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Stauff E, Xu W, Kecskemethy HH, Langhans SA, Kandula VVR, Averill LW, Yue X. Tryptophan Kynurenine Pathway-Based Imaging Agents for Brain Disorders and Oncology-From Bench to Bedside. Biomolecules 2025; 15:47. [PMID: 39858441 PMCID: PMC11762981 DOI: 10.3390/biom15010047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/23/2024] [Accepted: 12/28/2024] [Indexed: 01/27/2025] Open
Abstract
Tryptophan (Trp)-based radiotracers have excellent potential for imaging many different types of brain pathology because of their involvement with both the serotonergic and kynurenine (KYN) pathways. However, radiotracers specific to the kynurenine metabolism pathway are limited. In addition, historically Trp-based radiopharmaceuticals were synthesized with the short-lived isotope carbon-11. A newer generation of Trp-based imaging agents using the longer half-lived and commercially available isotopes, such as fluorine-18 and iodine-124, are being developed. The newly developed amino acid-based tracers have been demonstrated to have favorable radiochemical and imaging characteristics in pre-clinical studies. However, many barriers still exist in the clinical translation of KYN pathway-specific radiotracers.
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Affiliation(s)
- Erik Stauff
- Department of Radiology, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA; (E.S.); (W.X.); (H.H.K.); (V.V.R.K.); (L.W.A.)
- Diagnostic & Research PET/MR Center, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA;
| | - Wenqi Xu
- Department of Radiology, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA; (E.S.); (W.X.); (H.H.K.); (V.V.R.K.); (L.W.A.)
- Diagnostic & Research PET/MR Center, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA;
| | - Heidi H. Kecskemethy
- Department of Radiology, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA; (E.S.); (W.X.); (H.H.K.); (V.V.R.K.); (L.W.A.)
- Diagnostic & Research PET/MR Center, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA;
| | - Sigrid A. Langhans
- Diagnostic & Research PET/MR Center, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA;
- Division of Neurology, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA
| | - Vinay V. R. Kandula
- Department of Radiology, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA; (E.S.); (W.X.); (H.H.K.); (V.V.R.K.); (L.W.A.)
- Diagnostic & Research PET/MR Center, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA;
| | - Lauren W. Averill
- Department of Radiology, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA; (E.S.); (W.X.); (H.H.K.); (V.V.R.K.); (L.W.A.)
- Diagnostic & Research PET/MR Center, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA;
| | - Xuyi Yue
- Department of Radiology, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA; (E.S.); (W.X.); (H.H.K.); (V.V.R.K.); (L.W.A.)
- Diagnostic & Research PET/MR Center, Nemours Children’s Health, Delaware, Wilmington, DE 19803, USA;
- Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Willemse JRJ, Lambregts DMJ, Balduzzi S, Schats W, Snaebjornsson P, Marchetti S, Vollebergh MA, van Golen LW, Cheung Z, Vogel WV, Bodalal Z, Rostami S, Gerke O, Sivakumaran T, Beets-Tan RGH, Lahaye MJ. Identifying the primary tumour in patients with cancer of unknown primary (CUP) using [ 18F]FDG PET/CT: a systematic review and individual patient data meta-analysis. Eur J Nucl Med Mol Imaging 2024; 52:225-236. [PMID: 39141069 PMCID: PMC11599304 DOI: 10.1007/s00259-024-06860-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 07/26/2024] [Indexed: 08/15/2024]
Abstract
PURPOSE In this systematic review and individual patient data (IPD) meta-analysis, we analysed the diagnostic performance of [18F]FDG PET/CT in detecting primary tumours in patients with CUP and evaluated whether the location of the predominant metastatic site influences the diagnostic performance. METHODS A systematic literature search from January 2005 to February 2024 was performed to identify articles describing the diagnostic performance of [18F]FDG PET/CT for primary tumour detection in CUP. Individual patient data retrieved from original articles or obtained from corresponding authors were grouped by the predominant metastatic site. The diagnostic performance of [18F]FDG PET/CT in detecting the underlying primary tumour was compared between predominant metastatic sites. RESULTS A total of 1865 patients from 32 studies were included. The largest subgroup included patients with predominant bone metastases (n = 622), followed by liver (n = 369), lymph node (n = 358), brain (n = 316), peritoneal (n = 70), lung (n = 67), and soft tissue (n = 23) metastases, leaving a small group of other/undefined metastases (n = 40). [18F]FDG PET/CT resulted in pooled detection rates to identify the primary tumour of 0.74 (for patients with predominant brain metastases), 0.54 (liver-predominant), 0.49 (bone-predominant), 0.46 (lung-predominant), 0.38 (peritoneal-predominant), 0.37 (lymph node-predominant), and 0.35 (soft-tissue-predominant). CONCLUSION This individual patient data meta-analysis suggests that the ability of [18F]FDG PET/CT to identify the primary tumour in CUP depends on the distribution of metastatic sites. This finding emphasises the need for more tailored diagnostic approaches in different patient populations. In addition, alternative diagnostic tools, such as new PET tracers or whole-body (PET/)MRI, should be investigated.
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Affiliation(s)
- Jeroen R J Willemse
- Department of Radiology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands
- GROW Research Institute for Oncology and Reproduction - Maastricht University, Maastricht, Netherlands
| | - Doenja M J Lambregts
- Department of Radiology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands
- GROW Research Institute for Oncology and Reproduction - Maastricht University, Maastricht, Netherlands
| | - Sara Balduzzi
- Department of Biometrics, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Winnie Schats
- Department of Scientific Information Service, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Petur Snaebjornsson
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Serena Marchetti
- Department of Medical Oncology and Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Marieke A Vollebergh
- Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Larissa W van Golen
- Department of Nuclear Medicine, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Zing Cheung
- Department of Nuclear Medicine, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Wouter V Vogel
- Department of Nuclear Medicine, Netherlands Cancer Institute, Amsterdam, Netherlands
- Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Zuhir Bodalal
- Department of Radiology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands
- GROW Research Institute for Oncology and Reproduction - Maastricht University, Maastricht, Netherlands
| | - Sajjad Rostami
- Department of Radiology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands
- GROW Research Institute for Oncology and Reproduction - Maastricht University, Maastricht, Netherlands
| | - Oke Gerke
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark
| | - Tharani Sivakumaran
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne VIC, Melbourne, VIC, Australia
| | - Regina G H Beets-Tan
- Department of Radiology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands
- GROW Research Institute for Oncology and Reproduction - Maastricht University, Maastricht, Netherlands
- Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Max J Lahaye
- Department of Radiology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands.
- GROW Research Institute for Oncology and Reproduction - Maastricht University, Maastricht, Netherlands.
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Zhou X, Shi B, Huang G, Liu J, Wei W. Trends in cancer imaging. Trends Cancer 2024; 10:1023-1037. [PMID: 39232974 DOI: 10.1016/j.trecan.2024.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
Molecular imaging of cancer is a collaborative endeavor, uniting scientists and physicians from diverse fields. Such collaboration is actively developing and translating cutting-edge molecular imaging approaches to enhance the diagnostic landscape of human malignancies. The advent of positron emission tomography (PET) and PET imaging tracers has realized non-invasive target annotation and tumor characterization at the molecular level. In surgical procedures, novel imaging techniques, such as fluorescence or Cherenkov luminescence, help identify tumors and enhance surgical precision. Simultaneously, progress in imaging equipment, innovative algorithms, and artificial intelligence has opened avenues for next-generation cancer screening and imaging, augmenting the efficiency and accuracy of cancer diagnosis. In this review, we provide a panorama of molecular cancer imaging and ongoing developments in the field.
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Affiliation(s)
- Xinyuan Zhou
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Binyu Shi
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Gang Huang
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Jianjun Liu
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Weijun Wei
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
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Scalorbi F, Garanzini EM, Calareso G, Marzi C, Di Rocco G, Argiroffi G, Baccini M, Pusceddu S, Marchianò A, Maccauro M. Cylindrical TGR as early radiological predictor of RLT progression in GEPNETs: a proof of concept. Sci Rep 2024; 14:15782. [PMID: 38982134 PMCID: PMC11233714 DOI: 10.1038/s41598-024-66668-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 07/03/2024] [Indexed: 07/11/2024] Open
Abstract
This study aims to assess the predictive capability of cylindrical Tumor Growth Rate (cTGR) in the prediction of early progression of well-differentiated gastro-entero-pancreatic tumours after Radio Ligand Therapy (RLT), compared to the conventional TGR. Fifty-eight patients were included and three CT scans per patient were collected at baseline, during RLT, and follow-up. RLT response, evaluated at follow-up according to RECIST 1.1, was calculated as a percentage variation of lesion diameters over time (continuous values) and as four different RECIST classes. TGR between baseline and interim CT was computed using both conventional (approximating lesion volume to a sphere) and cylindrical (called cTGR, approximating lesion volume to an elliptical cylinder) formulations. Receiver Operating Characteristic (ROC) curves were employed for Progressive Disease class prediction, revealing that cTGR outperformed conventional TGR (area under the ROC equal to 1.00 and 0.92, respectively). Multivariate analysis confirmed the superiority of cTGR in predicting continuous RLT response, with a higher coefficient for cTGR (1.56) compared to the conventional one (1.45). This study serves as a proof of concept, paving the way for future clinical trials to incorporate cTGR as a valuable tool for assessing RLT response.
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Affiliation(s)
- Federica Scalorbi
- Nuclear Medicine Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Enrico Matteo Garanzini
- Department of Radiodiagnostics and Radiotherapy, IRCCS Fondazione Istituto Nazionale Tumori, Milan, Italy
| | - Giuseppina Calareso
- Department of Radiodiagnostics and Radiotherapy, IRCCS Fondazione Istituto Nazionale Tumori, Milan, Italy
| | - Chiara Marzi
- Department of Statistics, Computer Science, Applications "G. Parenti", University of Florence, Viale Morgagni 59, 50134, Florence, Italy.
| | - Gabriella Di Rocco
- Department of Radiodiagnostics and Radiotherapy, IRCCS Fondazione Istituto Nazionale Tumori, Milan, Italy
- Post-Graduation School of Radiology, Department of Health Sciences, University of Milan, Milan, Italy
| | - Giovanni Argiroffi
- Nuclear Medicine Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
| | - Michela Baccini
- Department of Statistics, Computer Science, Applications "G. Parenti", University of Florence, Viale Morgagni 59, 50134, Florence, Italy
| | - Sara Pusceddu
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alfonso Marchianò
- Department of Radiodiagnostics and Radiotherapy, IRCCS Fondazione Istituto Nazionale Tumori, Milan, Italy
| | - Marco Maccauro
- Nuclear Medicine Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
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Hesami M, Blake M, Anderson MA, Asmundo L, Kilcoyne A, Najmi Z, Caravan PD, Catana C, Czawlytko C, Esfahani SA, Kambadakone AR, Samir A, McDermott S, Domachevsky L, Ursprung S, Catalano OA. Diagnostic Anatomic Imaging for Neuroendocrine Neoplasms: Maximizing Strengths and Mitigating Weaknesses. J Comput Assist Tomogr 2024; 48:521-532. [PMID: 38657156 PMCID: PMC11245376 DOI: 10.1097/rct.0000000000001615] [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: 04/26/2024]
Abstract
ABSTRACT Neuroendocrine neoplasms are a heterogeneous group of gastrointestinal and lung tumors. Their diverse clinical manifestations, variable locations, and heterogeneity present notable diagnostic challenges. This article delves into the imaging modalities vital for their detection and characterization. Computed tomography is essential for initial assessment and staging. At the same time, magnetic resonance imaging (MRI) is particularly adept for liver, pancreatic, osseous, and rectal imaging, offering superior soft tissue contrast. The article also highlights the limitations of these imaging techniques, such as MRI's inability to effectively evaluate the cortical bone and the questioned cost-effectiveness of computed tomography and MRI for detecting specific gastric lesions. By emphasizing the strengths and weaknesses of these imaging techniques, the review offers insights into optimizing their utilization for improved diagnosis, staging, and therapeutic management of neuroendocrine neoplasms.
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Affiliation(s)
- Mina Hesami
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Michael Blake
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Mark A. Anderson
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Luigi Asmundo
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Postgraduation School in Radiodiagnostics, Università degli Studi di Milano, Milan, Italy
| | - Aoife Kilcoyne
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Zahra Najmi
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Peter D. Caravan
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ciprian Catana
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Cynthia Czawlytko
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Shadi Abdar Esfahani
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Avinash R. Kambadakone
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Anthony Samir
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Shaunagh McDermott
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Liran Domachevsky
- Department of Nuclear Medicine, The Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Stephan Ursprung
- Department of Radiology, University Hospital Tuebingen, Tuebingen, Germany
| | - Onofrio A. Catalano
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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Chapeau D, Beekman S, Handula M, Murce E, de Ridder C, Stuurman D, Seimbille Y. eTFC-01: a dual-labeled chelate-bridged tracer for SSTR2-positive tumors. EJNMMI Radiopharm Chem 2024; 9:44. [PMID: 38775990 PMCID: PMC11111636 DOI: 10.1186/s41181-024-00272-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 05/15/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Integrating radioactive and optical imaging techniques can facilitate the prognosis and surgical guidance for cancer patients. Using a single dual-labeled tracer ensures consistency in both imaging modalities. However, developing such molecule is challenging due to the need to preserve the biochemical properties of the tracer while introducing bulky labeling moieties. In our study, we designed a trifunctional chelate that facilitates the coupling of the targeting vector and fluorescent dye at opposite sites to avoid undesired steric hindrance effects. The synthesis of the trifunctional chelate N3-Py-DOTAGA-(tBu)3 (7) involved a five-step synthetic route, followed by conjugation to the linear peptidyl-resin 8 through solid-phase synthesis. After deprotection and cyclization, the near-infrared fluorescent dye sulfo-Cy.5 was introduced using copper free click chemistry, resulting in eTFC-01. Subsequently, eTFC-01 was labeled with [111In]InCl3. In vitro assessments of eTFC-01 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex-vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. RESULTS eTFC-01 demonstrated a two-fold higher IC50 value for SSTR2 compared to the gold standard DOTA-TATE. Labeling of eTFC-01 with [111In]InCl3 gave a high radiochemical yield and purity. The uptake of [111In]In-eTFC-01 in U2OS.SSTR2 cells was two-fold lower than the uptake of [111In]In-DOTA-TATE, consistent with the binding affinity. Tumor uptake in H69-xenografted mice was lower for [111In]In-eTFC-01 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eTFC-01 in highly vascularized tissues, such as lungs, skin, and heart. Fluorescence measurements in different organs correlated with the radioactive signal distribution. CONCLUSION The successful synthesis and coupling of the trifunctional chelate to the peptide and fluorescent dye support the potential of this synthetic approach to generate dual labeled tracers. While promising in vitro, the in vivo results obtained with [111In]In-eTFC-01 suggest the need for adjustments to enhance tracer distribution.
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Affiliation(s)
- Dylan Chapeau
- Erasmus MC, Department of Radiology and Nuclear Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Savanne Beekman
- Erasmus MC, Department of Radiology and Nuclear Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Maryana Handula
- Erasmus MC, Department of Radiology and Nuclear Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Erika Murce
- Erasmus MC, Department of Radiology and Nuclear Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Corrina de Ridder
- Erasmus MC, Department of Radiology and Nuclear Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Debra Stuurman
- Erasmus MC, Department of Radiology and Nuclear Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Yann Seimbille
- Erasmus MC, Department of Radiology and Nuclear Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands.
- Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
- TRIUMF, Life Sciences Division, Vancouver, Canada.
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Liu Y, Cui R, Wang Z, Lin Q, Tang W, Zhang B, Li G, Wang Z. Evaluating Prognosis of Gastrointestinal Metastatic Neuroendocrine Tumors: Constructing a Novel Prognostic Nomogram Based on NETPET Score and Metabolic Parameters from PET/CT Imaging. Pharmaceuticals (Basel) 2024; 17:373. [PMID: 38543159 PMCID: PMC10975134 DOI: 10.3390/ph17030373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/27/2024] [Accepted: 03/07/2024] [Indexed: 01/06/2025] Open
Abstract
INTRODUCTION The goal of this study is to compare the prognostic performance of NETPET scores, based on gallium-68 DOTANOC (68Ga-DOTANOC) and fluorine-18 fluorodeoxyglucose (18F-FDG) Positron Emission Tomography-Computed Tomography (PET-CT), and PET-CT metabolic parameters in metastatic gastrointestinal neuroendocrine tumors (GI-NET), while constructing and validating a nomogram derived from dual-scan PET-CT. METHODS In this retrospective study, G1-G3 GI-NET patients who underwent 68Ga-DOTANOC and 18F-FDG PET scans were enrolled and divided into training and internal validation cohorts. Three grading systems were constructed based on NETPET scores and standardized uptake value maximum (SUVmax). LASSO regression selected variables for a multivariable Cox model, and nomograms predicting progression-free survival (PFS) and overall survival (OS) were created. The prognostic performance of these systems was assessed using time-dependent receiver-operating characteristic (ROC) curves, concordance index (C-index), and other methods. Nomogram evaluation involved calibration curves, decision curve analysis (DCA), and the aforementioned methods in both cohorts. RESULTS In this study, 223 patients (130 males; mean age ± SD: 52.6 ± 12 years) were divided into training (148) and internal validation (75) cohorts. Dual scans were classified based on NETPET scores (D1-D3). Single 68Ga-DOTANOC and 18F-FDG PET-CT scans were stratified into S1-S3 and F1-F3 based on SUVmax. The NETPET score-based grading system demonstrated the best OS and PFS prediction (C-index, 0.763 vs. 0.727 vs. 0.566). Nomograms for OS and PFS exhibited superior prognostic performance in both cohorts (all AUCs > 0.8). CONCLUSIONS New classification based on NETPET score predicts patient OS/PFS best. PET-CT-based nomograms show accurate OS/PFS forecasts.
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Affiliation(s)
- Yifan Liu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Ruizhe Cui
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Zhixiong Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Qi Lin
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Wei Tang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Bing Zhang
- Department of Nuclear Medicine, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China;
| | - Guanghua Li
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
| | - Zhao Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-sen University, Zhongshan 2nd Street, No. 58, Guangzhou 510080, China; (Y.L.); (R.C.); (Z.W.); (Q.L.); (W.T.)
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Ensign SF, Agarwal M, Klanderman M, Badawy M, Halfdanarson TR, Johnson DR, Sonbol MB, Kendi AT. Clinical utility of somatostatin receptor positron emission tomography imaging biomarkers for characterization of meningioma among incidental central nervous system lesions. Nucl Med Commun 2023; 44:663-670. [PMID: 37158225 DOI: 10.1097/mnm.0000000000001706] [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: 05/10/2023]
Abstract
OBJECTIVES Somatostatin receptor (SSTR) PET imaging is utilized with increasing frequency in the clinical management of neuroendocrine tumors. Incidental PET-avid CNS lesions are commonly noted and presumed to be meningiomas. However, SSTR PET lacks specificity for meningioma identification. This study aimed to clarify the role of SSTR-based imaging in the classification of incidental CNS lesions based on current clinical practice. METHODS Patients who underwent both Ga-68-DOTATATE PET and brain MRI and had an incidental CNS lesion identified with a radiographic prediction of meningioma via one (discordant prediction) or both (concordant prediction) imaging modalities were retrospectively analyzed. Imaging indication, semiquantitative measures, and clinical history were recorded. RESULTS Among 48 patients with a CNS lesion identified on both imaging modalities, most scans were performed for a history of neuroendocrine tumor (64.6%). Cases with concordant lesion-type prediction of meningioma between imaging modalities ( N = 24) displayed a significantly higher SUV max (median 7.9 vs. 4.0; P = 0.008) and Krenning score (median 3.0 vs. 2.0; P = 0.005) on Ga-68-DOTATATE PET compared with cases with a discordant prediction of meningioma ( N = 24). In cases with lower SUV max values, Ga-68-DOTATATE was more likely to discordantly predict meningioma without agreement by the corresponding MRI. Prior cranial radiation or use of somatostatin mimetics did not affect quantitative radiographic measures, and MRI-based tumor size was similar across groups. CONCLUSION Lesions with increased avidity may be more confidently predicted as meningioma in Ga-68-DOTATATE PET scans, whereas there is more discrepancy in prediction among low SUV cases.
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Affiliation(s)
| | | | - Molly Klanderman
- Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, Arizona
| | - Mohamed Badawy
- Department of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center
| | | | - Derek R Johnson
- Department of Radiology
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
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Puranik A, Prasad S, Devi ID, Prasad V. Correlative Imaging in Neuroendocrine Tumors. RADIOLOGY‐NUCLEAR MEDICINE DIAGNOSTIC IMAGING 2023:512-520. [DOI: 10.1002/9781119603627.ch17] [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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10
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Rectal neuroendocrine neoplasms: what the radiologists should know. ABDOMINAL RADIOLOGY (NEW YORK) 2022; 47:4016-4031. [PMID: 35288791 DOI: 10.1007/s00261-022-03474-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/18/2022] [Accepted: 02/21/2022] [Indexed: 02/06/2023]
Abstract
Neuroendocrine neoplasms of the rectum (R-NENs) are rare; however, their incidence has increased almost threefold in the last few decades. Imaging of R-NENs includes two primary categories: anatomic/morphologic imaging comprised of endoscopic ultrasound (EUS), computed tomography (CT), magnetic resonance imaging (MRI), and functional/molecular imaging comprising of planar scintigraphy, single-photon emission computed tomography (SPECT), and positron emission tomography (PET). The management depends on stage, dimension, atypical features, histological grade, and lymphovascular invasion (LVI). Low-risk local R-NENs can be resected endoscopically, and high-risk or locally advanced neoplasms can be treated with radical surgery and lymphadenectomy and/or chemoradiation. The review article focuses on imaging illustrations and discusses applications of different imaging modalities in diagnosing and managing R-NENs.
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Kanellopoulos P, Nock BA, Greifenstein L, Baum RP, Roesch F, Maina T. [ 68Ga]Ga-DATA 5m-LM4, a PET Radiotracer in the Diagnosis of SST 2R-Positive Tumors: Preclinical and First Clinical Results. Int J Mol Sci 2022; 23:ijms232314590. [PMID: 36498918 PMCID: PMC9740503 DOI: 10.3390/ijms232314590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/21/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022] Open
Abstract
Radiolabeled somatostatin subtype 2 receptor (SST2R)-antagonists have shown advantageous profiles for cancer theranostics compared with agonists. On the other hand, the newly introduced hybrid chelator (6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate (DATA5m) rapidly binds Ga-68 (t1/2: 67.7 min) at much lower temperature, thus allowing for quick access to "ready-for-injection" [68Ga]Ga-tracers in hospitals. We herein introduce [68Ga]Ga-DATA5m-LM4 for PET/CT imaging of SST2R-positive human tumors. LM4 was obtained by 4Pal3/Tyr3-substitution in the known SST2R antagonist LM3 (H-DPhe-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2) and DATA5m was coupled at the N-terminus for labeling with radiogallium (Ga-67/68). [67Ga]Ga-DATA5m-LM4 was evaluated in HEK293-SST2R cells and mice models in a head-to-head comparison with [67Ga]Ga-DOTA-LM3. Clinical grade [68Ga]Ga-DATA5m-LM4 was prepared and injected in a neuroendocrine tumor (NET) patient for PET/CT imaging. DATA5m-LM4 displayed high SST2R binding affinity. [67Ga]Ga-DATA5m-LM4 showed markedly higher uptake in HEK293-SST2R cells versus [67Ga]Ga-DOTA-LM3 and was stable in vivo. In HEK293-SST2R xenograft-bearing mice, it achieved longer tumor retention and less kidney uptake than [67Ga]Ga-DOTA-LM3. [68Ga]Ga-DATA5m-LM4 accurately visualized tumor lesions with high contrast on PET/CT. In short, [68Ga]Ga-DATA5m-LM4 has shown excellent prospects for the PET/CT diagnosis of SST2R-positive tumors, further highlighting the benefits of Ga-68 labeling in a hospital environment via the DATA5m-chelator route.
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Affiliation(s)
| | - Berthold A. Nock
- Molecular Radiopharmacy, INRaSTES, NCSR “Demokritos”, GR-15310 Athens, Greece
| | - Lukas Greifenstein
- CURANOSTICUM Wiesbaden-Frankfurt, DKD Helios Klinik, D-65191 Wiesbaden, Germany
| | - Richard P. Baum
- CURANOSTICUM Wiesbaden-Frankfurt, DKD Helios Klinik, D-65191 Wiesbaden, Germany
| | - Frank Roesch
- Department Chemie, Standort TRIGA, Johannes Gutenberg-Universität Mainz, D-55126 Mainz, Germany
| | - Theodosia Maina
- Molecular Radiopharmacy, INRaSTES, NCSR “Demokritos”, GR-15310 Athens, Greece
- Correspondence: ; Tel.: +30-210-650-3908 (ext. 3891)
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12
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Langen Stokmo H, Aly M, Bowitz Lothe IM, Borja AJ, Mehdizadeh Seraj S, Ghorpade R, Miao X, Hjortland GO, Malinen E, Sorbye H, Werner TJ, Alavi A, Revheim M. Volumetric parameters from [ 18 F]FDG PET/CT predicts survival in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms. J Neuroendocrinol 2022; 34:e13170. [PMID: 35729738 PMCID: PMC9539477 DOI: 10.1111/jne.13170] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/12/2022] [Accepted: 05/23/2022] [Indexed: 11/30/2022]
Abstract
A positive fluorine-18 labelled 2-deoxy-2-fluoroglucose ([18 F]FDG) positron emission tomography/computed tomography (PET/CT) has been associated with more aggressive disease and less differentiated neuroendocrine neoplasms (NEN). Although a high maximum standardized uptake value (SUVmax ) predicts poor outcome in NEN, volumetric parameters from [18 F]FDG PET have not been evaluated for prognostication in a pure high-grade gastroenteropancreatic (GEP) NEN cohort. In this retrospective observational study, we evaluated the volumetric PET parameters total metabolic tumour volume (tMTV) and total total lesion glycolysis (tTLG) for independent prognostication of overall survival (OS). High-grade GEP NEN patients with [18 F]FDG PET/CT examination and biopsy within 90 days were included. Total MTV and tTLG were calculated using an adaptive thresholding software. Patients were dichotomised into low and high metabolic groups based on median tMTV and tTLG. OS was compared using Kaplan-Meier estimator and log-rank test. Uni and multivariable Cox regression was used to estimate effect sizes and adjust for tumour differentiation and SUVmax . Sixty-six patients (median age 64 years) were included with 14 NET G3 and 52 NEC cases after histological re-evaluation. Median tMTV was 208 cm3 and median tTLG 1899 g. Median OS in the low versus high tMTV-group was 21.2 versus 5.7 months (HR 2.53, p = 0.0007) and 22.8 versus 5.7 months (HR 2.42, p = 0.0012) in the tTLG-group. Adjusted for tumour differentiation and SUVmax , tMTV and tTLG still predicted for poor OS, and both tMTV and tTLG were stronger prognostic parameters than SUVmax . Both regression models showed a strong association between volumetric parameters and OS for both neuroendocrine tumours (NET) G3 and neuroendocrine carcinomas (NEC). OS for the tTLG low metabolic NEC was much higher than for the tTLG high metabolic NET G3 (18.3 vs. 5.7 months). High-grade GEP NEN patients with high tMTV or tTLG had a worse OS regardless of tumour differentiation (NET G3 or NEC). Volumetric PET parameters were stronger prognostic parameters than SUVmax .
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Affiliation(s)
- Henning Langen Stokmo
- Division of Radiology and Nuclear MedicineOslo University HospitalOsloNorway
- Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloOsloNorway
| | - Mahmoud Aly
- Department of RadiologyHospital of the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of RadiologyAsyut University HospitalAsyutEgypt
| | | | - Austin J. Borja
- Department of RadiologyHospital of the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | | | - Rina Ghorpade
- Department of RadiologyHospital of the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Xuan Miao
- Department of RadiologyHospital of the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | | | - Eirik Malinen
- Department of Medical PhysicsOslo University HospitalOsloNorway
- Department of PhysicsUniversity of OsloOsloNorway
| | - Halfdan Sorbye
- Department of OncologyHaukeland University HospitalBergenNorway
- Department of Clinical ScienceUniversity of BergenBergenNorway
| | - Thomas J. Werner
- Department of RadiologyHospital of the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Abass Alavi
- Department of RadiologyHospital of the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Mona‐Elisabeth Revheim
- Division of Radiology and Nuclear MedicineOslo University HospitalOsloNorway
- Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloOsloNorway
- Department of RadiologyHospital of the University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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13
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Fang JM, Li J, Shi J. An update on the diagnosis of gastroenteropancreatic neuroendocrine neoplasms. World J Gastroenterol 2022; 28:1009-1023. [PMID: 35431496 PMCID: PMC8968521 DOI: 10.3748/wjg.v28.i10.1009] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 11/26/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) arise from neuroendocrine cells found throughout the gastrointestinal tract and islet cells of the pancreas. The incidence and prevalence of GEP-NENs have been increasing each year due to higher awareness, improved diagnostic modalities, and increased incidental detection on cross-sectional imaging and endoscopy for cancer screening and other conditions and symptoms. GEP-NENs are a heterogeneous group of tumors and have a wide range in clinical presentation, histopathologic features, and molecular biology. Clinical presentation most commonly depends on whether the GEP-NEN secretes an active hormone. The World Health Organization recently updated the classification of GEP-NENs to introduce a distinction between high-grade neuroendocrine tumors and neuroendocrine carcinomas, which can be identified using histology and molecular studies and are more aggressive with a worse prognosis compared to high-grade neuroendocrine tumors. As our understanding of the biology of GEP-NENs has grown, new and improved diagnostic modalities can be developed and optimized. Here, we discuss clinical features and updates in diagnosis, including histopathological analysis, biomarkers, molecular techniques, and radiology of GEP-NENs. We review established diagnostic tests and discuss promising novel diagnostic tests that are currently in development or require further investigation and validation prior to broad utilization in patient care.
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Affiliation(s)
- Jiayun M Fang
- Department of Pathology & Clinical Labs, University of Michigan, Ann Arbor, MI 48109, United States
| | - Jay Li
- Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, United States
| | - Jiaqi Shi
- Department of Pathology & Clinical Labs, University of Michigan, Ann Arbor, MI 48109, United States
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Lee L, Ramos-Alvarez I, Jensen RT. Predictive Factors for Resistant Disease with Medical/Radiologic/Liver-Directed Anti-Tumor Treatments in Patients with Advanced Pancreatic Neuroendocrine Neoplasms: Recent Advances and Controversies. Cancers (Basel) 2022; 14:1250. [PMID: 35267558 PMCID: PMC8909561 DOI: 10.3390/cancers14051250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/08/2022] [Accepted: 02/23/2022] [Indexed: 12/14/2022] Open
Abstract
Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
- National Kyushu Cancer Center, Department of Hepato-Biliary-Pancreatology, Fukuoka 811-1395, Japan
| | - Irene Ramos-Alvarez
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
| | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA; (L.L.); (I.R.-A.)
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15
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Tabacchi E, Nanni C, Bossert I, Maffione AM, Fanti S. Diagnostic Applications of Nuclear Medicine: Pancreatic Cancer. NUCLEAR ONCOLOGY 2022:891-917. [DOI: 10.1007/978-3-031-05494-5_17] [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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Hu Y, Ye Z, Wang F, Qin Y, Xu X, Yu X, Ji S. Role of Somatostatin Receptor in Pancreatic Neuroendocrine Tumor Development, Diagnosis, and Therapy. Front Endocrinol (Lausanne) 2021; 12:679000. [PMID: 34093445 PMCID: PMC8170475 DOI: 10.3389/fendo.2021.679000] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 04/27/2021] [Indexed: 12/02/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are rare and part of the diverse family of neuroendocrine neoplasms (NENs). Somatostatin receptors (SSTRs), which are widely expressed in NENs, are G-protein coupled receptors that can be activated by somatostatins or its synthetic analogs. Therefore, SSTRs have been widely researched as a diagnostic marker and therapeutic target in pNETs. A large number of studies have demonstrated the clinical significance of SSTRs in pNETs. In this review, relevant literature has been appraised to summarize the most recent empirical evidence addressing the clinical significance of SSTRs in pNETs. Overall, these studies have shown that SSTRs have great value in the diagnosis, treatment, and prognostic prediction of pNETs; however, further research is still necessary.
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Affiliation(s)
- Yuheng Hu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Zeng Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Fei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xiaowu Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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Pettersson OJ, Fröss-Baron K, Crona J, Sundin A. Tumor growth rate in pancreatic neuroendocrine tumor patients undergoing PRRT with 177Lu-DOTATATE. Endocr Connect 2021; 10:422-431. [PMID: 33875614 PMCID: PMC8111309 DOI: 10.1530/ec-21-0027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 03/19/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND Monitoring of pancreatic neuroendocrine tumors (PanNET) undergoing peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE depends on changes in tumor size, which often occur late. Tumor growth rate (TGR) allows for quantitative assessment of the tumor kinetics expressed as %/month. We explored how TGR changes before and during/after PRRT and evaluated TGR as a biomarker for progression-free survival (PFS). METHODS In PanNET patients undergoing PRRT with 177Lu-DOTATATE from 2006 to 2018, contrast-enhanced CT or MRI was performed before and during the therapy. Patients with at least one hypervascular liver metastasis were included. TGR was calculated for the period preceding treatment and for two intervals during/after PRRT. Cox regression was used for the survival analysis. RESULTS Sixty-seven patients (43 men, 24 women), median age 60 years (range 29-77), median Ki-67 10% (range 1-30) were included. TGR before baseline (n = 57) (TGR0) was mean (s.d.) 6.0%/month (s.d. = 8.7). TGR at 4.5 months (n = 56) (TGR4) from baseline was -3.4 (s.d. = 4.2) %/month. TGR at 9.9 months (n = 57) (TGR10) from baseline was -3.0 (s.d. = 2.9) %/month. TGR4 and TGR10 were lower than TGR0 (TGR4 vs TGR0, P < 0.001 and TGR10 vs TGR0, P < 0.001). In the survival analysis, patients with TGR10 ≥ 0.5%/month (vs <0.5%/month) had shorter PFS (median = 16.0 months vs 31.5 months, hazard ratio 2.82; 95% CI 1.05-7.57, P = 0.040). DISCUSSION TGR in PanNET patients decreases considerably during PRRT with 177Lu-DOTATATE. TGR may be useful as a biomarker to identify patients with the shortest PFS.
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Affiliation(s)
- Olof Joakim Pettersson
- Radiology and Molecular Imaging, Uppsala University Hospital, Uppsala, Sweden
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
- Correspondence should be addressed to O J Pettersson:
| | - Katarzyna Fröss-Baron
- Radiology and Molecular Imaging, Uppsala University Hospital, Uppsala, Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Joakim Crona
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Anders Sundin
- Radiology and Molecular Imaging, Uppsala University Hospital, Uppsala, Sweden
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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Malla S, Kumar P, Madhusudhan KS. Radiology of the neuroendocrine neoplasms of the gastrointestinal tract: a comprehensive review. Abdom Radiol (NY) 2021; 46:919-935. [PMID: 32960304 DOI: 10.1007/s00261-020-02773-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 09/04/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023]
Abstract
Neuroendocrine neoplasms (NENs) are a group of neoplasms arising from the diffuse endocrine system (DES). The gastrointestinal tract (GIT) is the most common site of NEN. The WHO classification divides NEN into three broad categories viz. well-differentiated NENs, poorly differentiated NENs, and mixed neuroendocrine-non-neuroendocrine neoplasms. All GIT NEN have the potential to synthesize and secrete various bioactive substances which may lead to various clinical syndromes. The NEN may occur anywhere in the GIT and exhibit varying clinical presentation, prognosis, and metastatic potential. Further, some tumors show association with familial syndromes like multiple endocrine neoplasia type 1 and neurofibromatosis type 1. Ultrasonography, computed tomography (CT), magnetic resonance imaging, and positron emission tomography-CT are the imaging modalities useful in the diagnosis, localization, and staging of GIT NEN. Management depends on the site, size, grade, and stage of the tumor with interventional radiology playing a significant role in some cases. This imaging review describes the role of a radiologist in the management of GIT NEN.
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Affiliation(s)
- Sundeep Malla
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
| | - Pawan Kumar
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India
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Salahshour F, Taslimi R, Moosavi NS, Yazdi NA, Esfandbod M. Pancreatic Neuroendocrine Tumor presenting as a diffuse pancreatic enlargement, case report and review of literature. J Radiol Case Rep 2021; 15:11-20. [PMID: 33717403 DOI: 10.3941/jrcr.v15i1.3822] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Pancreatic neuroendocrine tumors are rare neoplasms that comprise 1-2% of all pancreatic tumors. However, they are the second most common solid pancreatic neoplasms. They have a wide range of imaging appearances and they can show common to very rare imaging presentations. Most of the time they are solitary well-marginated enhancing solid mass arising in a certain aspect of the pancreas. We present a case report of a 41-year-old female who underwent clinical work-up for abdominal pain, loss of appetite and weight loss for the past year. Ultrasound, computed tomography, and magnetic resonance imaging show diffuse homogenous pancreatic enlargement without contour deformity or a focal mass. Lymphoma and autoimmune pancreatitis were suggested based on imaging findings but IGg4 level and other lab data were normal. Endoscopic ultrasonography confirmed the diffuse enlargement of the pancreas without peripheral structures involvement. The pathological results of multiple fine-needle aspiration biopsy from all parts of the enlarged pancreas revealed a low-grade neuroendocrine tumor.
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Affiliation(s)
- Faeze Salahshour
- Department of Radiology, Advanced diagnostic and interventional radiology research center (ADIR), Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Liver Transplantation Research Center, Imam-Khomeini Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Reza Taslimi
- Department of Gastroenterology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Najme-Sadat Moosavi
- Department of Radiology, Advanced diagnostic and interventional radiology research center (ADIR), Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Niloofar Ayoobi Yazdi
- Department of Radiology, Advanced diagnostic and interventional radiology research center (ADIR), Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
- Liver Transplantation Research Center, Imam-Khomeini Hospital, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mohsen Esfandbod
- Department of Oncology and Hematology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
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20
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Pepe G, Matassa G, Piccoli F, Chiti A. Advances in Diagnostic Imaging. NEUROENDOCRINE NEOPLASIA MANAGEMENT 2021:75-98. [DOI: 10.1007/978-3-030-72830-4_6] [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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21
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Hernandez Vargas S, Lin C, Voss J, Ghosh SC, Halperin DM, AghaAmiri S, Cao HST, Ikoma N, Uselmann AJ, Azhdarinia A. Development of a drug-device combination for fluorescence-guided surgery in neuroendocrine tumors. JOURNAL OF BIOMEDICAL OPTICS 2020; 25:JBO-200129R. [PMID: 33300316 PMCID: PMC7725236 DOI: 10.1117/1.jbo.25.12.126002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 11/06/2020] [Indexed: 05/13/2023]
Abstract
SIGNIFICANCE The use of cancer-targeted contrast agents in fluorescence-guided surgery (FGS) has the potential to improve intraoperative visualization of tumors and surgical margins. However, evaluation of their translational potential is challenging. AIM We examined the utility of a somatostatin receptor subtype-2 (SSTR2)-targeted fluorescent agent in combination with a benchtop near-infrared fluorescence (NIRF) imaging system to visualize mouse xenografts under conditions that simulate the clinical FGS workflow for open surgical procedures. APPROACH The dual-labeled somatostatin analog, Ga67-MMC(IR800)-TOC, was injected into mice (n = 24) implanted with SSTR2-expressing tumors and imaged with the customized OnLume NIRF imaging system (Madison, Wisconsin). In vivo and ex vivo imaging were performed under ambient light. The optimal dose (0.2, 0.5, and 2 nmol) and imaging time point (3, 24, 48, and 72 h) were determined using contrast-to-noise ratio (CNR) as the image quality parameter. Video captures of tumor resections were obtained to provide an FGS readout that is representative of clinical utility. Finally, a log-transformed linear regression model was fitted to assess congruence between fluorescence readouts and the underlying drug distribution. RESULTS The drug-device combination provided high in vivo and ex vivo contrast (CNRs > 3, except lung at 3 h) at all time points with the optimal dose of 2 nmol. The optimal imaging time point was 24-h post-injection, where CNRs > 6.5 were achieved in tissues of interest (i.e., pancreas, small intestine, stomach, and lung). Intraoperative FGS showed excellent utility for examination of the tumor cavity pre- and post-resection. The relationship between fluorescence readouts and gamma counts was linear and strongly correlated (n = 334, R2 = 0.71; r = 0.84; P < 0.0001). CONCLUSION The innovative OnLume NIRF imaging system enhanced the evaluation of Ga67-MMC(IR800)-TOC in tumor models. These components comprise a promising drug-device combination for FGS in patients with SSTR2-expressing tumors.
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Affiliation(s)
- Servando Hernandez Vargas
- The University of Texas Health Science Center at Houston, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, Houston, Texas, United States
| | | | - Julie Voss
- The University of Texas Health Science Center at Houston, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, Houston, Texas, United States
| | - Sukhen C. Ghosh
- The University of Texas Health Science Center at Houston, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, Houston, Texas, United States
| | - Daniel M. Halperin
- The University of Texas MD Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, Houston, Texas, United States
| | - Solmaz AghaAmiri
- The University of Texas Health Science Center at Houston, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, Houston, Texas, United States
| | - Hop S. Tran Cao
- The University of Texas MD Anderson Cancer Center, Department of Surgical Oncology, Division of Surgery, Houston, Texas, United States
| | - Naruhiko Ikoma
- The University of Texas MD Anderson Cancer Center, Department of Surgical Oncology, Division of Surgery, Houston, Texas, United States
| | | | - Ali Azhdarinia
- The University of Texas Health Science Center at Houston, The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, Houston, Texas, United States
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22
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Peptide Receptor Radionuclide Therapy as First-Line Systemic Treatment in Advanced Inoperable/Metastatic Neuroendocrine Tumors. Clin Nucl Med 2020; 45:e393-e399. [PMID: 32604121 DOI: 10.1097/rlu.0000000000003170] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE Advanced inoperable/metastatic neuroendocrine tumors (NETs) pose a therapeutic challenge with limited treatment options. Peptide receptor radionuclide therapy (PRRT), being specific in targeting the somatostatin receptors, is a promising and viable option in this setting. In this study, we intended to evaluate the role of PRRT as the first-line systemic therapy in advanced inoperable/metastatic NETs. METHODS Data of consecutive patients of advanced inoperable/metastatic NETs treated with first-line Lu-DOTATATE at our center, from September 2012 to August 2019, were collected and analyzed. RESULTS Forty-five patients (median age, 50 years; range, 14-72 years) with treatment-naive advanced NETs received a median cumulative dose of 27 GBq (range, 13.3-41.3 GBq; over 2-7 cycles) Lu-DOTATATE and 1250 mg/m capecitabine from days 0 to 14 of each PRRT cycle. Three patients were lost to follow-up, 2 had nonmeasurable lesions on CT, and hence, radiological response using Response Evaluation Criteria in Solid Tumors version 1.1 could be assessed in 40 patients. Twelve of 40 patients (30%) showed a partial response, whereas stable disease was observed in 22 of 40 patients (55%). Disease progression was limited to 6 of 40 patients (15%). Treatment-related adverse effects were minimal with grade 3/4 anemia, leukopenia, neutropenia, and hepatotoxicity observed in 2%, 2%, 4%, and 4% of the patients, respectively. Median progression-free survival was 48 months (95% confidence interval, 34.7-61.3 months). CONCLUSIONS Our results indicate the efficacy and safety of first-line PRRT in advanced NETs. Future randomized trials, comparing PRRT and somatostatin analogs in treatment-naive patients, are required to identify the definite sequence of treatment options for these patients.
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23
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Binderup T, Knigge U, Johnbeck CB, Loft A, Berthelsen AK, Oturai P, Mortensen J, Federspiel B, Langer SW, Kjaer A. 18F-FDG PET is Superior to WHO Grading as a Prognostic Tool in Neuroendocrine Neoplasms and Useful in Guiding PRRT: A Prospective 10-Year Follow-up Study. J Nucl Med 2020; 62:808-815. [PMID: 33067340 DOI: 10.2967/jnumed.120.244798] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Accurate grading of patients with neuroendocrine neoplasms (NENs) is essential for risk stratification and optimal choice of therapy. Currently, grading is based on histologically assessed degree of tumor proliferation. The aim of the present study was to assess the long-term prognostic value of 18F-FDG PET imaging for risk stratification of NENs and compare it with tumor grading (World Health Organization 2010 classification). Methods: We conducted a prospective cohort study evaluating the prognostic value of 18F-FDG PET imaging and compared it with histologic grading. Enrolled were 166 patients of all grades and with histologically confirmed NENs of gastroenteropancreatic origin. The primary endpoint was overall survival (OS). Progression-free survival (PFS) was a secondary endpoint. In addition, OS in relation to peptide receptor radionuclide therapy (PRRT) was analyzed as an exploratory endpoint. The median follow-up time was 9.8 y. Results: Analysis of the whole cohort revealed that a positive 18F-FDG PET scan was associated with a shorter OS than a negative 18F-FDG PET scan (hazard ratio: 3.8; 95% CI: 2.4-5.9; P < 0.001). In G1 and G2 patients (n = 140), a positive 18F-FDG PET scan was the only identifier of high risk for death (hazard ratio: 3.6; 95% CI, 2.2-5.9; P < 0.001). In multivariate analysis, 18F-FDG PET, G3 tumor, ≥2 liver metastases, and ≥2 prior therapies were independent prognostic factors for OS, and 18F-FDG PET, G3 tumor, and ≥3 liver metastases were independent prognostic factors for PFS. For patients receiving PRRT, 18F-FDG-negative cases had a significantly longer survival than 18F-FDG-positive cases, whereas no difference was identified for tumor grading. 18F-FDG-positive patients receiving PRRT had a significantly longer median survival than patients not receiving PRRT (4.4 vs. 1.4 y, P = 0.001), whereas no difference was seen for 18F-FDG-negative patients. Conclusion: 18F-FDG PET is useful for risk stratification of all NEN grades and is superior to histologic grading. 18F-FDG PET could differentiate G1 and G2 tumors into low- and high-risk groups. In the selection of therapy and for risk stratification of NEN patients, 18F-FDG PET status should be considered.
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Affiliation(s)
- Tina Binderup
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet & University of Copenhagen, Copenhagen, Denmark.,European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark
| | - Ulrich Knigge
- European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark.,Department of Surgical Gastroenterology, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Endocrinology, Rigshospitalet, Copenhagen, Denmark
| | - Camilla Bardram Johnbeck
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet & University of Copenhagen, Copenhagen, Denmark.,European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark
| | - Annika Loft
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet & University of Copenhagen, Copenhagen, Denmark.,European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark
| | - Anne Kiil Berthelsen
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet & University of Copenhagen, Copenhagen, Denmark.,European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark
| | - Peter Oturai
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet & University of Copenhagen, Copenhagen, Denmark.,European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark
| | - Jann Mortensen
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet & University of Copenhagen, Copenhagen, Denmark.,European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark
| | - Birgitte Federspiel
- European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark.,Department of Pathology, Rigshospitalet, Copenhagen, Denmark; and
| | - Seppo W Langer
- European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark.,Department of Oncology, Rigshospitalet, Copenhagen, Denmark
| | - Andreas Kjaer
- Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet & University of Copenhagen, Copenhagen, Denmark .,European Neuroendocrine Tumors Society Center of Excellence, Rigshospitalet, Copenhagen, Denmark
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24
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Patil VA, Goroshi MR, Shah H, Malhotra G, Hira P, Sarathi V, Lele VR, Jadhav S, Lila A, Bandgar TR, Shah NS. Comparison of 68Ga-DOTA-NaI 3-Octreotide/tyr 3-octreotate positron emission tomography/computed tomography and contrast-enhanced computed tomography in localization of tumors in multiple endocrine neoplasia 1 syndrome. World J Nucl Med 2020; 19:99-105. [PMID: 32939195 PMCID: PMC7478292 DOI: 10.4103/wjnm.wjnm_24_19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 06/18/2019] [Indexed: 11/22/2022] Open
Abstract
The optimum imaging modality for the screening of multiple endocrine neoplasia type 1 (MEN1)-associated tumors is not well established. Here, we compare the performance of contrast-enhanced CT (CECT) versus 68Ga DOTA-NOC/TATE PET/CT in MEN1 patients. The retrospective case record study is conducted at a tertiary health-care center. Thirty-four patients, who have undergone both CECT and 68Ga DOTA-NOC/ TATE PET, were included in the analysis. CECT had higher per-lesion sensitivity than 68Ga DOTA-NOC/TATE PET/CT for the detection of parathyroid lesions, (82.6% vs. 24.6%, P < 0.001). 68Ga DOTA-NOC/TATE PET/CT had higher per-lesion sensitivity than CECT for the detection of metastases (85% vs. 47.5%, P < 0.001) and gastrinomas (90% vs. 10%, P = 0.003). When combined use of the two imaging modalities is compared to CECT alone (63.7% vs. 93.1%, P = 0.00012) and 68Ga-DOTA-NOC/TATE PET/CT alone (74.1% vs. 93.1%, P = 0.0057), it provided significantly higher per-lesion sensitivity for the detection of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). 68Ga-DOTA-NOC/ TATE PET was more sensitive for the detection of gastrinomas and metastases than CECT, whereas it was less sensitive for the detection of parathyroid lesions than CECT. The combined use of both the imaging modalities significantly increases the sensitivity for detection of GEP-NETs.
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Affiliation(s)
- Virendra A Patil
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
| | - Manjunath R Goroshi
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
| | - Hina Shah
- Department of Nuclear Medicine and Positron Emission Tomography/Computed Tomography, Jaslok Hospital and Research Centre, Mumbai, Maharashtra, India
| | - Gaurav Malhotra
- Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Centre, Mumbai, Maharashtra, India
| | - Priya Hira
- Department of Radiology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
| | - Vijaya Sarathi
- Department of Endocrinology, Narayana Medical College, Nellore, Andhra Pradesh, India
| | - Vikram R Lele
- Department of Nuclear Medicine and Positron Emission Tomography/Computed Tomography, Jaslok Hospital and Research Centre, Mumbai, Maharashtra, India
| | - Swati Jadhav
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
| | - Anurag Lila
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
| | - Tushar R Bandgar
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
| | - Nalini S Shah
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
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25
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Raheem SJ, Schmidt BW, Solomon VR, Salih AK, Price EW. Ultrasonic-Assisted Solid-Phase Peptide Synthesis of DOTA-TATE and DOTA- linker-TATE Derivatives as a Simple and Low-Cost Method for the Facile Synthesis of Chelator-Peptide Conjugates. Bioconjug Chem 2020; 32:1204-1213. [PMID: 32645261 DOI: 10.1021/acs.bioconjchem.0c00325] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Peptides have been widely adopted as biological targeting vectors for applications in molecular imaging and peptide-receptor radionuclide therapy (PRRT). Somatostatin (SST) analogues such as octreotate (TATE) are exogenous ligands for somatostatin receptors (SSTRs), which are highly expressed on neuroendocrine tumors (NETs). Recently, both [68Ga]Ga-DOTA-TATE (NETSPOT) and [177Lu]Lu-DOTA-TATE (LUTATHERA) received U.S. Food and Drug Administration approval for positron emission tomography (PET) imaging and PRRT of NETs, respectively. However, to the best of our knowledge a well-described synthesis of DOTA-TATE has not been reported in the literature. Herein, we report a fully reoptimized DOTA-TATE synthesis, including the application of a simple ultrasonic bath to greatly improve yields, reduce coupling times, and decrease the amount of reagents required for each coupling step by a half. The most prevalently used cyclizing agents such as iodine, thallium(III) trifluoroacetate, hydrogen peroxide, and dimethyl sulfoxide were compared. On-resin cyclizations using mechanical agitation showed higher yields (23% and 25% using I2 and Tl(III), respectively) than off-resin (1.3% and 11% using DMSO and H2O2, respectively), and the total synthesis time of DOTA-TATE was ∼540 min excluding the cyclization step, with a total synthesis yield of ∼23%. The same manual SPPS methods/reagents were reoptimized with ultrasonic (US) agitation, resulting in an immense reduction in the total synthesis time by ∼8-fold to ∼70 min for DOTA-TATE with a higher yield (∼29% yield), and ∼13-fold to 105 min for DOTA-PEG4-TATE (∼29% yield). Also, the use of US agitation reduces the need for excess molar equivalents of the reagents to a half, which is particularly important when coupling expensive or custom-synthesized groups such as bifunctional chelators and linkers. Finally, the synthesized DOTA-TATE was successfully radiolabeled with [68Ga]Ga3+ (t1/2 = 68 min) with high radiochemical yields (30 min, 95 °C). We believe this work opens the door to the facile and low-cost synthesis of many new chelator-linker-peptide conjugates that were previously cumbersome or cost-prohibitive to produce with manual SPPS.
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Affiliation(s)
- Shvan J Raheem
- Department of Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N-5C9, Canada
| | - Benjamin W Schmidt
- Department of Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N-5C9, Canada
| | - Viswas Raja Solomon
- Department of Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N-5C9, Canada
| | - Akam K Salih
- Department of Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N-5C9, Canada
| | - Eric W Price
- Department of Chemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N-5C9, Canada
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26
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Lindström E, Lindsjö L, Sundin A, Sörensen J, Lubberink M. Evaluation of block-sequential regularized expectation maximization reconstruction of 68Ga-DOTATOC, 18F-fluoride, and 11C-acetate whole-body examinations acquired on a digital time-of-flight PET/CT scanner. EJNMMI Phys 2020; 7:40. [PMID: 32542512 PMCID: PMC7295929 DOI: 10.1186/s40658-020-00310-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 06/01/2020] [Indexed: 01/12/2023] Open
Abstract
Background Block-sequential regularized expectation maximization (BSREM) is a fully convergent iterative image reconstruction algorithm. We hypothesize that tracers with different distribution patterns will result in different optimal settings for the BSREM algorithm. The aim of this study was to evaluate the image quality with variations in the applied β-value and acquisition time for three positron emission tomography (PET) tracers. NEMA image quality phantom measurements and clinical whole-body digital time-of-flight (TOF) PET/computed tomography (CT) examinations with 68Ga-DOTATOC (n = 13), 18F-fluoride (n = 10), and 11C-acetate (n = 13) were included. Each scan was reconstructed using BSREM with β-values of 133, 267, 400, and 533, and ordered subsets expectation maximization (OSEM; 3 iterations, 16 subsets, and 5-mm Gaussian post-processing filter). Both reconstruction methods included TOF and point spread function (PSF) recovery. Quantitative measures of noise, signal-to-noise ratio (SNR), and signal-to-background ratio (SBR) were analysed for various acquisition times per bed position (bp). Results The highest β-value resulted in the lowest level of noise, which in turn resulted in the highest SNR and lowest SBR. Noise levels equal to or lower than those of OSEM were found with β-values equal to or higher than 400, 533, and 267 for 68Ga-DOTATOC, 18F-fluoride, and 11C-acetate, respectively. The specified β-ranges resulted in increased SNR at a minimum of 25% (P < 0.0001) and SBR at a maximum of 23% (P < 0.0001) as compared to OSEM. At a reduced acquisition time by 25% for 68Ga-DOTATOC and 18F-fluoride, and 67% for 11C-acetate, BSREM with β-values equal to or higher than 533 resulted in noise equal to or lower than that of OSEM at full acquisition duration (2 min/bp for 68Ga-DOTATOC and 18F-fluoride, 3 min/bp for 11C-acetate). The reduced acquisition time with β 533 resulted in increased SNR (16–26%, P < 0.003) and SBR (6–18%, P < 0.0001 (P = 0.07 for 11C-acetate)) compared to the full acquisition OSEM. Conclusions Within tracer-specific ranges of β-values, BSREM reconstruction resulted in increased SNR and SBR with respect to conventional OSEM reconstruction. Similar SNR, SBR, and noise levels could be attained with BSREM at relatively shorter acquisition times or, alternatively, lower administered dosages, compared to those attained with OSEM.
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Affiliation(s)
- Elin Lindström
- Radiology & Nuclear Medicine, Department of Surgical Sciences, Uppsala University, SE-751 85, Uppsala, Sweden. .,Medical Physics, Uppsala University Hospital, SE-751 85, Uppsala, Sweden.
| | - Lars Lindsjö
- PET Centre, Uppsala University Hospital, SE-751 85, Uppsala, Sweden
| | - Anders Sundin
- Radiology & Nuclear Medicine, Department of Surgical Sciences, Uppsala University, SE-751 85, Uppsala, Sweden
| | - Jens Sörensen
- Radiology & Nuclear Medicine, Department of Surgical Sciences, Uppsala University, SE-751 85, Uppsala, Sweden.,PET Centre, Uppsala University Hospital, SE-751 85, Uppsala, Sweden
| | - Mark Lubberink
- Radiology & Nuclear Medicine, Department of Surgical Sciences, Uppsala University, SE-751 85, Uppsala, Sweden.,Medical Physics, Uppsala University Hospital, SE-751 85, Uppsala, Sweden
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27
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Czernin J, Sonni I, Razmaria A, Calais J. The Future of Nuclear Medicine as an Independent Specialty. J Nucl Med 2020; 60:3S-12S. [PMID: 31481589 DOI: 10.2967/jnumed.118.220558] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 07/06/2019] [Indexed: 02/07/2023] Open
Abstract
In this article, we provide an overview of established and emerging conventional nuclear medicine and PET imaging biomarkers, as the diagnostic nuclear medicine portfolio is rapidly expanding. Next, we review briefly nuclear theranostic approaches that have already entered or are about to enter clinical routine. Using some approximations and taking into account emerging applications, we also provide some simplified business forecasts for nuclear theranostics. We argue that an optimistic outlook by the nuclear medicine community is crucial to the growth of the specialty and emphasize the urgent need for training adaptations.
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Affiliation(s)
- Johannes Czernin
- Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Ida Sonni
- Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Aria Razmaria
- Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California
| | - Jeremie Calais
- Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California
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28
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Saha A, Tso S, Rabski J, Sadeghian A, Cusimano MD. Machine learning applications in imaging analysis for patients with pituitary tumors: a review of the current literature and future directions. Pituitary 2020; 23:273-293. [PMID: 31907710 DOI: 10.1007/s11102-019-01026-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE To provide an overview of fundamental concepts in machine learning (ML), review the literature on ML applications in imaging analysis of pituitary tumors for the last 10 years, and highlight the future directions on potential applications of ML for pituitary tumor patients. METHOD We presented an overview of the fundamental concepts in ML, its various stages used in healthcare, and highlighted the key components typically present in an imaging-based tumor analysis pipeline. A search was conducted across four databases (PubMed, Ovid, Embase, and Google Scholar) to gather research articles from the past 10 years (2009-2019) involving imaging related to pituitary tumor and ML. We grouped the studies by imaging modalities and analyzed the ML tasks in terms of the data inputs, reference standards, methodologies, and limitations. RESULTS Of the 16 studies included in our analysis, 10 appeared in 2018-2019. Most of the studies utilized retrospective data and followed a semi-automatic ML pipeline. The studies included use of magnetic resonance imaging (MRI), facial photographs, surgical microscopic video, spectrometry, and spectroscopy imaging. The objectives of the studies covered 14 distinct applications and majority of the studies addressed a binary classification problem. Only five of the 11 MRI-based studies had an external validation or a holdout set to test the performance of a final trained model. CONCLUSION Through our concise evaluation and comparison of the studies using the concepts presented, we highlight future directions so that potential ML applications using different imaging modalities can be developed to benefit the clinical care of pituitary tumor patients.
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Affiliation(s)
- Ashirbani Saha
- Division of Neurosurgery, St. Michael's Hospital, Toronto, ON, Canada.
| | - Samantha Tso
- Division of Neurosurgery, St. Michael's Hospital, Toronto, ON, Canada
| | - Jessica Rabski
- Division of Neurosurgery, St. Michael's Hospital, Toronto, ON, Canada
| | | | - Michael D Cusimano
- Division of Neurosurgery, St. Michael's Hospital, Toronto, ON, Canada
- Department of Surgery, University of Toronto, Toronto, ON, Canada
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29
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Liu F, Guo X, Liu T, Xu X, Li N, Xiong C, Li C, Zhu H, Yang Z. Evaluation of Pan-SSTRs Targeted Radioligand [ 64Cu]NOTA-PA1 Using Micro-PET Imaging in Xenografted Mice. ACS Med Chem Lett 2020; 11:445-450. [PMID: 32292548 DOI: 10.1021/acsmedchemlett.9b00544] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/12/2020] [Indexed: 12/25/2022] Open
Abstract
64Cu-labeled new pan-somatostatin receptors (pan-SSTRs) probe PA1 was synthesized, characterized, and evaluated by in vitro and in vivo experiments. [64Cu]NOTA-PA1 was obtained with high specific activity, high radiochemical purity, and good stability. Cell uptake of [64Cu]NOTA-PA1 was higher than that of [64Cu]DOTA-TATE in MCF-7, A549, BGC823, and HT-29 cell lines. [64Cu]NOTA-PA1 showed high binding affinity for SSTRs expressed in A549 cells. The in vivo biodistribution and micropositron emission tomography (micro-PET) imaging studies of [64Cu]NOTA-PA1 revealed good detection ability in MCF-7 and A549 xenografted nude mice. The radiosynthesis, quality control, and preliminary biological evaluation of [64Cu]NOTA-PA1 have broaden the application of radiolabeled octreotide for SSTRs imaging, which could act as a potential multisubtypes targeted radiotracer for imaging SSTRs-positive tumors.
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Affiliation(s)
- Fei Liu
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiaoyi Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Teli Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiaoxia Xu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Nan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Chiyi Xiong
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - Chun Li
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States
| | - Hua Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhi Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
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30
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Signore A, Lauri C, Auletta S, Varani M, Onofrio L, Glaudemans AWJM, Panzuto F, Marchetti P. Radiopharmaceuticals for Breast Cancer and Neuroendocrine Tumors: Two Examples of How Tissue Characterization May Influence the Choice of Therapy. Cancers (Basel) 2020; 12:cancers12040781. [PMID: 32218303 PMCID: PMC7226069 DOI: 10.3390/cancers12040781] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 12/12/2022] Open
Abstract
Molecular medicine has gained clinical relevance for the detection and staging of oncological diseases, to guide therapy decision making and for therapy follow-up due to the availability of new highly sensitive hybrid imaging camera systems and the development of new tailored radiopharmaceuticals that target specific molecules. The knowledge of the expression of different receptors on the primary tumor and on metastases is important for both therapeutic and prognostic purposes and several approaches are available aiming to achieve personalized medicine in different oncological diseases. In this review, we describe the use of specific radiopharmaceuticals to image and predict therapy response in breast cancer and neuroendocrine tumors since they represent a paradigmatic example of the importance of tumoral characterization of hormonal receptors in order to plan a tailored treatment. The most attractive radiopharmaceuticals for breast cancer are 16α-[18F]-fluoro-17β-estradiol for PET assessment of the estrogen expression, radiolabeled monoclonal antibody trastuzumab to image the human epidermal growth factor receptor 2, but also the imaging of androgen receptors with [18F]-fluorodihydrotestosterone.
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Affiliation(s)
- Alberto Signore
- Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, 00189 Rome, Italy; (C.L.); (S.A.); (M.V.); (L.O.)
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, 9700 Groningen, The Netherlands;
- Correspondence:
| | - Chiara Lauri
- Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, 00189 Rome, Italy; (C.L.); (S.A.); (M.V.); (L.O.)
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, 9700 Groningen, The Netherlands;
| | - Sveva Auletta
- Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, 00189 Rome, Italy; (C.L.); (S.A.); (M.V.); (L.O.)
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, 9700 Groningen, The Netherlands;
| | - Michela Varani
- Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, 00189 Rome, Italy; (C.L.); (S.A.); (M.V.); (L.O.)
| | - Livia Onofrio
- Nuclear Medicine Unit, Department of Medical-Surgical Sciences and of Translational Medicine, “Sapienza” University of Rome, 00189 Rome, Italy; (C.L.); (S.A.); (M.V.); (L.O.)
| | - Andor W. J. M. Glaudemans
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, 9700 Groningen, The Netherlands;
| | - Francesco Panzuto
- Digestive Disease Unit, AOU Sant’Andrea and ENETS Center of Excellence, 00189 Rome, Italy;
| | - Paolo Marchetti
- Oncology Unit, Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, and IDI-IRCCS, 00189 Rome, Italy;
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Pettersson O, Fröss-Baron K, Crona J, Sundin A. Tumor Contrast-Enhancement for Monitoring of PRRT 177Lu-DOTATATE in Pancreatic Neuroendocrine Tumor Patients. Front Oncol 2020; 10:193. [PMID: 32154181 PMCID: PMC7047407 DOI: 10.3389/fonc.2020.00193] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 02/05/2020] [Indexed: 01/14/2023] Open
Abstract
Background: Therapy monitoring of cancer treatment by contrast-enhanced CT (CECT), applying response evaluation criteria in solid tumors criteria version 1. 1 (RECIST 1.1) is less suitable for neuroendocrine tumors (NETs) which, when responding, tend to show stabilization rather than shrinkage. New methods are needed to further classify patients in order to identify non-responders at an early stage and avoid unnecessary adverse effects and costs. Changes in arterial tumor attenuation and contrast-enhancement could be used to identify the effect of therapy, perhaps even in early stages of treatment. Methods: Patients with metastatic pancreatic NETs (PNETs) receiving peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE underwent CECT at baseline, mid-treatment (PRRT cycles 3–5) and at follow-up, 3 months after the last PRRT cycle. At baseline CECT, the liver metastasis with the highest arterial attenuation was identified in each patient. The fold changes in arterial tumor attenuation (Hounsfield Units, HU), contrast-enhancement (HU), and transversal tumor area (cm2) between CECT at baseline, mid-treatment and follow-up were calculated. Correlation of the tumor metrics to outcome parameters such as progression-free survival (PFS) and time to best response was performed. Results: Fifty-two patients were included (27 men, 25 women), median age 60 years (range 29–80), median Ki-67 8% (range 1–30). Six patients had grade 1 PNETs, forty had grade 2 and four had grade 3 tumors. As an internal control, it was first tested and established that the tumor contrast-enhancement was not merely related to that of the abdominal aorta. The mean ± SD arterial attenuation of the liver metastases was similar at baseline, 217 ± 62 HU and at mid-treatment, 238 ± 80 HU and then decreased to 198 ± 62 HU at follow-up, compared to baseline (p = 0.024, n = 52) and mid-treatment (p = 0.0004, n = 43). The transversal tumor area decreased 25% between baseline and follow-up (p = 0.013, n = 52). Tumor contrast-enhancement increased slightly from baseline to mid-treatment and these fold changes correlated with PFS (R2 = 0.33, p = 0.0002, n = 37) and with time to best response (R2 = 0.34, p < 0.0001, n = 37). Conclusions: Early changes in contrast-enhancement and arterial attenuation in PNET liver metastases may for CECT monitoring of PRRT yield complementary information to evaluation by RECIST 1.1.
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Affiliation(s)
- Olof Pettersson
- Section of Radiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Joakim Crona
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Anders Sundin
- Section of Radiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
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Coriat R. Les nouvelles techniques diagnostiques des tumeurs neuroendocrines pancréatiques. ONCOLOGIE 2020. [DOI: 10.3166/onco-2019-0046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Les tumeurs neuroendocrines pancréatiques (TNEp) sont des tumeurs développées aux dépens du pancréas et nécessitent un bilan diagnostique spécifique. Le bilan d’imagerie d’une TNEp est utile pour le diagnostic ainsi que pour le traitement chirurgical/médical. Récemment, un certain nombre de progrès ont été réalisés dans le domaine de l’imagerie des TNEp, en particulier en ce qui concerne l’imagerie fonctionnelle utilisant des analogues de la somatostatine radiomarqués. Dans cette mise au point, nous abordons les progrès diagnostiques en nous focalisant sur les avancées des dernières années. Ainsi, il est abordé l’intérêt de l’imagerie conventionnelle (scanner, échographie abdominale, imagerie par résonance magnétique), de l’échoendoscopie et la place de l’imagerie fonctionnelle, principalement avec des analogues de la somatostatine radiomarqués.
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Kamikihara Y, Tanoue S, Kawahira M, Iwaya H, Arima S, Sasaki F, Nasu Y, Hashimoto S, Kanmura S, Higashi M, Gejima K, Ido A. A case of gallbladder neuroendocrine carcinoma diagnosed preoperatively using somatostatin receptor scintigraphy. Oncol Lett 2019; 19:247-254. [PMID: 31897136 PMCID: PMC6924094 DOI: 10.3892/ol.2019.11101] [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: 05/20/2019] [Accepted: 10/08/2019] [Indexed: 11/22/2022] Open
Abstract
Gallbladder neuroendocrine carcinoma (NEC) is a rare gallbladder tumor. The current report is a case of a patient preoperatively diagnosed with gallbladder NEC using somatostatin receptor scintigraphy (SRS). A 63-year-old man was admitted to our hospital by a family doctor after abdominal ultrasonography revealed thickened walls of the neck of his gallbladder. At Kagoshima University Hospital, CT and MRI of the abdomen and endoscopic ultrasonography confirmed the thickening of the walls of the neck of the gallbladder. However, it did not resemble a typical gallbladder cancer or tumor, such as a neuroendocrine tumor or malignant lymphoma. Positron emission tomography and SRS showed abnormal accumulation at the tumor site. Endoscopic retrograde cholangiopancreatography was performed, adenocarcinoma was suspected based on intra-gallbladder bile cytology, and a cholecystectomy with lymphadenectomy was performed. The postoperative pathological diagnosis was small cell NEC (pT3a, N0, M0, stage II). Immunohistochemistry indicated that the gallbladder tumor cells were positive for synaptophysin, chromogranin A, and cluster of differentiation (CD) 56, and negative for somatostatin receptors (SSTR) 2 and 5. Gene expression assays revealed the expression of all SSTR subtypes (SSTR1-5) in the tumor. Generally, NECs exhibit poor accumulation in SRS, however, the results of the current case suggest that SRS may be useful in the preoperative diagnosis of NEC.
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Affiliation(s)
- Yusuke Kamikihara
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shiroh Tanoue
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Machiko Kawahira
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Hiromichi Iwaya
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shiho Arima
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Fumisato Sasaki
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Yuichiro Nasu
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shinichi Hashimoto
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shuji Kanmura
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Michiyo Higashi
- Department of Pathology, Kagoshima University Hospital, Kagoshima 890-8544, Japan
| | - Kentaro Gejima
- Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
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The multidisciplinary team for gastroenteropancreatic neuroendocrine tumours: the radiologist's challenge. Radiol Oncol 2019; 53:373-387. [PMID: 31652122 PMCID: PMC6884929 DOI: 10.2478/raon-2019-0040] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 07/15/2019] [Indexed: 02/07/2023] Open
Abstract
Background Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are a heterogeneous group of tumours. An effective diagnosis requires a multimodal approach that combines evaluation of clinical symptoms, hormonelevels, radiological and nuclear imaging, and histological confirmation. Imaging plays a critical role in NETs diagnosis, prognosis and management, so the radiologists are important members of the multidisciplinary team. During diagnostic work-up two critical issues are present: firstly the need to identify tumor presence and secondly to define the primary site and assess regional and distant metastases. Conclusions The most appropriate imaging technique depends on the type of neuroendocrine tumour and the availability of specialized imaging techniques and expertise. There is no general consensus on the most efficient imaging pathway, reflecting the challenge in reliably detection of these tumours.
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Andersen TL, Baun C, Olsen BB, Dam JH, Thisgaard H. Improving Contrast and Detectability: Imaging with [ 55Co]Co-DOTATATE in Comparison with [ 64Cu]Cu-DOTATATE and [ 68Ga]Ga-DOTATATE. J Nucl Med 2019; 61:228-233. [PMID: 31519803 DOI: 10.2967/jnumed.119.233015] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 08/15/2019] [Indexed: 02/06/2023] Open
Abstract
PET imaging at late time points after injection may allow tracer clearance from normal tissue and hence improve image contrast and detectability. 55Co is a promising isotope with high positron yield and a long half-life suitable for imaging at delayed time points. Here, we compared the 3 radioconjugates [68Ga]Ga-DOTATATE, [64Cu]Cu-DOTATATE, and [55Co]Co-DOTATATE by PET/CT imaging in NOD-SCID mice bearing subcutaneous somatostatin receptor-expressing AR42J tumors. Methods: 55Co and 64Cu were produced by the 54Fe(d,n)55Co and 64Ni(p,n)64Cu nuclear reactions, whereas 68Ga was obtained from a 68Ge/68Ga generator. 55Co and 64Cu were labeled with DOTATATE by heating in a sodium acetate buffer and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, respectively. AR42J tumor-bearing mice were dynamically scanned 0-1 h after injection. For 64Cu and 55Co, additional imaging was also performed at late time points after 4 and 24 h. Dose calculations were based on a known biodistribution. The cumulated disintegrations in each organ were calculated by integration of a fitted exponential function to the biodistribution of each respective organ. Equivalent doses were calculated by OLINDA/EXM using the MIRD formalism. Results: Tumor uptake was rapid from 0 to 1 h after injection for all 3 radioconjugates. Normal-tissue ratios as represented by tumor-to-liver, tumor-to-kidney, and tumor-to-muscle ratios increased significantly over time, with [55Co]Co-DOTATATE reaching the highest ratio of all radioconjugates. For [55Co]Co-DOTATATE, the tumor-to-liver ratio increased to 65 ± 16 at 4 h and 50 ± 6 at 24 h, which were 15 (P < 0.001) and 30 (P < 0.001) times higher, respectively, than the corresponding ratios for [64Cu]Cu-DOTATATE and 5 (P < 0.001) times higher than that of [68Ga]Ga-DOTATATE at 1 h. Correspondingly, tumor-to-kidney and tumor-to-muscle ratios for [55Co]Co-DOTATATE were 4 (P < 0.001) and 11 (P < 0.001) times higher than that of [64Cu]Cu-DOTATATE at 24 h. An equivalent dose was calculated as 9.6E-02 mSv/MBq for [55Co]Co-DOTATATE. Conclusion: [55Co]Co-DOTATATE demonstrated superior image contrast compared with [64Cu]Cu-DOTATATE and [68Ga]Ga-DOTATATE for PET imaging of somatostatin receptor-expressing tumors, warranting translation into clinical trials. Dosimetry calculations found that effective doses for [55Co]Co-DOTATATE were comparable to those for both [64Cu]Cu-DOTATATE and [68Ga]Ga-DOTATATE.
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Affiliation(s)
- Thomas L Andersen
- PET Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; and.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Christina Baun
- PET Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; and
| | - Birgitte B Olsen
- PET Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; and.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Johan H Dam
- PET Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; and.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Helge Thisgaard
- PET Unit, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; and .,Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Kanduluru AK, Srinivasarao M, Wayua C, Low PS. Evaluation of a Neurokinin-1 Receptor-Targeted Technetium-99m Conjugate for Neuroendocrine Cancer Imaging. Mol Imaging Biol 2019; 22:377-383. [PMID: 31292915 DOI: 10.1007/s11307-019-01391-w] [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: 11/28/2022]
Abstract
PURPOSE Neuroendocrine tumors (NETs) have reasonably high 5-year survival rates when diagnosed at an early stage but are significantly more lethal when discovered only after metastasis. Although several imaging modalities such as computed tomography (CT), positron emission tomography, and magnetic resonance imaging can detect neuroendocrine tumors, their high false positive rates suggest that more specific diagnostic tests are required. Targeted imaging agents such as Octreoscan® have met some of this need for improved specificity, but their inability to image poorly differentiated NETs suggests that improved NET imaging agents are still needed. Because neurokinin 1 receptors (NK1Rs) are widely over-expressed in neuroendocrine tumors, but show limited expression in healthy tissues, we have undertaken to develop an NK1R-targeted imaging agent for improved diagnosis and staging of neuroendocrine tumors. PROCEDURE A small molecule NK1R antagonist was conjugated via a flexible spacer to a Tc-99m chelating peptide. After complexation with Tc-99m, binding of the conjugate to human embryonic kidney (HEK293) cells transfected with the human NK1R was evaluated as a function of radioimaging agent concentration. In vivo imaging of HEK293-NK1R tumor xenografts in mice was also performed by single-photon emission computed tomography/computed tomography (γ-SPECT/CT), and the distribution of the conjugate in various tissues was quantified by tissue resection and γ-counting. RESULTS NK1R-targeted Tc-99m-based radioimaging agent displayed excellent affinity (Kd = 16.8 nM) and specificity for HEK293-NK1R tumor xenograft. SPECT/CT analysis of tumor-bearing mice demonstrated significant tumor uptake and high tumor to background ratio as early as 2 h post injection. CONCLUSION The excellent tumor contrast afforded by our NK1R-targeted radioimaging agent exhibits properties that could improve early diagnosis and staging of many neuroendocrine tumors.
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Affiliation(s)
| | - Madduri Srinivasarao
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA
| | - Charity Wayua
- Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA
| | - Philip S Low
- On Target Laboratories Inc., West Lafayette, IN, 47906, USA. .,Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA.
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Rozenblum L, Mokrane FZ, Yeh R, Sinigaglia M, Besson F, Seban RD, Chougnet CN, Revel-Mouroz P, Zhao B, Otal P, Schwartz LH, Dercle L. The role of multimodal imaging in guiding resectability and cytoreduction in pancreatic neuroendocrine tumors: focus on PET and MRI. Abdom Radiol (NY) 2019; 44:2474-2493. [PMID: 30980115 DOI: 10.1007/s00261-019-01994-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms that secrete peptides and neuro-amines. pNETs can be sporadic or hereditary, syndromic or non-syndromic with different clinical presentations and prognoses. The role of medical imaging includes locating the tumor, assessing its extent, and evaluating the feasibility of curative surgery or cytoreduction. Pancreatic NETs have very distinctive phenotypes on CT, MRI, and PET. PET have been demonstrated to be very sensitive to detect either well-differentiated pNETs using 68Gallium somatostatin receptor (SSTR) radiotracers, or more aggressive undifferentiated pNETS using 18F-FDG. A comprehensive interpretation of multimodal imaging guides resectability and cytoreduction in pNETs. The imaging phenotype provides information on the differentiation and proliferation of pNETs, as well as the spatial and temporal heterogeneity of tumors with prognostic and therapeutic implications. This review provides a structured approach for standardized reading and reporting of medical imaging studies with a focus on PET and MR techniques. It explains which imaging approach should be used for different subtypes of pNET and what a radiologist should be looking for and reporting when interpreting these studies.
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Affiliation(s)
- Laura Rozenblum
- Sorbonne Université, Service de Médecine Nucléaire, AP-HP, Hôpital La Pitié-Salpêtrière, 75013, Paris, France
| | - Fatima-Zohra Mokrane
- Radiology Department, Toulouse University Hospital, 1 Avenue du Professeur Jean Poulhes, 31059, Toulouse, France
- Department of Radiology, New York Presbyterian Hospital, Columbia University, New York, NY, USA
| | - Randy Yeh
- Memorial Sloan Kettering Cancer Center, Molecular Imaging and Therapy Service, New York, NY, USA
| | - Mathieu Sinigaglia
- Department of Imaging and Nuclear Medicine, Institut Claudius Regaud - Institut Universitaire du Cancer de Toulouse - Oncopole, Toulouse, France
| | - Florent Besson
- Paris Sud University, Kremlin Bicêtre Hospital, Paris, France
| | - Romain-David Seban
- Department of Nuclear Medicine, Institut Curie-René Huguenin, Saint-Cloud, France
| | - Cecile N Chougnet
- Department of Endocrine Oncology, Hôpital Saint Louis, Paris, France
| | - Paul Revel-Mouroz
- Radiology Department, Toulouse University Hospital, 1 Avenue du Professeur Jean Poulhes, 31059, Toulouse, France
| | - Binsheng Zhao
- Department of Radiology, New York Presbyterian Hospital, Columbia University, New York, NY, USA
| | - Philippe Otal
- Radiology Department, Toulouse University Hospital, 1 Avenue du Professeur Jean Poulhes, 31059, Toulouse, France
| | - Lawrence H Schwartz
- Department of Radiology, New York Presbyterian Hospital, Columbia University, New York, NY, USA
| | - Laurent Dercle
- Department of Radiology, New York Presbyterian Hospital, Columbia University, New York, NY, USA.
- UMR 1015, Gustave Roussy Institute, Université Paris-Saclay, Villejuif, 94805, France.
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Yohanathan L, Dossa F, St Germain AT, Golbafian F, Moulton CA, McGilvray ID, Greig PD, Serra S, Wei AC, Jhaveri KS, Gallinger S, Cleary SP. Management and surveillance of non-functional pancreatic neuroendocrine tumours: Retrospective review. Pancreatology 2019; 19:360-366. [PMID: 30803874 DOI: 10.1016/j.pan.2019.02.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 02/11/2019] [Accepted: 02/12/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND /Objective. To determine the outcomes of a non-operative management approach for sporadic, small, non-functional pancreatic neuroendocrine tumours. METHODS A retrospective chart review of patients with non-functional pancreatic neuroendocrine tumours initially managed non-operatively at a single institution was performed. Patients were identified through a search of radiologic reports, and individuals with ≥2 cross-sectional imaging studies performed >6 months apart from Jan. 1, 2000 to Dec. 31, 2013 were included. Data on tumour size, radiologic characteristics at diagnosis, interval radiologic growth, and surgical outcomes were recorded. RESULTS Over the thirteen-year study period, 95 patients met inclusion criteria and were followed radiologically for a median of 36 months (18-69 months). Median initial tumour size on first imaging was 14.0 mm (IQR 10-19 mm). Median overall tumour growth rate was 0.03 mm/month (IQR: 0.00-0.14 mm/month). There was no significant relationship between initial tumour size and growth rate for tumours ≤ 2 cm or for lesions between 2 and 4 cm. Thirteen (14%) patients initially managed non-operatively underwent resection during the follow-up period. Reasons for surgery included interval tumour growth, patient anxiety or preference, or diagnostic uncertainty. Median time to surgery was 14 months (IQR 8-19 months). No patients progressed beyond resectability or developed metastatic disease during the observation period. CONCLUSION For patients with sporadic, small, non-functional pancreatic neuroendocrine tumours, radiologic surveillance appears to be a safe initial approach to management.
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Affiliation(s)
- Lavanya Yohanathan
- Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Fahima Dossa
- Division of General Surgery, University of Toronto, Toronto, ON, Canada
| | | | | | - Carol-Anne Moulton
- Division of General Surgery, University of Toronto, Toronto, ON, Canada; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Ian D McGilvray
- Division of General Surgery, University of Toronto, Toronto, ON, Canada; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Paul D Greig
- Division of General Surgery, University of Toronto, Toronto, ON, Canada; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Stefano Serra
- Department of Pathology, University Health Network/University of Toronto, Canada
| | - Alice C Wei
- Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Kartik S Jhaveri
- Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital and Women's College Hospital, University of Toronto, Toronto, ON, Canada
| | - Steve Gallinger
- Division of General Surgery, University of Toronto, Toronto, ON, Canada; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Sean P Cleary
- Division of General Surgery, University of Toronto, Toronto, ON, Canada; Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
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Treatment challenges in and outside a network setting: Gastrointestinal neuroendocrine tumours. Eur J Surg Oncol 2019; 45:52-59. [DOI: 10.1016/j.ejso.2018.03.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 03/14/2018] [Indexed: 01/06/2023] Open
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Franco Machado J, Silva RD, Melo R, G Correia JD. Less Exploited GPCRs in Precision Medicine: Targets for Molecular Imaging and Theranostics. Molecules 2018; 24:E49. [PMID: 30583594 PMCID: PMC6337414 DOI: 10.3390/molecules24010049] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 12/07/2018] [Accepted: 12/09/2018] [Indexed: 12/18/2022] Open
Abstract
Precision medicine relies on individually tailored therapeutic intervention taking into account individual variability. It is strongly dependent on the availability of target-specific drugs and/or imaging agents that recognize molecular targets and patient-specific disease mechanisms. The most sensitive molecular imaging modalities, Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), rely on the interaction between an imaging radioprobe and a target. Moreover, the use of target-specific molecular tools for both diagnostics and therapy, theranostic agents, represent an established methodology in nuclear medicine that is assuming an increasingly important role in precision medicine. The design of innovative imaging and/or theranostic agents is key for further accomplishments in the field. G-protein-coupled receptors (GPCRs), apart from being highly relevant drug targets, have also been largely exploited as molecular targets for non-invasive imaging and/or systemic radiotherapy of various diseases. Herein, we will discuss recent efforts towards the development of innovative imaging and/or theranostic agents targeting selected emergent GPCRs, namely the Frizzled receptor (FZD), Ghrelin receptor (GHSR-1a), G protein-coupled estrogen receptor (GPER), and Sphingosine-1-phosphate receptor (S1PR). The pharmacological and clinical relevance will be highlighted, giving particular attention to the studies on the synthesis and characterization of targeted molecular imaging agents, biological evaluation, and potential clinical applications in oncology and non-oncology diseases. Whenever relevant, supporting computational studies will be also discussed.
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Affiliation(s)
- João Franco Machado
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
- Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal.
| | - Rúben D Silva
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
| | - Rita Melo
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
- Center for Neuroscience and Cell Biology; Rua Larga, Faculdade de Medicina, Polo I, 1ºandar, Universidade de Coimbra, 3004-504 Coimbra, Portugal.
| | - João D G Correia
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
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Rosenkranz AA, Slastnikova TA, Karmakova TA, Vorontsova MS, Morozova NB, Petriev VM, Abrosimov AS, Khramtsov YV, Lupanova TN, Ulasov AV, Yakubovskaya RI, Georgiev GP, Sobolev AS. Antitumor Activity of Auger Electron Emitter 111In Delivered by Modular Nanotransporter for Treatment of Bladder Cancer With EGFR Overexpression. Front Pharmacol 2018; 9:1331. [PMID: 30510514 PMCID: PMC6252321 DOI: 10.3389/fphar.2018.01331] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 10/29/2018] [Indexed: 12/18/2022] Open
Abstract
Gamma-ray emitting 111In, which is extensively used for imaging, is also a source of short-range Auger electrons (AE). While exhibiting negligible effect outside cells, these AE become highly toxic near DNA within the cell nucleus. Therefore, these radionuclides can be used as a therapeutic anticancer agent if delivered precisely into the nuclei of tumor target cells. Modular nanotransporters (MNTs) designed to provide receptor-targeted delivery of short-range therapeutic cargoes into the nuclei of target cells are perspective candidates for specific intracellular delivery of AE emitters. The objective of this study was to evaluate the in vitro and in vivo efficacy of 111In attached MNTs to kill human bladder cancer cells overexpressing epidermal growth factor receptor (EGFR). The cytotoxicity of 111In delivered by the EGFR-targeted MNT (111In-MNT) was greatly enhanced on EJ-, HT-1376-, and 5637-expressing EGFR bladder cancer cell lines compared with 111In non-targeted control. In vivo microSPECT/CT imaging and antitumor efficacy studies revealed prolonged intratumoral retention of 111In-MNT with t½ = 4.1 ± 0.5 days as well as significant dose-dependent tumor growth delay (up to 90% growth inhibition) after local infusion of 111In-MNT in EJ xenograft-bearing mice.
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Affiliation(s)
- Andrey A Rosenkranz
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.,Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
| | | | - Tatiana A Karmakova
- National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Maria S Vorontsova
- National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Natalia B Morozova
- National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | - Vasiliy M Petriev
- National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation, Moscow, Russia.,National Research Nuclear University MEPhI (Moscow Engineering Physics Institute), Moscow, Russia
| | | | - Yuri V Khramtsov
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | | | - Alexey V Ulasov
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - Raisa I Yakubovskaya
- National Medical Research Radiology Center of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
| | | | - Alexander S Sobolev
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.,Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
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Lee L, Ito T, Jensen RT. Imaging of pancreatic neuroendocrine tumors: recent advances, current status, and controversies. Expert Rev Anticancer Ther 2018; 18:837-860. [PMID: 29973077 PMCID: PMC6283410 DOI: 10.1080/14737140.2018.1496822] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Recently, there have been a number of advances in imaging pancreatic neuroendocrine tumors (panNETs), as well as other neuroendocrine tumors (NETs), which have had a profound effect on the management and treatment of these patients, but in some cases are also associated with controversies. Areas covered: These advances are the result of numerous studies attempting to better define the roles of both cross-sectional imaging, endoscopic ultrasound, with or without fine-needle aspiration, and molecular imaging in both sporadic and inherited panNET syndromes; the increased attempt to develop imaging parameters that correlate with tumor classification or have prognostic value; the rapidly increasing use of molecular imaging in these tumors and the attempt to develop imaging parameters that correlate with treatment/outcome results. Each of these areas and the associated controversies are reviewed. Expert commentary: There have been numerous advances in all aspects of the imaging of panNETs, as well as other NETs, in the last few years. The advances are leading to expanded roles of imaging in the management of these patients and the results being seen in panNETs/GI-NETs with these newer techniques are already being used in more common tumors.
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Affiliation(s)
- Lingaku Lee
- a Department of Medicine and Bioregulatory Science , Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan
- b Digestive Diseases Branch , NIDDK, NIH , Bethesda , MD , USA
| | - Tetsuhide Ito
- c Neuroendocrine Tumor Centra, Fukuoka Sanno Hospital International University of Health and Welfare 3-6-45 Momochihama , Sawara-Ku, Fukuoka , Japan
| | - Robert T Jensen
- b Digestive Diseases Branch , NIDDK, NIH , Bethesda , MD , USA
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Norlén O, Montan H, Hellman P, Stålberg P, Sundin A. Preoperative 68Ga-DOTA-Somatostatin Analog-PET/CT Hybrid Imaging Increases Detection Rate of Intra-abdominal Small Intestinal Neuroendocrine Tumor Lesions. World J Surg 2018; 42:498-505. [PMID: 29159606 PMCID: PMC5762814 DOI: 10.1007/s00268-017-4364-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Background Small intestinal neuroendocrine tumors (SI-NETs) are the most common form of neoplasm in the small bowel. Radiological identification of primary tumors (PT), which may be multiple, is difficult, and therefore palpation of the entire small bowel is routinely performed during laparotomy. The aim was to determine detection rates of PT and peritoneal carcinomatosis (PC) with 68Ga-DOTATOC/TATE-PET/CT in comparison with i.v. contrast-enhanced computed tomography (CE-CT) and thus to clarify whether modern functional imaging can mitigate the need for palpation of bowel during surgery enabling oncologically adequate laparoscopic resection. Methods A total of 28 patients with SI-NET who preoperatively underwent both 68Ga-DOTATOC/TATE-PET/CT and CE-CT were included. The detection rates of PT and PC for PET/CT and CE-CT were compared to the findings in the surgical and histopathological reports. Appropriate statistical tests were used, and significance was set to p < 0.05. Results Out of 82 PT, 43 PT were not detected by any imaging modality. More PT lesions were detected with PET/CT (n = 39 [47.5%]) than with CE-CT (n = 10 [12.2%], p < 0.001). