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Prasad V, Koumarianou A, Denecke T, Sundin A, Deroose CM, Pavel M, Christ E, Lamarca A, Caplin M, Castaño JP, Dromain C, Falconi M, Grozinsky-Glasberg S, Hofland J, Knigge UP, Kos-Kudla B, Krishna BA, Reed NS, Scarpa A, Srirajaskanthan R, Toumpanakis C, Kjaer A, Hicks RJ, Ambrosini V. Challenges in developing response evaluation criteria for peptide receptor radionuclide therapy: A consensus report from the European Neuroendocrine Tumor Society Advisory Board Meeting 2022 and the ENETS Theranostics Task Force. J Neuroendocrinol 2025; 37:e13479. [PMID: 39653582 DOI: 10.1111/jne.13479] [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: 10/05/2024] [Revised: 11/18/2024] [Accepted: 11/25/2024] [Indexed: 01/06/2025]
Abstract
Assessing the response to systemic therapy in neuroendocrine tumors (NET) is challenging since morphological imaging response is often delayed and not necessarily reflective of clinical benefit. Peptide receptor radionuclide therapy (PRRT) has a complex mechanism of action, further complicating response assessment. In response to these challenges, the European Neuroendocrine Tumor Society (ENETS) Theranostics Task Force conducted a statement-based survey among experts to identify the current landscape and unmet needs in PRRT response assessment. The survey, presented at the 2022 ENETS Advisory Board (AB) meeting in Vienna, was completed by 70% of AB members, most of whom (81%) were from ENETS Centers of Excellence (CoE). It comprised a set of 13 questions with two substatements in three questions. Six (46%) of the statements achieved more than 75% agreement, while five (39%) additional statements reached over 60% consensus. Key points from the survey include: AB members agreed that lesions deemed equivocal on computed tomography (CT) or magnetic resonance imaging (MRI) should be characterized by somatostatin receptor (SST) positron emission tomography (PET)/CT before being designated as target lesions. It was agreed that interim response assessments should occur after the second or third PRRT cycle. Over half (54%) preferred using both conventional cross-sectional imaging (CT and/or MRI) and hybrid imaging (SST PET/CT) for this purpose. Almost all AB members supported further response assessment 3 months after the final PRRT cycle. A majority (62%) preferred using a combination of conventional cross-sectional imaging and SST PET/CT. For cases showing equivocal progression (ambiguous lesions or nontarget lesions) on CT and/or MRI, further confirmation using SST PET/CT was recommended. A significant majority (74%) preferred assessing pseudo-progression and delayed response by combining SST PET with diagnostic CT and/ or MRI. Though just below the 75% consensus threshold, there was substantial agreement on selecting target lesions based on SST PET/CT uptake intensity and homogeneity. Sixty-nine percent noted the importance of documenting and closely following heterogeneity in lesions in liver, lymph nodes, primary tumors, or other organs. As to the statement on parameters for new response criteria, AB members recommended exploring maximum standard unit value, tumor-to-background ratio, Hounsfield Unit (Choi Criteria), total tumor burden, and novel serum or molecular markers for future response evaluation criteria. Sixty-five percent supported the use of a single SST PET/CT for response assessment of NET lesions treated with PRRT. These findings highlight the importance of integrating advanced imaging techniques and recognizing the need for more nuanced criteria in assessing the efficacy of PRRT in NET patients. This approach aims to enhance the accuracy of treatment monitoring and improve patient outcomes.
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Affiliation(s)
- Vikas Prasad
- Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine in Saint Louis, St. Louis, Missouri, USA
| | - Anna Koumarianou
- Hematology Oncology Unit, Fourth Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Timm Denecke
- Department of Diagnostic and Interventional Radiology, University Medical Centre Leipzig, Leipzig, Germany
| | - Anders Sundin
- Radiology and Molecular Imaging, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Christophe M Deroose
- Nuclear Medicine, University Hospitals Leuven and Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Marianne Pavel
- Department of Medicine 1, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Emanuel Christ
- Center of Endocrine and Neuroendocrine Tumors, ENETS Center of Excellence (CoE), Division of Endocrinology, Diabetology and Metabolism, University Hospital of Basel, Basel, Switzerland
| | - Angela Lamarca
- Department of Oncology-OncoHealth Institute-Instituto de Investigaciones Sanitarias FJD, Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Martyn Caplin
- Neuroendocrine Tumour Unit, ENETS Center of Excellence, Royal Free Hospital, London, UK
| | - Justo P Castaño
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Córdoba, Spain
| | - Clarisse Dromain
- Department of Diagnostic and Interventional Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Massimo Falconi
- Pancreatic Surgery, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Simona Grozinsky-Glasberg
- Neuroendocrine Tumor Unit, ENETS Center of Excellence, Division of Medicine, Hadassah Medical Organization and Faculty of Medicine, The Hebrew University, Jerusalem, Israel
| | - Johannes Hofland
- Department of Internal Medicine, Section of Endocrinology, ENETS Center of Excellence, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Ulrich Peter Knigge
- Department of Surgery and Transplantation, Department of Nephrology and Endocrinology, Center of Cancer and Transplantation, ENETS Center of Excellence, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Beata Kos-Kudla
- Department of Endocrinology and Neuroendocrine Tumours, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland
| | - Balkundi A Krishna
- Department of Nuclear Medicine & PET imaging, Lilavati Hospital & Research Centre, Mumbai, India
| | | | - Aldo Scarpa
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | | | - Christos Toumpanakis
- Neuroendocrine Tumour Unit, ENETS Center of Excellence, Royal Free Hospital, London, UK
| | - Andreas Kjaer
- Department of Clinical Physiology and Nuclear Medicine & Cluster for Molecular Imaging, Copenhagen University Hospital-Rigshospitalet
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rodney J Hicks
- St Vincent's Hospital, Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, Translational Medicine, the Alfred Hospital, Monash University, Melbourne, Victoria, Australia
| | - Valentina Ambrosini
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy
- Nuclear Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Nalbant H, Mingels C, Sen F, Spencer B, Riess JW, Nardo L. Glove Phenomenon Detected by Total-Body PET/CT With 68 GA-DOTATATE. Clin Nucl Med 2024; 49:1098-1099. [PMID: 39466637 PMCID: PMC11530305 DOI: 10.1097/rlu.0000000000005488] [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] [Indexed: 10/30/2024]
Abstract
ABSTRACT Accidental intra-arterial injections of radiotracers are rare events resulting in a specific imaging pattern, described as "hot-forearm," "hot-hand," "glove-phenomenon," or "glove-like pattern." We present a case 68 Ga-DOTATATE total-body PET/CT for restaging of a neuroendocrine tumor, where intra-arterial misinjection resulted in a glove phenomenon. Since patients may present with minimal symptoms, like in this case, and PET findings may only be seen at the distal upper extremity (placed above the head), these accidental injections may be more frequently detected with total-body PET/CT due to the longer field-of-view. Radiologists and technologists should be aware of this possibility to avoid accidental misinjections.
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Affiliation(s)
- Hande Nalbant
- Department of Radiology, University of California Davis, Sacramento, California, United States of America
| | - Clemens Mingels
- Department of Radiology, University of California Davis, Sacramento, California, United States of America
- Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Fatma Sen
- Department of Radiology, University of California Davis, Sacramento, California, United States of America
| | - Benjamin Spencer
- Department of Radiology, University of California Davis, Sacramento, California, United States of America
| | - Jonathan W. Riess
- Department of Hematology and Oncology, University of California Davis, Sacramento, California, United States of America
| | - Lorenzo Nardo
- Department of Radiology, University of California Davis, Sacramento, California, United States of America
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Rudd SE, Noor A, Morgan KA, Donnelly PS. Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside. Acc Chem Res 2024; 57:1421-1433. [PMID: 38666539 DOI: 10.1021/acs.accounts.4c00092] [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: 05/08/2024]
Abstract
Molecular imaging with antibodies radiolabeled with positron-emitting radionuclides combines the affinity and selectivity of antibodies with the sensitivity of Positron Emission Tomography (PET). PET imaging allows the visualization and quantification of the biodistribution of the injected radiolabeled antibody, which can be used to characterize specific biological interactions in individual patients. This characterization can provide information about the engagement of the antibody with a molecular target such as receptors present in elevated levels in tumors as well as providing insight into the distribution and clearance of the antibody. Potential applications of clinical PET with radiolabeled antibodies include identifying patients for targeted therapies, characterization of heterogeneous disease, and monitoring treatment response.Antibodies often take several days to clear from the blood pool and localize in tumors, so PET imaging with radiolabeled antibodies requires the use of a radionuclide with a similar radioactive half-life. Zirconium-89 is a positron-emitting radionuclide that has a radioactive half-life of 78 h and relatively low positron emission energy that is well suited to radiolabeling antibodies. It is essential that the zirconium-89 radionuclide be attached to the antibody through chemistry that provides an agent that is stable in vivo with respect to the dissociation of the radionuclide without compromising the biological activity of the antibody.This Account focuses on our research using a simple derivative of the bacterial siderophore desferrioxamine (DFO) with a squaramide ester functional group, DFO-squaramide (DFOSq), to link the chelator to antibodies. In our work, we produce conjugates with an average ∼4 chelators per antibody, and this does not compromise the binding of the antibody to the target. The resulting antibody conjugates of DFOSq are stable and can be easily radiolabeled with zirconium-89 in high radiochemical yields and purity. Automated methods for the radiolabeling of DFOSq-antibody conjugates have been developed to support multicenter clinical trials. Evaluation of several DFOSq conjugates with antibodies and low molecular weight targeting agents in tumor mouse models gave PET images with high tumor uptake and low background. The promising preclinical results supported the translation of this chemistry to human clinical trials using two different radiolabeled antibodies. The potential clinical impact of these ongoing clinical trials is discussed.The use of DFOSq to radiolabel relatively low molecular weight targeting molecules, peptides, and peptide mimetics is also presented. Low molecular weight molecules typically clear the blood pool and accumulate in target tissue more rapidly than antibodies, so they are usually radiolabeled with positron-emitting radionuclides with shorter radioactive half-lives such as fluorine-18 (t1/2 ∼ 110 min) or gallium-68 (t1/2 ∼ 68 min). Radiolabeling peptides and peptide mimetics with zirconium-89, with its longer radioactive half-life (t1/2 = 78 h), could facilitate the centralized manufacture and distribution of radiolabeled tracers. In addition, the ability to image patients at later time points with zirconium-89 based agents (e.g. 4-24 h after injection) may also allow the delineation of small or low-uptake disease sites as the delayed imaging results in increased clearance of the tracer from nontarget tissue and lower background signal.
