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1
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Puranik AD, Dev ID, Prasad V. Frontiers in radiopharmaceuticals for neuroendocrine tumors. J Neuroendocrinol 2025; 37:e70006. [PMID: 39961670 DOI: 10.1111/jne.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 03/20/2025]
Abstract
Neuroendocrine tumors encompass a wide range of tumors which originate from neural crest cells. These tumors were thought to be rare tumors, however, with the advent of advanced diagnostic techniques along with better understanding of the clinical presentation and histology of these tumors, the incidence of these tumors is exponentially rising. As the incidence and detection rate of NENs increased, the concept of 'heterogeneity' came into picture, which in turn led to dual-tracer imaging with addition of FDG PET/CT. Despite an imaging-based decision-making approach for NENs, there is still a significant subset of patients where the imaging-based biomarkers fall short in disease assessment, prognostication and improving outcomes. Alternate pathways as well as better peptide vectors for targeting the somatostatin receptor need to be studied. In this article, we address the existing as well as emerging trends in radiopharmaceuticals used for NENs, which are likely to impact not just the diagnostic algorithms in future, but also management strategies.
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Affiliation(s)
- Ameya D Puranik
- Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Indraja D Dev
- Department of Nuclear Medicine and Molecular Imaging, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Center, Homi Bhabha National Institute, Mumbai, India
| | - Vikas Prasad
- Mallinckrodt Institute of Radiology, Washington University in Saint Louis, Saint Louis, Missouri, USA
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2
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Kong G, Noe G, Chiang C, Herrmann K, Hope TA, Michael M. Assessment of response to PRRT including anatomical and molecular imaging as well as novel biomarkers. J Neuroendocrinol 2025; 37:e13461. [PMID: 39520276 PMCID: PMC11919480 DOI: 10.1111/jne.13461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 09/05/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Peptide receptor radionuclide therapy (PRRT) is an effective treatment for both oncological and hormone control and is a widely accepted standard of care treatment for patients with neuroendocrine neoplasms (NEN). Its use is anticipated to increase significantly, and this demands accurate tools and paradigms to assess treatment response post PRRT. This article outlines the current role and future developments of anatomical, molecular imaging and biomarkers for response assessment to PRRT, highlighting the challenges and provides perspectives for the need to focus on a multimodality, multidisciplinary and individualised approach for patients with this complex heterogeneous disease.
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Affiliation(s)
- Grace Kong
- Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - Geertje Noe
- Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Cherie Chiang
- Department of Internal Medicine, Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
- Department of Diabetes and Endocrinology, Melbourne Health, University of Melbourne, Parkville, Victoria, Australia
| | - Ken Herrmann
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany
| | - Thomas A Hope
- Department of Radiology, San Francisco VA Medical Center, San Francisco, California, USA
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA
| | - Michael Michael
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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3
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Nair G, Black M, Baer K, Welch S, Laidley DT, Goodwin R, Leung M, Phillips WJ, Vickers M, Asmis T, Marginean H, Tsvetkova E. Treatment Patterns of Pancreatic Neuroendocrine Tumor (pNET) Patients at Two Canadian Cancer Centres. Curr Oncol 2025; 32:86. [PMID: 39996886 PMCID: PMC11853972 DOI: 10.3390/curroncol32020086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 02/26/2025] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are rare but increasingly prevalent malignancies with varied prognoses and a diverse range of treatment options, including surgery, somatostatin analogues (SSAs), chemotherapy, targeted therapy, and peptide receptor radionuclide therapy (PRRT). This retrospective cohort study analyzed treatment patterns among 189 pNET patients treated between January 2010 and June 2021 at two Canadian cancer centres: the Verspeeten Family Cancer Centre (VFCC), which offers PRRT, and the Ottawa Hospital Cancer Centre (TOHCC), which does not at the time of the study. Data on demographics, tumor characteristics, and treatment modalities were collected, and statistical analyses were conducted using chi-square, Fisher's exact test, and the Kruskal-Wallis test. Among eligible patients, 53% presented with stage IV disease. Surgical resection was the most common treatment, followed by SSAs, chemotherapy, PRRT, and targeted therapy. Stage IV patients at VFCC were significantly more likely to receive PRRT (60%) compared to TOHCC (6%) and underwent more PRRT cycles, with a higher prevalence of well-differentiated tumors observed at VFCC. With these differences it was clear that the non-PRRT centre was unable to provide patients with the same level of PRRT access during the study period compared to patients seen at the PRRT site. The findings underscore the critical role of PRRT availability in influencing treatment patterns and highlight the need for equitable access to specialized therapies across Canada to optimize outcomes for pNET patients.
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Affiliation(s)
- Gautham Nair
- Schulich School of Medicine and Dentistry, Western University, London, ON N6A 3K7, Canada;
| | - Morgan Black
- London Health Sciences Centre, London, ON N6A 5W9, Canada; (M.B.); (K.B.); (S.W.); (D.T.L.)
| | - Kathie Baer
- London Health Sciences Centre, London, ON N6A 5W9, Canada; (M.B.); (K.B.); (S.W.); (D.T.L.)
| | - Stephen Welch
- London Health Sciences Centre, London, ON N6A 5W9, Canada; (M.B.); (K.B.); (S.W.); (D.T.L.)
| | - David T. Laidley
- London Health Sciences Centre, London, ON N6A 5W9, Canada; (M.B.); (K.B.); (S.W.); (D.T.L.)
| | - Rachel Goodwin
- The Ottawa Hospital (TOH), Ottawa, ON K1H 8L6, Canada; (R.G.); (M.V.); (T.A.)
- Department of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Macyn Leung
- The Ottawa Hospital Research Institute (OHRI), Ottawa, ON K1H 8L6, Canada; (M.L.); (H.M.)
| | | | - Michael Vickers
- The Ottawa Hospital (TOH), Ottawa, ON K1H 8L6, Canada; (R.G.); (M.V.); (T.A.)
- Department of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Tim Asmis
- The Ottawa Hospital (TOH), Ottawa, ON K1H 8L6, Canada; (R.G.); (M.V.); (T.A.)
- Department of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada
| | - Horia Marginean
- The Ottawa Hospital Research Institute (OHRI), Ottawa, ON K1H 8L6, Canada; (M.L.); (H.M.)
| | - Elena Tsvetkova
- London Health Sciences Centre, London, ON N6A 5W9, Canada; (M.B.); (K.B.); (S.W.); (D.T.L.)
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4
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Loree JM, Chan D, Lim J, Stuart H, Fidelman N, Koea J, Posavad J, Cummins M, Doucette S, Myrehaug S, Naraev B, Bailey DL, Bellizzi A, Laidley D, Boyle V, Goodwin R, Del Rivero J, Michael M, Pasieka J, Singh S. Biomarkers to Inform Prognosis and Treatment for Unresectable or Metastatic GEP-NENs. JAMA Oncol 2024; 10:1707-1720. [PMID: 39361298 DOI: 10.1001/jamaoncol.2024.4330] [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: 12/20/2024]
Abstract
Importance Evidence-based treatment decisions for advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) require individualized patient-centered decision-making that accounts for patient and cancer characteristics. Objective To create an accessible guidance document to educate clinicians and patients on biomarkers informing prognosis and treatment in unresectable or metastatic GEP-NENs. Methods A multidisciplinary panel in-person workshop was convened to define methods. English language articles published from January 2016 to January 2023 in PubMed (MEDLINE) and relevant conference abstracts were reviewed to investigate prognostic and treatment-informing features in unresectable or metastatic GEP-NENs. Data from included studies were used to form evidence-based recommendations. Quality of evidence and strength of recommendations were determined using the Grading of Recommendations, Assessment, Development and Evaluations framework. Consensus was reached via electronic survey following a modified Delphi method. Findings A total of 131 publications were identified, including 8 systematic reviews and meta-analyses, 6 randomized clinical trials, 29 prospective studies, and 88 retrospective cohort studies. After 2 rounds of surveys, 24 recommendations and 5 good clinical practice statements were developed, with full consensus among panelists. Recommendations focused on tumor and functional imaging characteristics, blood-based biomarkers, and carcinoid heart disease. A single strong recommendation was made for symptomatic carcinoid syndrome informing treatment in midgut neuroendocrine tumors. Conditional recommendations were made to use grade, morphology, primary site, and urinary 5-hydroxyindoleacetic levels to inform treatment. The guidance document was endorsed by the Commonwealth Neuroendocrine Tumour Collaboration and the North American Neuroendocrine Tumor Society. Conclusions and Relevance The study results suggest that select factors have sufficient evidence to inform care in GEP-NENs, but the evidence for most biomarkers is weak. This article may help guide management and identify gaps for future research to advance personalized medicine and improve outcomes for patients with GEP-NENs.
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Affiliation(s)
- Jonathan M Loree
- BC Cancer, Vancouver Centre, Vancouver, British Columbia, Canada
| | - David Chan
- Northern Clinical School, University of Sydney, Sydney, Australia
- ENETS Centre of Excellence, Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
| | - Jennifer Lim
- St George Hospital, Sydney, New South Wales, Australia
- University of New South Wales, Sydney, New South Wales, Australia
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Heather Stuart
- University of British Columbia and BC Cancer Agency, Vancouver, British Columbia, Canada
| | | | - Jonathan Koea
- Te Whatu Ora Waitemata and the University of Auckland, Auckland, New Zealand
| | - Jason Posavad
- Canadian Neuroendocrine Tumours Society, Cornwall, Ontario, Canada
| | | | | | - Sten Myrehaug
- Odette Cancer Centre, Toronto, Ontario, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Boris Naraev
- Tampa General Hospital Cancer Institute, Tampa, Florida
| | - Dale L Bailey
- Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | | | - David Laidley
- Western University, London, Ontario, Canada
- Lawson Health Research Institute, London, Ontario, Canada
| | - Veronica Boyle
- School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Oncology, Auckland City Hospital, Te Whatu Ora Tamaki Makaurau, Auckland, New Zealand
| | - Rachel Goodwin
- Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Ontario, Canada
| | - Jaydi Del Rivero
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Michael Michael
- NET Unit and ENETS Centre of Excellence, Peter MacCallum Cancer Centre, Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - Janice Pasieka
- Section of General Surgery, Division of Endocrine Surgery and Surgical Oncology, Department of Surgery and Oncology, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
| | - Simron Singh
- University of Toronto, Toronto, Ontario, Canada
- Sunnybrook Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada
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Hoff CO, Manzi J, Ferreira R, Chauhan A, Housein P, Merchant N, Livingstone A, Vianna R, Abreu P. A neuroendocrine biomarker revolution from monoanalyte to multianalyte biomarkers in non-functioning gastro-entero-pancreatic neuroendocrine neoplasms. Crit Rev Oncol Hematol 2024; 203:104460. [PMID: 39153703 DOI: 10.1016/j.critrevonc.2024.104460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/19/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) arise from neuroendocrine cells in a wide variety of organs. One of the most affected disease sites is the gastrointestinal system, which originates the gastro-entero-pancreatic NENs (GEP-NENs), a heterogenous group of malignancies that are rapidly increasing in incidence. These tumors can be functioning, with secretory activity leading to identifiable clinical syndromes, or non-functioning, with no secretory activity but with local symptoms of tumor growth and metastasis. A limitation in biomarkers is a crucial unmet need in non-secretory NEN management, as clinical decision-making is made more difficult by obstacles in tumor classification, prognostic evaluation, assessment of treatment response and surveillance. The objective of this review is to present existing and novel biomarkers for NENs that can function as prognostic factors and monitor disease progression or regression longitudinally, with a special emphasis on innovative research into novel multianalyte biomarkers.
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Affiliation(s)
- Camilla O Hoff
- University of Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, Brazil; Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, USA
| | - Joao Manzi
- University of Sao Paulo Medical School, University of Sao Paulo, Sao Paulo, Brazil
| | - Raphaella Ferreira
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, USA
| | - Aman Chauhan
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Peter Housein
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Nipun Merchant
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Alan Livingstone
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Rodrigo Vianna
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, USA
| | - Phillipe Abreu
- Division of Transplant Surgery, University of Colorado Anschutz Medical Campus, USA.
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Sorbye H, Hjortland GO, Vestermark LW, Sundlov A, Assmus J, Couvelard A, Perren A, Langer SW. NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms. J Neuroendocrinol 2024; 36:e13428. [PMID: 38937137 DOI: 10.1111/jne.13428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/10/2024] [Accepted: 06/11/2024] [Indexed: 06/29/2024]
Abstract
Molecular blood biomarkers are lacking for high-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). To histologically distinguish between neuroendocrine carcinoma (NEC), neuroendocrine tumors G3 (NET G3), adenocarcinoma and MINEN is often challenging. The mRNA-based NETest has diagnostic, prognostic and predictive value in neuroendocrine tumors G1-2 but has not been studied in HG GEP-NEN. Patients with advanced HG GEP-NEN were prospectively included in an observational study. A blood sample was collected before the start of chemotherapy and pseudonymised before NETest was performed. NETest results are expressed as an activity index (NETest score) from 0 to 100. The normal score cut-off is 20. Histological sections were pseudonymised before centralized pathological re-evaluation. Samples from 60 patients were evaluable with the NETest. Main primary tumor sites were colon (14), rectum (12), pancreas (11) and esophagus (7). Re-classification: 30 NEC, 12 NET G3, 3 HG-NEN ambiguous morphology, 8 MiNEN, 3 adenocarcinomas with neuroendocrine differentiation (ADNE), 3 adenocarcinomas and 1 NET G2. Elevated NETest (>20) was seen in 38/45 (84%) HG GEP-NEN, all 17 large-cell NEC (100%), 11/13 (85%) small-cell NEC, all ambiguous cases and 7/12 (64%) NET G3. NETest was elevated in 5/8 (63%) MiNEN, 2/3 ADNE, however not in 3 adenocarcinomas. Median survival was 10.2 months (9.6-10.8 95%CI) for evaluable HG GEP-NEN treated with palliative chemotherapy (n = 39), and survival was significantly shorter in patients with NETest >60 with an OS of only 6.5 months. This is the first study to evaluate use of the NETest in advanced HG GEP-NEN. The NETest was almost always elevated in GEP-NEC and in all large-cell NEC. The NETest was also frequently elevated in NET G3 and MiNEN, however cases were limited. Baseline NETest was not predictive for benefit of chemotherapy, however a NETest >60 was prognostic with a shorter survival for patients receiving chemotherapy.
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Affiliation(s)
- H Sorbye
- Department of Oncology, Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
| | - G O Hjortland
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | | | - A Sundlov
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - J Assmus
- Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway
| | - A Couvelard
- Department of Pathology, AP-HP Bichat Hospital, Université Paris Cité, Paris, France
| | - A Perren
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - S W Langer
- Department of Oncology, Copenhagen University Hospital - Rigshospitalet and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Almeida C, Gervaso L, Frigè G, Spada F, Benini L, Cella CA, Mazzarella L, Fazio N. The Role of Liquid Biopsy in Gastroenteropancreatic Neuroendocrine Neoplasms. Cancers (Basel) 2024; 16:3349. [PMID: 39409968 PMCID: PMC11475604 DOI: 10.3390/cancers16193349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
Neuroendocrine neoplasms incidence has been increasing, arising the need for precise and early diagnostic tools. Liquid biopsy (LB) offers a less invasive alternative to tissue biopsy, providing real-time molecular information from circulating tumour components in body fluids. The aim of this review is to analyse the current evidence concerning LB in NENs and its role in clinical practice. We conducted a systematic review in July 2024 focusing on LB applications in NENs, including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), micro RNA (miRNA), messenger RNA (mRNA) and extracellular vesicles. Sixty-five relevant articles were analysed. The LB showed potential in diagnosing and monitoring NENs. While CTCs face limitations due to low shedding, ctDNA provides valuable information on high-grade neoplasms. MiRNA and mRNA (e.g., the NETest) offer high sensitivity and specificity for diagnosis and prognosis, outperforming traditional markers like chromogranin A. The LB has significant potential for NEN diagnosis and monitoring but lacks widespread clinical integration due to limited prospective studies and guidelines, requiring further validation. Advances in sequencing technologies may enhance the clinical utility of LB in NENs. Future research should focus on refining LB methods, standardising protocols and exploring applications in high-grade NENs.
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Affiliation(s)
- Catarina Almeida
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy; (C.A.); (F.S.); (L.B.); (C.A.C.); (L.M.)
- Department of Medical Oncology, São João University Hospital Center, 4200-319 Porto, Portugal
| | - Lorenzo Gervaso
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy; (C.A.); (F.S.); (L.B.); (C.A.C.); (L.M.)
| | - Gianmaria Frigè
- Laboratory of Translational Oncology, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy;
| | - Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy; (C.A.); (F.S.); (L.B.); (C.A.C.); (L.M.)
| | - Lavinia Benini
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy; (C.A.); (F.S.); (L.B.); (C.A.C.); (L.M.)
| | - Chiara Alessandra Cella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy; (C.A.); (F.S.); (L.B.); (C.A.C.); (L.M.)
| | - Luca Mazzarella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy; (C.A.); (F.S.); (L.B.); (C.A.C.); (L.M.)
- Laboratory of Translational Oncology, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy;
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO IRCCS, 20141 Milan, Italy; (C.A.); (F.S.); (L.B.); (C.A.C.); (L.M.)
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8
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Zhang H, Tsuchikawa T, Takeuchi S, Hirata K, Tanaka K, Matsui A, Nakanishi Y, Asano T, Noji T, Nakamura T, Takeuchi S, Wada M, Hirano S. Initial validation of the clinical significance of the NETest in Japanese gastroenteropancreatic neuroendocrine tumor patients. Endocr J 2024; 71:873-880. [PMID: 39069495 DOI: 10.1507/endocrj.ej24-0090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/30/2024] Open
Abstract
As novel biomarkers for gastroenteropancreatic neuroendocrine tumors (GEPNET) are in demand, we aimed to validate the clinical value of the NETest in Japanese patients. Between 2021 and 2023, blood and clinical data were collected from patients with GEPNET. Among 35 patients (median age: 59 [49-66] years), 27 cases originated from the pancreas and eight from the gastrointestinal tract. Of 69 samples sent to the laboratory, 56 (81.2%) underwent NETest. The diagnostic sensitivity was 97.1%. Among three patients who underwent R0 resection and four treated with peptide receptor radionuclide therapy, the changes in NETest scores closely correlated with disease progression. The NETest demonstrated high diagnostic efficacy and accurate therapeutic monitoring capabilities in a Japanese population.
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Affiliation(s)
- Hao Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
| | - Takahiro Tsuchikawa
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Satoshi Takeuchi
- Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Kenji Hirata
- Department of Diagnostic Imaging, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Kimitaka Tanaka
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Aya Matsui
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Yoshitsugu Nakanishi
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Toshimichi Asano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Takehiro Noji
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Shintaro Takeuchi
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Masataka Wada
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo 060-8638, Japan
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9
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De Jesus-Acosta A, Mohindroo C. Genomic Landscape of Pancreatic Neuroendocrine Tumors and Implications for Clinical Practice. JCO Precis Oncol 2024; 8:e2400221. [PMID: 39231376 DOI: 10.1200/po.24.00221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 07/16/2024] [Accepted: 08/05/2024] [Indexed: 09/06/2024] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are the second most prevalent neoplasms of the pancreas with variable prognosis and clinical course. Our knowledge of the genetic alterations in patients with pNETs has expanded in the past decade with the availability of whole-genome sequencing and germline testing. This review will focus on potential clinical applications of the genetic testing in patients with pNETs. For somatic testing, we discuss the commonly prevalent somatic mutations and their impact on prognosis and treatment of patients with pNET. We also highlight the relevant genomic biomarkers that predict response to specific treatments. Previously, germline testing was only recommended for high-risk patients with syndromic features (MEN1, VHL, TSC, and NF1), we review the evolving paradigm of germline testing in pNETs as recent studies have now shown that sporadic-appearing pNETs can also harbor germline variants.
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Affiliation(s)
- Ana De Jesus-Acosta
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Chirayu Mohindroo
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
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10
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Ohlsson H, Spaak E, Gålne A, Sundlöv A, Almquist M. Optimal follow-up with somatostatin receptor PET/CT imaging in patients with small intestinal neuroendocrine tumours. J Neuroendocrinol 2024; 36:e13396. [PMID: 38679928 DOI: 10.1111/jne.13396] [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: 03/24/2023] [Revised: 10/07/2023] [Accepted: 04/03/2024] [Indexed: 05/01/2024]
Abstract
Somatostatin receptor positron emission tomography with computerised tomography imaging (SRI) has a high sensitivity for the detection of small intestinal neuroendocrine tumors (siNET), which makes it ideal for follow-up. The aim of the present study was to investigate whether follow-up with SRI in patients with siNET led to any change in the treatment of the patient and if patient and/or tumour factors were associated with such change. Adults with siNET who had undergone at least two SRI scans between 2013 and 2021 were identified. Data on age, sex, comorbidities, tumour stage, grade, and most recent levels of serum Chromogranin A (CgA) and 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) before each SRI scan were obtained. The major change was defined as new treatment previously not received or discontinuation of ongoing treatment. Univariate and multivariate mixed models logistic regression on variables with a presumed biological relationship with major change and with backwards stepwise exclusion of variables with p > .1 was performed. A total of 164 patients with siNET diagnosis had undergone 570 SRI scans. The median follow-up was 3.1 years. Only 82 of 570, 14%, of SRI scans led to a major change in treatment. Female sex, age below 75 years, elevated or missing CgA, elevated or missing urine 5-HIAA, progress on last SRI scan and distant extrahepatic disease were all independently associated with increased odds ratios for major change after follow-up with SRI. A small proportion of SRI scans (14%) led to a major change in treatment. Six independent risk factors with increased odds of major change, all available before each SRI scan, were identified. While validation of these risk factors is needed in a separate cohort, these findings could help clinicians individualise follow-up for siNET patients in the future.
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Affiliation(s)
- Håkan Ohlsson
- Department of Surgery, Ystad Hospital, Ystad, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Elisabeth Spaak
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Department of Surgery, Skåne University Hospital, Lund, Sweden
| | - Anni Gålne
- Department of Medical Imaging and Physiology, Skåne University Hospital, Lund, Sweden
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Anna Sundlöv
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Department of Oncology, Skåne University Hospital, Lund, Sweden
| | - Martin Almquist
- Department of Clinical Sciences, Lund University, Lund, Sweden
- Endocrine-Sarcoma Unit, Department of Surgery, Skåne University Hospital, Lund, Sweden
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11
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Gertner J, Tsoli M, Hayes AR, O’Mahony LF, Laskaratos FM, Glover T, Karia P, Butt MF, Eastwood O, Mandair D, Caplin M, Toumpanakis C. The Clinical Utility of the NETest in Patients with Small Intestinal Neuroendocrine Neoplasms (Si-NENs): A "Real-Life" Study. Cancers (Basel) 2024; 16:2506. [PMID: 39061146 PMCID: PMC11274476 DOI: 10.3390/cancers16142506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 06/24/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Current biomarkers do not adequately predict the behaviour of neuroendocrine neoplasms (NENs). This study assessed the NETest, a multianalyte blood biomarker, in patients with small intestinal NENs (Si-NENs). We studied two patient groups: Group 1: metastatic Si-NENs (n = 102) and Group 2: post-operatively disease-free according to 68Ga-DOTATATE PET (n = 16). NETest scores were ≤20% (normal), 21-40% (low), 41-79% (intermediate), or ≥80% (high). Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. In Group 1, the median NETest score was 40% (IQR: 33.3-46.7%). The NETest value (HR: 1.032, 95% CI: 1.003-1.062, p = 0.033) and high-risk NETest category (HR: 10.5, 95% CI: 1.35-81.7, p = 0.025) were independent predictors of PFS, along with presence of lung metastases, CgA levels > 10 × ULN, and tumour growth rate (TGR). Independent predictors of OS were the NETest value (HR: 1.035, 95% CI: 1.005-1.066, p = 0.024) and high-risk NETest category (HR: 15.2, 95% CI: 1.52-151, p = 0.02), along with presence of lung metastases and CgA levels > 10 × ULN. In Group 2, ROC analysis identified an AUC of 0.909 (95% CI: 0.75-0.100) for prediction of local or metastatic recurrence. Blood NETest scores were associated with PFS and OS in patients with metastatic Si-NENs, along with TGR, CgA > 10 × ULN, and presence of lung metastases.
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Affiliation(s)
| | - Marina Tsoli
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London NW3 2QG, UK; (M.T.); (A.R.H.); (O.E.); (D.M.); (M.C.); (C.T.)
| | - Aimee R. Hayes
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London NW3 2QG, UK; (M.T.); (A.R.H.); (O.E.); (D.M.); (M.C.); (C.T.)
| | | | | | - Thomas Glover
- St Mark’s Hospital, London HA1 3UJ, UK; (F.-M.L.); (T.G.)
| | | | - Mohsin F. Butt
- NIHR Nottingham Biomedical Research Centre, Nottingham NG7 2UH, UK;
| | - Oliver Eastwood
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London NW3 2QG, UK; (M.T.); (A.R.H.); (O.E.); (D.M.); (M.C.); (C.T.)
| | - Dalvinder Mandair
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London NW3 2QG, UK; (M.T.); (A.R.H.); (O.E.); (D.M.); (M.C.); (C.T.)
| | - Martyn Caplin
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London NW3 2QG, UK; (M.T.); (A.R.H.); (O.E.); (D.M.); (M.C.); (C.T.)
| | - Christos Toumpanakis
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London NW3 2QG, UK; (M.T.); (A.R.H.); (O.E.); (D.M.); (M.C.); (C.T.)
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12
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Franchina M, Cavalcoli F, Falco O, La Milia M, Elvevi A, Massironi S. Biochemical Markers for Neuroendocrine Tumors: Traditional Circulating Markers and Recent Development-A Comprehensive Review. Diagnostics (Basel) 2024; 14:1289. [PMID: 38928704 PMCID: PMC11203125 DOI: 10.3390/diagnostics14121289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/13/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms presenting unique challenges in diagnosis and management. Traditional markers such as chromogranin A (CgA), pancreatic polypeptide (PP), and neuron-specific enolase (NSE) have limitations in terms of specificity and sensitivity. Specific circulating markers such as serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and various gastrointestinal hormones such as gastrin, glucagon, somatostatin, and vasoactive intestinal peptide (VIP) have a role in identifying functional NENs. Recent advances in molecular and biochemical markers, also accounting for novel genomic and proteomic markers, have significantly improved the landscape for the diagnosis and monitoring of NENs. This review discusses these developments, focusing on both traditional markers such as CgA and NSE, as well as specific hormones like gastrin, insulin, somatostatin, glucagon, and VIP. Additionally, it covers emerging genomic and proteomic markers that are shaping current research. The clinical applicability of these markers is highlighted, and their role in improving diagnostic accuracy, predicting surgical outcomes, and monitoring response to treatment is demonstrated. The review also highlights the need for further research, including validation of these markers in larger studies, development of standardized assays, and integration with imaging techniques. The evolving field of biochemical markers holds promise for improving patient outcomes in the treatment of NENs, although challenges in standardization and validation remain.
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Affiliation(s)
- Marianna Franchina
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Federica Cavalcoli
- Gastroenterology and Digestive Endoscopy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Olga Falco
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
| | - Marta La Milia
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Sara Massironi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
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13
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Battistella A, Tacelli M, Mapelli P, Schiavo Lena M, Andreasi V, Genova L, Muffatti F, De Cobelli F, Partelli S, Falconi M. Recent developments in the diagnosis of pancreatic neuroendocrine neoplasms. Expert Rev Gastroenterol Hepatol 2024; 18:155-169. [PMID: 38647016 DOI: 10.1080/17474124.2024.2342837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 04/10/2024] [Indexed: 04/25/2024]
Abstract
INTRODUCTION Pancreatic Neuroendocrine Neoplasms (PanNENs) are characterized by a highly heterogeneous clinical and biological behavior, making their diagnosis challenging. PanNENs diagnostic work-up mainly relies on biochemical markers, pathological examination, and imaging evaluation. The latter includes radiological imaging (i.e. computed tomography [CT] and magnetic resonance imaging [MRI]), functional imaging (i.e. 68Gallium [68 Ga]Ga-DOTA-peptide PET/CT and Fluorine-18 fluorodeoxyglucose [18F]FDG PET/CT), and endoscopic ultrasound (EUS) with its associated procedures. AREAS COVERED This review provides a comprehensive assessment of the recent advancements in the PanNENs diagnostic field. PubMed and Embase databases were used for the research, performed from inception to October 2023. EXPERT OPINION A deeper understanding of PanNENs biology, recent technological improvements in imaging modalities, as well as progresses achieved in molecular and cytological assays, are fundamental players for the achievement of early diagnosis and enhanced preoperative characterization of PanNENs. A multimodal diagnostic approach is required for a thorough disease assessment.
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Affiliation(s)
- Anna Battistella
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Matteo Tacelli
- Vita-Salute San Raffaele University, Milan, Italy
- Pancreato-biliary Endoscopy and EUS Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paola Mapelli
- Vita-Salute San Raffaele University, Milan, Italy
- Nuclear Medicine Department, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Valentina Andreasi
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Luana Genova
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Francesca Muffatti
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco De Cobelli
- Vita-Salute San Raffaele University, Milan, Italy
- Radiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Partelli
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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14
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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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15
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Toyohara T, Yoshida M, Miyabe K, Hayashi K, Naitoh I, Kondo H, Hori Y, Kato A, Kachi K, Asano G, Sahashi H, Adachi A, Kuno K, Kito Y, Matsuo Y, Kataoka H. Dual role of autotaxin as novel biomarker and therapeutic target in pancreatic neuroendocrine neoplasms. Cancer Sci 2023; 114:4571-4582. [PMID: 37770812 PMCID: PMC10728022 DOI: 10.1111/cas.15980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/12/2023] [Accepted: 09/15/2023] [Indexed: 09/30/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (panNENs) are rare pancreatic neoplasms, and descriptions of treatment remain limited. Autotaxin (ATX) is a secreted autocrine motility factor involved in the production of lysophosphatidic acid (LPA), a lipid mediator that promotes the progression of various cancers. The aim of this study was to clarify the importance of the ATX-LPA axis in panNENs and to confirm its contribution to panNEN progression using clinical data, cell lines, and a mouse model. Serum ATX level was higher in patients with panNEN than in patients with other pancreatic diseases (chronic pancreatitis, pancreatic ductal adenocarcinoma [PDAC], intraductal papillary mucinous neoplasm, autoimmune pancreatitis) and healthy controls, and 61% of clinical specimens stained strongly for ATX. In a case we encountered, serum ATX level fluctuated with disease progression. An in vitro study showed higher ATX mRNA expression in panNEN cell lines than in PDAC cell lines. Cell proliferation and migration in panNEN cell lines were stimulated via the ATX-LPA axis and suppressed by RNA interference or inhibitors. An in vivo study showed that intraperitoneal injection of GLPG1690, an ATX inhibitor, suppressed tumor progression in a xenograft model. These findings revealed that ATX expression is significantly elevated in panNEN and is related to the progression of panNEN. We showed the potential of ATX as a novel biomarker and therapeutic target.
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Affiliation(s)
- Tadashi Toyohara
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Michihiro Yoshida
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Katsuyuki Miyabe
- Department of GastroenterologyJapanese Red Cross Aichi Medical Center Nagoya Daini HospitalNagoyaJapan
| | - Kazuki Hayashi
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Itaru Naitoh
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Hiromu Kondo
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Yasuki Hori
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Akihisa Kato
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Kenta Kachi
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Go Asano
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Hidenori Sahashi
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Akihisa Adachi
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Kayoko Kuno
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Yusuke Kito
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Yoichi Matsuo
- Department of Gastroenterological SurgeryNagoya City University Graduate School of Medical SciencesNagoyaJapan
| | - Hiromi Kataoka
- Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
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16
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Gabiache G, Zadro C, Rozenblum L, Vezzosi D, Mouly C, Thoulouzan M, Guimbaud R, Otal P, Dierickx L, Rousseau H, Trepanier C, Dercle L, Mokrane FZ. Image-Guided Precision Medicine in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas. Cancers (Basel) 2023; 15:4666. [PMID: 37760633 PMCID: PMC10526298 DOI: 10.3390/cancers15184666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/11/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
In this comprehensive review, we aimed to discuss the current state-of-the-art medical imaging for pheochromocytomas and paragangliomas (PPGLs) diagnosis and treatment. Despite major medical improvements, PPGLs, as with other neuroendocrine tumors (NETs), leave clinicians facing several challenges; their inherent particularities and their diagnosis and treatment pose several challenges for clinicians due to their inherent complexity, and they require management by multidisciplinary teams. The conventional concepts of medical imaging are currently undergoing a paradigm shift, thanks to developments in radiomic and metabolic imaging. However, despite active research, clinical relevance of these new parameters remains unclear, and further multicentric studies are needed in order to validate and increase widespread use and integration in clinical routine. Use of AI in PPGLs may detect changes in tumor phenotype that precede classical medical imaging biomarkers, such as shape, texture, and size. Since PPGLs are rare, slow-growing, and heterogeneous, multicentric collaboration will be necessary to have enough data in order to develop new PPGL biomarkers. In this nonsystematic review, our aim is to present an exhaustive pedagogical tool based on real-world cases, dedicated to physicians dealing with PPGLs, augmented by perspectives of artificial intelligence and big data.
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Affiliation(s)
- Gildas Gabiache
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
| | - Charline Zadro
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
| | - Laura Rozenblum
- Department of Nuclear Medicine, Sorbonne Université, AP-HP, Hôpital La Pitié-Salpêtrière, 75013 Paris, France
| | - Delphine Vezzosi
- Department of Endocrinology, Rangueil University Hospital, 31400 Toulouse, France
| | - Céline Mouly
- Department of Endocrinology, Rangueil University Hospital, 31400 Toulouse, France
| | | | - Rosine Guimbaud
- Department of Oncology, Rangueil University Hospital, 31400 Toulouse, France
| | - Philippe Otal
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
| | - Lawrence Dierickx
- Department of Nuclear Medicine, IUCT-Oncopole, 31059 Toulouse, France;
| | - Hervé Rousseau
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
| | - Christopher Trepanier
- New York-Presbyterian Hospital/Department of Radiology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Laurent Dercle
- New York-Presbyterian Hospital/Department of Radiology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Fatima-Zohra Mokrane
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
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17
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Tsoli M, Koumarianou A, Angelousi A, Kaltsas G. Established and novel circulating neuroendocrine tumor biomarkers for diagnostic, predictive and prognostic use. Best Pract Res Clin Endocrinol Metab 2023; 37:101785. [PMID: 37336711 DOI: 10.1016/j.beem.2023.101785] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/21/2023]
Abstract
The management of neuroendocrine tumors (NETs) represents a clinical challenge due to heterogeneity of their clinical behaviour, molecular biology and response to treatment. Over the years, several circulating biomarkers have been developed for the early diagnosis and follow-up of NETs. The specific secretory products of tumors associated with a secretory syndrome (functioning tumors) may be used as diagnostic and/or prognostic biomarkers while the most common non-specific circulating biomarkers, that may be increased in both functioning and non-functioning tumors, are chromogranin A and the neuron specific enolase. However, the diagnostic accuracy as well as the prognostic and predictive value of these biomarkers are limited and novel techniques of multianalyte analysis of regulators of tumor biology have been developed. The NETest has been most extensively studied and proved to be useful in NET diagnosis, early detection of post-operative recurrence and prediction of response to treatment but further investigation establishing higher level of evidence is required for implementation in clinical practice.
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Affiliation(s)
- Marina Tsoli
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Greece.
| | - Anna Koumarianou
- Haematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon Hospital, National and Kapodistrian University of Athens, 12462, Greece
| | - Anna Angelousi
- Unit of Endocrinology, First Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Greece
| | - Gregory Kaltsas
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Greece
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18
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Bevere M, Masetto F, Carazzolo ME, Bettega A, Gkountakos A, Scarpa A, Simbolo M. An Overview of Circulating Biomarkers in Neuroendocrine Neoplasms: A Clinical Guide. Diagnostics (Basel) 2023; 13:2820. [PMID: 37685358 PMCID: PMC10486716 DOI: 10.3390/diagnostics13172820] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/14/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of diseases that are characterized by different behavior and clinical manifestations. The diagnosis and management of this group of tumors are challenging due to tumor complexity and lack of precise and widely validated biomarkers. Indeed, the current circulating mono-analyte biomarkers (such as chromogranin A) are ineffective in describing such complex tumors due to their poor sensitivity and specificity. In contrast, multi-analytical circulating biomarkers (including NETest) are emerging as more effective tools to determine the real-time profile of the disease, both in terms of accurate diagnosis and effective treatment. In this review, we will analyze the capabilities and limitations of different circulating biomarkers focusing on three relevant questions: (1) accurate and early diagnosis; (2) monitoring of disease progression and response to therapy; and (3) detection of early relapse.
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Affiliation(s)
- Michele Bevere
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
| | - Francesca Masetto
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
| | - Maria Elena Carazzolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
| | - Alice Bettega
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
| | - Anastasios Gkountakos
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
| | - Aldo Scarpa
- ARC-Net Research Center, University of Verona, 37134 Verona, Italy; (M.B.); (F.M.); (A.G.); (A.S.)
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
| | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (M.E.C.); (A.B.)
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19
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Elkelany OO, Karaisz FG, Davies B, Krishna SG. An Overview of Pancreatic Neuroendocrine Tumors and an Update on Endoscopic Techniques for Their Management. Curr Oncol 2023; 30:7566-7580. [PMID: 37623030 PMCID: PMC10453483 DOI: 10.3390/curroncol30080549] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
The growing importance of advanced endoscopy in the diagnosis and treatment of pancreatic neuroendocrine neoplasms (PanNETs) necessitates a comprehensive understanding of various biochemical markers, genetic testing methods, radiological techniques, and treatment approaches that encompass multiple disciplines within and beyond gastrointestinal oncology. This review aims to highlight key aspects of these topics, with a specific focus on emerging EUS-guided procedures for the management of PanNETs.
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Affiliation(s)
- Osama O. Elkelany
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Fred G. Karaisz
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Benjamin Davies
- College of Medicine, The Ohio State University, Columbus, OH 43201, USA
| | - Somashekar G. Krishna
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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20
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An Insight on Functioning Pancreatic Neuroendocrine Neoplasms. Biomedicines 2023; 11:biomedicines11020303. [PMID: 36830839 PMCID: PMC9953748 DOI: 10.3390/biomedicines11020303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms arising from islets of the Langerhans in the pancreas. They can be divided into two groups, based on peptide hormone secretion, functioning and nonfunctioning PanNENs. The first group is characterized by different secreted peptides causing specific syndromes and is further classified into subgroups: insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma and tumors producing serotonin and adrenocorticotrophic hormone. Conversely, the second group does not release peptides and is usually associated with a worse prognosis. Today, although the efforts to improve the therapeutic approaches, surgery remains the only curative treatment for patients with PanNENs. The development of high-throughput techniques has increased the molecular knowledge of PanNENs, thereby allowing us to understand better the molecular biology and potential therapeutic vulnerabilities of PanNENs. Although enormous advancements in therapeutic and molecular aspects of PanNENs have been achieved, there is poor knowledge about each subgroup of functioning PanNENs.Therefore, we believe that combining high-throughput platforms with new diagnostic tools will allow for the efficient characterization of the main differences among the subgroups of functioning PanNENs. In this narrative review, we summarize the current landscape regarding diagnosis, molecular profiling and treatment, and we discuss the future perspectives of functioning PanNENs.
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21
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Liu X, Chen B, Chen J, Su Z, Sun S. The incidence, prevalence, and survival analysis of pancreatic neuroendocrine tumors in the United States. J Endocrinol Invest 2022:10.1007/s40618-022-01985-2. [PMID: 36522587 DOI: 10.1007/s40618-022-01985-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 09/27/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE The incidence of pancreatic neuroendocrine tumors (pNETs) was increasing. The main purpose of this study was to statistically analyze the incidence and prevalence of pNETs and the main risk factors for the prognosis. METHODS Based on the Surveillance, Epidemiology, and End Results (SEER) database, with three registries integrated, this study comprehensively displayed the annual age adjust incidence of pNETs from 1975 to 2018, the estimated 20-year limited-duration prevalence, and conducted the univariate and multivariate survival analysis. RESULTS The incidence of pNETs has increased to about 1.5 per 100,000 population, and the prevalence has reached about 0.008% with the aged, Grade 1 and nonfunctional tumors accounting for the majority. The average median overall survival (OS), 5-year survival rate, and median disease-free survival (DFS) of pNETs patients from 1975 to 2018 were 85 months, 57.55%, and 220 months, respectively. From 2000 to 2018, the median OS was 94 months, and the 5-year survival rate was 59.94%. In multivariate survival analysis, the greatest risk factor was Grade 3&4 with HR = 3.62 (3.10-4.28), followed by distant stage with HR = 2.77 (2.28-3.36), and aged over 80 years old with HR = 2.26 (1.33-3.83). Surgery was a protective prognostic factor with HR = 0.34 (0.29-0.40). CONCLUSION The incidence and prevalence of pNETs were still increasing, but the trend was gradual and aging in recent years. The survival time of pNETs was longer but has not changed much in recent years. The degrees of malignancy, stage, and operation were the most important prognosis factors.
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Affiliation(s)
- X Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - B Chen
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - J Chen
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Z Su
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - S Sun
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
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22
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Chen H, Li Z, Hu Y, Xu X, Ye Z, Lou X, Zhang W, Gao H, Qin Y, Zhang Y, Chen X, Chen J, Tang W, Yu X, Ji S. Maximum Value on Arterial Phase Computed Tomography Predicts Prognosis and Treatment Efficacy of Sunitinib for Pancreatic Neuroendocrine Tumours. Ann Surg Oncol 2022; 30:2988-2998. [PMID: 36310316 DOI: 10.1245/s10434-022-12693-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 10/06/2022] [Indexed: 12/15/2022]
Abstract
PURPOSE This study was designed to assess the computed tomography maximum (CTmax) value on pretherapeutic arterial phase computed tomography (APCT) images to predict pancreatic neuroendocrine tumours (pNETs) recurrence and clarify its role in predicting the outcome of tumour therapy. METHODS This retrospective study enrolled 250 surgical patients and 24 nonsurgical patients with sunitinib-based treatment in our hospital from 2008 to 2019. CT images were assessed, the maximum value was defined as "CTmax," and recurrence-free survival (RFS) or progression-free survival (PFS) was compared between a high-CTmax group and a low-CTmax group among patients who underwent surgical resection or nonsurgical, sunitinib-based treatment according to the CTmax cutoff value. RESULTS In ROC curve analysis, a CTmax of 108 Hounsfield units, as the cutoff value, achieved an AUC of 0.796 in predicting recurrence. Compared with the low-CTmax group, the high-CTmax group had a longer RFS (p < 0.001). Low CTmax was identified as an independent factor for RFS (p < 0.001) in multivariate analysis; these results were confirmed using the internal validation set. The CTmax value was significantly correlated with the microvascular density (MVD) value (p < 0.001) and the vascular endothelial growth factor receptor 2 (VEGFR2) score (p < 0.001). Furthermore, the high-CTmax group had a better PFS than the low-CTmax group among the sunitinib treatment group (p = 0.007). CONCLUSIONS The tumour CTmax on APCT might be a potential and independent indicator for predicting recurrence in patients who have undergone surgical resection and assessing the efficacy of sunitinib for patients with advanced metastatic pNETs.
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Affiliation(s)
- Haidi Chen
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Zheng Li
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yuheng Hu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xiaowu Xu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Zeng Ye
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xin Lou
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wuhu Zhang
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Heli Gao
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yi Qin
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yue Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Suzhou University, The First People's Hospital of Changzhou, Changzhou, China
| | - Xuemin Chen
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Suzhou University, The First People's Hospital of Changzhou, Changzhou, China
| | - Jie Chen
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wei Tang
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Xianjun Yu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Shunrong Ji
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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23
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van Treijen MJC, Korse CM, Verbeek WH, Tesselaar MET, Valk GD. NETest: serial liquid biopsies in gastroenteropancreatic NET surveillance. Endocr Connect 2022; 11:e220146. [PMID: 35951312 PMCID: PMC9513663 DOI: 10.1530/ec-22-0146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/11/2022] [Indexed: 11/27/2022]
Abstract
Objective Up to now, serial NETest measurements in individuals assessing the disease course of gastroenteropancreatic neuroendocrine tumors (GEPNETs) at long-term follow-up and treatment response were not studied. Design The study was a longitudinal validation study of serial NETest measurements - a blood-based gene expression signature - in 132 patients with GEPNETs on therapy or watch-and-wait strategy. Methods Serial samples were collected during 46 (range: 6-71) months of follow-up. NETest scores were compared with Response Evaluation Criteria in Solid Tumors version 1.1-defined treatment response (e.g. no evidence of disease (NED), stable disease (SD) or progressive disease (PD)). Results Consecutive NETest scores fluctuated substantially (range: 0-100) over time in individuals with SD (n = 28) and NED (n = 30). Follow-up samples were significantly higher in SD (samples 3-5) and NED subgroups (samples 2-5) compared with baseline results, without changes in imaging. In 82% of untreated patients with PD, consecutive NETest scores consistently remained high. In patients undergoing systemic treatment, the median pre-treatment NETest score in treatment-responders was 76.5 (n = 22) vs 33 (n = 12) in non-responders (P = 0.001). Patients with low pre-treatment scores had 21 months reduced progression-free survival (10 vs 31 months; P = 0.01). The accuracy of the NETest for treatment response prediction was 0.73 (P = 0.009). Conclusion In patients not undergoing treatment, consecutive low NETest scores are associated with indolent behavior. Patients who develop PD exhibit elevated scores. Elevated results have important predictive value for treatment responsiveness and could be used for individualizing decisions on systemic therapy. The clinical value of follow-up NETest scores for patients who choose to watch and wait requires further study.
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Affiliation(s)
- Mark J C van Treijen
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Catharina M Korse
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wieke H Verbeek
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Gastroenterology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Margot E T Tesselaar
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Gerlof D Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
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24
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Komarnicki P, Musiałkiewicz J, Stańska A, Maciejewski A, Gut P, Mastorakos G, Ruchała M. Circulating Neuroendocrine Tumor Biomarkers: Past, Present and Future. J Clin Med 2022; 11:5542. [PMID: 36233409 PMCID: PMC9570647 DOI: 10.3390/jcm11195542] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/12/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022] Open
Abstract
Neuroendocrine tumors are a heterogeneous group of neoplasms originating from the diffuse endocrine system. Depending on primary location and hormonal status, they range in terms of clinical presentation, prognosis and treatment. Functional tumors often develop symptoms indicating an excess of hormones produced by the neoplasm (exempli gratia insulinoma, glucagonoma and VIPoma) and can be diagnosed using monoanalytes. For non-functional tumors (inactive or producing insignificant amounts of hormones), universal biomarkers have not been established. The matter remains an important unmet need in the field of neuroendocrine tumors. Substances researched over the years, such as chromogranin A and neuron-specific enolase, lack the desired sensitivity and specificity. In recent years, the potential use of Circulating Tumor Cells or multianalytes such as a circulating microRNA and NETest have been widely discussed. They offer superior diagnostic parameters in comparison to traditional biomarkers and depict disease status in a more comprehensive way. Despite a lot of promise, no international standards have yet been developed regarding their routine use and clinical application. In this literature review, we describe the analytes used over the years and cover novel biomarkers that could find a use in the future. We discuss their pros and cons while showcasing recent advances in the field of neuroendocrine tumor biomarkers.
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Affiliation(s)
- Paweł Komarnicki
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznań, Poland
| | - Jan Musiałkiewicz
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznań, Poland
| | - Alicja Stańska
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznań, Poland
| | - Adam Maciejewski
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznań, Poland
| | - Paweł Gut
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznań, Poland
| | - George Mastorakos
- Unit of Endocrinology, Diabetes Mellitus and Metabolism, Aretaieion University Hospital, Medical School, National and Kapodistrian University of Athens, 157 72 Athens, Greece
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznań, Poland
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25
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Role of Chromogranin A in the Diagnosis and Follow-up of Neuroendocrine Tumors: Real-World Experience. Pancreas 2022; 51:1007-1010. [PMID: 36607947 DOI: 10.1097/mpa.0000000000002132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE The aim of this study was to assess the utility of serum chromogranin A (CgA) along the clinical pathway of patients with neuroendocrine tumors (NETs). METHODS A retrospective review of medical records was conducted of patients with NET who had at least 1 measurement of CgA between January 2015 and April 2021 at a large metropolitan Australian hospital. Chromogranin A was classified as increased or decreased if there was at least a 25% change in sequential levels and was compared with disease response by anatomical or functional imaging if within 6 weeks (considered concurrent). RESULTS Of 102 patients with NETs, 67 had at least 1 serum CgA level: 50 had been ordered during diagnostic workup, of which 33 were elevated (sensitivity: 66%; 95% confidence interval, 51%-79%). Of 129 CgA results concurrent with imaging, the sensitivity for detecting progressive disease was 28% (95% confidence interval, 15%-44%). CONCLUSIONS Our findings support previous concerns that CgA adds little value in clinical decision-making.
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26
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Pancreatic Incidentaloma. J Clin Med 2022; 11:jcm11164648. [PMID: 36012893 PMCID: PMC9409921 DOI: 10.3390/jcm11164648] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatic incidentalomas (PIs) represent a clinical entity increasingly recognized due to advances in and easier access to imaging techniques. By definition, PIs should be detected during abdominal imaging performed for indications other than a pancreatic disease. They range from small cysts to invasive cancer. The incidental diagnosis of pancreatic cancer can contribute to early diagnosis and treatment. On the other hand, inadequate management of PIs may result in overtreatment and unneeded morbidity. Therefore, there is a strong need to evaluate the nature and clinical features of individual PIs. In this review, we summarize the major characteristics related to PIs and present suggestions for their management.
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27
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Andreasi V, Partelli S, Manzoni MF, Muffatti F, Di Filippo L, Crippa S, Corti A, Falconi M. Role of chromogranin A-derived fragments after resection of nonfunctioning pancreatic neuroendocrine tumors. J Endocrinol Invest 2022; 45:1209-1217. [PMID: 35122631 DOI: 10.1007/s40618-022-01750-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/18/2022] [Indexed: 10/19/2022]
Abstract
PURPOSE No single reliable biomarker is available for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). Vasostatin-1 (VS-1), the N-terminal fragment of chromogranin A (CgA), seems to be a more accurate biomarker compared to its precursor. Primary aim was to investigate the ability of VS-1, compared to total-CgA, to assess the effectiveness of surgical resection performed for NF-PanNETs. Secondary aim was to evaluate two additional CgA-derived fragments, pancreastatin (PST) and vasostatin-2 (VS-2), as possible biomarkers for NF-PanNETs. METHODS Consecutive patients who underwent surgery for NF-PanNETs at San Raffaele Scientific Institute were included (n = 35). Plasma levels of CgA and CgA-derived fragments were measured by Enzyme-Linked ImmunoSorbent Assay (ELISA), preoperatively and postoperatively. RESULTS Preoperative VS-1 was significantly higher compared to VS-1 measured on postoperative day 5 (POD5) (pre: 0.338 nM versus POD5: 0.147 nM, P < 0.001), whereas total-CgA significantly increased after surgery (pre: 1.123 nM versus POD5: 1.949 nM, P = 0.006). Overall, 24 patients showed ≥ 1 feature of tumor aggressiveness (T3-T4, nodal/distant metastases, Ki67 > 5%, microvascular/perineural invasion, necrosis). The median percentage decrease in VS-1 plasma levels was 63% (IQR 28-88%) among patients with aggressive tumors, compared to 13% (IQR 0-57%) in the remaining population (P = 0.033). No significant differences in terms of PST (P = 0.870) and VS-2 (P = 0.909) were observed between preoperative and postoperative time. CONCLUSION VS-1 provides an early assessment of surgical efficacy in patients who undergo resection for NF-PanNETs, especially in those with aggressive neoplasms. Total-CgA, PST and VS-2 have no clinical utility in this setting.
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Affiliation(s)
- V Andreasi
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), Milan, Italy
- Tumor Biology and Vascular Targeting Unit, Experimental Oncology Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - S Partelli
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), Milan, Italy
| | - M F Manzoni
- San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), Milan, Italy
- Endocrinology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - F Muffatti
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy
- San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), Milan, Italy
| | - L Di Filippo
- San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), Milan, Italy
- Endocrinology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - S Crippa
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), Milan, Italy
| | - A Corti
- Vita-Salute San Raffaele University, Milan, Italy
- San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), Milan, Italy
- Tumor Biology and Vascular Targeting Unit, Experimental Oncology Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - M Falconi
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
- San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), Milan, Italy.
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Armentano DPD, Monteiro MR, Aguiar PN, Tsukamoto JS, Pio RB, Arakelian R, Araujo RLC, Usón PLS. Laboratory variables as predictors of progression in gastroenteropancreatic neuroendocrine tumors in different lines of antineoplastic treatments. EINSTEIN-SAO PAULO 2022; 20:eAO6985. [PMID: 35674592 PMCID: PMC9165565 DOI: 10.31744/einstein_journal/2022ao6985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 01/21/2022] [Indexed: 11/05/2022] Open
Abstract
Objective: To determine the association of red cell blood counts, and liver panel tests to predict outcomes in patients with gastroenteropancreatic neuroendocrine tumors who underwent systemic antineoplastic treatments. Methods: Patients with gastroenteropancreatic neuroendocrine tumors in systemic treatment were assessed according to laboratory tests within the same period. Progression free survival was determined by the period between the beginning of treatment and the date of progression. We used conditional models (PWP model) to verify the association between laboratory tests and tumor progression. The level of significance used was 5%. Results: A total of 30 treatments given to 17 patients in the intention-to-treat population were evaluated. Treatment included octreotide, lanreotide, everolimus, lutetium, and chemotherapy. We had statistically significant results in chromogranin A, neutrophils and platelets-to-lymphocyte ratio. The risk of progression increases by 2% with the addition of 100ng/mL of chromogranin A (p=0.034), 4% with the increase of 100 neutrophil units (p=0.006), and 21% with the addition of 10 units in platelets-to-lymphocyte ratio (p=0.002). Conclusion: Chromogranin A, neutrophils and platelets-to-lymphocyte ratio were associated with disease progression during systemic treatment in gastroenteropancreatic neuroendocrine tumors. Further prospective studies with larger cohorts are necessary to validate our findings.
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Fang JM, Li J, Shi J. An update on the diagnosis of gastroenteropancreatic neuroendocrine neoplasms. World J Gastroenterol 2022; 28:1009-1023. [PMID: 35431496 PMCID: PMC8968521 DOI: 10.3748/wjg.v28.i10.1009] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 11/26/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) arise from neuroendocrine cells found throughout the gastrointestinal tract and islet cells of the pancreas. The incidence and prevalence of GEP-NENs have been increasing each year due to higher awareness, improved diagnostic modalities, and increased incidental detection on cross-sectional imaging and endoscopy for cancer screening and other conditions and symptoms. GEP-NENs are a heterogeneous group of tumors and have a wide range in clinical presentation, histopathologic features, and molecular biology. Clinical presentation most commonly depends on whether the GEP-NEN secretes an active hormone. The World Health Organization recently updated the classification of GEP-NENs to introduce a distinction between high-grade neuroendocrine tumors and neuroendocrine carcinomas, which can be identified using histology and molecular studies and are more aggressive with a worse prognosis compared to high-grade neuroendocrine tumors. As our understanding of the biology of GEP-NENs has grown, new and improved diagnostic modalities can be developed and optimized. Here, we discuss clinical features and updates in diagnosis, including histopathological analysis, biomarkers, molecular techniques, and radiology of GEP-NENs. We review established diagnostic tests and discuss promising novel diagnostic tests that are currently in development or require further investigation and validation prior to broad utilization in patient care.
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Affiliation(s)
- Jiayun M Fang
- Department of Pathology & Clinical Labs, University of Michigan, Ann Arbor, MI 48109, United States
| | - Jay Li
- Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, United States
| | - Jiaqi Shi
- Department of Pathology & Clinical Labs, University of Michigan, Ann Arbor, MI 48109, United States
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Lee L, Ramos-Alvarez I, Jensen RT. Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies. Cancers (Basel) 2022; 14:cancers14051250. [PMID: 35267558 PMCID: PMC8909561 DOI: 10.3390/cancers14051250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/08/2022] [Accepted: 02/23/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Tumor resistance, both primary and acquired, is leading to increased complexity in the nonsurgical treatment of patients with advanced panNENs, which would be greatly helped by reliable prognostic/predictive factors. The importance in identifying resistance is being contributed to by the increased array of possible treatments available for treating resistant advanced disease; the variable clinical course as well as response to any given treatment approach of patients within one staging or grading system, the advances in imaging which are providing increasing promising results/parameters that correlate with grading/outcome/resistance, the increased understanding of the molecular pathogenesis providing promising prognostic markers, all of which can contribute to selecting the best treatment to overcome resistance disease. Several factors have been identified that have prognostic/predictive value for identifying development resistant disease and affecting overall survival (OS)/PFS with various nonsurgical treatments of patients with advanced panNENs. Prognostic factors identified for patients with advanced panNENs for both OS/PFSs include various clinically-related factors (clinical, laboratory/biological markers, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors. Particularly important prognostic factors for the different treatment modalities studies are the recent grading systems. Most prognostic factors for each treatment modality for OS/PFS are not specific for a given treatment option. These advances have generated several controversies and new unanswered questions, particularly those related to their possible role in predicting the possible sequence of different anti-tumor treatments in patients with different presentations. Each of these areas is reviewed in this paper. Abstract Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- National Kyushu Cancer Center, Department of Hepato-Biliary-Pancreatology, Fukuoka 811-1395, Japan
| | - Irene Ramos-Alvarez
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- Correspondence: ; Tel.: +1-301-496-4201
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Bodei L, Jayaprakasam VS, Kidd M, Gilardi L, Volterrani D, Paganelli G, Grana CM, Modlin IM. Diagnostic Applications of Nuclear Medicine: Neuroendocrine Tumors. NUCLEAR ONCOLOGY 2022:933-974. [DOI: 10.1007/978-3-031-05494-5_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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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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Tsai HJ, Hsiao CF, Chang JS, Chen LT, Chao YJ, Yen CJ, Shan YS. The Prognostic and Predictive Role of Chromogranin A in Gastroenteropancreatic Neuroendocrine Tumors - A Single-Center Experience. Front Oncol 2021; 11:741096. [PMID: 34868938 PMCID: PMC8632826 DOI: 10.3389/fonc.2021.741096] [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: 07/14/2021] [Accepted: 10/28/2021] [Indexed: 11/13/2022] Open
Abstract
Chromogranin A (CgA) is a non-specific biomarker excreted by neuroendocrine tumor (NET) cells. Elevation of circulating CgA level can be detected in gastroenteropancreatic (GEP)-NET patients and has been shown to correlate with tumor burden. The prognostic and predictive roles of CgA level and the change of CgA level are controversial. In this study, we retrospectively analyzed 102 grade 1/2 GEP-NET patients with available baseline or serial follow-up CgA levels from the National Cheng Kung University Hospital to evaluate the association between circulating CgA level and the tumor extent, overall survival (OS), and tumor response prediction. The baseline characteristics, baseline CgA level, and change of CgA level during follow-up and their association was analyzed. Sixty cases had baseline CgA levels available prior to any treatment and ninety-four cases had serial follow-up CgA levels available during treatment or surveillance. Baseline CgA levels were associated with stage and sex. Higher baseline CgA levels were associated with worse OS after adjusting for sex, stage, grade, primary site, and functionality (hazard ratio=13.52, 95% confidence interval (CI), 1.06-172.47, P=0.045). The cross-sectional analysis for the change of CgA level during follow-up showed that a ≥ 40% increase of CgA meant a higher probability of developing tumor progression or recurrence than those with a < 40% increase of CgA level (odds ratio=5.04, 95% CI, 1.31-19.4, P=0.019) after adjusting for sex, age, grade, stage, and functionality. Our study results suggest that CgA may be a predictive marker for tumor burden, OS, and tumor progression in GEP-NET patients.
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Affiliation(s)
- Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chin-Fu Hsiao
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Jeffrey S Chang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.,Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ying-Jui Chao
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Ju Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yan-Shen Shan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Patterns and predictors of pancreatic neuroendocrine tumor prognosis: Are no two leaves alike? Crit Rev Oncol Hematol 2021; 167:103493. [PMID: 34653597 DOI: 10.1016/j.critrevonc.2021.103493] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 02/20/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous; thus, individual prognostic prediction is important. Clinicopathological features, like TNM stage, grade, and differentiation, are independent clinical predictors. However, single predictors are insufficient, as patients sharing similar clinicopathological features usually show distinct prognoses. Accordingly, novel nomograms and risk stratifications have been developed for more accurate PanNET prognostic prediction. Moreover, the exploration of molecular mechanisms has identified novel prognostic predictors for PanNET. Multi-analyte assays of molecular biomarkers provide a deeper understanding of PanNET features; however, the priority, and the optimal combination of classic and novel predictors for PanNET prognosis prediction remain unclear. In this review, we summarized the patterns and predictors of PanNET prognosis and discussed their clinical utility; we emphasized that PanNET at different stages have different superior predictor, and that multi-analyte assays are more sensitive than mono-analyte biomarkers. Therefore, combined biomarkers improve the accuracy of surveillance and optimize decision-making in clinical practice.
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35
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The role of biomarker in pancreatic neuroendocrine tumor. JOURNAL OF PANCREATOLOGY 2021. [DOI: 10.1097/jp9.0000000000000076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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36
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Kečkéš Š, Palaj J, Waczulíková I, Dyttert D, Mojtová E, Kováč G, Durdík Š. Pretreatment Levels of Chromogranin A and Neuron-specific Enolase in Patients With Gastroenteropancreatic Neuroendocrine Neoplasia. In Vivo 2021; 35:2863-2868. [PMID: 34410979 DOI: 10.21873/invivo.12574] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/03/2021] [Accepted: 06/07/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND/AIM Chromogranin A (CgA) and neuron-specific enolase (NSE) are applied in the diagnosis of neuroendocrine neoplasms (NENs), especially non-functional ones. The aim of this study was to investigate the predictive values of CgA and NSE in long-term survival. PATIENTS AND METHODS Our retrospective analysis included 65 patients with histologically verified gastroenteropancreatic NEN between 2005 and 2019. We performed bivariate and multivariable analyses to evaluate the relationship between CgA and NSE values before histological assessment and overall survival. Distribution of time-to-event was analyzed using Kaplan-Meier survival curves and modelled by Cox regression models. RESULTS Elevated NSE levels prior to histology were significantly associated with worse survival (HR=1.13, p=0.004) and were associated with low-differentiated NENs (rs=0.321, p=0.0338). CgA was associated with well-differentiated tumors (rs=0.233), but not significantly. CONCLUSION Pretreatment serum levels of NSE can serve as a valuable additional predictor of long-term survival in patients with NEN.
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Affiliation(s)
- Štefan Kečkéš
- Department of Hematology and Transfusiology, St. Elizabeth Cancer Institute, Bratislava, Slovak Republic; .,St. Elizabeth University of Health and Social Sciences, Bratislava, Slovak Republic
| | - Július Palaj
- Department of Oncological Surgery, St. Elizabeth Cancer Institute, and Faculty of Medicine in Bratislava of the Comenius University, Bratislava, Slovak Republic
| | - Iveta Waczulíková
- Department of Nuclear Physics and Biophysics, Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, Slovak Republic
| | - Daniel Dyttert
- Department of Oncological Surgery, St. Elizabeth Cancer Institute, and Faculty of Medicine in Bratislava of the Comenius University, Bratislava, Slovak Republic
| | - Emília Mojtová
- Department of Endocrinology, St. Elizabeth Cancer Institute, Bratislava, Slovak Republic
| | - Gustáv Kováč
- Department of Clinical Chemistry, Biochemistry and Laboratory Medicine, Slovak Medical University, Faculty of Medicine, Bratislava, Slovak Republic
| | - Štefan Durdík
- St. Elizabeth University of Health and Social Sciences, Bratislava, Slovak Republic.,Department of Oncological Surgery, St. Elizabeth Cancer Institute, and Faculty of Medicine in Bratislava of the Comenius University, Bratislava, Slovak Republic
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Modlin IM, Kidd M, Falconi M, Filosso PL, Frilling A, Malczewska A, Toumpanakis C, Valk G, Pacak K, Bodei L, Öberg KE. A multigenomic liquid biopsy biomarker for neuroendocrine tumor disease outperforms CgA and has surgical and clinical utility. Ann Oncol 2021; 32:1425-1433. [PMID: 34390828 DOI: 10.1016/j.annonc.2021.08.1746] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/30/2021] [Accepted: 08/06/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Biomarkers are key tools in cancer management. In neuroendocrine tumors (NETs), Chromogranin A (CgA) was considered acceptable as a biomarker. We compared the clinical efficacy of a multigenomic blood biomarker (NETest) to CgA over a 5-year period. PATIENTS AND METHODS An observational, prospective, cross-sectional, multicenter, multinational, comparative cohort assessment. Cohort 1: NETest evaluation in NETs (n = 1684) and cancers, benign diseases, controls (n = 731). Cohort 2: (n = 1270): matched analysis of NETest/CgA in a sub-cohort of NETs (n = 922) versus other diseases and controls (n = 348). Disease status was assessed by response evaluation criteria in solid tumors (RECIST). NETest measurement: qPCR [upper limit of normal (ULN: 20)], CgA (EuroDiagnostica, ULN: 108 ng/ml). STATISTICS Mann-Whitney U-test, AUROC, chi-square and McNemar' test. RESULTS Cohort 1: NETest diagnostic accuracy was 91% (P < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%). NETest reflected grading: G1: 40 ± 1, G2 (50 ± 1) and G3 (52 ± 1). Locoregional disease levels were lower (38 ± 1) than metastatic (52 ± 1, P < 0.0001). NETest accurately stratified RECIST-assessed disease extent: no disease (21 ± 1), stable (43 ± 2), progressive (62 ± 2) (P < 0.0001). NETest concordance with imaging (CT/MRI/68Ga-SSA-PET) 91%. Presurgery, all NETs (n = 153) were positive (100%). After palliative R1/R2 surgery (n = 51) all (100%) remained elevated. After curative R0-surgery (n = 102), NETest levels were normal in 81 (70%) with no recurrence at 2 years. In the 31 (30%) with elevated levels, 25 (81%) recurred within 2 years. Cohort #2: NETest diagnostic accuracy was 87% and CgA 54% (P < 0.0001). NETest was more accurate than CgA for grading (chi-square = 7.7, OR = 18.5) and metastatic identification (chi-square = 180, OR = 8.4). NETest identified progressive disease (95%) versus CgA (57%, P < 0.0001). Imaging concordance for NETest was 91% versus CgA (46%) (P < 0.0001). Recurrence prediction after surgery was NETest-positive in >94% versus CgA 11%. CONCLUSION NETest accurately diagnoses NETs and is an effective surrogate marker for imaging, grade, metastases and disease status compared to CgA. A multigenomic liquid biopsy is an accurate biomarker of NET disease.
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Affiliation(s)
- I M Modlin
- Department of Surgery, Yale University School of Medicine, New Haven, USA
| | - M Kidd
- Wren Laboratories, Branford, USA
| | - M Falconi
- Department of Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - P L Filosso
- Department of Surgical Sciences, Università degli Studi di Torino, Turin, Italy
| | - A Frilling
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - A Malczewska
- Department of Endocrinology and Neuroendocrine Tumours, Medical University of Silesia, Katowice, Poland
| | - C Toumpanakis
- Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
| | - G Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - K Pacak
- Medical Neuroendocrinology, National Institutes of Health, Bethesda, USA
| | - L Bodei
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA
| | - K E Öberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden.
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Target Heterogeneity in Oncology: The Best Predictor for Differential Response to Radioligand Therapy in Neuroendocrine Tumors and Prostate Cancer. Cancers (Basel) 2021; 13:cancers13143607. [PMID: 34298822 PMCID: PMC8304541 DOI: 10.3390/cancers13143607] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/04/2021] [Accepted: 07/07/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary In the era of precision medicine, novel targets have emerged on the surface of cancer cells, which have been exploited for the purpose of radioligand therapy. However, there have been variations in the way these receptors are expressed, especially in prostate cancers and neuroendocrine tumors. This variable expression of receptors across the grades of cancers led to the concept of ‘target heterogeneity’, which has not just impacted therapeutic decisions but also their outcomes. Radiopharmaceuticals targeting receptors need to be used when there are specific indicators—either clinical, radiological, or at molecular level—warranting their use. In addition, response to these radioligands can be assessed using different techniques, whereby we can prognosticate further outcomes. We shall also discuss, in this review, the conventional as well as novel approaches of detecting heterogeneity in prostate cancers and neuroendocrine tumors. Abstract Tumor or target heterogeneity (TH) implies presence of variable cellular populations having different genomic characteristics within the same tumor, or in different tumor sites of the same patient. The challenge is to identify this heterogeneity, as it has emerged as the most common cause of ‘treatment resistance’, to current therapeutic agents. We have focused our discussion on ‘Prostate Cancer’ and ‘Neuroendocrine Tumors’, and looked at the established methods for demonstrating heterogeneity, each with its advantages and drawbacks. Also, the available theranostic radiotracers targeting PSMA and somatostatin receptors combined with targeted systemic agents, have been described. Lu-177 labeled PSMA and DOTATATE are the ‘standard of care’ radionuclide therapeutic tracers for management of progressive treatment-resistant prostate cancer and NET. These approved therapies have shown reasonable benefit in treatment outcome, with improvement in quality of life parameters. Various biomarkers and predictors of response to radionuclide therapies targeting TH which are currently available and those which can be explored have been elaborated in details. Imaging-based features using artificial intelligence (AI) need to be developed to further predict the presence of TH. Also, novel theranostic tools binding to newer targets on surface of cancer cell should be explored to overcome the treatment resistance to current treatment regimens.
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Molecular Genomic Assessment Using a Blood-based mRNA Signature (NETest) is Cost-effective and Predicts Neuroendocrine Tumor Recurrence With 94% Accuracy. Ann Surg 2021; 274:481-490. [PMID: 34183517 DOI: 10.1097/sla.0000000000005026] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Identification of residual disease after neuroendocrine tumor (NET) resection is critical for management. Post-surgery imaging is insensitive, expensive, and current biomarkers ineffective. We evaluated whether the NETest, a multigene liquid biopsy blood biomarker, correlated with surgical resection and could predict recurrence. METHODS Multicenter evaluation of NET resections over 24 months (n = 103): 47 pancreas, 26 small bowel, 26 lung, 2 appendix, 1 duodenum, 1 stomach. Surgery: R0 (83), R1/R2 (20). One millilitre of blood was collected at D0 and posroperative day (POD) 30. Transcript quantification by polymerase chain reaction (normal: ≤20), CgA by NEOLISA (normal ≤108 ng/mL). Standard-of-care (SoC) follow-up costs were calculated and compared to POD30 NETest-stratification approach. Analyses: Wilcoxon-paired test, Chi-square test. RESULTS D BIOMARKERS NETest: 103 of 103 (100%)-positive, whereas 23 of 103 (22%) were CgA-positive (Chi-square = 78, P < 0.0001).In the R0 group, the NETest decreased 59 ± 28 to 26 ± 23 (P < 0.0001); 36% (30/83) remained elevated. No significant decrease was evident for CgA. In the R1/R2 group the NETest decreased but 100% remained elevated. CgA levels did not decrease.An elevated POD30 NETest was present in R0 and 25 (83%) developed radiological recurrences. Normal score R0 s (n = 53) did not develop recurrence (Chi-square = 56, P < 0.0001). Recurrence prediction was 94% accurate with the NETest. COST EVALUATION Using the NETest to stratify postoperative imaging resulted in a cost-savings of 42%. CONCLUSION NETest diagnosis is more accurate than CgA (100% vs 22%). Surgery significantly decreased NETest. An elevated POD30 NETest predicted recurrence with 94% accuracy and post-surgical POD30 NETest follow-up stratification decreased costs by 42%. CgA had no surgical utility. Further studies would define the accuracy and cost-effectiveness of the NETest in the detection of postoperative recurrent disease.
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Modlin IM, Kidd M, Oberg K, Falconi M, Filosso PL, Frilling A, Malczewska A, Salem R, Toumpanakis C, Laskaratos FM, Partelli S, Roffinella M, von Arx C, Kudla BK, Bodei L, Drozdov IA, Kitz A. Early Identification of Residual Disease After Neuroendocrine Tumor Resection Using a Liquid Biopsy Multigenomic mRNA Signature (NETest). Ann Surg Oncol 2021; 28:7506-7517. [PMID: 34008138 DOI: 10.1245/s10434-021-10021-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 03/31/2021] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Surgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence. METHODS This was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0-100; normal ≤20). Statistical analyses were performed using the Mann-Whitney U-test, Chi-square test, Kaplan-Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean ± standard deviation. RESULTS The NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3-68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 ± 28). In the R0 cohort, POD30 levels decreased from 62 ± 28 to 22 ± 20 (p < 0.0001), but remained elevated in 30% (31/102) of patients: 28% lung, 29% pancreas, 27% small bowel, and 33% gastric. By 18 months, 25/31 (81%) patients with a POD30 NETest >20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p < 0.0001). AUROC analysis identified an AUC of 0.97 (p < 0.0001) for recurrence-prediction. In the R1 (n = 29) and R2 (n = 22) cohorts, the score decreased (R1: 74 ± 28 to 45 ± 24, p = 0.0012; R2: 72 ± 24 to 60 ± 28, p = non-significant). At POD30, 100% of NETest scores were elevated despite surgery (p < 0.0001). CONCLUSION The preoperative NETest accurately identified all NETs (100%). All resections decreased NETest levels and a POD30 NETest score >20 predicted radiologically recurrent disease with 94% accuracy and 100% sensitivity. R0 resection appears to be ineffective in approximately 30% of patients. NET mRNA blood levels provide early objective genomic identification of residual disease and may facilitate management.
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Affiliation(s)
| | - Mark Kidd
- Wren Laboratories, Branford, CT, USA
| | | | | | | | | | | | - Ronald Salem
- Yale University School of Medicine, New Haven, CT, USA
| | | | | | | | | | | | | | - Lisa Bodei
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Roll W, Weckesser M, Seifert R, Bodei L, Rahbar K. Imaging and liquid biopsy in the prediction and evaluation of response to PRRT in neuroendocrine tumors: implications for patient management. Eur J Nucl Med Mol Imaging 2021; 48:4016-4027. [PMID: 33903926 PMCID: PMC8484222 DOI: 10.1007/s00259-021-05359-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/05/2021] [Indexed: 12/16/2022]
Abstract
Purpose The aim of this narrative review is to give an overview on current and emerging imaging methods and liquid biopsy for prediction and evaluation of response to PRRT. Current limitations and new perspectives, including artificial intelligence, are discussed. Methods A literature review of PubMed/Medline was performed with representative keywords. The search included articles published online through August 31, 2020. All searches were restricted to English language manuscripts. Results Peptide radio receptor therapy (PRRT) is a prospectively evaluated and approved therapy option in neuroendocrine tumors (NETs). Different ligands targeting the somatostatin receptor (SSTR) are used as theranostic pairs for imaging NET and for PRRT. Response assessment in prospective trials often relies on the morphological RECIST 1.1 criteria, based on lesion size in CT or MRI. The role of SSTR-PET and quantitative uptake parameters and volumetric data is still not defined. Monoanalyte tumor marker chromogranin A has a limited value for response assessment after PRRT. New emerging liquid biopsy techniques are offering prediction of response to PRRT and prognostic value. Conclusions New response criteria for NET patients undergoing PRRT will comprise multiparametric hybrid imaging and blood-based multianalyte markers. This represents tumor biology and heterogeneity.
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Affiliation(s)
- Wolfgang Roll
- Department of Nuclear Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.,West German Cancer Center, Muenster and Essen, Essen, Germany
| | - Matthias Weckesser
- Department of Nuclear Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.,West German Cancer Center, Muenster and Essen, Essen, Germany
| | - Robert Seifert
- Department of Nuclear Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.,West German Cancer Center, Muenster and Essen, Essen, Germany.,Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
| | - Lisa Bodei
- Department of Nuclear Medicine, Radiology, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Kambiz Rahbar
- Department of Nuclear Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany. .,West German Cancer Center, Muenster and Essen, Essen, Germany.
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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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Al-Toubah T, Cives M, Valone T, Blue K, Strosberg J. Sensitivity and Specificity of the NETest: A Validation Study. Neuroendocrinology 2021; 111:580-585. [PMID: 32615553 DOI: 10.1159/000509866] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/02/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Secretory tumor markers traditionally measured in patients with neuroendocrine tumors (NET) are lacking sensitivity and specificity, and consequently they are of limited clinical utility. The NETest, a novel blood multigene RNA transcript assay, has been found to be highly sensitive and specific. We sought to validate the sensitivity of the NETest in a population of metastatic well-differentiated NETs of gastroenteropancreatic and lung origin and to evaluate NETest specificity in a mixed population of metastatic non-NET gastrointestinal (GI) malignancies and healthy individuals. DESIGN AND METHODS Forty-nine patients with metastatic NETs, 21 patients with other metastatic GI cancers, and 26 healthy individuals were enrolled in the study. Samples were sent in a blinded fashion to a central laboratory, and an NETest value of 0-13% was considered normal. RESULTS Using 13% as the upper limit of normal, the sensitivity of the NETest was 98% (95% CI 89-100%). The overall specificity was 66% (95% CI 51-79%), with 16 false-positive results. Specificity was 81% (95% CI 62-92%) among 26 healthy individuals and 48% (95% CI 26-70%) among patients with other GI malignancies. Using an updated normal range of 0-20%, sensitivity was unchanged, but specificity improved to 100% among healthy participants and to 67% among patients with other cancers. CONCLUSIONS The sensitivity of the NETest is exceptionally high (>95%) in a population of metastatic, well-differentiated NETs. Specificity within a healthy population of patients is exceptionally high when using a normal range of 0-20% but relatively low when evaluating patients with other GI malignancies.
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Affiliation(s)
- Taymeyah Al-Toubah
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
| | - Mauro Cives
- Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy
| | - Tiffany Valone
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
| | - Kirsten Blue
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
| | - Jonathan Strosberg
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA,
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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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Malczewska A, Oberg K, Kos-Kudla B. NETest is superior to chromogranin A in neuroendocrine neoplasia: a prospective ENETS CoE analysis. Endocr Connect 2021; 10:110-123. [PMID: 33289691 PMCID: PMC7923057 DOI: 10.1530/ec-20-0417] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 12/03/2020] [Indexed: 12/16/2022]
Abstract
INTRODUCTION The absence of a reliable, universal biomarker is a significant limitation in neuroendocrine neoplasia (NEN) management. We prospectively evaluated two CgA assays, (NEOLISA, EuroDiagnostica) and (CgA ELISA, Demeditec Diagnostics (DD)) and compared the results to the NETest. METHODS NEN cohort (n = 258): pancreatic, n = 67; small intestine, n = 40; appendiceal, n = 10; rectal, n = 45; duodenal, n = 9; gastric, n = 44; lung, n = 43. Image-positive disease (IPD) (n = 123), image & histology- negative (IND) (n = 106), and image-negative and histology positive (n = 29). CgA metrics: NEOLISA, ULN: 108 ng/mL, DD: ULN: 99 ng/mL. Data mean ± s.e.m. NETest: qRT-PCR - multianalyte analyses, ULN: 20. All samples de-identified and assessed blinded. Statistics: Mann-Whitney U-test, Pearson correlation and McNemar-test. RESULTS CgA positive in 53/258 (NEOLISA), 32 (DD) and NETest-positive in 157/258. In image- positive disease (IPD, n = 123), NEOLISA-positive: 33% and DD: 19%. NETest-positive: 122/123 (99%; McNemar's Chi2= 79-97, P < 0.0001). NEOLISA was more accurate than DD (P = 0.0003). In image- negative disease (IND), CgA was NEOLISA-positive (11%), DD (8%), P = NS, and NETest (33%). CgA assays could not distinguish progressive (PD) from stable disease (SD) or localized from metastatic disease (MD). NETest was significantly higher in PD (47 ± 5) than SD (29 ± 1, P = 0.0009). NETest levels in MD (35 ± 2) were elevated vs localized disease (24 ± 1.3, P = 0.008). CONCLUSIONS NETest, a multigenomic mRNA biomarker, was ~99% accurate in the identification of NEN disease. The CgA assays detected NEN disease in 19-33%. Multigenomic blood analysis using NETest is more accurate than CgA and should be considered the biomarker standard of care.
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Affiliation(s)
- Anna Malczewska
- Department of Endocrinology and Neuroendocrine Tumours, Medical University of Silesia, Katowice, Poland
| | - Kjell Oberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden
| | - Beata Kos-Kudla
- Department of Endocrinology and Neuroendocrine Tumours, Medical University of Silesia, Katowice, Poland
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van Treijen MJC, van der Zee D, Heeres BC, Staal FCR, Vriens MR, Saveur LJ, Verbeek WHM, Korse CM, Maas M, Valk GD, Tesselaar MET. Blood Molecular Genomic Analysis Predicts the Disease Course of Gastroenteropancreatic Neuroendocrine Tumor Patients: A Validation Study of the Predictive Value of the NETest®. Neuroendocrinology 2021; 111:586-598. [PMID: 32492680 DOI: 10.1159/000509091] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 06/02/2020] [Indexed: 11/19/2022]
Abstract
Reliable prediction of disease status is a major challenge in managing gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aim of the study was to validate the NETest®, a blood molecular genomic analysis, for predicting the course of disease in individual patients compared to chromogranin A (CgA). NETest® score (normal ≤20%) and CgA level (normal <100 µg/L) were measured in 152 GEP-NETs. The median follow-up was 36 (4-56) months. Progression-free survival was blindly assessed (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Optimal cutoffs (area under the receiver operating characteristic curve [AUC]), odds ratios, as well as negative and positive predictive values (NPVs/PPVs) were calculated for predicting stable disease (SD) and progressive disease (PD). Of the 152 GEP-NETs, 86% were NETest®-positive and 52% CgA-positive. -NETest® AUC was 0.78 versus CgA 0.73 (p = ns). The optimal cutoffs for predicting SD/PD were 33% for the NETest® and 140 µg/L for CgA. Multivariate analyses identified NETest® as the strongest predictor for PD (odds ratio: 5.7 [score: 34-79%]; 12.6 [score: ≥80%]) compared to CgA (odds ratio: 3.0), tumor grade (odds ratio: 3.1), or liver metastasis (odds ratio: 7.7). The NETest® NPV for SD was 87% at 12 months. The PPV for PD was 47 and 64% (scores 34-79% and ≥80%, respectively). NETest® metrics were comparable in the watchful waiting, treatment, and no evidence of disease (NED) subgroups. For CgA (>140 ng/mL), NPV and PPV were 83 and 52%. CgA could not predict PD in the watchful waiting or NED subgroups. The NETest® reliably predicted SD and was the strongest predictor of PD. CgA had lower utility. The -NETest® anticipates RECIST-defined disease status up to 1 year before imaging alterations are apparent.
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Affiliation(s)
- Mark J C van Treijen
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands,
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands,
| | | | - Birthe C Heeres
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Femke C R Staal
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Menno R Vriens
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lisette J Saveur
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Gastroenterology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wieke H M Verbeek
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Gastroenterology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Catharina M Korse
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Monique Maas
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Radiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Gerlof D Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Margot E T Tesselaar
- Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Malczewska A, Witkowska M, Wójcik-Giertuga M, Kuśnierz K, Bocian A, Walter A, Rydel M, Robek A, Pierzchała S, Malczewska M, Leś-Zielińska I, Czyżewski D, Ziora D, Pilch-Kowalczyk J, Zajęcki W, Kos-Kudła B. Prospective Evaluation of the NETest as a Liquid Biopsy for Gastroenteropancreatic and Bronchopulmonary Neuroendocrine Tumors: An ENETS Center of Excellence Experience. Neuroendocrinology 2021; 111:304-319. [PMID: 32335553 DOI: 10.1159/000508106] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 04/21/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND There is a substantial unmet clinical need for an accurate and effective blood biomarker for neuroendocrine neoplasms (NEN). We therefore evaluated, under real-world conditions in an ENETS Center of Excellence (CoE), the clinical utility of the NETest as a liquid biopsy and compared its utility with chromogranin A (CgA) measurement. METHODS The cohorts were: gastroenteropancreatic NEN (GEP-NEN; n = 253), bronchopulmonary NEN (BPNEN; n = 64), thymic NEN (n = 1), colon cancer (n = 37), non-small-cell lung cancer (NSCLC; n = 63), benign lung disease (n = 59), and controls (n = 86). In the GEPNEN group, 164 (65%) had image-positive disease (IPD, n = 135) or were image-negative but resection-margin/biopsy-positive (n = 29), and were graded as G1 (n = 106), G2 (n = 49), G3 (n = 7), or no data (n = 2). The remainder (n = 71) had no evidence of disease (NED). In the BPNEN group, 43/64 (67%) had IPD. Histology revealed typical carcinoids (TC, n = 14), atypical carcinoids (AC, n = 14), small-cell lung cancer (SCLC, n = 11), and large-cell neuroendocrine carcinoma (LCNEC, n = 4). Disease status (stable or progressive) was evaluated according to RECIST v1.1. Blood sampling involved NETest (n = 563) and NETest/CgA analysis matched samples (n = 178). NETest was performed by PCR (on a scale of 0-100), with a score ≥20 reflecting a disease-positive status and >40 reflecting progressive disease. CgA positivity was determined by ELISA. Samples were deidentified and measurements blinded. The Kruskal-Wallis, Mann-Whitney U, and McNemar tests, and the area under the curve (AUC) of the receiver-operating characteristics (ROC) were used in the statistical analysis. RESULTS In the GEPNEN group, NETest was significantly higher (34.4 ± 1.8, p < 0.0001) in disease-positive patients than in patients with NED (10.5 ± 1, p < 0.0001), colon cancer patients (18 ± 4, p < 0.0004), and controls (7 ± 0.5, p < 0.0001). Sensitivity for detecting disease compared to controls was 89% and specificity was 94%. NETest levels were increased in G2 vs. G1 (39 ± 3 vs. 32 ± 2, p = 0.02) and correlated with stage (localized: 26 ± 2 vs. regional/distant: 40 ± 3, p = 0.0002) and progression (55 ± 5 vs. 34 ± 2 in stable disease, p = 0.0005). In the BPNEN group, diagnostic sensitivity was 100% and levels were significantly higher in patients with bronchopulmonary carcinoids (BPC; 30 ± 1.3) who had IPD than in controls (7 ± 0.5, p < 0.0001), patients with NED (24.1 ± 1.3, p < 0.005), and NSCLC patients (17 ± 3, p = 0.0001). NETest levels were higher in patients with poorly differentiated BPNEN (LCNEC + SCLC; 59 ± 7) than in those with BPC (30 ± 1.3, p = 0.0005) or progressive disease (57.8 ± 7), compared to those with stable disease (29.4 ± 1, p < 0.0001). The AUC for differentiating disease from controls was 0.87 in the GEPNEN group and 0.99 in BPC patients (p < 0.0001). Matched CgA analysis was performed in 178 patients. In the GEPNEN group (n = 135), NETest was significantly more accurate for detecting disease (99%) than CgA positivity (53%; McNemar test χ2 = 87, p < 0.0001). In the BPNEN group (n = 43), NETest was significantly more accurate for disease detection (100%) than CgA positivity (26%; McNemar's test χ2 = 30, p < 0.0001). CONCLUSIONS The NETest is an accurate diagnostic for GEPNEN and BPNEN. It exhibits tumor biology correlation with grading, staging, and progression. CgA as a biomarker is significantly less accurate than NETest. The NETest has substantial clinical utility that can facilitate patient management.
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Affiliation(s)
- Anna Malczewska
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland,
| | - Magdalena Witkowska
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Monika Wójcik-Giertuga
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Katarzyna Kuśnierz
- Department of Gastrointestinal Surgery, Medical University of Silesia, Katowice, Poland
| | - Agnes Bocian
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Agata Walter
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Mateusz Rydel
- Department of Thoracic Surgery, Medical University of Silesia, Zabrze, Poland
| | - Amanda Robek
- Department of Oncology, Medical University of Silesia, Katowice, Poland
| | - Sylwia Pierzchała
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | - Magdalena Malczewska
- Department of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland
| | | | - Damian Czyżewski
- Department of Thoracic Surgery, Medical University of Silesia, Zabrze, Poland
| | - Dariusz Ziora
- Department of Pulmonology, Medical University of Silesia, Zabrze, Poland
| | - Joanna Pilch-Kowalczyk
- Department of Radiology and Nuclear Medicine, Medical University of Silesia, Katowice, Poland
| | - Wojciech Zajęcki
- Department of Pathology, Medical University of Silesia, Zabrze, Poland
| | - Beata Kos-Kudła
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
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Kidd M, Kitz A, Drozdov I, Modlin I. Neuroendocrine Tumor Omic Gene Cluster Analysis Amplifies the Prognostic Accuracy of the NETest. Neuroendocrinology 2021; 111:490-504. [PMID: 32392558 DOI: 10.1159/000508573] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 05/11/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND The NETest is a multigene assay comprising 51 circulating neuroendocrine tumor (NET)-specific transcripts. The quotient of the 51-gene assay is based upon an ensemble of machine learning algorithms. Eight cancer hallmarks or "omes" (apoptome, epigenome, growth factor signalome, metabolome, proliferome, plurome, secretome, SSTRome) represent 29 genes. The NETest is an accurate diagnostic (>90%) test, but its prognostic utility has not been assessed. In this study, we describe the expansion of the NETest omic cluster components and demonstrate that integration amplifies NETest prognostic accuracy. METHODS Group 1: n = 222; including stable disease (SD, n = 146), progressive disease (PD, n = 76), and controls (n = 139). Group 2: NET Registry NCT02270567; n = 88; prospective samples (SD, n = 54; PD, n = 34) with up to 24 months follow-up. We used PubMed literature review, interactomic analysis, nonparametric testing, Kaplan-Meier survival curves, and χ2 analyses to inform and define the prognostic significance of NET genomic "hallmarks." RESULTS 2020 analyses: In-depth analyses of 47 -NETest genes identified a further six omes: fibrosome, inflammasome, metastasome, NEDome, neurome, and TFome. Group 1 analysis: Twelve omes, excluding the inflammasome and apoptome, were significantly (p < 0.05, 2.1- to 8.2-fold) elevated compared to controls. In the PD group, seven omes (proliferome, NEDome, epigenome, SSTRome, neurome, metastasome, and fibrosome) were elevated (both expression levels and fold change >2) versus SD. Group 2 analysis: All these seven omes were upregulated. In PD, they were significantly more elevated (p < 0.02) than in SD. The septet omic expression exhibited a 69% prognostic accuracy. The NETest alone was 70.5% accurate. A low NETest (≤40) integrated with epigenome/metastasome levels was an accurate prognostic for PD (90%). A high NETest (>40) including the fibrosome/NEDome predicted PD development within 3 months (100%). Using decision tree analysis to integrate the four omes (epigenome, metastasome, fibrosome, and NEDome) with the NETest score generated an overall prognostic accuracy of 93%. CONCLUSIONS Examination of NETest omic gene cluster analysis identified five additional clinically relevant cancer hallmarks. Identification of seven omic clusters (septet) provides a molecular pathological signature of disease progression. The integration of the quartet (epigenome, fibrosome, metastasome, NEDome) and the NETest score yielded a 93% accuracy in the prediction of future disease status.
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Affiliation(s)
- Mark Kidd
- Wren Laboratories, Branford, Connecticut, USA
| | | | | | - Irvin Modlin
- Yale University School of Medicine, New Haven, Connecticut, USA,
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Rindi G, Wiedenmann B. Neuroendocrine neoplasia of the gastrointestinal tract revisited: towards precision medicine. Nat Rev Endocrinol 2020; 16:590-607. [PMID: 32839579 DOI: 10.1038/s41574-020-0391-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2020] [Indexed: 02/06/2023]
Abstract
Over the past 5 years, a number of notable research advances have been made in the field of neuroendocrine cancer, specifically with regard to neuroendocrine cancer of the gastrointestinal tract. The aim of this Review is to provide an update on current knowledge that has proven effective for the clinical management of patients with these tumours. For example, for the first time in the tubular gastrointestinal tract, well-differentiated high-grade (grade 3) tumours and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are defined in the WHO classification. This novel classification enables efficient identification of the most aggressive well-differentiated neuroendocrine tumours and helps in defining the degree of aggressiveness of MiNENs. The Review also discusses updates to epidemiology, cell biology (including vesicle-specific components) and the as-yet-unresolved complex genetic background that varies according to site and differentiation status. The Review summarizes novel diagnostic instruments, including molecules associated with the secretory machinery, novel radiological approaches (including pattern recognition techniques), novel PET tracers and liquid biopsy combined with DNA or RNA assays. Surgery remains the treatment mainstay; however, peptide receptor radionuclide therapy with novel radioligands and new emerging medical therapies (including vaccination and immunotherapy) are evolving and being tested in clinical trials, which are summarized and critically reviewed here.
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Affiliation(s)
- Guido Rindi
- Università Cattolica del Sacro Cuore, Rome, Italy.
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
| | - Bertram Wiedenmann
- Charité, Campus Virchow Klinikum and Charité Mitte, University Medicine Berlin, Berlin, Germany
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Laskaratos FM, Liu M, Malczewska A, Ogunbiyi O, Watkins J, Luong TV, Mandair D, Caplin M, Toumpanakis C. Evaluation of circulating transcript analysis (NETest) in small intestinal neuroendocrine neoplasms after surgical resection. Endocrine 2020; 69:430-440. [PMID: 32291735 PMCID: PMC7392928 DOI: 10.1007/s12020-020-02289-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 03/25/2020] [Indexed: 12/29/2022]
Abstract
PURPOSE Surgical resection is the only effective curative strategy for small intestinal neuroendocrine neoplasms (SINENs). Nevertheless, the evaluation of residual disease and prediction of disease recurrence/progression remains a problematic issue. METHODS We evaluated 13 SINENs that underwent surgical resection of the primary tumour and/or mesenteric mass. Patients were divided in three groups: (a) Group 1: SINENs that underwent resection with curative intent, (b) Group 2: SINENs treated with resection in the setting of metastatic disease, which remained stable and (c) Group 3: SINENs treated with resection in the setting of metastatic disease, with evidence of any progression at follow-up. NETest and chromogranin A were measured pre-operatively and post-operatively during a 22-month median follow-up period and compared with imaging studies. NETest score <20% was determined as normal, 20-40% low, 41-79% intermediate and ≥80% high score. RESULTS NETest score was raised in all (100%) SINENs pre-operatively. Surgery with curative intent resulted in NETest score reduction from 78.25 ± 15.32 to 25.25 ± 1.75 (p < 0.05). Low NETest scores post-operatively were evident in all cases without clinical evidence of residual disease (Group 1). However, the low disease activity score suggested the presence of microscopic residual disease. In three cases (75%) with stable disease (Group 2) the NETest score was low consistent with indolent disease. In the progressive disease group (Group 3), a high NETest score was present in three cases (60%) and an intermediate NETest score in the remainder (40%). CONCLUSIONS Blood NETest scores accurately identified SINENs and were significantly decreased by curative surgery. Monitoring NETest post-operatively may facilitate management by identifying the presence of residual/progressive disease.
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Affiliation(s)
- Faidon-Marios Laskaratos
- Centre for Gastroenterology, Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK.
| | - Man Liu
- Centre for Gastroenterology, Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Anna Malczewska
- Department of Endocrinology and Neuroendocrine Tumors, Medical University of Silesia, Katowice, Poland
| | | | | | - Tu Vinh Luong
- Histopathology Department, Royal Free Hospital, London, UK
| | - Dalvinder Mandair
- Centre for Gastroenterology, Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Martyn Caplin
- Centre for Gastroenterology, Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Christos Toumpanakis
- Centre for Gastroenterology, Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
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