SA levels can predict the prognosis of NECs.
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Affiliation(s)
- Changhao Gao
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Zhiyao Fan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Jian Yang
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Ming Shi
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Yongzheng Li
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China
| | - Hanxiang Zhan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, China.
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Koffas A, Giakoustidis A, Papaefthymiou A, Bangeas P, Giakoustidis D, Papadopoulos VN, Toumpanakis C. Diagnostic work-up and advancement in the diagnosis of gastroenteropancreatic neuroendocrine neoplasms. Front Surg 2023; 10:1064145. [PMID: 36950054 PMCID: PMC10025557 DOI: 10.3389/fsurg.2023.1064145] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 02/07/2023] [Indexed: 03/08/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms ranging from well-differentiated, slowly growing tumors to poorly differentiated carcinomas. These tumors are generally characterized by indolent course and quite often absence of specific symptoms, thus eluding diagnosis until at an advanced stage. This underscores the importance of establishing a prompt and accurate diagnosis. The gold-standard remains histopathology. This should contain neuroendocrine-specific markers, such as chromogranin A; and also, an estimate of the proliferation by Ki-67 (or MIB-1), which is pivotal for treatment selection and prognostication. Initial work-up involves assessment of serum Chromogranin A and in selected patients gut peptide hormones. More recently, the measurement of multiple NEN-related transcripts, or the detection of circulating tumor cells enhanced our current diagnostic armamentarium and appears to supersede historical serum markers, such as Chromogranin A. Standard imaging procedures include cross-sectional imaging, either computed tomography or magnetic resonance, and are combined with somatostatin receptor scintigraphy. In particular, the advent of 111In-DTPA-octreotide and more recently PET/CT and 68Ga-DOTA-Octreotate scans revolutionized the diagnostic landscape of NENs. Likewise, FDG PET represents an invaluable asset in the management of high-grade neuroendocrine carcinomas. Lastly, endoscopy, either conventional, or more advanced modalities such as endoscopic ultrasound, capsule endoscopy and enteroscopy, are essential for the diagnosis and staging of gastroenteropancreatic neuroendocrine neoplasms and are routinely integrated in clinical practice. The complexity and variability of NENs necessitate the deep understanding of the current diagnostic strategies, which in turn assists in offering optimal patient-tailored treatment. The current review article presents the diagnostic work-up of GEP-NENs and all the recent advances in the field.
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Affiliation(s)
- Apostolos Koffas
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- Correspondence: Apostolos Koffas
| | - Alexandros Giakoustidis
- 1st Department of Surgery, General Hospital Papageorgiou, School of Medicine, Faculty of Medical Sciences, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Apostolis Papaefthymiou
- Pancreaticobiliary Medicine Unit, University College London Hospitals (UCLH), London, United Kingdom
| | - Petros Bangeas
- 1st Department of Surgery, General Hospital Papageorgiou, School of Medicine, Faculty of Medical Sciences, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Giakoustidis
- 1st Department of Surgery, General Hospital Papageorgiou, School of Medicine, Faculty of Medical Sciences, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Vasileios N Papadopoulos
- 1st Department of Surgery, General Hospital Papageorgiou, School of Medicine, Faculty of Medical Sciences, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Christos Toumpanakis
- Centre for Gastroenterology, Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, United Kingdom
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Melone V, Salvati A, Palumbo D, Giurato G, Nassa G, Rizzo F, Palo L, Giordano A, Incoronato M, Vitale M, Mian C, Di Biase I, Cristiano S, Narciso V, Cantile M, Di Mauro A, Tatangelo F, Tafuto S, Modica R, Pivonello C, Salvatore M, Colao A, Weisz A, Tarallo R. Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis. J Transl Med 2022; 20:306. [PMID: 35794609 PMCID: PMC9258165 DOI: 10.1186/s12967-022-03511-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 06/28/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Neuroendocrine neoplasms (NENs) represent a heterogeneous class of rare tumors with increasing incidence. They are characterized by the ability to secrete peptide hormones and biogenic amines but other reliable biomarkers are lacking, making diagnosis and identification of the primary site very challenging. While in some NENs, such as the pancreatic ones, next generation sequencing technologies allowed the identification of new molecular hallmarks, our knowledge of the molecular profile of NENs from other anatomical sites is still poor. METHODS Starting from the concept that NENs from different organs may be clinically and genetically correlated, we applied a multi-omics approach by combining multigene panel testing, CGH-array, transcriptome and miRNome profiling and computational analyses, with the aim to highlight common molecular and functional signatures of gastroenteropancreatic (GEP)-NENs and medullary thyroid carcinomas (MTCs) that could aid diagnosis, prognosis and therapy. RESULTS By comparing genomic and transcriptional profiles, ATM-dependent signaling emerged among the most significant pathways at multiple levels, involving gene variations and miRNA-mediated regulation, thus representing a novel putative druggable pathway in these cancer types. Moreover, a set of circulating miRNAs was also selected as possible diagnostic/prognostic biomarkers useful for clinical management of NENs. CONCLUSIONS These findings depict a complex molecular and functional landscape of NENs, shedding light on novel therapeutic targets and disease biomarkers to be exploited.
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Affiliation(s)
- Viola Melone
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy
| | - Annamaria Salvati
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy
- Medical Genomics Program and Division of Oncology, AOU 'S. Giovanni di Dio e Ruggi d'Aragona' University of Salerno, Rete Oncologica Campana, 84131, Salerno, Italy
| | - Domenico Palumbo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy
| | - Giorgio Giurato
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy
- Medical Genomics Program and Division of Oncology, AOU 'S. Giovanni di Dio e Ruggi d'Aragona' University of Salerno, Rete Oncologica Campana, 84131, Salerno, Italy
- Genome Research Center for Health, 84081, Baronissi, SA, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy
- Medical Genomics Program and Division of Oncology, AOU 'S. Giovanni di Dio e Ruggi d'Aragona' University of Salerno, Rete Oncologica Campana, 84131, Salerno, Italy
- Genome Research Center for Health, 84081, Baronissi, SA, Italy
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy
- Medical Genomics Program and Division of Oncology, AOU 'S. Giovanni di Dio e Ruggi d'Aragona' University of Salerno, Rete Oncologica Campana, 84131, Salerno, Italy
- Genome Research Center for Health, 84081, Baronissi, SA, Italy
| | - Luigi Palo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy
| | - Alessandro Giordano
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy
| | | | - Mario Vitale
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081, Baronissi, SA, Italy
| | - Caterina Mian
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Immacolata Di Biase
- MeriGen Diagnostic & c sas, traversa M. Pietravalle 11, 80131, Naples, Italy
| | - Stefano Cristiano
- MeriGen Diagnostic & c sas, traversa M. Pietravalle 11, 80131, Naples, Italy
| | - Viviana Narciso
- MeriGen Diagnostic & c sas, traversa M. Pietravalle 11, 80131, Naples, Italy
| | - Monica Cantile
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 80131, Naples, Italy
| | - Annabella Di Mauro
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 80131, Naples, Italy
| | - Fabiana Tatangelo
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 80131, Naples, Italy
| | - Salvatore Tafuto
- Sarcomas and Rare Tumors Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Via Mariano Semmola, 80131, Naples, Italy
| | - Roberta Modica
- Department of Clinical Medicine and Surgery, Endocrinology Unit, Federico II University, Naples, Italy
| | - Claudia Pivonello
- Department of Clinical Medicine and Surgery, Endocrinology Unit, Federico II University, Naples, Italy
| | - Marco Salvatore
- IRCCS Synlab SDN s.p.a, Via Gianturco 113, 80143, Naples, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, Endocrinology Unit, Federico II University, Naples, Italy
- UNESCO Chair for Health Education and Sustainable Development, Federico II University, Naples, Italy
| | - Alessandro Weisz
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy.
- Medical Genomics Program and Division of Oncology, AOU 'S. Giovanni di Dio e Ruggi d'Aragona' University of Salerno, Rete Oncologica Campana, 84131, Salerno, Italy.
- Genome Research Center for Health, 84081, Baronissi, SA, Italy.
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, via S. Allende, 84081, Baronissi, SA, Italy.
- Medical Genomics Program and Division of Oncology, AOU 'S. Giovanni di Dio e Ruggi d'Aragona' University of Salerno, Rete Oncologica Campana, 84131, Salerno, Italy.
- Genome Research Center for Health, 84081, Baronissi, SA, Italy.
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9
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Yin B, Gao R, Xu Q, Wang X, Wu W. Surgical management for pancreatic neuroendocrine neoplasms with synchronous hepatic metastases: A literature review. SURGERY IN PRACTICE AND SCIENCE 2022. [DOI: 10.1016/j.sipas.2021.100055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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10
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Puliani G, Di Vito V, Feola T, Sesti F, Centello R, Pandozzi C, Tarsitano MG, Verrico M, Lenzi A, Isidori AM, Giannetta E, Faggiano A. NETest: A Systematic Review Focusing on the Prognostic and Predictive Role. Neuroendocrinology 2022; 112:523-536. [PMID: 34515175 DOI: 10.1159/000518873] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 08/02/2021] [Indexed: 11/19/2022]
Abstract
The NETest is a standardized and reproducible liquid biopsy for neuroendocrine tumors (NETs). It evaluates the expression of 51 NET genes by real-time polymerase chain reaction, providing an accurate molecular profile of the neoplasm. Diagnostic utility of NETest has been widely demonstrated, while its role in predicting prognosis and treatment response is less studied. This systematic review aims to collect and discuss the available evidence on the prognostic and predictive role of NETest, trying to answer 3 questions, frequently raised in clinical practice. Is NETest able to differentiate stable from progressive disease? Increased NETest levels (at least >40%) correlate with disease progression. Is NETest able to predict tumor progression and tumor response to treatment? Some studies demonstrated that the baseline NETest score >33-40% could predict tumor progression. Moreover, NETest performed after treatment (as peptide receptor radionuclide therapy) could predict treatment response also before radiological findings, since the decrease or stability of NETest score predicts tumor response to treatment. Is NETest able to evaluate tumor recurrence risk after surgery? NETest can predict surgical treatment outcome detecting minimal residual disease after radical surgery, which is characterized by a lower but positive NETest score (20-40%), while a higher score (>33-40%) is associated with nonradical surgery. In conclusion, in addition to its demonstrated diagnostic role, this systematic review highlights the efficacy of NETest to assess disease status at the moment of the NETest execution and to predict tumor recurrence after surgery. The efficacy for other applications should be proven by additional studies.
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Affiliation(s)
- Giulia Puliani
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer institute, Rome, Italy
| | - Valentina Di Vito
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Tiziana Feola
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli, Italy
| | - Franz Sesti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Roberta Centello
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Carla Pandozzi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Monica Verrico
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Elisa Giannetta
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
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11
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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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12
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Yozgat A, Kekilli M, Altay M. Time to give up traditional methods for the management of gastrointestinal neuroendocrine tumours. World J Clin Cases 2021; 9:8627-8646. [PMID: 34734042 PMCID: PMC8546836 DOI: 10.12998/wjcc.v9.i29.8627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 05/19/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Neuroendocrine tumors (NETs) are a rare and heterogeneous disease group and constitute 0.5% of all malignancies. The annual incidence of NETs is increasing worldwide. The reason for the increase in the incidence of NETs is the detection of benign lesions, incidental detection due to the highest use of endoscopic and imaging procedures, and higher recognition rates of pathologists. There have been exciting developments regarding NET biology in recent years. Among these, first of all, somatostatin receptors and downstream pathways in neuroendocrine cells have been found to be important regulatory mechanisms for protein synthesis, hormone secretion, and proliferation. Subsequently, activation of the mammalian target of rapamycin pathway was found to be an important mechanism in angiogenesis and tumor survival and cell metabolism. Finally, the importance of proangiogenic factors (platelet-derived growth factor, vascular endothelial growth factor, fibroblastic growth factor, angiopoietin, and semaphorins) in the progression of NET has been determined. Using the combination of biomarkers and imaging methods allows early evaluation of the appropriateness of treatment and response to treatment.
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Affiliation(s)
- Ahmet Yozgat
- Department of Gastroenterology, Ufuk University, Ankara, 06510, Turkey
| | - Murat Kekilli
- Department of Gastroenterology, Gazi University, Ankara 06560, Turkey
| | - Mustafa Altay
- Department of Endocrinology and Metabolism, University of Health Sciences Turkey, Keçiören Health Administration and Research Center, Ankara 06190, Turkey
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Xiao Y, Tai Y, Quan X, Zhao C, Liu R, Tong H, Huang Z, Tang C, Gao J. Quantification of chromogranin A using a surface plasmon resonance-based biosensor. ANALYTICAL METHODS 2021; 13:3772-3778. [PMID: 34378549 DOI: 10.1039/d1ay00782c] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The chromogranin A (CgA) level in the blood is an important biomarker for neuroendocrine tumors and other diseases. Traditional methods for detecting CgA are expensive and time-consuming with low reproducibility. In this study, surface plasmon resonance (SPR), a simple and label-free technique, was validated for quantifying CgA. CgA antibody (CgA-Ab) was immobilized on the CM5 sensor chip (CgA-Ab-CM5) at optimal conditions (pH 5.0, 10 μg mL-1). Next, different concentrations of CgA were measured by CgA-Ab-CM5. The binding and regeneration conditions were optimized and used in each measurement. A binding time of 240 s, and flow rate of 30 μL min-1 were chosen as the optimal binding conditions. A pH of 1.75 was the optimal regeneration condition. Compared to the detection range of 23.4-187 ng mL-1 for enzyme-linked immunosorbent assay (ELISA), a linear range of 0.2-187 ng mL-1 was detected based on the response unit (RU), showing high sensitivity and reliability of SPR. Finally, the reproducibility of the CgA-Ab-CM5 chip was accessed by consecutive binding-regeneration cycles for 300 times. In conclusion, the SPR-based CgA-Ab-CM5 chip is a sensitive and reproducible method for quantifying CgA levels in a real-time manner.
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Affiliation(s)
- Yang Xiao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, NO. 1, 4th Keyuan Road, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Tai
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, NO. 1, 4th Keyuan Road, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Quan
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, NO. 1, 4th Keyuan Road, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Zhao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, NO. 1, 4th Keyuan Road, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Liu
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, NO. 1, 4th Keyuan Road, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Huan Tong
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, NO. 1, 4th Keyuan Road, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyin Huang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chengwei Tang
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, NO. 1, 4th Keyuan Road, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, NO. 1, 4th Keyuan Road, Chengdu, 610041, People's Republic of China. .,Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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Mineur L, Boustany R, Vazquez L. Paraneoplastic Cushing Syndrome in Gastrointestinal Neuroendocrine Tumour. Case Rep Oncol 2021; 14:1407-1413. [PMID: 34720949 PMCID: PMC8525292 DOI: 10.1159/000518316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/05/2021] [Indexed: 11/19/2022] Open
Abstract
Ectopic production of adrenocorticotropic hormone (ACTH) by gastrointestinal neuroendocrine tumours (NETs) is relatively uncommon. We report a rare case of a liver metastatic G1 low-grade NET of the intestine that induced hypercortisolism after surgical resection. A 50-year-old man was admitted for an intestinal obstruction caused by a tumour of the intestine. Paraneoplastic Cushing syndrome was diagnosed more than a year later following the appearance of cushingoid symptoms, despite stable disease according to RECIST criteria but chromogranin A increase. Ketoconazole and sandostatin medical treatment and liver chemoembolization never managed to control the hypercortisolism unlike the bilateral adrenalectomy. The identification and effective management of this uncommon statement of ectopic ACTH secretion is important to improve the patient's prognosis and quality of life.
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Affiliation(s)
| | | | - Léa Vazquez
- Institute Sainte Catherine, Gastrointestinal and Liver Cancer Unit, Avignon, France
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15
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Kjellman M, Knigge U, Welin S, Thiis-Evensen E, Gronbaek H, Schalin-Jäntti C, Sorbye H, Joergensen MT, Johanson V, Metso S, Waldum H, Søreide JA, Ebeling T, Lindberg F, Landerholm K, Wallin G, Salem F, Schneider MDP, Belusa R. A Plasma Protein Biomarker Strategy for Detection of Small Intestinal Neuroendocrine Tumors. Neuroendocrinology 2021; 111:840-849. [PMID: 32721955 PMCID: PMC8686712 DOI: 10.1159/000510483] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/27/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. METHODS At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. RESULTS Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. CONCLUSION This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.
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Affiliation(s)
- Magnus Kjellman
- Endocrine Surgery Unit, Karolinska Hospital, Stockholm, Sweden,
| | - Ulrich Knigge
- Department of Endocrinology and Gastrointestinal Surgery, ENETS Neuroendocrine Tumor Centre of Excellence, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Staffan Welin
- Department of Endocrine Oncology, ENETS Neuroendocrine Tumor Centre of Excellence, Uppsala University Hospital, Uppsala, Sweden
| | - Espen Thiis-Evensen
- Department of Gastroenterology, ENETS Neuroendocrine Tumor Centre of Excellence, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Henning Gronbaek
- Department of Hepatology and Gastroenterology, ENETS Neuroendocrine Tumor Centre of Excellence, Aarhus University Hospital, Aarhus, Denmark
| | - Camilla Schalin-Jäntti
- Department of Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Halfdan Sorbye
- Department of Oncology and Department of Clinical Science, Haukeland University Hospital, Bergen, Norway
| | | | - Viktor Johanson
- Department of Surgery, Institute of Clinical Sciences at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Saara Metso
- Unit of Endocrinology, Department of Internal Medicine, Tampere University Hospital, Teiskontie Tampere, Tampere, Finland
| | | | - Jon Arne Søreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
| | - Tapani Ebeling
- Faculty of Medicine, University of Oulu, Finland and Division of Endocrinology, Oulu University Hospital, Oulu, Finland
| | - Fredrik Lindberg
- Department of Surgery, Norrland University Hospital, Umeå, Sweden
| | - Kalle Landerholm
- Department of Clinical and Experimental Medicine, Linköping University and Department of Surgery, Ryhov County Hospital, Jönköping, Sweden
| | - Goran Wallin
- Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden
| | - Farhad Salem
- Skånes University Hospital, Unit for Endocrine and Sarcoma Surgery, Lund, Sweden
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Muniraj T, Aslanian HR. Pancreatic Neuroendocrine Tumors. GERIATRIC GASTROENTEROLOGY 2021:1933-1951. [DOI: 10.1007/978-3-030-30192-7_81] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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17
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Cavalcoli F, Rossi RE, Massironi S. Circulating Biochemical Markers of Gastro-Entero-Pancreatic (GEP) Neuroendocrine Neoplasms (NENs). NEUROENDOCRINE NEOPLASIA MANAGEMENT 2021:55-74. [DOI: 10.1007/978-3-030-72830-4_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Rossi RE, Invernizzi P, Mazzaferro V, Massironi S. Response and relapse rates after treatment with long-acting somatostatin analogs in multifocal or recurrent type-1 gastric carcinoids: A systematic review and meta-analysis. United European Gastroenterol J 2020; 8:140-147. [PMID: 32213066 PMCID: PMC7079271 DOI: 10.1177/2050640619890465] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 10/29/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Type-1 gastric neuroendocrine tumors represent a recurring disease and long-acting somatostatin analogs can inhibit both gastrin release and endocrine cell proliferation. The efficacy and timing of this treatment are still unclear. We performed a systematic review of the literature to clarify the role of somatostatin analog treatment in type-1 gastric neuroendocrine tumors. METHODS A computerized literature search was performed using relevant keywords to identify all the pertinent articles published in the last 15 years. RESULTS Eight studies were included in this systematic review on somatostatin analogs in type-1 gastric neuroendocrine tumors. A complete response rate ranged from 25-100%. When only the six prospective studies were considered, no significant heterogeneity was observed, and the pooled cumulative complete response rate was 84.5% (confidence interval 73.8-92.8). Three studies evaluated the type-1 gastric neuroendocrine tumor recurrence, with a cumulative relapse rate of 30.2% (confidence interval 13.1-50.6) after 34 months. CONCLUSION Somatostatin analogs, namely lanreotide and octreotide, have an excellent response rate, with a good safety profile in selected type-1 gastric neuroendocrine tumors, which cannot be safely managed by endoscopic follow-up or resection due to multiple or frequently recurring disease. After therapy discontinuation, the cumulative relapse rate observed after a median 34-month follow-up was relatively high (30.2%).
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Affiliation(s)
- Roberta Elisa Rossi
- Gastrointestinal and Hepato-Pancreatic Surgery and Liver Transplantation Unit, Fondazione, RCCS Istituto Nazionale Tumori (INT, National Cancer Institute) and Università degli Studi di Milano, Milan, Italy
| | - Pietro Invernizzi
- Department of Gastroenterology and Center for Liver Autoimmune Diseases, San Gerardo Hospital, Monza, Italy
| | - Vincenzo Mazzaferro
- Gastrointestinal and Hepato-Pancreatic Surgery and Liver Transplantation Unit, Fondazione, RCCS Istituto Nazionale Tumori (INT, National Cancer Institute) and Università degli Studi di Milano, Milan, Italy
| | - Sara Massironi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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19
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Malczewska A, Kos-Kudła B, Kidd M, Drozdov I, Bodei L, Matar S, Oberg K, Modlin IM. The clinical applications of a multigene liquid biopsy (NETest) in neuroendocrine tumors. Adv Med Sci 2020; 65:18-29. [PMID: 31841822 PMCID: PMC7453408 DOI: 10.1016/j.advms.2019.10.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/19/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE There are few effective biomarkers for neuroendocrine tumors. Precision oncology strategies have provided liquid biopsies for real-time and tailored decision-making. This has led to the development of the first neuroendocrine tumor liquid biopsy (the NETest). The NETest represents a transcriptomic signature of neuroendocrine tumor (NETs) that captures tumor biology and disease activity. The data have direct clinical application in terms of identifying residual disease, disease progress and the efficacy of treatment. In this overview we assess the available published information on the metrics and clinical efficacy of the NETest. MATERIAL AND METHODS Published data on the NETest have been collated and analyzed to understand the clinical application of this multianalyte biomarker in NETs. RESULTS NETest assay has been validated as a standardized and reproducible clinical laboratory measurement. It is not affected by demographic characteristics, or acid suppressive medication. Clinical utility of the NETest has been documented in gastroenteropancreatic, bronchopulmonary NETs, in paragangliomas and pheochromocytomas. The test facilitates accurate diagnosis of a NET disease, and real-time monitoring of the disease status (stable/progressive disease). It predicts aggressive tumor behavior, identifies operative tumor resection, and efficacy of the medical treatment (e.g. somatostatin analogues), or peptide receptor radionuclide therapy (PRRT). NETest metrics and clinical applications out-perform standard biomarkers like chromogranin A. CONCLUSIONS The NETest exhibits clinically competent metrics as an effective biomarker for neuroendocrine tumors. Measurement of NET transcripts in blood is a significant advance in neuroendocrine tumor management and demonstrates that blood provides a viable source to identify and monitor tumor status.
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Affiliation(s)
- Anna Malczewska
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland.
| | - Beata Kos-Kudła
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Mark Kidd
- Wren Laboratories, Branford, CT, USA
| | | | - Lisa Bodei
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Kjell Oberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden
| | - Irvin M Modlin
- Gastroenterological Surgery, Yale University School of Medicine, New Haven, CT, USA
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The impact of surgery for metastatic pancreatic neuroendocrine tumor: a contemporary evaluation matching for chromogranin a level. HPB (Oxford) 2020; 22:83-90. [PMID: 31239188 DOI: 10.1016/j.hpb.2019.05.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 05/07/2019] [Accepted: 05/16/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Studies supporting surgical management of metastatic pancreatic neuroendocrine tumor (PNET) are limited by selection bias. Chromogranin A (CgA) has been used as a biomarker for PNET and may reflect disease burden or biology. This study aimed to correlate CgA level with overall survival and to use it to match patients selected for different treatment approaches in an analysis of the impact of surgical management. METHODS 1478 patients diagnosed with PNET in the National Cancer Database (2004-2014) were retrospectively identified, and logistic regression analyses were used to evaluate associations between the presence of metastatic disease and CgA level. After matching patients by CgA level and other factors predictive of surgical management, Kaplan-Meier survival analysis was performed. RESULTS Median CgA level was significantly higher in metastatic versus localized PNET(169 ng/mL versus 66 ng/mL, p < 0.001). On multivariate logistic regression, CgA level was predictive of metastatic disease(OR 1.002, p < 0.001) and survival in metastatic and non-metastatic patients. After matching for CgA level, surgery was associated with improved overall survival. DISCUSSION CgA level is predictive of the presence of distant metastatic disease and overall survival in PNET. When matched by CgA and other predictors of treatment approach, patients with metastatic PNET undergoing surgery have improved survival.
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21
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Asban A, Patel AJ, Reddy S, Wang T, Balentine CJ, Chen H. Cancer of the Endocrine System. ABELOFF'S CLINICAL ONCOLOGY 2020:1074-1107.e11. [DOI: 10.1016/b978-0-323-47674-4.00068-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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22
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Dam G, Grønbæk H, Sorbye H, Thiis Evensen E, Paulsson B, Sundin A, Jensen C, Ebbesen D, Knigge U, Tiensuu Janson E. Prospective Study of Chromogranin A as a Predictor of Progression in Patients with Pancreatic, Small-Intestinal, and Unknown Primary Neuroendocrine Tumors. Neuroendocrinology 2020; 110:217-224. [PMID: 31578011 DOI: 10.1159/000503833] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 09/24/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND Retrospective studies are conflicting but most of them report that an increase in plasma chromogranin A (CgA) predicts tumor progression in neuroendocrine tumor (NET) patients. Prospectively, we investigated if a change in plasma CgA is associated with tumor burden changes in NET patients with disseminated disease. METHODS We included 239 patients treated at 5 NET centers from December 2010 to December 2013. CgA was measured within 6 weeks of a CT or MRI in a patient undergoing at least 2 scan examinations performed over a period of 1-24 months. In a post hoc analysis, CgA measured 3-6 months prior to the CT/MRI was analyzed. Changes in tumor size were evaluated by RECIST1.1. A 25% change in CgA was chosen to discriminate between increased, decreased, or unchanged levels. RESULTS In 671 events (2 CT/MRI scans and 2 corresponding CgA measurements), we found a weak positive correlation between the RECIST 1.1 responses and change in plasma CgA from baseline (Spearman's rank correlation coefficient: 0.15; p < 0.05). Of 304 events in the post hoc analysis, 58 showed progression, 228 showed stable disease, and 18 showed regression, with a median change in CgA of 19% (IQR: 57 to -20%), -12% (23 to -38%), and -73% (-55 to -83%), respectively. The correlation coefficient for all sites was 0.17 (p = 0.003), and it was 0.16 (p = 0.07), 0.18 (p = 0.04), and 0.20 (p = 0.21) for small-intestinal (n = 137), pancreatic (n = 123), and unknown primary NET (n = 40), respectively. In the 58 patients showing tumor progression, the sensitivity and specificity of an increased CgA concentration were 36 and 82%, respectively, with positive and negative predictive values of 32 and 85%. CONCLUSIONS In this prospective study of gastroenteropancreatic NET patients, we observed only a weak association between a change in plasma CgA and changes in tumor burden. CgA as a single biomarker was thus inadequate to predict tumor progression.
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Affiliation(s)
- Gitte Dam
- Department of Hepatology and Gastroenterology, Neuroendocrine Tumour Centre of Excellence, Aarhus University Hospital, Aarhus, Denmark,
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Neuroendocrine Tumour Centre of Excellence, Aarhus University Hospital, Aarhus, Denmark
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, and Clinical Science, University of Bergen, Bergen, Norway
| | - Espen Thiis Evensen
- Neuroendocrine Tumor Center of Excellence, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | | | - Anders Sundin
- Department of Radiology, Institute of Surgical Sciences, Uppsala University, and Neuroendocrine Tumor Centre of Excellence, Uppsala University Hospital, Uppsala, Sweden
| | - Claus Jensen
- Department of Radiology, Neuroendocrine Tumour Centre of Excellence, Rigshospitalet, Copenhagen, Denmark
| | - Dyveke Ebbesen
- Department of Radiology, Neuroendocrine Tumour Centre of Excellence, Aarhus University Hospital, Aarhus, Denmark
| | - Ulrich Knigge
- Departments of Endocrinology and Surgical Gastroenterology, Neuroendocrine Tumour Centre of Excellence, Rigshospitalet, Copenhagen, Denmark
| | - Eva Tiensuu Janson
- Department of Medical Sciences, Neuroendocrine Tumor Centre of Excellence, Uppsala University, Uppsala, Sweden
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23
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Amiri FS. Prevalence of Diagnostic Methods and Treatment Modalities in Vipoma Patients: A Rare Cause of Hormone-Mediated Diarrhea. Indian J Endocrinol Metab 2019; 23:318-325. [PMID: 31641634 PMCID: PMC6683692 DOI: 10.4103/ijem.ijem_105_19] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION VIPoma is a neuroendocrine tumor that secrets vasoactive intestinal peptide and produces a well-defined clinical syndrome characterized by watery diarrhea, hypokalemia, hypochlorhydria and metabolic acidosis. The aim of this study to investigate clinical studies about diagnostic and therapeutic modalities of vipoma patients. In this retrospective study, all patients of vipoma were investigated. Clinical features, laboratory data at initial presentation, management and outcomes were collected. SUBJECTS AND METHODS The paper has written based on searching PubMed and Google Scholar to identify potentially relevant articles or abstracts. Categorical variables as percentage and continuous variables were reported as mean ± standard deviation (SD). RESULTS All the patients presented with watery diarrhea (30/30, 100%) and dehydration was reported in 33.3% of them. Prevalence of laboratory findings in these patients were assessed for hypokalaemia (25/30, 83.3%), metabolic acidosis (9/30, 33.6%), hypochloremia and achlorhydria (2/30, 6.6%). Elevated VIP levels have been seen in 73.3% patients with mean values of 882.85 ± 1134.87 pg/ml. Prevalence of diagnostic methods included CT scan in 19 patients (19/30, 63.3%), ultrasonography (15/50, 50%), and somatostatin receptor scintigraphy (8/30, 26.6%). Medical treatments included somatostatin and analogues in 18 patients (18/30, 60%). Surgery included less percentage of treatment in these patients. CONCLUSION CT scan can be used as a reliable modality for diagnosis of vipoma and somatostatin analogues can be used as the most effective treatment in vipoma patients. Surveillance of these patients needs to close monitoring of patients via history, physical examination, laboratory and imaging.
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Affiliation(s)
- Fateme Shamekhi Amiri
- Imam Khomeini Hospital Complex, Faculty of Medicine, National Tehran University of Medical Sciences, Tehran, Iran
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24
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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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Moschovis D, Vasilaki E, Tzouvala M, Karamanolis G, Katifelis H, Legaki E, Vezakis A, Aravantinos G, Gazouli M. Association between genetic polymorphisms in long non-coding RNAs and pancreatic cancer risk. Cancer Biomark 2019; 24:117-123. [PMID: 30475759 DOI: 10.3233/cbm-181959] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are emerging as candidate biomarkers of cancer, having regulatory functions in both oncogenic and tumor-suppressive pathways. Concerning pancreatic cancer (PC), deregulation of lncRNAs involved in tumor initiation, invasion, and metastasis seem to play a key role. However, data is scarce about regulatory mechanism of lncRNA expression. OBJECTIVE The aim of our study was to investigate the contribution of two lncRNAs polymorphisms (rs1561927 and rs4759313 of PVT1 and HOTAIR, respectively) in PC susceptibility. METHODS A case-control study was conducted analysing rs1561927 and rs4759313 polymorphisms using DNA collected in a population-based case-control study of pancreatic cancer (111 pancreatic ductal adenocarcinoma cases (PDAC), 56 pancreatic neuroendocrine tumor (PNET), and 125 healthy controls). RESULTS Regarding the PVT1 rs1561927 polymorphism the G allele was significantly overrepresented in both PDAC and PNET patients compared to the controls, while the presence of the HOTAIR rs4759314 G allele was found to be overrepresented in the PNET patients only compared to the controls. The PVT1 rs1561927 AG/GG genotypes were associated with poor overall survival in PDAC patients. CONCLUSIONS Our results suggested that polymorphisms of these two lncRNA polymorphisms implicated in pancreatic carcinogenesis. Further large-scale and functional studies are needed to confirm our results.
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Affiliation(s)
- D Moschovis
- Department of Gastroenterology, General Hospital of Nikea and Piraeus "Agios Panteleimon", Nikea, Greece
| | - E Vasilaki
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - M Tzouvala
- Department of Gastroenterology, General Hospital of Nikea and Piraeus "Agios Panteleimon", Nikea, Greece
| | - G Karamanolis
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - H Katifelis
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - E Legaki
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - A Vezakis
- Second Department of Surgery, Aretaieion University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - G Aravantinos
- Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece
| | - M Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Baudin E, Hayes AR, Scoazec JY, Filosso PL, Lim E, Kaltsas G, Frilling A, Chen J, Kos-Kudła B, Gorbunova V, Wiedenmann B, Nieveen van Dijkum E, Ćwikła JB, Falkerby J, Valle JW, Kulke MH, Caplin ME. Unmet Medical Needs in Pulmonary Neuroendocrine (Carcinoid) Neoplasms. Neuroendocrinology 2019; 108:7-17. [PMID: 30248673 DOI: 10.1159/000493980] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 09/16/2018] [Indexed: 11/19/2022]
Abstract
Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future.
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Affiliation(s)
- Eric Baudin
- Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave Roussy, Villejuif, France
| | - Aimee R Hayes
- Neuroendocrine Tumour Unit, Royal Free Hospital, London, United Kingdom
| | | | | | - Eric Lim
- Department of Thoracic Surgery, Royal Brompton Hospital, London, United Kingdom
| | - Gregory Kaltsas
- Department of Pathophysiology, Division of Endocrinology, National University of Athens, Athens, Greece
| | - Andrea Frilling
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Jie Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Beata Kos-Kudła
- Slaska Akademia Medyczna Klinika Endokrynologii, Zabrze, Poland
| | - Vera Gorbunova
- FSBI "N.N Blokhin Russian Cancer Research Centre," Russian Academy of Medical Sciences, Moscow, Russian Federation
| | - Bertram Wiedenmann
- Department of Hepatology and Gastroenterology, Campus Charité Mitte and Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | | | - Jaroslaw B Ćwikła
- Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland
| | - Jenny Falkerby
- Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, University of Manchester/Institute of Cancer Sciences, Manchester, United Kingdom
| | - Matthew H Kulke
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Martyn E Caplin
- Neuroendocrine Tumour Unit, Royal Free Hospital, London, United
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Grozinsky-Glasberg S, Alexandraki KI, Angelousi A, Chatzellis E, Sougioultzis S, Kaltsas G. Gastric Carcinoids. Endocrinol Metab Clin North Am 2018; 47:645-660. [PMID: 30098721 DOI: 10.1016/j.ecl.2018.04.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastric carcinoids, formally named gastric neuroendocrine neoplasms (NENs), are derived from enterochromaffin-like cells of the stomach and are increasingly diagnosed. A majority are designated as type I (related to autoimmune gastritis) and type II (related to gastrinoma) neoplasms that develop secondary to gastrin hypersecretion. Types I and II gastric carcinoids are mostly small-sized (1-2 cm), multiple, low-malignancy potential lesions mainly confined to the gastric mucosa/submucosa. These lesions have an indolent course and low metastatic potential. In contrast, type III gastric carcinoids are single, larger-sized (>2 cm), non-gastrin-related lesions that infiltrate the muscular layers associated with local and distant metastases.
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Affiliation(s)
- Simona Grozinsky-Glasberg
- Neuroendocrine Tumor Unit, Department of Endocrinology, Hadassah-Hebrew University Medical Center, P.O.B. 12000, Jerusalem 91120, Israel
| | - Krystallenia I Alexandraki
- 1st Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, Athens 11527, Greece
| | - Anna Angelousi
- 1st Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, Athens 11527, Greece
| | - Eleftherios Chatzellis
- 1st Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, Athens 11527, Greece
| | - Stavros Sougioultzis
- Department of Pathophysiology, National and Kapodistrian University of Athens, Mikras Asias 75, Athens 11527, Greece
| | - Gregory Kaltsas
- 1st Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens, Mikras Asias 75, Athens 11527, Greece.
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Marotta V, Zatelli MC, Sciammarella C, Ambrosio MR, Bondanelli M, Colao A, Faggiano A. Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame. Endocr Relat Cancer 2018; 25:R11-R29. [PMID: 29066503 DOI: 10.1530/erc-17-0269] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 10/24/2017] [Indexed: 12/13/2022]
Abstract
Owing to the heterogeneity of neuroendocrine neoplasms (NENs), the availability of reliable circulating markers is critical for improving diagnostics, prognostic stratification, follow-up and definition of treatment strategy. This review is focused on chromogranin A (CgA), a hydrophilic glycoprotein present in large dense core vesicles of neuroendocrine cells. Despite being long identified as the most useful NEN-related circulating marker, clinical application of CgA is controversial. CgA assays still lack standardization, thus hampering not only clinical management but also the comparison between different analyses. In the diagnostic setting, clinical utility of CgA is limited as hampered by (a) the variety of oncological and non-oncological conditions affecting marker levels, which impairs specificity; (b) the fact that 30-50% of NENs show normal CgA, which impairs sensitivity. Regarding the prognostic phase, there is prospective evidence which demonstrates that advanced NENs secreting CgA have poorer outcome, as compared with those showing non-elevated marker levels. Although the identification of cut-offs allowing a proper risk stratification of CgA-secreting patients has not been performed, this represents the most important clinical application of the marker. By contrast, based on prospective studies, the trend of elevated circulating CgA does not represent a valid indicator of morphological evolution and has therefore no utility for the follow-up phase. Ultimately, current knowledge about the role of the marker for the definition of treatment strategy is poor and is limited by the small number of available studies, their prevalent retrospective nature and the absence of control groups of untreated subjects.
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Affiliation(s)
- Vincenzo Marotta
- Department of Clinical Medicine and SurgeryFederico II University, Naples, Italy
| | - Maria Chiara Zatelli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | | | - Maria Rosaria Ambrosio
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Marta Bondanelli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and SurgeryFederico II University, Naples, Italy
| | - Antongiulio Faggiano
- Thyroid and Parathyroid Surgery UnitIstituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione G. Pascale' - IRCCS, Naples, Italy
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Rossi RE, Ciafardini C, Sciola V, Conte D, Massironi S. Chromogranin A in the Follow-up of Gastroenteropancreatic Neuroendocrine Neoplasms: Is It Really Game Over? A Systematic Review and Meta-analysis. Pancreas 2018; 47:1249-1255. [PMID: 30325865 DOI: 10.1097/mpa.0000000000001184] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Little is known about chromogranin A (CgA) during follow-up of gastroenteropancreatic neuroendocrine neoplasms. We hypothesized that serial CgA monitoring might be useful for the assessment of tumor progression, and we performed a systematic review of the literature and meta-analysis. METHODS A bibliographical search was performed in PubMed using "chromogranin A" and "neuroendocrine tumors" and "follow-up" and "biomarker" to identify all pertinent articles published in the last 10 years. RESULTS Eight studies were included in current meta-analysis. Chromogranin A as a follow-up marker shows sensitivity between 46% and 100% and specificity between 68% and 90%. The meta-analysis results showed an overall accuracy of 84% (95% confidence interval [CI], 81-86.6), a cumulative sensitivity of 74.6% (95% CI, 61.9-85.4), and a cumulative specificity of 84.7% (95% CI, 81.3-87.7). These data indicate that circulating CgA has a better overall accuracy in the follow-up setting; it can be used to rule the diagnosis of recurrence/progression in, rather than to rule it out. CONCLUSIONS Chromogranin A is more reliable when used to monitor disease progression and response to treatment and for the early detection of recurrence after treatment rather than in the diagnostic setting. It is more sensible to use this marker in those cases where the initial values were impaired.
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Affiliation(s)
- Roberta Elisa Rossi
- From the Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Department of Pathofisiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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Koenig A, Krug S, Mueller D, Barth PJ, Koenig U, Scharf M, Ellenrieder V, Michl P, Moll R, Homayunfar K, Kann PH, Stroebel P, Gress TM, Rinke A. Clinicopathological hallmarks and biomarkers of colorectal neuroendocrine neoplasms. PLoS One 2017; 12:e0188876. [PMID: 29232390 PMCID: PMC5726657 DOI: 10.1371/journal.pone.0188876] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 11/14/2017] [Indexed: 12/29/2022] Open
Abstract
Chromogranin A (CgA) is a well-established marker for diagnosis and follow up of patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Recently, it has been shown that plasma levels of CgA correlate with tumor load and predict survival of patients with NEN of the small bowel. It is assumed that this is as well valid for NEN of the colon and rectum, however, this is not supported by data. To evaluate this assumption, we analyzed 62 patients with NEN of the colon and rectum listed in the Marburg GEP-NEN registry for clinicopathological characteristics, expression and plasma levels of CgA. The present study demonstrates that immunohistochemical CgA and synaptophysin are good markers for histological diagnosis in patients with NEN of the colon and rectum. However, plasma CgA is a poor marker to follow-up these patients because only a minority exhibited increased levels which did not increase significantly during tumor progression. In contrast to NEN of the small bowel, there is no correlation of CgA plasma levels with tumor burden or survival. Patients with NEN of the colon and rectum displayed a relatively good prognosis resulting in a median survival of 8.5 years. However, a subset of patients affected by G3 neoplasms, exhibited a poorer prognosis with a median survival of 2.5 years. Taken together, CgA is a valuable marker for immunohistochemical diagnosis, but CgA plasma concentration is not suitable to mirror tumor burden or prognosis in patients with NEN of the colon and rectum.
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Affiliation(s)
- Alexander Koenig
- Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany
- * E-mail: (AK); (AR)
| | - Sebastian Krug
- Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany
- Department of Internal Medicine I, University Halle, Halle, Germany
| | - Daniela Mueller
- Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany
| | - Peter J. Barth
- Gerhard-Domagk-Institute of Pathology, University of Muenster, Muenster, Germany
- Department of Pathology, Philipps-University of Marburg, Marburg, Germany
| | - Ute Koenig
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany
| | - Michael Scharf
- Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany
| | - Volker Ellenrieder
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Goettingen, Germany
| | - Patrick Michl
- Department of Internal Medicine I, University Halle, Halle, Germany
| | - Roland Moll
- Department of Pathology, Philipps-University of Marburg, Marburg, Germany
| | - Kia Homayunfar
- Department of General-, Visceral- and Pediatric Surgery University Medical Center Goettingen, Goettingen, Germany
| | - Peter Herbert Kann
- Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany
| | - Philipp Stroebel
- Department of Pathology, University Medical Center Goettingen, Goettingen, Germany
| | - Thomas M. Gress
- Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany
| | - Anja Rinke
- Department of Gastroenterology and Endocrinology, Philipps-University of Marburg, Marburg, Germany
- * E-mail: (AK); (AR)
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31
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Luo G, Jin K, Cheng H, Liu C, Guo M, Lu Y, Yang C, Xu J, Wang W, Gao H, Zhang S, Long J, Xu J, Ni Q, Chen J, Yu X. Carbohydrate antigen 19-9 as a prognostic biomarker in pancreatic neuroendocrine tumors. Oncol Lett 2017; 14:6795-6800. [PMID: 29163700 PMCID: PMC5688789 DOI: 10.3892/ol.2017.7071] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 03/07/2017] [Indexed: 12/11/2022] Open
Abstract
Carbohydrate antigen 19-9 (CA19-9) is not generally considered to be a biomarker in pancreatic neuroendocrine tumors (pNETs), as the majority of pNETs present with a normal range of CA19-9. The present study aimed to evaluate the role of serum CA19-9 levels as a prognostic factor in a relatively large number of patients with pNETs. Consecutive patients were retrospectively collected from a single institution between June 2006 and February 2015. The receiver operating characteristic (ROC) curve and the area under the ROC curve were used to select the cut-off values for the baseline CA19-9 levels. The primary end point was set as overall survival. Potential factors associated with the abnormal elevation of CA19-9 expression levels in pNETs were also investigated. The cut-off value for CA19-9 was 16 U/ml as determined by the ROC curve, and for the area under the ROC curve it was 0.68. In total, 32.7% of patients (51/156) had CA19-9 expression levels higher than the cut-off value. Univariate analysis demonstrated that CA19-9 >16 U/ml was an adverse prognostic factor for patients' overall survival. The CA19-9 >16 U/ml group had a statistically higher proportion of tumor node metastasis (TNM) stage III or IV, as compared with the CA19-9 ≤16 U/ml group. To the best of our knowledge, the present study is the first to demonstrate that CA19-9 is a prognostic biomarker of pNETs, one that may reflect its aggressiveness and severity.
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Affiliation(s)
- Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - He Cheng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Chen Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Meng Guo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Yu Lu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Chao Yang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Jinzhi Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Wenquan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Heli Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Shirong Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Jiang Long
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
| | - Jie Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, P.R. China
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Hontani K, Tsuchikawa T, Hiwasa T, Nakamura T, Ueno T, Kushibiki T, Takahashi M, Inoko K, Takano H, Takeuchi S, Dosaka-Akita H, Kuwatani M, Sakamoto N, Hatanaka Y, Mitsuhashi T, Shimada H, Shichinohe T, Hirano S. Identification of novel serum autoantibodies against EID3 in non-functional pancreatic neuroendocrine tumors. Oncotarget 2017; 8:106206-106221. [PMID: 29290942 PMCID: PMC5739727 DOI: 10.18632/oncotarget.22175] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 10/14/2017] [Indexed: 12/16/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are relatively rare heterogenous tumors, comprising only 1–2% of all pancreatic neoplasms. The majority of pNETs are non-functional tumors (NF-pNETs) that do not produce hormones, and as such, do not cause any hormone-related symptoms. As a result, these tumors are often diagnosed at an advanced stage because patients do not present with specific symptoms. Although tumor markers are used to help diagnosis and predict some types of cancers, chromogranin A, a widely used tumor marker of pNETs, has significant limitations. To identify novel NF-pNET-associated antigens, we performed serological identification of antigens by recombinant cDNA expression cloning (SEREX) and identified five tumor antigens (phosphatase and tensin homolog, EP300-interacting inhibitor of differentiation 3 [EID3], EH domain-containing protein 1, galactoside-binding soluble 9, and BRCA1-associated protein). Further analysis using the AlphaLISA® immunoassay to compare serum antibody levels revealed that antibody levels against the EID3 antigen was significantly higher in the patient group than in the healthy donor group (n = 25, both groups). In addition, higher serum anti-EID3 antibody levels in NF-pNET patients correlated with shorter disease-free survival. The AUC calculated by ROC analysis was 0.784 with moderate diagnostic accuracy. In conclusion, serum anti-EID3 antibody levels may be useful as a tumor marker for prediction of tumor recurrence in NF-pNETs.
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Affiliation(s)
- Koji Hontani
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takahiro Tsuchikawa
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takaki Hiwasa
- Department of Biochemistry and Genetics, Chiba University, Chuo Ku, Chiba 260-8670, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takashi Ueno
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Toshihiro Kushibiki
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Mizuna Takahashi
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Kazuho Inoko
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Hironobu Takano
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Satoshi Takeuchi
- Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Hirotoshi Dosaka-Akita
- Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Masaki Kuwatani
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Yutaka Hatanaka
- Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Tomoko Mitsuhashi
- Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Hideaki Shimada
- Department of Surgery, School of Medicine, Toho University, Ota-ku, Tokyo 143-8541, Japan
| | - Toshiaki Shichinohe
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
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Corti A, Marcucci F, Bachetti T. Circulating chromogranin A and its fragments as diagnostic and prognostic disease markers. Pflugers Arch 2017; 470:199-210. [PMID: 29018988 DOI: 10.1007/s00424-017-2030-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 07/04/2017] [Accepted: 07/06/2017] [Indexed: 12/19/2022]
Abstract
Chromogranin A (CgA), a secretory protein released in the blood by neuroendocrine cells and neurons, is the precursor of various bioactive fragments involved in the regulation of the cardiovascular system, metabolism, innate immunity, angiogenesis, and tissue repair. After the original demonstration that circulating CgA can serve as a biomarker for a wide range of neuroendocrine tumors, several studies have shown that increased levels of CgA can be present also in the blood of patients with cardiovascular, gastrointestinal, and inflammatory diseases with, in certain cases, important diagnostic and prognostic implications. Considering the high structural and functional heterogeneity of the CgA system, comprising precursor and fragments, it is not surprising that the different immunoassays used in these studies led, in some cases, to discrepant results. Here, we review these notions and we discuss the importance of measuring total-CgA, full-length CgA, specific fragments, and their relative levels for a more thorough assessment of the pathophysiological function and diagnostic/prognostic value of the CgA system.
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Affiliation(s)
- Angelo Corti
- Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. .,Vita-Salute San Raffaele University, Milan, Italy.
| | - Fabrizio Marcucci
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
| | - Tiziana Bachetti
- Clinical Trials Centre, Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Pavia, Italy
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Jun E, Kim SC, Song KB, Hwang DW, Lee JH, Shin SH, Hong SM, Park KM, Lee YJ. Diagnostic value of chromogranin A in pancreatic neuroendocrine tumors depends on tumor size: A prospective observational study from a single institute. Surgery 2017; 162:120-130. [DOI: 10.1016/j.surg.2017.01.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Revised: 01/10/2017] [Accepted: 01/26/2017] [Indexed: 12/25/2022]
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35
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Campana D, Ravizza D, Ferolla P, Faggiano A, Grimaldi F, Albertelli M, Ricci C, Santini D, Brighi N, Fazio N, Colao A, Ferone D, Tomassetti P. Risk factors of type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis. A retrospective, multicentre study. Endocrine 2017; 56:633-638. [PMID: 27592118 DOI: 10.1007/s12020-016-1099-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 08/18/2016] [Indexed: 12/11/2022]
Abstract
The aim of this retrospective study was to evaluate the presence of risk factors for a type 1 gastric neuroendocrine neoplasia in a large cohort of patients with chronic atrophic gastritis. The study design consisted of an Italian multicentre, retrospective analysis. The study included all consecutive patients with chronic atrophic gastritis with or without type 1 gastric neuroendocrine neoplasias followed at the participating centres. Two hundred and twenty-nine patients with chronic atrophic gastritis were enroled at the participating centres. A total of 207 patients (154 female, 53 males, median age: 56.0 years) were included in the final analysis. One hundred and twenty-six patients had chronic atrophic gastritis without a gastric neuroendocrine neoplasia and 81 had a chronic atrophic gastritis with type 1 gastric neuroendocrine neoplasia. The median Chromogranin A level, evaluated in 141 patients, was 52.0 U/L. At upper gastrointestinal endoscopy, atrophy of the gastric mucosa was mild/moderate in 137 patients and severe in 68. Intestinal metaplasia of the corpus was present in 168 patients. At histological examination, 81 patients had a gastric neuroendocrine neoplasia (42 patients had a NET G1 and 33 a NET G2). The median Ki67 index was 2.0 %. At univariate and multivariate analysis, the risk factors for a gastric neuroendocrine neoplasia were: male gender, chromogranin A greater than 61 U/L, presence of intestinal metaplasia and age equal to or greater than 59 years. Chromogranin A greater than 61 U/L, the presence of intestinal metaplasia and male gender were independent risk factors for a type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis.
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Affiliation(s)
- Davide Campana
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi University Hospital, Bologna, Italy.
| | - Davide Ravizza
- Division of Endoscopy and Unit of Gastrointestinal and Neuroendocrine Tumours, European Institute of Oncology, Milan, Italy
| | - Piero Ferolla
- Department of Medical Oncology, Multidisciplinary NET Centre, Umbria Regional Cancer Network, Umbria, Italy
| | - Antongiulio Faggiano
- Division of Endocrinology, Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Franco Grimaldi
- Endocrinology and Metabolism Unit, University Hospital S. Maria della Misericordia, Udine, Italy
| | - Manuela Albertelli
- Endocrinology, Department of Internal Medicine and Medical Specialties (DiMI) and Centre of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy
- IRCCS-AOU San Martino-IST, Genova, Italy
| | - Claudio Ricci
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi University Hospital, Bologna, Italy
| | - Donatella Santini
- Dipartimento della medicina diagnostica e della prevenzione, S.Orsola-Malpighi University Hospital, Bologna, Italy
| | - Nicole Brighi
- Department of Experimental, Diagnostic and Specialty medicine S.Orsola-Malpighi University Hospital, Bologna, Italy
| | - Nicola Fazio
- Division of Endoscopy and Unit of Gastrointestinal and Neuroendocrine Tumours, European Institute of Oncology, Milan, Italy
| | - Annamaria Colao
- Division of Endocrinology, Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Diego Ferone
- Endocrinology, Department of Internal Medicine and Medical Specialties (DiMI) and Centre of Excellence for Biomedical Research (CEBR), University of Genova, Genoa, Italy
- IRCCS-AOU San Martino-IST, Genova, Italy
| | - Paola Tomassetti
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi University Hospital, Bologna, Italy
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Rogowski W, Wachuła E, Lewczuk A, Kolasińska-Ćwikła A, Iżycka-Świeszewska E, Sulżyc-Bielicka V, Ćwikła JB. Baseline chromogranin A and its dynamics are prognostic markers in gastroenteropancreatic neuroendocrine tumors. Future Oncol 2017; 13:1069-1079. [DOI: 10.2217/fon-2016-0455] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: This study assessed whether absolute chromogranin A (CgA) values at various stages of treatment have prognostic value in patients with pancreatic and midgut neuroendocrine tumors, subjected to peptide receptor radionuclide therapy with 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. Patients & methods: CgA was determined before peptide receptor radionuclide therapy, 6 weeks, 6, 12, 18 and 24 months after the last dose of 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. The primary end point was overall survival. Results: Elevated baseline CgA concentrations and their relative increase within the first year of observation were unfavorable predictors of overall survival, but not progression. Conclusion: Even a single baseline measurement of CgA can be useful in establishing prognosis in this group, if this parameter exceeds its upper normal limit more than tenfold.
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Affiliation(s)
- Wojciech Rogowski
- Clinical Department of Chemotherapy, Hospital Ministry of the Interior & Administration & Warmia & Mazury Oncology Centre, Olsztyn, Poland
- Department of Medical Science, University of Varmia & Masuria, Olsztyn, Poland
| | - Ewa Wachuła
- Clinical Department of Chemotherapy, Hospital Ministry of the Interior & Administration & Warmia & Mazury Oncology Centre, Olsztyn, Poland
| | - Anna Lewczuk
- Department of Endocrinology, Medical University of Gdańsk, Gdańsk, Poland
| | - Agnieszka Kolasińska-Ćwikła
- Department of Clinical Oncology, Maria-Skłodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland
| | | | | | - Jarosław B Ćwikła
- Department of Medical Science, University of Varmia & Masuria, Olsztyn, Poland
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Gkolfinopoulos S, Tsapakidis K, Papadimitriou K, Papamichael D, Kountourakis P. Chromogranin A as a valid marker in oncology: Clinical application or false hopes? World J Methodol 2017; 7:9-15. [PMID: 28396845 PMCID: PMC5366937 DOI: 10.5662/wjm.v7.i1.9] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 12/15/2016] [Accepted: 01/03/2017] [Indexed: 02/06/2023] Open
Abstract
Chromogranin A, due to its primary expression throughout the neuroendocrine system, is a widely accepted biomarker for the assessment of neuro-endocrine tumors. It has been traditionally used in the management of patients with tumors of gastro-enteropancreatic origin. Lately, it has also been implicated in various conditions and diseases, both benign and malignant. However, the paucity of data of adequate strength, as well as its relation with common physiologic conditions and its interaction with commonly prescribed medications, limit its clinical use in only a narrow spectrum. Herein, we present a thorough review to the most frequent conditions where its levels are affected, focusing specifically on its potential use as a prognostic and predictive biomarker in oncology.
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Dubash SR, Keat N, Mapelli P, Twyman F, Carroll L, Kozlowski K, Al-Nahhas A, Saleem A, Huiban M, Janisch R, Frilling A, Sharma R, Aboagye EO. Clinical Translation of a Click-Labeled 18F-Octreotate Radioligand for Imaging Neuroendocrine Tumors. J Nucl Med 2016; 57:1207-13. [PMID: 27173162 DOI: 10.2967/jnumed.115.169532] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 01/29/2016] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED We conducted the first-in-human study of (18)F-fluoroethyl triazole [Tyr(3)] octreotate ((18)F-FET-βAG-TOCA) in patients with neuroendocrine tumors (NETs) to evaluate biodistribution, dosimetry, and safety. Despite advances in clinical imaging, detection and quantification of NET activity remains a challenge, with no universally accepted imaging standard. METHODS Nine patients were enrolled. Eight patients had sporadic NETs, and 1 had multiple endocrine neoplasia type 1 syndrome. Patients received 137-163 MBq (mean ± SD, 155.7 ± 8 MBq) of (18)F-FET-βAG-TOCA. Safety data were obtained during and 24 h after radioligand administration. Patients underwent detailed whole-body PET/CT multibed scanning over 4 h with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated with OLINDA 1.1. RESULTS All patients tolerated (18)F-FET-βAG-TOCA with no adverse events. Over 60% parent radioligand was present in plasma at 60 min. High tumor (primary and metastases)-to-background contrast images were observed. Physiologic distribution was seen in the pituitary, salivary glands, thyroid, and spleen, with low background distribution in the liver, an organ in which metastases commonly occur. The organs receiving highest absorbed dose were the gallbladder, spleen, stomach, liver, kidneys, and bladder. The calculated effective dose over all subjects (mean ± SD) was 0.029 ± 0.004 mSv/MBq. CONCLUSION The favorable safety, imaging, and dosimetric profile makes (18)F-FET-βAG-TOCA a promising candidate radioligand for staging and management of NETs. Clinical studies in an expanded cohort are ongoing to clinically qualify this agent.
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Affiliation(s)
- Suraiya R Dubash
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Nicholas Keat
- Imanova Centre for Imaging Sciences, London, United Kingdom
| | - Paola Mapelli
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Frazer Twyman
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Laurence Carroll
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Kasia Kozlowski
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Adil Al-Nahhas
- Department of Radiology/Nuclear Medicine, Imperial College Healthcare NHS Trust, London, United Kingdom; and
| | - Azeem Saleem
- Imanova Centre for Imaging Sciences, London, United Kingdom
| | - Mickael Huiban
- Imanova Centre for Imaging Sciences, London, United Kingdom
| | - Ryan Janisch
- Imanova Centre for Imaging Sciences, London, United Kingdom
| | - Andrea Frilling
- Department of Surgery, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Eric O Aboagye
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
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39
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Tian T, Gao J, Li N, Li Y, Lu M, Li Z, Lu Z, Li J, Shen L. Circulating Chromogranin A as A Marker for Monitoring Clinical Response in Advanced Gastroenteropancreatic Neuroendocrine Tumors. PLoS One 2016; 11:e0154679. [PMID: 27159453 PMCID: PMC4861261 DOI: 10.1371/journal.pone.0154679] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Accepted: 04/18/2016] [Indexed: 01/28/2023] Open
Abstract
Chromogranin A (CgA), present in the chromaffin granules of neuroendocrine cells, is a useful biomarker for the diagnosis of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This study was conducted to investigate the potential role of circulating CgA in monitoring clinical response in Chinese patients with advanced GEP-NETs. Eighty patients with advanced GEP-NETs treated in Peking University Cancer Hospital from September 2011 to May 2014 and 65 healthy individuals were included in this study. Serum CgA levels were analyzed for relationship with patient's baseline characteristics and clinical outcome. Median CgA levels were significantly higher in patients with advanced GEP-NETs than in healthy individuals (93.8 ng/mL vs. 37.1 ng/mL; P<0.01), as well as significantly higher in patients with carcinoid syndrome or liver metastasis than in those without carcinoid syndrome (298.8 ng/mL vs. 82.9 ng/mL; P = 0.011) or liver metastasis (137.0 ng/mL vs. 64.4 ng/mL; P = 0.023). A CgA cutoff value of 46.2 ng/mL was used in this study with a sensitivity of 78.8% and specificity of 73.8%. Patients with CgA levels higher than 46.2 ng/mL had a worse prognosis than patients with CgA levels lower than 46.2 ng/mL (P = 0.045). Notably, a weak correlation was observed between changes in serum CgA levels and clinical response to the IP regimen as well as SSAs. Our data also indicate that serum CgA could be a useful indicator of patient prognosis though there is more research required in order to validate such claims.
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Affiliation(s)
- Tiantian Tian
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jing Gao
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Na Li
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanyan Li
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ming Lu
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhongwu Li
- Department of Pathology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhihao Lu
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jie Li
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
- * E-mail: (LS); (JL)
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
- * E-mail: (LS); (JL)
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Abstract
As our knowledge of the mechanisms underlying cancer development and progression has increased, so too have more effective, less toxic, and targeted therapies begun to reach the clinic. However, the full impact of these clinical advances and the practical success of the emerging field of precision medicine are dependent on the discovery and validation of sensitive and accurate biomarkers that can enable appropriate and rigorous sample type and patient selection, reliable longitudinal monitoring of therapeutic efficacy, and even risk assessment and early detection. Within the context of this review, we examine state-of-the-art approaches to the discovery and validation of noninvasive cancer biomarkers, with a specific emphasis on those that are protein or protein-associated ones. We also review sample selection strategies, currently utilized proteomic approaches for both discovery and validation requirements, and data analysis standards. Finally, we provide examples of these elements of biomarker discovery and validation from our own biomarker research.
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Anderson CW, Bennett JJ. Clinical Presentation and Diagnosis of Pancreatic Neuroendocrine Tumors. Surg Oncol Clin N Am 2016; 25:363-74. [PMID: 27013370 DOI: 10.1016/j.soc.2015.12.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic neuroendocrine tumors are a rare group of neoplasms that arise from multipotent stem cells in the pancreatic ductal epithelium. Although they comprise only 1% to 2% of pancreatic neoplasms, their incidence is increasing. Most pancreatic neuroendocrine tumors are nonfunctioning, but they can secrete various hormones resulting in unique clinical syndromes. Clinicians must be aware of the diverse manifestations of this disease, as the key step to management of these rare tumors is to first suspect the diagnosis.
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Affiliation(s)
- Carinne W Anderson
- Department of Surgery, Helen F. Graham Cancer Center, 4701 Ogletown-Stanton Road, S-4000, Newark, DE 19713, USA.
| | - Joseph J Bennett
- Department of Surgery, Helen F. Graham Cancer Center, 4701 Ogletown-Stanton Road, S-4000, Newark, DE 19713, USA
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Gut P, Czarnywojtek A, Fischbach J, Bączyk M, Ziemnicka K, Wrotkowska E, Gryczyńska M, Ruchała M. Chromogranin A - unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls. Arch Med Sci 2016; 12:1-9. [PMID: 26925113 PMCID: PMC4754364 DOI: 10.5114/aoms.2016.57577] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 05/20/2014] [Indexed: 12/13/2022] Open
Abstract
Chromogranin A, despite a number of limitations, is still the most valuable marker of neuroendocrine tumors (NETs). Granins belong to the family of acidic proteins that constitute a major component of secretory granules of various endocrine and neuroendocrine cells, which are components of both the classical endocrine glands and the diffuse neuroendocrine system. These cells are a potential source of transformation into neuroendocrine tumors. The awareness of potential causes influencing the false results of its concentrations simplifies diagnosis and treatment. One of the disadvantages of this marker is its non-specificity and the existence of a number of pathological processes leading to an increase in its concentration, which often results in confusion and diagnostic difficulties. The molecular structure is characterized by a number of sites susceptible to the proteolytic activity of enzymes, resulting in the formation of a number of biologically active peptides. Presumably they act as precursors of active proteins. Chromogranin expression correlates with the amount of secretory vesicles in neuroendocrine cells. The peptide chain during biochemical changes becomes a precursor of biologically active proteins with a wide range of activities. There are a number of commercially available kits for the determination of chromogranin A, which differ in methodology. We present the evaluation of chromogranin A as a marker of neuroendocrine tumors in clinical practice and the possible factors that may affect the outcome of its concentration.
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Affiliation(s)
- Paweł Gut
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Agata Czarnywojtek
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Jakub Fischbach
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Maciej Bączyk
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Elżbieta Wrotkowska
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Maria Gryczyńska
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
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Henderson-Jackson E, Sheikh U, Muhammad J, Coppola D, Nasir A. Neuroendocrine Neoplasms of the Stomach. NEUROENDOCRINE TUMORS: REVIEW OF PATHOLOGY, MOLECULAR AND THERAPEUTIC ADVANCES 2016:217-244. [DOI: 10.1007/978-1-4939-3426-3_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Modlin IM, Bodei L, Kidd M. Neuroendocrine tumor biomarkers: From monoanalytes to transcripts and algorithms. Best Pract Res Clin Endocrinol Metab 2016; 30:59-77. [PMID: 26971844 DOI: 10.1016/j.beem.2016.01.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The management of neuroendocrine neoplasia remains a perplexing problem because of the lack of knowledge of the biology of the disease, its late presentation, the relative insensitivity of imaging modalities and a paucity of predictably effective treatment options. A critical limitation is posed by the lack of accurate biomarkers to guide management, monitor the efficacy of therapy and provide a prognostic assessment of disease progress. Currently utilized monoanalyte biomarkers (e.g. chromogranin, serotonin, pancreastatin etc.) exhibit variable metrics, poor sensitivity, specificity, and predictive ability and are rarely used to guide clinical decision making. A National Cancer Institute Neuroendocrine Tumor summit conference held in 2007 noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumors. Nevertheless little progress has been made in this field until recently with the consideration of blood transcript analysis, circulating tumor cells and miRNA measurement. Given the complexity and multidimensionality of the neoplastic process itself, the heterogeneity of neuroendocrine tumors (NET) as well as the interaction of the tumor microenvironment, it is not unexpected that no single (monoanalyte) biomarker has proven to be effective. This deduction reflects the growing recognition that use of a monoanalyte to define a multidimensional disease process has inherent flaws. Logic dictates that no single measured parameter can capture the pathobiological diversity of neoplasia and monoanalytes cannot define the multiple variables (proliferation, metabolic activity, invasive potential and metastatic propensity) that constitute tumor growth. Thus far, most biomarkers whether in tissue or blood/urine have been single analytes with varying degrees of sensitivity and specificity and in general have failed to exhibit robust metrics or lacked methodological rigor. Neuroendocrine (NE) disease represents an area of biomarker paucity since the individual biomarkers (gastrin, insulin etc) are not widely applicable to the diverse types of NE neoplasia (NEN). Broad spectrum markers such as CgA have limitations in sensitivity, specificity and reproducibility. This review serves to provide a general background of the evolution of NET biomarkers. It provides an assessment of their current and past usage and limitations in assessing their diagnostic, pathologic and prognostic aspects in respect of NET. It provides a view of the changing methodology of biomarker development and the application of biomathematical analyses to redefining detection and treatment. Finally, it presents a description and consensus on current advances in transcript analysis, miRNA measurement and circulating tumor cell identification.
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Affiliation(s)
- Irvin M Modlin
- Emeritus Professor Gastroenterological Surgery, Yale University, School of Medicine, USA.
| | - Lisa Bodei
- Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy
| | - Mark Kidd
- Wren Laboratories, 35 NE Industrial Road, Branford, CT 06405, USA
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Serum chromogranin A levels for the diagnosis and follow-up of well-differentiated non-functioning neuroendocrine tumors. Tumour Biol 2015; 37:2863-9. [DOI: 10.1007/s13277-015-4114-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 09/20/2015] [Indexed: 12/13/2022] Open
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Basuroy R, Sarker D, Quaglia A, Srirajaskanthan R, Ramage J. Personalized medicine for gastroenteropancreatic neuroendocrine tumors: a distant dream? INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2015. [DOI: 10.2217/ije.15.9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Neuroendocrine tumors are heterogeneous cancers that can present with advanced disease. Treatment stratification is often based on limited characterization of tumor behavior from histological grade and imaging assessments. Personalized medicine strategies focus on tailoring therapy through characterization of cancer pathways and the development of biomarkers. This review article explores the current personalized medicine landscape in gastroenteropancreatic neuroendocrine tumors, from tissue and circulating biomarkers development through to tumor heterogeneity and reimbursement issues.
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Affiliation(s)
- Ron Basuroy
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
| | - Debashis Sarker
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
- Department of Research Oncology, Division of Cancer Studies, King's College London, Strand, WC2R 2LS, UK
| | - Alberto Quaglia
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
- Histopathology Department, Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | - Rajaventhan Srirajaskanthan
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
- Gastroenterology Department, University Hospital Lewisham, London, SE13 6LH, UK
| | - John Ramage
- ENETS Neuroendocrine Centre of Excellence, Institute of Liver studies, King's College Hospital, London, SE5 9RS, UK
- Gastroenterology Department, Hampshire Hospitals NHS Trust, Hampshire, RG24 9NA, UK
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A Comparison Between Appendiceal and Nonappendiceal Neuroendocrine Tumors in Children and Young Adults: A Single-institution Experience. J Pediatr Hematol Oncol 2015; 37:438-42. [PMID: 25985239 DOI: 10.1097/mph.0000000000000350] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Pediatric neuroendocrine tumors (NETs) are rare tumors. The purpose of this study is to report the clinical characteristics and outcomes of pediatric patients treated for NET at a single institution. PROCEDURE A retrospective record review. RESULTS There were 33 evaluable patients with median age of 17.9 years (range, 9.9 to 21.9 y) and predominantly females (58%). There were 17 patients with well-differentiated appendiceal NET, whereas 16 were nonappendiceal. Most common nonappendiceal sites were unknown primary (N=6) and pancreas (N=4). Majority of tumors were low grade (N=24, 73%) and small (T1, N=22, 67%). Nonappendiceal tumors were more likely to be larger or high-grade tumors (5/16, 31%), or with metastasis. All appendiceal NET patients underwent curative surgery. All patients who experienced treatment failure had nonappendiceal NET, despite prior chemotherapy in 8 of 9 patients. The 5-year overall survival rates for patients with appendiceal and nonappendiceal NET were 100% and 66% (95% CI, 45%-95%; P=0.006); and 5-year relapse-free survival rate for patients with appendiceal and nonappendiceal NET were 100% and 41% (95% CI, 22%-75%; P=0.002). CONCLUSIONS Well-differentiated appendiceal tumors were the most common pediatric NET and have an excellent prognosis. Better therapies are needed for patients with nonappendiceal NET.
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Rossi RE, Garcia-Hernandez J, Meyer T, Thirlwell C, Watkins J, Martin NG, Caplin ME, Toumpanakis C. Chromogranin A as a predictor of radiological disease progression in neuroendocrine tumours. ANNALS OF TRANSLATIONAL MEDICINE 2015. [PMID: 26207246 DOI: 10.3978/j.issn.2305-5839.2015.04.23] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Chromogranin A (CgA) is the best established neuroendocrine biomarker. This study was aimed at investigating the prognostic value of CgA as a predictor of radiological disease progression in neuroendocrine tumour (NET) patients. METHODS Patients with metastatic NETs and evidence of radiological progression (RP) according to RECIST 1.1 were identified from a NET database. Plasma CgA levels were measured 6 and 12 months before RP and at the event of RP. CgA was measured with the Supra-regional-Assay-Service radioimmunoassay (Hammersmith Hospital). RESULTS A total of 152 patients were evaluated including 91 midgut NETs and 61 pancreatic NETs (PNETs). Of these, 56 were G1 NETs, 65 G2, 10 G3, 21 of unknown histology. For all NETs, there was a positive trend in terms of increase of CgA values 6 months prior to RP compared to 12 months before RP. Subgroup analysis at first episode of RP showed that for PNETs there was evidence of a difference in the median CgA levels. CgA 6 months before RP was 100 pmol/L [interquartile 1 (Q1) =53 and Q3 =286.25 pmol/L) and 12 months before was 52 pmol/L (Q1 =36.25 and Q3 =128 pmol/L), W=52, P=0.48. This observation was not confirmed in midgut NETs, where median CgA 6 months before RP was 389.5 pmol/L (Q1 =131.5 and Q3 =791.5 pmol/L) and 12 months before was 319 pmol/L (Q1 =158 and Q3 =753 pmol/L), W=191, P=0.39]. Low grade tumours (G1) had a median CgA value at 6 months significantly higher than at 12 months [181 (Q1 =56.25, Q3 =624) vs. 149.5 (Q1 =44, Q3 =247.25) pmol/L, W=70, P=0.48]. CONCLUSIONS CgA seems to have predictive value 6 months prior to RP for PNETs and G1 tumours. Further prospective analyses are needed to enable more definitive conclusions.
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Affiliation(s)
- Roberta Elisa Rossi
- 1 Neuroendocrine Tumour Unit, Centre of Gastroenterology, Royal Free Hospital, London, UK ; 2 Gastroenterology and Endoscopy Unit Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy ; 3 Cancer Institute, University College London, London, UK ; 4 Department of Histopathology, 5 Department of Clinical Biochemistry, Royal Free Hospital, London, UK
| | - Jorge Garcia-Hernandez
- 1 Neuroendocrine Tumour Unit, Centre of Gastroenterology, Royal Free Hospital, London, UK ; 2 Gastroenterology and Endoscopy Unit Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy ; 3 Cancer Institute, University College London, London, UK ; 4 Department of Histopathology, 5 Department of Clinical Biochemistry, Royal Free Hospital, London, UK
| | - Tim Meyer
- 1 Neuroendocrine Tumour Unit, Centre of Gastroenterology, Royal Free Hospital, London, UK ; 2 Gastroenterology and Endoscopy Unit Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy ; 3 Cancer Institute, University College London, London, UK ; 4 Department of Histopathology, 5 Department of Clinical Biochemistry, Royal Free Hospital, London, UK
| | - Christina Thirlwell
- 1 Neuroendocrine Tumour Unit, Centre of Gastroenterology, Royal Free Hospital, London, UK ; 2 Gastroenterology and Endoscopy Unit Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy ; 3 Cancer Institute, University College London, London, UK ; 4 Department of Histopathology, 5 Department of Clinical Biochemistry, Royal Free Hospital, London, UK
| | - Jennifer Watkins
- 1 Neuroendocrine Tumour Unit, Centre of Gastroenterology, Royal Free Hospital, London, UK ; 2 Gastroenterology and Endoscopy Unit Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy ; 3 Cancer Institute, University College London, London, UK ; 4 Department of Histopathology, 5 Department of Clinical Biochemistry, Royal Free Hospital, London, UK
| | - Nicholas Guy Martin
- 1 Neuroendocrine Tumour Unit, Centre of Gastroenterology, Royal Free Hospital, London, UK ; 2 Gastroenterology and Endoscopy Unit Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy ; 3 Cancer Institute, University College London, London, UK ; 4 Department of Histopathology, 5 Department of Clinical Biochemistry, Royal Free Hospital, London, UK
| | - Martyn Evan Caplin
- 1 Neuroendocrine Tumour Unit, Centre of Gastroenterology, Royal Free Hospital, London, UK ; 2 Gastroenterology and Endoscopy Unit Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy ; 3 Cancer Institute, University College London, London, UK ; 4 Department of Histopathology, 5 Department of Clinical Biochemistry, Royal Free Hospital, London, UK
| | - Christos Toumpanakis
- 1 Neuroendocrine Tumour Unit, Centre of Gastroenterology, Royal Free Hospital, London, UK ; 2 Gastroenterology and Endoscopy Unit Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy ; 3 Cancer Institute, University College London, London, UK ; 4 Department of Histopathology, 5 Department of Clinical Biochemistry, Royal Free Hospital, London, UK
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Yang X, Yang Y, Li Z, Cheng C, Yang T, Wang C, Liu L, Liu S. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: a systematic review and meta-analysis. PLoS One 2015; 10:e0124884. [PMID: 25894842 PMCID: PMC4403810 DOI: 10.1371/journal.pone.0124884] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 03/18/2015] [Indexed: 02/07/2023] Open
Abstract
Background In previous decades, chromogranin A (CgA) has been demonstrated to be the most promising biomarker for the diagnosis of neuroendocrine tumors (NETs), but its diagnostic value is still controversial. This meta-analysis aimed to estimate the potential diagnostic value of circulating CgA for NETs. Methods We collected relevant studies from several electronic databases as well as from reference lists. Diagnostic indices of CgA were pooled with random effects models. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and summary receiver operating characteristic (SROC) curves for the diagnosis of NETs were used to estimate the overall diagnostic efficiency. Results Through a search strategy, 13 studies met the inclusion criteria and were included. These studies contained 1260 patients with NETs and 967 healthy controls in the total sample. As a result, the overall sensitivity, specificity and diagnostic odds ratio (DOR) were 0.73 (95% CI: 0.71 to 0.76), 0.95 (95% CI: 0.93 to 0.96) and 56.29 (95% CI: 25.27 to 125.38), respectively, while the summary positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 14.56 (95% CI: 6.62 to 32.02) and 0.26 (95% CI: 0.18 to 0.38), respectively. In addition, the area under the curve (AUC) of the circulating CgA in the diagnosis of NETs was 0.8962. Conclusions These data demonstrate that circulating CgA is an efficient biomarker for the diagnosis of NETs with high sensitivity and specificity, which indicates that it may be helpful for the clinical management of NETs. However, further studies are needed to clarify this issue.
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Affiliation(s)
- Xin Yang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan Yang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhilu Li
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chen Cheng
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ting Yang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Cheng Wang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shengchun Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- * E-mail:
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50
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Kim M, Lee S, Lee J, Park SH, Park JO, Park YS, Kang WK, Kim ST. The Role of Plasma Chromogranin A as Assessment of Treatment Response in Non-functioning Gastroenteropancreatic Neuroendocrine Tumors. Cancer Res Treat 2015; 48:153-61. [PMID: 25779359 PMCID: PMC4720067 DOI: 10.4143/crt.2014.183] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 12/30/2014] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Chromogranin A (CgA) has been considered to be valuable not only in the diagnosis but also in monitoring the disease response to treatment. However, only a few studies have been published on this issue. We purposed to evaluate whether biochemical response using plasma CgA level is reliable in concordance with the clinical response of grade 1-3 nonfunctiong gastroenteropancreatic neuroendocrine tumors (GEP-NETs). MATERIALS AND METHODS Between March 2011 and September 2013, a total of 27 cases in 18 patients were analysed, clinically and radiologically while serial CgA tests were also conducted during treatment. Tumor responses were defined by both Response Evaluation Criteria in Solid Tumors (RECIST) criteria ver. 1.1 and biochemical criteria based on the CgA level. RESULTS Among the 27 cases analysed, no difference in the basal CgA level was observed with regard to gender, primary tumor site, tumor grade (World Health Organization classification), liver metastasis, number of metastatic site, and line of chemotherapy. The overall response rate (RR) by RECIST criteria ver. 1.1 was six out of the 27 cases (22.2%) and eight out of the 27 cases (29.6%) for biochemical RR. The overall concordance rates of the response based on RECIST and biochemical criteria were 74%. In grades 1 and 2 GEP-NETs (n=17), the concordance rate of the disease control was 94.1%. There was a significant difference for progression-free survival (PFS) between responders and non-responder in accordance to biochemical criteria (35.73 months vs. 5.93 months, p=0.05). CONCLUSION This study revealed that changes of the plasma CgA levels were associated with tumour response. Additionally, biochemical response based on serial CgA may be a predictive marker for PFS in GEP-NETs.
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Affiliation(s)
- Moonjin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sujin Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Gastrointestinal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Gastrointestinal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Gastrointestinal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Gastrointestinal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Gastrointestinal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Gastrointestinal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea ; Gastrointestinal Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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