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Affiliation(s)
- Stacey E Rudd
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Asif Noor
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Katherine A Morgan
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Paul S Donnelly
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
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Morgan KA, Rudd SE, Noor A, Donnelly PS. Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides. Chem Rev 2023; 123:12004-12035. [PMID: 37796539 DOI: 10.1021/acs.chemrev.3c00456] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term "theranostics" describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or β+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, β-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain β+-emitting gallium-68 and β-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.
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Affiliation(s)
- Katherine A Morgan
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Stacey E Rudd
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Asif Noor
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Paul S Donnelly
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Melbourne 3010, Australia
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Eads JR, Halfdanarson TR, Asmis T, Bellizzi AM, Bergsland EK, Dasari A, El-Haddad G, Frumovitz M, Meyer J, Mittra E, Myrehaug S, Nakakura E, Raj N, Soares HP, Untch B, Vijayvergia N, Chan JA. Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms. Endocr Relat Cancer 2023; 30:e220206. [PMID: 37184955 PMCID: PMC10388681 DOI: 10.1530/erc-22-0206] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 05/15/2023] [Indexed: 05/16/2023]
Abstract
High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.
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Affiliation(s)
- Jennifer R Eads
- Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Pennsylvania, USA
| | | | - Tim Asmis
- Division of Medical Oncology, University of Ottawa, Ottawa, Ontario, Canada
| | - Andrew M Bellizzi
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Emily K Bergsland
- Department of Medicine, University of California, San Francisco, California, USA
| | - Arvind Dasari
- Division of Gastrointestinal Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ghassan El-Haddad
- Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Michael Frumovitz
- Division of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Joshua Meyer
- Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Erik Mittra
- Division of Molecular Imaging and Therapy, Oregon Health & Science University, Portland, Oregon, USA
| | - Sten Myrehaug
- Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Eric Nakakura
- Department of Surgery, University of California, San Francisco, California, USA
| | - Nitya Raj
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Heloisa P Soares
- Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Salt Lake City, Utah, USA
| | - Brian Untch
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Namrata Vijayvergia
- Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Jennifer A Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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6
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Hope TA, Allen-Auerbach M, Bodei L, Calais J, Dahlbom M, Dunnwald LK, Graham MM, Jacene HA, Heath CL, Mittra ES, Wright CL, Fendler WP, Herrmann K, Taïeb D, Kjaer A. SNMMI Procedure Standard/EANM Practice Guideline for SSTR PET: Imaging Neuroendocrine Tumors. J Nucl Med 2023; 64:204-210. [PMID: 36725249 DOI: 10.2967/jnumed.122.264860] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 08/30/2022] [Indexed: 02/03/2023] Open
Affiliation(s)
- Thomas A Hope
- Department of Radiology, San Francisco VA Medical Center, San Francisco, California; .,Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California
| | - Martin Allen-Auerbach
- Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
| | - Lisa Bodei
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York
| | - Jeremie Calais
- Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
| | - Magnus Dahlbom
- Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California
| | - Lisa K Dunnwald
- Department of Radiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Michael M Graham
- Department of Radiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Heather A Jacene
- Department of Imaging, Dana-Farber Cancer Institute, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Courtney Lawhn Heath
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California
| | - Erik S Mittra
- Department of Diagnostic Radiology, Oregon Health & Science University, Portland, Oregon
| | - Chadwick L Wright
- Wright Center of Innovation and Biomedical Imaging, Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Wolfgang P Fendler
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany
| | - David Taïeb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France; and
| | - Andreas Kjaer
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
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McDonald JA, Scott L, Van Zuylekom J, Holloway S, Blyth BJ, Sutherland KD. On Target: An Intrapulmonary Transplantation Method for Modelling Lung Tumor Development in its Native Microenvironment. Methods Mol Biol 2023; 2691:31-41. [PMID: 37355535 DOI: 10.1007/978-1-0716-3331-1_3] [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] [Indexed: 06/26/2023]
Abstract
The development of in vivo lung cancer models that faithfully mimic the human disease is a crucial research tool for understanding the molecular mechanisms driving tumorigenesis. Subcutaneous transplantation assays are commonly employed, likely due to their amenability to easily monitor tumor growth and the simplistic nature of the technique to deliver tumor cells. Importantly however, subcutaneous tumors grow in a microenvironment that differs from that resident within the lung. To circumvent this limitation, here we describe the development of an intrapulmonary (iPUL) orthotopic transplantation method that enables the delivery of lung cancer cells, with precision, to the left lung lobe of recipient mice. Critically, this allows for the growth of lung cancer cells within their native microenvironment. The coupling of iPUL transplantation with position emission tomography (PET) imaging permits the serial detection of tumors in vivo and serves as a powerful tool to trace lung tumor growth and dissemination over time in mouse disease models.
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Affiliation(s)
- Jackson A McDonald
- ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Leanne Scott
- ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Jessica Van Zuylekom
- Models of Cancer Translational Research Centre, Peter MacCallum Cancer Centre, Parkville, VIC, Australia
| | - Steven Holloway
- Bioservices Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Benjamin J Blyth
- Models of Cancer Translational Research Centre, Peter MacCallum Cancer Centre, Parkville, VIC, Australia.
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
| | - Kate D Sutherland
- ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
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Fine GC, Covington MF, Koppula BR, Salem AE, Wiggins RH, Hoffman JM, Morton KA. PET-CT in Clinical Adult Oncology-VI. Primary Cutaneous Cancer, Sarcomas and Neuroendocrine Tumors. Cancers (Basel) 2022; 14:2835. [PMID: 35740501 PMCID: PMC9221374 DOI: 10.3390/cancers14122835] [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: 04/29/2022] [Revised: 06/03/2022] [Accepted: 06/06/2022] [Indexed: 11/16/2022] Open
Abstract
PET-CT is an advanced imaging modality with many oncologic applications, including staging, therapeutic assessment, restaging and surveillance for recurrence. The goal of this series of six review articles is to provide practical information to providers and imaging professionals regarding the best use of PET-CT for specific oncologic indications, the potential pitfalls and nuances that characterize these applications, and guidelines for image interpretation. Tumor-specific clinical information and representative PET-CT images are provided. The current, sixth article in this series addresses PET-CT in an evaluation of aggressive cutaneous malignancies, sarcomas and neuroendocrine tumors. A discussion of the role of FDG PET for all types of tumors in these categories is beyond the scope of this review. Rather, this article focuses on the most common malignancies in adult patients encountered in clinical practice. It also focuses on Food and Drug Agency (FDA)-approved and clinically available radiopharmaceuticals rather than research tracers or those requiring a local cyclotron. This information will serve as a guide to primary providers for the appropriate role of PET-CT in managing patients with cutaneous malignancies, sarcomas and neuroendocrine tumors. The nuances of PET-CT interpretation as a practical guide for imaging providers, including radiologists, nuclear medicine physicians and their trainees, are also addressed.
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Affiliation(s)
- Gabriel C. Fine
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA; (G.C.F.); (M.F.C.); (B.R.K.); (A.E.S.); (R.H.W.); (J.M.H.)
| | - Matthew F. Covington
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA; (G.C.F.); (M.F.C.); (B.R.K.); (A.E.S.); (R.H.W.); (J.M.H.)
| | - Bhasker R. Koppula
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA; (G.C.F.); (M.F.C.); (B.R.K.); (A.E.S.); (R.H.W.); (J.M.H.)
| | - Ahmed Ebada Salem
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA; (G.C.F.); (M.F.C.); (B.R.K.); (A.E.S.); (R.H.W.); (J.M.H.)
- Faculty of Medicine, Department of Radiodiagnosis and Intervention, Alexandria University, Alexandria 21526, Egypt
| | - Richard H. Wiggins
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA; (G.C.F.); (M.F.C.); (B.R.K.); (A.E.S.); (R.H.W.); (J.M.H.)
| | - John M. Hoffman
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA; (G.C.F.); (M.F.C.); (B.R.K.); (A.E.S.); (R.H.W.); (J.M.H.)
| | - Kathryn A. Morton
- Department of Radiology and Imaging Sciences, University of Utah, Salt Lake City, UT 84132, USA; (G.C.F.); (M.F.C.); (B.R.K.); (A.E.S.); (R.H.W.); (J.M.H.)
- Intermountain Healthcare Hospitals, Summit Physician Specialists, Murray, UT 84123, USA
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Grey N, Silosky M, Lieu CH, Chin BB. Current status and future of targeted peptide receptor radionuclide positron emission tomography imaging and therapy of gastroenteropancreatic-neuroendocrine tumors. World J Gastroenterol 2022; 28:1768-1780. [PMID: 35633909 PMCID: PMC9099199 DOI: 10.3748/wjg.v28.i17.1768] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/07/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Theranostics is the highly targeted molecular imaging and therapy of tumors. Targeted peptide receptor radionuclide therapy has taken the lead in demonstrating the safety and effectiveness of this molecular approach to treating cancers. Metastatic, well-differentiated gastroenteropancreatic neuroendocrine tumors may be most effectively imaged and treated with DOTATATE ligands. We review the current practice, safety, advantages, and limitations of DOTATATE based theranostics. Finally, we briefly describe the exciting new areas of development and future directions of gastroenteropancreatic neuroendocrine tumor theranostics.
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Affiliation(s)
- Neil Grey
- Radiology-Nuclear Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Michael Silosky
- Department of Radiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Christopher H Lieu
- Medical Oncology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Bennett B Chin
- Department of Radiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
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Hicks RJ, Dromain C, de Herder WW, Costa FP, Deroose CM, Frilling A, Koumarianou A, Krenning EP, Raymond E, Bodei L, Sorbye H, Welin S, Wiedenmann B, Wild D, Howe JR, Yao J, O’Toole D, Sundin A, Prasad V. ENETS standardized (synoptic) reporting for molecular imaging studies in neuroendocrine tumours. J Neuroendocrinol 2022; 34:e13040. [PMID: 34668262 PMCID: PMC11042683 DOI: 10.1111/jne.13040] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 11/27/2022]
Abstract
The European Neuroendocrine Tumor Society (ENETS) promotes practices and procedures that aim to improve the standard of care delivered to patients diagnosed with or suspected of having neuroendocrine neoplasia (NEN). At its annual Scientific Advisory Board Meeting in 2018, experts in imaging, pathology and clinical care of patients with NEN drafted guidance for the standardised reporting of diagnostic studies critical to the diagnosis, grading, staging and treatment of NEN. These included pathology, radiology, endoscopy and molecular imaging procedures. In an iterative process, a synoptic reporting template for molecular imaging procedures was developed to guide personalised therapies. Following pilot implementation and refinement within the ENETS Center of Excellence network, harmonisation with specialist imaging societies including the Society of Nuclear Medicine, European Association of Nuclear Medicine and the International Cancer Imaging Society will be pursued.
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Affiliation(s)
- RJ Hicks
- Neuroendocrine Service, the Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - C Dromain
- Lausanne University Hospital, Department of Radiology and University of Lausanne, Lausanne, Switzerland
| | - W W de Herder
- Erasmus MC, Department of Internal Medicine, Section of Endocrinology, Rotterdam, The Netherlands
| | - FP Costa
- Centro de Oncologia of Hospital Sírio Libanês, Sao Paulo, Brazil
| | - C M Deroose
- University Hospitals Leuven, Nuclear Medicine and KU Leuven, Department of Imaging and Pathology, Nuclear Medicine & Molecular Imaging, Leuven, Belgium
| | - A Frilling
- Imperial College London, Department of Surgery and Cancer, Hammersmith Hospital, London, United Kingdom
| | - A Koumarianou
- National and Kapodistrian University of Athens, Hematology Oncology Unit, 4th Department of Internal Medicine, Athens, Greece
| | - EP Krenning
- Erasmus MC, Cyclotron Rotterdam BV, Rotterdam, The Netherlands
| | - E Raymond
- Medical Oncology, Hôspital Paris Saint-Joseph, Paris, France
| | - L Bodei
- Memorial Sloan Kettering Cancer Center, Department of Radiology, Molecular Imaging and Therapy Service, New York, USA
| | - H Sorbye
- Haukeland University Hospital, Department of Oncology and Department of Clinical Science, Bergen, Norway
| | - S Welin
- Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
| | - B Wiedenmann
- Charité Universitätsmedizin Berlin, Berlin, Germany
| | - D Wild
- University of Basel Hospital, Department of Radiology and Nuclear Medicine, Basel, Switzerland
| | - JR Howe
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - J Yao
- University of Texas M.D. Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, Houston, Texas, USA
| | - D O’Toole
- St. James’s and St. Vincent’s University Hospitals & Trinity College Dublin, Dublin, Ireland
| | - A Sundin
- Department of Surgical Sciences, Uppsala University, Radiology and Molecular Imaging, Uppsala University Hospital, Uppsala, Sweden
| | - V Prasad
- Department of Nuclear Medicine, University Ulm, Ulm Germany
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11
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Hicks RJ. Molecular imaging with FLT: a case of Cassandra's curse? Eur J Nucl Med Mol Imaging 2021; 48:2687-2689. [PMID: 34081154 DOI: 10.1007/s00259-021-05437-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
- Rodney J Hicks
- Cancer Imaging, Level 5, The Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia.
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12
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Mihailovic J, Killeen RP, Duignan JA. PET/CT Variants and Pitfalls in Head and Neck Cancers Including Thyroid Cancer. Semin Nucl Med 2021; 51:419-440. [PMID: 33947603 DOI: 10.1053/j.semnuclmed.2021.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PET/CT imaging is a dual-modality diagnostic technology that merges metabolic and structural imaging. There are several currently available radiotracers, but 18F-FDG is the most commonly utilized due to its widespread availability. 18F-FDG PET/CT is a cornerstone of head and neck squamous cell carcinoma imaging. 68Ga-DOTA-TOC is another widely used radiotracer. It allows for whole-body imaging of cellular somatostatin receptors, commonly expressed by neuroendocrine tumors and is the standard of reference for the characterization and staging of neuroendocrine tumors. The normal biodistribution of these PET radiotracers as well as the technical aspects of image acquisition and inadequate patient preparation affect the quality of PET/CT imaging. In addition, normal variants, artifacts and incidental findings may impede accurate image interpretation and can potentially lead to misdiagnosis. In order to correctly interpret PET/CT imaging, it is necessary to have a comprehensive knowledge of the normal anatomy of the head and neck and to be cognizant of potential imaging pitfalls. The interpreter must be familiar with benign conditions which may accumulate radiotracer potentially mimicking neoplastic processes and also be aware of malignancies which can demonstrate low radiotracer uptake. Appropriate use of structural imaging with either CT, MR or ultrasound can serve a complimentary role in several head and neck pathologies including local tumor staging, detection of bone marrow involvement or perineural spread, and classification of thyroid nodules. It is important to be aware of the role of these complementary modalities to maximize diagnostic accuracy and patient outcomes. The purpose of this article is to outline the basic principles of PET/CT imaging, with a focus on 18F-FDG PET/CT and 68Ga-DOTA PET/CT. Basic physiology, variant imaging appearances and potential pitfalls of image interpretation are presented within the context of common use cases of PET technology in patients with head and neck cancers and other pathologies, benign and malignant.
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Affiliation(s)
- Jasna Mihailovic
- Department of Radiology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia; Centre of Nuclear Medicine, Oncology Institute of Vojvodina, Sremska Kamenica, Serbia.
| | - Ronan P Killeen
- Department of Radiology, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland; UCD - SVUH PET CT Research Centre, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - John A Duignan
- Department of Radiology, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland; UCD - SVUH PET CT Research Centre, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
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13
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Noor A, Van Zuylekom JK, Rudd SE, Roselt PD, Haskali MB, Yan E, Wheatcroft M, Hicks RJ, Cullinane C, Donnelly PS. Imaging Somatostatin Positive Tumors with Tyr 3-Octreotate/Octreotide Conjugated to Desferrioxamine B Squaramide Radiolabeled with either Zirconium-89 or Gallium-68. Bioconjug Chem 2021; 32:1192-1203. [PMID: 33788556 DOI: 10.1021/acs.bioconjchem.1c00109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Radiolabeled derivatives of Tyr3-octreotide and Tyr3-octreotate, synthetic analogues of the peptide hormone somatostatin, can be used for positron emission tomography (PET) imaging of somatostatin receptor expression in neuroendocrine tumors. In this work, a squaramide ester derivative of desferrioxamine B (H3DFOSq) was used attach either Tyr3-octreotide or Tyr3-octreotate to the metal binding ligand to give H3DFOSq-TIDE and H3DFOSq-TATE. These new peptide-H3DFOSq conjugates form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or zirconium-89 (t1/2 = 3.3 days). The new complexes were evaluated in an AR42J xenograft model that has endogenous expression of SSTR2. All four agents displayed good tumor uptake and produced high-quality PET images. For both radionuclides, the complexes formed with H3DFOSq-TATE performed better, with higher tumor uptake and retention than the complexes formed with H3DFOSq-TIDE. The versatile ligands presented here can be radiolabeled with either gallium-68 or zirconium-89 at room temperature. The long radioactive half-life of zirconium-89 makes distribution of pre-synthesized tracers produced to certified standards feasible and could increase the number of clinical centers that can perform diagnostic PET imaging of neuroendocrine tumors.
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Affiliation(s)
- Asif Noor
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia
| | | | - Stacey E Rudd
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Peter D Roselt
- Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
| | - Mohammad B Haskali
- Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
| | - Eddie Yan
- Telix Pharmaceuticals Limited, Suite 401, 55 Flemington Road, North Melbourne, Victoria 3051, Australia
| | - Michael Wheatcroft
- Telix Pharmaceuticals Limited, Suite 401, 55 Flemington Road, North Melbourne, Victoria 3051, Australia
| | - Rodney J Hicks
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Carleen Cullinane
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Paul S Donnelly
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia
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14
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Iravani A, Mitchell C, Akhurst T, Sandhu S, Hofman MS, Hicks RJ. Molecular Imaging of Neuroendocrine Differentiation of Prostate Cancer: A Case Series. Clin Genitourin Cancer 2021; 19:e200-e205. [PMID: 33678552 DOI: 10.1016/j.clgc.2021.01.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/30/2021] [Accepted: 01/31/2021] [Indexed: 12/14/2022]
Affiliation(s)
- Amir Iravani
- Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
| | - Catherine Mitchell
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Tim Akhurst
- Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
| | - Shahneen Sandhu
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
| | - Michael S Hofman
- Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
| | - Rodney J Hicks
- Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
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15
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Hall AJ, Haskali MB. Radiolabelled Peptides: Optimal Candidates for Theranostic Application in Oncology. Aust J Chem 2021. [DOI: 10.1071/ch21118] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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AGTR1 Is Overexpressed in Neuroendocrine Neoplasms, Regulates Secretion and May Potentially Serve as a Target for Molecular Imaging and Therapy. Cancers (Basel) 2020; 12:cancers12113138. [PMID: 33120925 PMCID: PMC7693775 DOI: 10.3390/cancers12113138] [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: 10/06/2020] [Revised: 10/20/2020] [Accepted: 10/22/2020] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Clinical management of neuroendocrine neoplasms (NEN), especially of those low in target molecules such as somatostatin receptors, may benefit from the discovery of novel targets. This study identified and confirmed angiotensin II (ATII) as a strong activator of signaling in NEN cells and its cognate receptor AGTR1 as overexpressed in human small intestinal NEN. NEN cells with high AGTR1 expression exhibited cellular activation and secretion upon stimulation with ATII. AGTR1 ligand saralasin coupled to a fluorescent dye demonstrated tumor accumulation in an animal model of NEN. This proof of concept establishes AGTR1 as a novel target in NEN, paving the way for its potential use in diagnostic PET imaging and radioligand therapy. Abstract This study identified and confirmed angiotensin II (ATII) as a strong activator of signaling in neuroendocrine neoplasm (NEN) cells. Expression analyses of the ATII receptor type 1 (AGTR1) revealed an upregulation of mRNA levels (RT-qPCR) and radioligand binding (autoradiography) in small-intestinal (n = 71) NEN tissues compared to controls (n = 25). NEN cells with high AGTR1 expression exhibited concentration-dependent calcium mobilization and chromogranin A secretion upon stimulation with ATII, blocked by AGTR1 antagonism and Gαq inhibition. ATII also stimulated serotonin secretion from BON cells. AGTR1 ligand saralasin was coupled to a near-infrared fluorescent (NIRF) dye and tested for its biodistribution in a nude mouse model bearing AGTR1-positive BON and negative QGP-1 xenograft tumors. NIRF imaging showed significantly higher uptake in BON tumors. This proof of concept establishes AGTR1 as a novel target in NEN, paving the way for translational chelator-based probes for diagnostic PET imaging and radioligand therapy.
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Abstract
CLINICAL/METHODICAL ISSUE Conventional imaging tests like computed tomography (CT) cannot visualize somatostatin receptor (SSTR) expression on the tumor cell surface. STANDARD RADIOLOGICAL METHODS For imaging of SSTR-expressing tumors conventional morphological imaging tests such as CT or magnetic resonance imaging (MRI) are employed. METHODICAL INNOVATIONS Molecular imaging of SSTR expression on the tumor cell surface, in particular by using (whole body) single photon emission computed tomography (SPECT) and positron emission tomography (PET), are considered the current standard of care. Only the use of CT enables for exact localization of putative sites of disease (hybrid imaging). PERFORMANCE Hybrid SPECT/CT and PET/CT are of utmost importance for staging and monitoring of treatment efficacy. SSTR-PET is superior to SPECT and the PET radiotracer 68Ga-DOTATATE has been approved in multiple countries. In addition, SSTR positivity revealed by SPECT or PET pave the way for a peptide receptor radionuclide therapy (PRRT). Such a theranostic approach enables for systemic or locoregional radiation with β‑emitting radionuclides, which are linked to the identical amino acid peptide used for PET or SPECT imaging. The prospective, randomized Netter‑1 trial has shown significant benefit for patients receiving PRRT. ACHIEVEMENTS A combined use of conventional and functional imaging tests is superior to conventional imaging alone and allows for identification of suitable candidates for a theranostic approach. PRACTICAL RECOMMENDATIONS In case of clinical suspicion or after having obtained histological evidence, hybrid SSTR-SPECT/CT or -PET/CT should be performed, preferably in a dedicated molecular imaging center.
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18
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Cullinane C, Waldeck K, Kirby L, Rogers BE, Eu P, Tothill RW, Hicks RJ. Enhancing the anti-tumour activity of 177Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP. Sci Rep 2020; 10:10196. [PMID: 32576907 PMCID: PMC7311440 DOI: 10.1038/s41598-020-67199-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 06/02/2020] [Indexed: 01/25/2023] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) is an important treatment option for patients with somatostatin receptor-2 (SSTR2)-expressing neuroendocrine tumour (NET) though tumour regression occurs in only a minority of patients. Therefore, novel PRRT regimens with improved therapeutic activity are needed. Radiation induced DNA damage repair is an attractive therapeutic target to increase PRRT efficacy and consequently, we have characterised a panel of preclinical models for their SSTR2 expression, in vivo growth properties and response to 177Lu-DOTA-octreotate (LuTate) PRRT to identify models with features suitable for evaluating novel therapeutic combinations. In vitro studies using the SSTR2 expressing AR42J model demonstrate that the combination of LuTate and the small molecule Poly(ADP-ribose) polymerase-1 (PARP) inhibitor, talazoparib led to increased DNA double strand breaks, as assessed by γ-H2AX foci formation, as compared to LuTate alone. Furthermore, using the AR42J tumour model in vivo we demonstrate that the combination of LuTate and talazoparib significantly improved the anti-tumour efficacy of LuTate alone. These findings support the clinical evaluation of the combination of LuTate and PARP inhibition in SSTR2-expressing NET.
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Affiliation(s)
- Carleen Cullinane
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
| | - Kelly Waldeck
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Laura Kirby
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Buck E Rogers
- Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, 63110, USA
| | - Peter Eu
- Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - Richard W Tothill
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Department of Clinical Pathology and Centre for Cancer Research, University of Melbourne, Parkville, Victoria, Australia
| | - Rodney J Hicks
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
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Zidan L, Iravani A, Kong G, Akhurst T, Michael M, Hicks RJ. Theranostic implications of molecular imaging phenotype of well-differentiated pulmonary carcinoid based on 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT. Eur J Nucl Med Mol Imaging 2020; 48:204-216. [PMID: 32572559 DOI: 10.1007/s00259-020-04915-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 06/07/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE This study aimed to analyse the molecular imaging (MI) phenotype of typical carcinoid (TC) and atypical carcinoid (AC) by 68Ga-DOTATATE (GaTATE) and 18F-FDG (FDG) PET/CT with the emphasis on its potential theranostic implications for peptide receptor radionuclide therapy (PRRT). METHODS Retrospective review of patients with biopsy-proven TC or AC undergoing both GaTATE and FDG PET/CT at presentation. Based on correlative CT or MRI, positive lesions on either scan were defined by uptake above liver parenchyma. Per patient MI phenotypic pattern was classified as score 1, if all lesions were negative on both scans; score 2, if all were GaTATE positive/FDG negative; score 3, if all lesions were GaTATE positive but some or all were also FDG positive and score 4, if there were any GaTATE negative/FDG positive lesions. Scores 1 and 4 were deemed unsuitable for PRRT. RESULTS Of 56 patients (median age 66.5 years, 32 female), 22 had TC, and 34 had AC. Distant metastases were seen in 32% of TC and 94% of AC. At a median follow-up of 37 months for TC and 38 months for AC, 100% and 63% were alive, respectively. Median OS for AC was 56 months (95% CI 43, not reached [NR]), and TC was NR. On inter-patient dual-tracer analysis, scores 1, 2, 3 and 4 were 23%, 18%, 36% and 23% in TC and 3%, 15%, 32% and 50% in AC, respectively. In 16 patients (score 2, N = 3; score 3, N = 12; score 4, N = 1) who were treated with PRRT, disease control rate at 3 months and OS were, 85% and 54.6 months (95% CI 44-70), respectively. CONCLUSIONS TC and AC showed a wide inter-patient phenotypic heterogeneity on GaTATE and FDG with around half of patients (46% TC and 53% AC) having an unsuitable phenotype for PRRT. Dual-tracer MI phenotype can be used to select the most suitable patients for PRRT.
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Affiliation(s)
- Lamiaa Zidan
- Cancer imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. .,Clinical Oncology and Nuclear Medicine department, Cairo University, Cairo, Egypt.
| | - Amir Iravani
- Cancer imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Grace Kong
- Cancer imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Tim Akhurst
- Cancer imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Michael Michael
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.,Division of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Rodney J Hicks
- Cancer imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
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20
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Cullinane C, Jeffery CM, Roselt PD, van Dam EM, Jackson S, Kuan K, Jackson P, Binns D, van Zuylekom J, Harris MJ, Hicks RJ, Donnelly PS. Peptide Receptor Radionuclide Therapy with 67Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model. J Nucl Med 2020; 61:1800-1805. [PMID: 32414949 DOI: 10.2967/jnumed.120.243543] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 04/16/2020] [Indexed: 01/13/2023] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) using radiolabeled octreotate is an effective treatment for somatostatin receptor 2-expressing neuroendocrine tumors. The diagnostic and therapeutic potential of 64Cu and 67Cu, respectively, offers the possibility of using a single somatostatin receptor-targeted peptide conjugate as a theranostic agent. A sarcophagine cage amine ligand, MeCOSar (5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid), conjugated to (Tyr3)-octreotate, called 64Cu-CuSarTATE, was demonstrated to be an imaging agent and potential prospective dosimetry tool in 10 patients with neuroendocrine tumors. This study aimed to explore the antitumor efficacy of 67Cu-CuSarTATE in a preclinical model of neuroendocrine tumors and compare it with the standard PRRT agent, 177Lu-LuDOTA-Tyr3-octreotate (177Lu-LuTATE). Methods: The antitumor efficacy of various doses of 67Cu-CuSarTATE in AR42J (rat pancreatic exocrine) tumor-bearing mice was compared with 177Lu-LuTATE. Results: Seven days after a single administration of 67Cu-CuSarTATE (5 MBq), tumor growth was inhibited by 75% compared with vehicle control. Administration of 177Lu-LuTATE (5 MBq) inhibited tumor growth by 89%. Survival was extended from 12 d in the control group to 21 d after treatment with both 67Cu-CuSarTATE and 177Lu-LuTATE. In a second study, the efficacy of fractionated delivery of PRRT was assessed, comparing the efficacy of 30 MBq of 67Cu-CuSarTATE or 177Lu-LuTATE, either as a single intravenous injection or as two 15-MBq fractions 2 wk apart. Treatment of tumors with 2 fractions significantly improved survival over delivery as a single fraction (67Cu-CuSarTATE: 47 vs. 36 d [P = 0.036]; 177Lu-LuTATE: 46 vs. 29 d [P = 0.040]). Conclusion: This study demonstrates that 67Cu-CuSarTATE is well tolerated in BALB/c nude mice and highly efficacious against AR42J tumors in vivo. Administration of 67Cu-CuSarTATE and 177Lu-LuTATE divided into 2 fractions over 2 wk was more efficacious than administration of a single fraction. The antitumor activity of 67Cu-CuSarTATE in the AR42J tumor model demonstrated the suitability of this novel agent for clinical assessment in the treatment of somatostatin receptor 2-expressing neuroendocrine tumors.
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Affiliation(s)
- Carleen Cullinane
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | | | - Peter D Roselt
- Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Ellen M van Dam
- Clarity Pharmaceuticals Ltd., Eveleigh, New South Wales, Australia
| | - Susan Jackson
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Kevin Kuan
- Molecular Imaging and Therapy Research Unit, SAHMRI, Adelaide, South Australia, Australia; and
| | - Price Jackson
- Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - David Binns
- Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Jessica van Zuylekom
- Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Matthew J Harris
- Clarity Pharmaceuticals Ltd., Eveleigh, New South Wales, Australia
| | - Rodney J Hicks
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Paul S Donnelly
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia
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21
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Patient Selection and Toxicities of PRRT for Metastatic Neuroendocrine Tumors and Research Opportunities. Curr Treat Options Oncol 2020; 21:25. [PMID: 32172368 DOI: 10.1007/s11864-020-0711-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OPINION STATEMENT Neuroendocrine tumors (NETs) are a heterogenous group of neoplasms characterized by varied biological hallmarks and behavior, ranging from indolent to aggressive. For many decades, somatostatin analogues and few targeted therapies were available for NETs and these therapies had minimal response rates. However, there have been a number of recent treatment advances. Peptide receptor radionuclide therapy (PRRT) is a novel approach to treatment of NETs and has changed the landscape of treatment for NETs. It is a form of targeted therapy in which a radiolabeled somatostatin analogue delivers radiation specifically to tumor cells expressing the somatostatin receptor.
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22
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Wan DQ. Advances in Functional Imaging in the Assessment of Head and Neck Cancer. Oral Maxillofac Surg Clin North Am 2019; 31:627-635. [PMID: 31473063 DOI: 10.1016/j.coms.2019.07.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
This article discusses the application of fludeoxyglucose PET/computed tomography (CT) technology in head and neck cancer diagnosis and management, as well as advantages and disadvantages relative to traditional imaging modalities. A successful scan relies on precise patient preparation, and compliance to specific protocols before and during the scan. Finally, this article briefly introduces a PET/CT scan recently approved by the Food and Drug Administration for neuroendocrine tumors.
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Affiliation(s)
- David Q Wan
- Department of Diagnostic and Interventional Imaging, McGovern Medical School, Health Science Center in Houston, University of Texas, MSB 2.130B, 6431 Fannin Street, Houston, TX 77030, USA.
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Wannachalee T, Turcu AF, Bancos I, Habra MA, Avram AM, Chuang HH, Waguespack SG, Auchus RJ. The Clinical Impact of [ 68 Ga]-DOTATATE PET/CT for the Diagnosis and Management of Ectopic Adrenocorticotropic Hormone - Secreting Tumours. Clin Endocrinol (Oxf) 2019; 91:288-294. [PMID: 31066920 PMCID: PMC6689243 DOI: 10.1111/cen.14008] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/17/2019] [Accepted: 05/07/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Localization of ectopic ACTH-secreting tumours causing Cushing syndrome (ECS) is essential for clinical management, yet often difficult. [68 Ga]-DOTATATE PET/CT ([68 Ga]-DOTA-(Tyr3 )-octreotate)] is an FDA-approved high-resolution diagnostic tool for imaging neuroendocrine tumours. Data on the clinical utility of [68 Ga]-DOTATATE in patients with ECS, however, are scarce. The objectives of this study were to determine the efficacy for ECS localization and the clinical benefit of [68 Ga]-DOTATATE imaging. METHOD We conducted a retrospective review of all cases with ECS evaluated with [68 Ga]-DOTATATE from November 2016 through October 2018 at three referral centres. The clinical benefit of [68 Ga]-DOTATATE was based on detection of new tumours and resultant changes in management. RESULTS Over the study period, 28 patients with ECS underwent [68 Ga]-DOTATATE: 17 for identification of the primary tumour and 11 during follow-up. [68 Ga]-DOTATATE identified the suspected primary ECS in 11/17 patients (65%). Of these, nine patients underwent surgery: eight with confirmed ECS (5 bronchial, 1 thymic, 1 pancreatic and 1 metastatic neuroendocrine tumour of unknown primary origin) and one patient with a false-positive scan (adrenal gland). Of the 11 patients with ECS who underwent [68 Ga]-DOTATATE evaluation during follow-up, the study led to changes in clinical management in 7/11 (64%) patients. CONCLUSIONS [68 Ga]-DOTATATE is sensitive in detecting primary and metastatic ECS, often identifies occult tumours after conventional imaging, and impacts clinical care in the majority of patients.
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Affiliation(s)
- Taweesak Wannachalee
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA
- Division of Endocrinology and Metabolism, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Adina F. Turcu
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Irina Bancos
- Division of Endocrinology, Diabetes, Metabolism & Nutrition, Mayo Clinic Rochester, MN, USA
| | - Mouhammed Amir Habra
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anca M. Avram
- Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, MI, USA
| | - Hubert H. Chuang
- Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Steven G. Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Richard J. Auchus
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA
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Abstract
OBJECTIVE. The purpose of this article is to provide a multimodality imaging review of ileal carcinoid tumor. CONCLUSION. Ileal carcinoid tumors display a variety of radiologic findings. Delay in diagnosis is common because of initial nonspecific symptoms and subtle imaging findings. Reviewing the multimodality imaging appearance of the primary tumor, metastatic disease, and associated ancillary findings can help improve patient care.
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Diagnostic strategy with a solid pancreatic mass. Presse Med 2019; 48:e125-e145. [DOI: 10.1016/j.lpm.2019.02.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 02/13/2019] [Indexed: 12/14/2022] Open
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Expression and selective activation of somatostatin receptor subtypes induces cell cycle arrest in cancer cells. Oncol Lett 2018; 17:1723-1731. [PMID: 30675231 PMCID: PMC6341781 DOI: 10.3892/ol.2018.9773] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 10/18/2018] [Indexed: 12/12/2022] Open
Abstract
Somatostatin receptors (SSTRs) are G-protein-coupled plasma membrane receptors that have been determined to be expressed in normal and cancer tissues. Activation of SSTRs frequently results in inhibition of cell proliferation and therefore somatostatin analogues (SSAs) have been used in cancer treatment. However, the variable outcomes of SSA treatment were considered to be the consequences of loss-of-expression of SSTRs and/or subtype-specific effects. In the present study, the patterns of SSTR expression in 160 breast cancer tissues were investigated, and the mechanisms of SSTR activation and the influence on cell proliferation were further characterized. The expression levels of SSTR1-5 were determined using immunohistology. Hemagglutinin-SSTR1 and MYC-SSTR4 were transiently overexpressed in MDA-MB-435S cells, and the potential receptor dimerization was determined using immunofluorescence and co-immunoprecipitation. The influence of SSTR1 and SSTR4 expression/activation on cell proliferation was monitored using flow cytometry. The results demonstrated that all five SSTR subtypes were expressed at variable levels in tumor tissues, with the highest positive expression instance being determined for SSTR1 and SSTR4, with positive expression levels in 90.0 and 71.3% of tumor tissues, respectively. Immunofluorescence and co-immunoprecipitation revealed SSTR1/SSTR4 heterodimerization, which was increased in response to receptor activation using the subtype-specific SSA L-803087. The translocation of SSTR1/SSTR4 dimers into the cytoplasm upon receptor activation was also observed. Additionally, it was identified using flow cytometry that co-expression and activation of SSTR1 and SSTR4 in MDA-MB-435S cells resulted in a decreased proportion of S-phase cells. The results of the present study revealed that SSTR1 and SSTR4 are the most frequently expressed SSTR subtypes in breast cancer, and that the cell cycle arrest was mediated by SSTR1/SSTR4 dimerization/activation.
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Hicks RJ, Jackson P, Kong G, Ware RE, Hofman MS, Pattison DA, Akhurst TA, Drummond E, Roselt P, Callahan J, Price R, Jeffery CM, Hong E, Noonan W, Herschtal A, Hicks LJ, Hedt A, Harris M, Paterson BM, Donnelly PS. 64Cu-SARTATE PET Imaging of Patients with Neuroendocrine Tumors Demonstrates High Tumor Uptake and Retention, Potentially Allowing Prospective Dosimetry for Peptide Receptor Radionuclide Therapy. J Nucl Med 2018; 60:777-785. [PMID: 30442752 DOI: 10.2967/jnumed.118.217745] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 11/01/2018] [Indexed: 01/08/2023] Open
Abstract
Imaging of somatostatin receptor expression is an established technique for staging of neuroendocrine neoplasia and determining the suitability of patients for peptide receptor radionuclide therapy. PET/CT using 68Ga-labeled somatostatin analogs is superior to earlier agents, but the rapid physical decay of the radionuclide poses logistic and regulatory challenges. 64Cu has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide 67Cu. Based on promising preclinical studies, we have performed a first-time-in-humans trial of 64Cu-MeCOSar-Tyr3-octreotate (64Cu-SARTATE) to assess its safety and ability to localize disease at early and late imaging time-points. Methods: In a prospective trial, 10 patients with known neuroendocrine neoplasia and positive for uptake on 68Ga-DOTA-octreotate (68Ga-DOTATATE) PET/CT underwent serial PET/CT imaging at 30 min, 1 h, 4 h, and 24 h after injection of 64Cu-SARTATE. Adverse reactions were recorded, and laboratory testing was performed during infusion and at 1 and 7 d after imaging. Images were analyzed for lesion and normal-organ uptake and clearance to assess lesion contrast and perform dosimetry estimates. Results: 64Cu-SARTATE was well tolerated during infusion and throughout the study, with 3 patients experiencing mild infusion-related events. High lesion uptake and retention were observed at all imaging time-points. There was progressive hepatic clearance over time, providing the highest lesion-to-liver contrast at 24 h. Image quality remained high at this time. Comparison of 64Cu-SARTATE PET/CT obtained at 4 h to 68Ga-DOTATATE PET/CT obtained at 1 h indicated comparable or superior lesion detection in all patients, especially in the liver. As expected, the highest early physiologic organ uptake was in the kidneys, liver, and spleen. Conclusion: 64Cu-SARTATE is safe and has excellent imaging characteristics. High late-retention in tumor and clearance from the liver suggest suitability for diagnostic studies and for prospective dosimetry for 67Cu-SARTATE peptide receptor radionuclide therapy, and the half-life of 64Cu would also facilitate good-manufacturing-practice production and distribution to sites without access to 68Ga.
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Affiliation(s)
- Rodney J Hicks
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia .,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - Price Jackson
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Grace Kong
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Robert E Ware
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Michael S Hofman
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - David A Pattison
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Timothy A Akhurst
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Elizabeth Drummond
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Peter Roselt
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Jason Callahan
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Roger Price
- Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, Washington, Australia
| | - Charmaine M Jeffery
- Medical Technology and Physics, Sir Charles Gairdner Hospital, Nedlands, Washington, Australia
| | - Emily Hong
- Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Wayne Noonan
- Liverpool Hospital, Liverpool, New South Wales, Australia
| | - Alan Herschtal
- Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Lauren J Hicks
- Mercy Hospital for Women, Heidelberg, Victoria, Australia
| | - Amos Hedt
- Clarity Pharmaceuticals Ltd., Eveleigh, New South Wales, Australia
| | - Matthew Harris
- Clarity Pharmaceuticals Ltd., Eveleigh, New South Wales, Australia
| | - Brett M Paterson
- School of Chemistry, Monash University, Victoria, Australia; and
| | - Paul S Donnelly
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
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Günther T, Tulipano G, Dournaud P, Bousquet C, Csaba Z, Kreienkamp HJ, Lupp A, Korbonits M, Castaño JP, Wester HJ, Culler M, Melmed S, Schulz S. International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. Pharmacol Rev 2018; 70:763-835. [PMID: 30232095 PMCID: PMC6148080 DOI: 10.1124/pr.117.015388] [Citation(s) in RCA: 165] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.
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Affiliation(s)
- Thomas Günther
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Giovanni Tulipano
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Pascal Dournaud
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Corinne Bousquet
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Zsolt Csaba
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Hans-Jürgen Kreienkamp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Márta Korbonits
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Justo P Castaño
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Hans-Jürgen Wester
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Michael Culler
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Shlomo Melmed
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
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Pencharz D, Gnanasegaran G, Navalkissoor S. Theranostics in neuroendocrine tumours: somatostatin receptor imaging and therapy. Br J Radiol 2018; 91:20180108. [PMID: 30102557 DOI: 10.1259/bjr.20180108] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Theranostics and its principles: pre-treatment selection of patients who are most likely to benefit from treatment by the use of a related, specific diagnostic test are integral to the treatment of patients with neuroendocrine tumours (NETs). This is due to NETs' important, but variable, somatostatin receptor (SSTR) expression, their heterogeneity and variation in site of primary and rate of progression. Only patients whose tumours have sufficient expression of SSTRs will benefit from SSTR-based radionuclide therapy and demonstrating this expression prior to therapy is essential. This article provides a relevant overview of NETs and the multiple facets of SSTR based theranostics, including imaging and therapy radionuclides; clinical efficacy and toxicity; patient selection and treatment and finally emerging radiopharmaceuticals and newer clinical applications.
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Affiliation(s)
- Deborah Pencharz
- 1 Department of Nuclear Medicine, Brighton and Sussex University Hospitals NHS Trust , Brighton , UK
| | - Gopinath Gnanasegaran
- 2 Department of Nuclear Medicine, Royal Free London NHS Foundation Trust , London , UK
| | - Shaunak Navalkissoor
- 2 Department of Nuclear Medicine, Royal Free London NHS Foundation Trust , London , UK
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Abstract
OBJECTIVE The purposes of this article are to increase understanding of the concepts of theranostics and peptide receptor radionuclide therapy (PRRT) as they apply to neuroendocrine tumors (NETs); review the key 1, 2, and 3 clinical trial data leading to the approval of 177Lu-tetraazacyclododecanetetraacetic acid-octreotide (177Lu-DOTATATE); and foster understanding of the practical aspects and future directions of PRRT for NETs. CONCLUSION In January 2018, 177Lu-DOTATATE therapy was approved in the United States (previously approved in Europe in September 2017) for adult patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, including those of the foregut, midgut, and hindgut. The results of the phase 3 Neuroendocrine Tumors Therapy (NETTER-1) trial show favorable outcomes with respect to the primary endpoint of progression-free survival and a host of secondary objectives, including overall survival, objective response rate, and quality of life measures. Patient selection is based on a number of specific factors and should be sequenced carefully with respect to other available therapies, ideally in multidisciplinary cancer conferences. Establishing the therapy at a new institution can be somewhat involved, but once it is established, the therapy is fairly straightforward to administer and is well tolerated with limited side-effects and toxicity. A number of approaches and issues are still to be worked out, and this therapy will continue to be studied and optimized.
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Exner S, Prasad V, Wiedenmann B, Grötzinger C. Octreotide Does Not Inhibit Proliferation in Five Neuroendocrine Tumor Cell Lines. Front Endocrinol (Lausanne) 2018; 9:146. [PMID: 29681888 PMCID: PMC5897986 DOI: 10.3389/fendo.2018.00146] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 03/19/2018] [Indexed: 12/18/2022] Open
Abstract
Somatostatin analogs (SSA) are well-established antisecretory drugs in functionally active neuroendocrine tumors (NET). Two placebo-controlled trials have recently demonstrated significant improvement of progression-free survival under SSA treatment. Furthermore, somatostatin receptor (SSTR) overexpression in NET has also been utilized for diagnostic imaging and peptide receptor radionuclide therapy (PRRT). However, PRRT in NET is associated mostly with partial and minor remission, while other radionuclide therapies reach complete remissions in up to 75% of cases. This study assessed a potential radiosensitizing effect of SSA treatment in five established NET cell line models: BON, QGP-1, LCC-18, H727, and UMC-11. Irradiation was found to significantly inhibit proliferation, while no additional effect by octreotide treatment was observed. Intriguingly, no impact of SSA treatment alone was found in any of these NET cell lines when systematically analyzing cell viability, proliferation, and cell cycle distribution. Investigation of the causes for this octreotide resistance led to demonstration of low octreotide binding and scarce SSTR, specifically SSTR2 expression as compared to levels found in human NETs. The resistance toward SSA treatment in viability and proliferation assays could not be overcome by re-expression of SSTR2 in two of the cell lines. These results provide systematic evidence for a lack of authentic, tumor-like SSTR expression, and function in five frequently used NET cell line models and point to the need for more physiologic tumor model systems.
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Affiliation(s)
- Samantha Exner
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Partner Site Berlin, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Vikas Prasad
- Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Nuclear Medicine, Universitätsklinikum Ulm, Ulm, Germany
| | - Bertram Wiedenmann
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Carsten Grötzinger
- Department of Hepatology and Gastroenterology, Charité – Universitätsmedizin Berlin, Berlin, Germany
- Partner Site Berlin, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
- *Correspondence: Carsten Grötzinger,
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Abstract
The majority of neuroendocrine tumours (NETs) are well-differentiated tumours that follow an indolent course, in contrast to a minority of poorly differentiated neuroendocrine carcinomas (NECs) which exhibit an aggressive course and assocaited with an overall short survival. Although surgery is the only curative treatment for NETs it is not always feasible,necessitating the application of other therapies including chemotherapy. Streptozotocin (STZ)-based regimens have long been used for advanced or metastatic well-to-moderately differentiated (G1-G2) NETs, especially those originating from the pancreas (pNETs). In poorly differentiated grade 3 (G3) tumours, platinum-based chemotherapy is recommended as first-line therapy, albeit without durable responses. Although data for temozolomide (TMZ)-based chemotherapy are still evolving, this treatment may replace STZ-based regimens in pNETs due to its better tolerability and side effect profile. In addition, there is evidence that TMZ could also be used in the subgroup of well-differentiated G3 NETs. There is less clear-cut evidence of a benefit for chemotherapy in intestinal NETs, but still evolving data suggest that TMZ may be efficacious in particular patients. In lung and thymic carcinoids, chemotherapy is reserved for patients with progressive metastatic disease in whom other treatment options are unavailable. Overall, chemotherapy is indicated in patients who have progressed on first-line treatment with somatostatin analogues, have extensive tumour load or exhibit rapid growth following a period of follow-up, and/or have a high proliferative rate; it may occasionally can be used in a neo-adjuvant setting. Prospective randomised studies are awaited to substantiate the role of chemotherapy in the therapeutic algorithm of NETs along with other evolving treatments.
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Affiliation(s)
- Anna Angelousi
- Department of Pathophysiology, Endocrine Oncology Unit, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| | - Gregory Kaltsas
- Department of Pathophysiology, Endocrine Oncology Unit, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Department of Endocrinology, University of Warwick Medical School, Coventry, UK
| | - Anna Koumarianou
- Hematology- Oncology Unit, Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Attikon Hospital, Athens, Greece
| | - Martin O Weickert
- Department of Endocrinology, University of Warwick Medical School, Coventry, UK
| | - Ashley Grossman
- Neuroendocrine Tumour Centre, Royal Free Hospital, London, UK
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Taïeb D, Hicks RJ, Pacak K. New Challenges in Nuclear Endocrinology. J Nucl Med 2017; 59:573-574. [PMID: 29123009 DOI: 10.2967/jnumed.117.199729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 10/30/2017] [Indexed: 11/16/2022] Open
Affiliation(s)
- David Taïeb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Rodney J Hicks
- Cancer Imaging and Neuroendocrine Tumour Service, Peter MacCallum Cancer Centre, and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; and
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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Scharwächter C, Haage P. State of the Art Diagnosis of Pancreatic Ductal Adenocarcinoma. CURRENT RADIOLOGY REPORTS 2017. [DOI: 10.1007/s40134-017-0233-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, Grozinsky-Glasberg S, Arnold R, Borbath I, Cwikla J, Toumpanakis C, Kaltsas G, Davies P, Hörsch D, Tiensuu Janson E, Ramage J. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues. Neuroendocrinology 2017; 105:295-309. [PMID: 28402980 DOI: 10.1159/000475526] [Citation(s) in RCA: 239] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 04/06/2017] [Indexed: 12/13/2022]
Abstract
The purpose of these guidelines is to assist physicians caring for patients with neuroendocrine neoplasia in considering eligibility criteria for peptide receptor radionuclide therapy (PRRT) and in defining the minimum requirements for PRRT. It is not these guidelines' aim to give recommendations on the use of specific radiolabelled somatostatin analogues for PRRT as different analogues are being used, and their availability is governed by varying international regulations. However, a recent randomized controlled trial, NETTER-1, has provided evidence that may establish <sup>177</sup>Lu-DOTA-octreotate (LutaThera®) as the first widely approved agent. It also makes recommendations on what minimal patient, tumour, and treatment outcome characteristics should be reported for PRRT to facilitate robust comparisons between studies.
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Affiliation(s)
- Rodney J Hicks
- Cancer Imaging and Neuroendocrine Service, the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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Imperiale A, Deroose CM, Hindié E, Goichot B. Radionuclide Imaging of Gastrointestinal Neuroendocrine Tumors. DIAGNOSTIC AND THERAPEUTIC NUCLEAR MEDICINE FOR NEUROENDOCRINE TUMORS 2017:321-349. [DOI: 10.1007/978-3-319-46038-3_15] [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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Hicks RJ. Citius, Altius, Fortius: An Olympian Dream for Theranostics. J Nucl Med 2016; 58:194-195. [DOI: 10.2967/jnumed.116.182188] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 09/08/2016] [Indexed: 12/19/2022] Open
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Haage P, Schwartz CA, Scharwächter C. [Ductal adenocarcinoma and unusual differential diagnosis]. Radiologe 2016; 56:325-37. [PMID: 27000276 DOI: 10.1007/s00117-016-0090-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Ductal pancreatic adenocarcinoma is by far the most common solid tumor of the pancreas. It has a very poor prognosis, especially in the more advanced stages which are no longer locally confined. Due to mostly unspecific symptoms, imaging is key in the diagnostic process. Because of the widespread use of imaging techniques, incidental findings are to a greater extent discovered in the pancreas, which subsequently entail further work-up. Ductal pancreatic adenocarcinoma can be mimicked by a large number of different lesions, such as anatomical variants, peripancreatic structures and tumors, rarer primary solid pancreatic tumors, cystic tumors, metastases or different variants of pancreatitis. Additionally, a number of precursor lesions can be differentiated. The correct classification is thus important as an early diagnosis of ductal pancreatic adenocarcinoma is relevant for the prognosis and because the possibly avoidable treatment is very invasive. All major imaging techniques are principally suitable for pancreatic imaging. In addition to sonography of the abdomen, usually the baseline diagnostic tool, computed tomography (CT) with its superior spatial resolution, magnetic resonance imaging (MRI) with its good soft tissue differentiation capabilities, possibly in combination with MR cholangiopancreatography (MRCP), endosonography with its extraordinary spatial resolution, conceivably with additional endoscopic retrograde CP or the option of direct biopsy and finally positron emission tomography CT (PET-CT) as a molecular imaging tool are all particularly useful modalities. The various techniques all have its advantages and disadvantages; depending on the individual situation they may need to be combined.
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Affiliation(s)
- P Haage
- Zentrum für Radiologie HELIOS Universitätsklinikum Wuppertal, Universität Witten/Herdecke, Heusnerstr. 40, 42283, Wuppertal, Deutschland.
| | - C A Schwartz
- Zentrum für Radiologie HELIOS Universitätsklinikum Wuppertal, Universität Witten/Herdecke, Heusnerstr. 40, 42283, Wuppertal, Deutschland
| | - C Scharwächter
- Zentrum für Radiologie HELIOS Universitätsklinikum Wuppertal, Universität Witten/Herdecke, Heusnerstr. 40, 42283, Wuppertal, Deutschland
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Tothill R, Estall V, Rischin D. Merkel cell carcinoma: emerging biology, current approaches, and future directions. Am Soc Clin Oncol Educ Book 2016:e519-26. [PMID: 25993218 DOI: 10.14694/edbook_am.2015.35.e519] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous cancer that predominantly occurs in patients who are older, and is associated with a high rate of distant failure and mortality. Current management strategies that incorporate surgery and radiotherapy achieve high rates of locoregional control, but distant failure rates remain problematic, highlighting the need for new effective systemic therapies. Chemotherapy can achieve high response rates of limited duration in the metastatic setting, but its role in definitive management remains unproven. Recent developments in our knowledge about the biology of MCC have led to the identification of new potential therapeutic targets and treatments. A key finding has been the discovery that a human polyomavirus may be a causative agent. However, emerging data suggests that MCC may actually be two distinct entities, viral-associated and viral-negative MCC, which is likely to have implications for the management of MCC in the future and for the development of new treatments. In this review, we discuss recent discoveries about the biology of MCC, current approaches to management, and new therapeutic strategies that are being investigated.
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Affiliation(s)
- Richard Tothill
- From the Division of Research, Peter MacCallum Cancer Centre, and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Radiation Oncology and Skin and Melanoma Tumour Stream, Peter MacCallum Cancer Centre, and the Department of Pathology, University of Melbourne, Melbourne, Australia; Division of Cancer Medicine, and Head and Neck Tumour Stream, Peter MacCallum Cancer Centre, the Sir Peter MacCallum Department of Oncology and Department of Medicine, University of Melbourne, Melbourne, Australia
| | - Vanessa Estall
- From the Division of Research, Peter MacCallum Cancer Centre, and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Radiation Oncology and Skin and Melanoma Tumour Stream, Peter MacCallum Cancer Centre, and the Department of Pathology, University of Melbourne, Melbourne, Australia; Division of Cancer Medicine, and Head and Neck Tumour Stream, Peter MacCallum Cancer Centre, the Sir Peter MacCallum Department of Oncology and Department of Medicine, University of Melbourne, Melbourne, Australia
| | - Danny Rischin
- From the Division of Research, Peter MacCallum Cancer Centre, and the Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Department of Radiation Oncology and Skin and Melanoma Tumour Stream, Peter MacCallum Cancer Centre, and the Department of Pathology, University of Melbourne, Melbourne, Australia; Division of Cancer Medicine, and Head and Neck Tumour Stream, Peter MacCallum Cancer Centre, the Sir Peter MacCallum Department of Oncology and Department of Medicine, University of Melbourne, Melbourne, Australia
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40
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Maxwell JE, Howe JR. Imaging in neuroendocrine tumors: an update for the clinician. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2015; 2:159-168. [PMID: 26257863 DOI: 10.2217/ije.14.40] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Neuroendocrine tumors are a heterogeneous group of neoplasms that are best worked up and managed using a variety of clinical and imaging studies. They are often diagnosed after they have already metastasized, though this does not necessarily preclude an attempt at curative surgical treatment or surgical debulking. Tumor burden assessment often requires use of multiple imaging modalities including computed tomography, magnetic resonance imaging and ultrasound. Somatostatin receptor-based imaging is also of great utility in looking for primaries and determining the extent of metastatic disease. This paper will review the most common imaging modalities used in the diagnosis and treatment of neuroendocrine tumors.
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Affiliation(s)
- Jessica E Maxwell
- Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - James R Howe
- Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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Hofman MS, Lau WFE, Hicks RJ. Somatostatin Receptor Imaging with68Ga DOTATATE PET/CT: Clinical Utility, Normal Patterns, Pearls, and Pitfalls in Interpretation. Radiographics 2015; 35:500-16. [DOI: 10.1148/rg.352140164] [Citation(s) in RCA: 327] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Bahri H, Laurence L, Edeline J, Leghzali H, Devillers A, Raoul JL, Cuggia M, Mesbah H, Clement B, Boucher E, Garin E. High prognostic value of 18F-FDG PET for metastatic gastroenteropancreatic neuroendocrine tumors: a long-term evaluation. J Nucl Med 2014; 55:1786-90. [PMID: 25286923 DOI: 10.2967/jnumed.114.144386] [Citation(s) in RCA: 139] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
UNLABELLED This study aimed to evaluate the long-term prognostic usefulness of (18)F-FDG PET for patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEPNETs). METHODS Thirty-eight patients with metastatic GEPNETs were prospectively enrolled. Initial check-up comprised CT scan, (111)In-pentetreotide scintigraphy (SRS), and (18)F-FDG PET. Only (18)F-FDG PET-positive lesions with a maximum standardized uptake value (SUVmax) greater than 4.5 or an SUV ratio (SUVmax tumor to SUVmax nontumoral liver tissue, or T/NT ratio) of 2.5 or greater were considered positive for prognosis-that is, indicating a poor prognosis. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Factors associated with survival were assessed with univariate and multivariate analyses, using the Cox regression model. RESULTS Median PFS and OS were significantly higher for patients with a negative (18)F-FDG PET finding, with an OS of 119.5 mo (95% confidence interval [CI], 72-∞), than for patients with a positive (18)F-FDG PET finding (only 15 mo [95% CI, 4-27]) (P < 10(-3)). Median PFS and OS were significantly higher for the patient group that had a positive SRS than the group with a negative SRS (P = 0.0002). For patients with a positive SRS, PFS and OS were significantly shorter when the (18)F-FDG PET finding was positive: 19.5 mo (95% CI, 4-37) for PFS and 119.5 mo (95% CI, 81-∞) for OS (P < 10(-3)). In the patient group with a low-grade GEPNET and a positive SRS, PFS and OS were also significantly lower for patients with a positive (18)F-FDG PET. At 48-mo follow-up, 100% of patients who had a positive (18)F-FDG PET for disease progression (of which 47% were also SRS-positive) were deceased, and 87% of patients with a negative (18)F-FDG PET were alive (P < 0.0001). The T/NT ratio was the only parameter associated with OS on multivariate analysis. CONCLUSION Overall, (18)F-FDG PET appears to be of major importance in the prognostic evaluation of metastatic GEPNET. A positive (18)F-FDG PET with an SUV ratio (T/NT) of 2.5 or greater was a poor prognostic factor, with a 4-y survival rate of 0%. A positive SRS does not eliminate the need for performing (18)F-FDG PET, which is of greater prognostic utility.
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Affiliation(s)
- Haïfa Bahri
- Department of Nuclear Medicine, Cancer Institute Eugène Marquis, Rennes, France
| | - Lenoir Laurence
- Department of Nuclear Medicine, Cancer Institute Eugène Marquis, Rennes, France Inserm, UMR991, Liver Metabolisms and Cancer, Rennes, France University of Rennes 1, Rennes, France
| | - Julien Edeline
- Inserm, UMR991, Liver Metabolisms and Cancer, Rennes, France University of Rennes 1, Rennes, France Department of Medical Oncology, Cancer Institute Eugène Marquis, Rennes, France
| | - Houda Leghzali
- Department of Nuclear Medicine, Cancer Institute Eugène Marquis, Rennes, France
| | - Anne Devillers
- Department of Nuclear Medicine, Cancer Institute Eugène Marquis, Rennes, France
| | - Jean-Luc Raoul
- Department of Medical Oncology, Comprehensive Cancer Center, Institute Paoli Calmette, Marseille, France
| | - Marc Cuggia
- Department of Medical Computing, CHU Pontchaillou, Rennes, France; and
| | - Habiba Mesbah
- Department of Medical Informations, Cancer Institute Eugène Marquis, Rennes, France
| | - Bruno Clement
- Inserm, UMR991, Liver Metabolisms and Cancer, Rennes, France
| | - Eveline Boucher
- Inserm, UMR991, Liver Metabolisms and Cancer, Rennes, France Department of Medical Oncology, Cancer Institute Eugène Marquis, Rennes, France
| | - Etienne Garin
- Department of Nuclear Medicine, Cancer Institute Eugène Marquis, Rennes, France Inserm, UMR991, Liver Metabolisms and Cancer, Rennes, France University of Rennes 1, Rennes, France
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Indium-111 labeled gold nanoparticles for in-vivo molecular targeting. Biomaterials 2014; 35:7050-7. [DOI: 10.1016/j.biomaterials.2014.04.098] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 04/24/2014] [Indexed: 12/22/2022]
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Fikri ASF, Kroiss A, Ahmad AZF, Zanariah H, Lau WFE, Uprimny C, Donnemiller E, Kendler D, Nordin AJ, Virgolini IJ. Localization and prediction of malignant potential in recurrent pheochromocytoma/paraganglioma (PCC/PGL) using 18F-FDG PET/CT. Acta Radiol 2014; 55:631-40. [PMID: 24037430 DOI: 10.1177/0284185113504330] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND To our knowledge, data are lacking on the role of 18F-FDG PET/CT in the localization and prediction of neuroendocrine tumors, in particular the pheochromocytoma/paraganglioma (PCC/PGL) group. PURPOSE To evaluate the role of 18F-FDG PET/CT in localizing and predicting the malignant potential of PCC/PGL. MATERIAL AND METHODS Twenty-three consecutive patients with a history of PCC/PGL, presenting with symptoms related to catecholamine excess, underwent 18F-FDG PET/CT. Final confirmation of the diagnosis was made using the composite references. PET/CT findings were analyzed on a per-lesion basis and a per-patient basis. Tumor SUVmax was analyzed to predict the dichotomization of patient endpoints for the local disease and metastatic groups. RESULTS We investigated 23 patients (10 men, 13 women) with a mean age of 46.43 ± 3.70 years. Serum catecholamine levels were elevated in 82.60% of these patients. There were 136 sites (mean SUVmax: 16.39 ± 3.47) of validated disease recurrence. The overall sensitivities for diagnostic CT, FDG PET, and FDG PET/CT were 86.02%, 87.50%, and 98.59%, respectively. Based on the composite references, 39.10% of patients had local disease. There were significant differences in the SUVmax distribution between the local disease and metastatic groups; a significant correlation was noted when a SUVmax cut-off was set at 9.2 (P<0.05). CONCLUSION In recurrent PCC/PGL, diagnostic 18F-FDG PET/CT is a superior tool in the localization of recurrent tumors. Tumor SUVmax is a potentially useful predictor of malignant tumor potential.
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Affiliation(s)
- Ahmad Saad Fathinul Fikri
- Centre for Diagnostic Nuclear Imaging, Faculty of Medicine and Health Science, University Putra Malaysia, Serdang, Selangor, Malaysia
| | - A Kroiss
- Univ.-KlinikfürNuklearmedizin, Innsbruck, Austria
| | - AZF Ahmad
- Centre for Diagnostic Nuclear Imaging, Faculty of Medicine and Health Science, University Putra Malaysia, Serdang, Selangor, Malaysia
| | - H Zanariah
- Medical Department, Hospital Putrajaya, Putrajaya, Malaysia
| | - WFE Lau
- Department of Radiology, the University of Melbourne, Centre for Molecular Imaging, The Peter MacCallum, Cancer Centre, East Melbourne, Victoria, Australia
| | - C Uprimny
- Univ.-KlinikfürNuklearmedizin, Innsbruck, Austria
| | | | - D Kendler
- Univ.-KlinikfürNuklearmedizin, Innsbruck, Austria
| | - AJ Nordin
- Centre for Diagnostic Nuclear Imaging, Faculty of Medicine and Health Science, University Putra Malaysia, Serdang, Selangor, Malaysia
| | - IJ Virgolini
- Univ.-KlinikfürNuklearmedizin, Innsbruck, Austria
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Woodbridge LR, Murtagh BM, Yu DFQC, Planche KL. Midgut Neuroendocrine Tumors: Imaging Assessment for Surgical Resection. Radiographics 2014; 34:413-26. [DOI: 10.1148/rg.342135504] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Schillaci O. 18F-DOPA and Other Radiopharmaceuticals for Imaging Unknown Primary Neuroendocrine Tumors. J Nucl Med 2014; 55:357-9. [DOI: 10.2967/jnumed.113.133116] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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Hofman MS, Hicks RJ. Peptide receptor radionuclide therapy for neuroendocrine tumours: standardized and randomized, or personalized? Eur J Nucl Med Mol Imaging 2013; 41:211-3. [DOI: 10.1007/s00259-013-2621-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 10/18/2013] [Indexed: 12/16/2022]
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Paterson BM, Roselt P, Denoyer D, Cullinane C, Binns D, Noonan W, Jeffery CM, Price RI, White JM, Hicks RJ, Donnelly PS. PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate. Dalton Trans 2013; 43:1386-96. [PMID: 24202174 DOI: 10.1039/c3dt52647j] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The use of copper radioisotopes in cancer diagnosis and radionuclide therapy is possible using chelators that are capable of binding Cu(II) with sufficient stability in vivo to provide high tumour-to-background contrast. Here we report the design and synthesis of a new bifunctional chelator, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar), that forms copper complexes of exceptional stability by virtue of a cage amine (sarcophagine) ligand and a new conjugate referred to as SarTATE, obtained by the conjugation of MeCOSar to the tumour-targeting peptide Tyr(3)-octreotate. Radiolabeling of SarTATE with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (~20 min), easily performed at room temperature and consistently resulted in high radiochemical purity (>99%). In vitro and in vivo evaluation of (64)CuSarTATE demonstrated its high selectivity for tumour cells expressing somatostatin receptor 2 (sstr2). Biodistribution and PET imaging comparisons were made between (64)CuSarTATE and (64)Cu-labeled DOTA-Tyr(3)-octreotate ((64)CuDOTATATE). Both radiopharmaceuticals showed excellent uptake in sstr2-positive tumours at 2 h post-injection. While tumour uptake of (64)CuDOTATATE decreased significantly at 24 h, (64)CuSarTATE activity was retained, improving contrast at later time points. (64)CuSarTATE accumulated less than (64)CuDOTATATE in the non-target organs, liver and lungs. The uptake of (64)CuSarTATE in the kidneys was high at 2 h but showed significant clearance by 24 h. The new chemistry and pre-clinical evaluation presented here demonstrates that MeCOSar is a promising bifunctional chelator for Tyr(3)-octreotate that could be applied to a combined imaging and therapeutic regimen using a combination of (64)Cu- and (67)CuSarTATE complexes, owing to improved tumour-to-non-target organ ratios compared to (64)CuDOTATATE at longer time points.
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Affiliation(s)
- Brett M Paterson
- School of Chemistry, The University of Melbourne, Parkville, VIC, Australia.
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Chemometric evaluation of urinary steroid hormone levels as potential biomarkers of neuroendocrine tumors. Molecules 2013; 18:12857-76. [PMID: 24135941 PMCID: PMC6269673 DOI: 10.3390/molecules181012857] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 09/25/2013] [Accepted: 10/10/2013] [Indexed: 01/08/2023] Open
Abstract
Neuroendocrine tumors (NETs) are uncommon tumors which can secrete specific hormone products such as peptides, biogenic amines and hormones. So far, the diagnosis of NETs has been difficult because most NET markers are not specific for a given tumor and none of the NET markers can be used to fulfil the criteria of high specificity and high sensitivity for the screening procedure. However, by combining the measurements of different NET markers, they become highly sensitive and specific diagnostic tests. The aim of the work was to identify whether urinary steroid hormones can be identified as potential new biomarkers of NETs, which could be used as prognostic and clinical course monitoring factors. Thus, a rapid and sensitive reversed-phase high-performance liquid chromatographic method (RP-HPLC) with UV detection has been developed for the determination of cortisol, cortisone, corticosterone, testosterone, epitestosterone and progesterone in human urine. The method has been validated for accuracy, precision, selectivity, linearity, recovery and stability. The limits of detection and quantification were 0.5 and 1 ng mL−1 for each steroid hormone, respectively. Linearity was confirmed within a range of 1–300 ng mL−1 with a correlation coefficient greater than 0.9995 for all analytes. The described method was successfully applied for the quantification of six endogenous steroid levels in human urine. Studies were performed on 20 healthy volunteers and 19 patients with NETs. Next, for better understanding of tumor biology in NETs and for checking whether steroid hormones can be used as potential biomarkers of NETs, a chemometric analysis of urinary steroid hormone levels in both data sets was performed.
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Ganeshan D, Bhosale P, Yang T, Kundra V. Imaging features of carcinoid tumors of the gastrointestinal tract. AJR Am J Roentgenol 2013; 201:773-786. [PMID: 24059366 DOI: 10.2214/ajr.12.9758] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Recent studies have provided a better understanding of the biologic behavior of gastrointestinal carcinoid tumors. This article focusing on imaging of gastrointestinal carcinoids will emphasize epidemiology, molecular biology, taxonomy, histopathology, and management. CONCLUSION Gastrointestinal carcinoids are a biologically heterogeneous group of tumors, with variable clinical presentation and biologic behavior. Imaging can play an important role in multidisciplinary identification and management of this disease.
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Affiliation(s)
- Dhakshina Ganeshan
- 1 All authors: Division of Diagnostic Imaging, Body Imaging Section, Unit 1473, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009
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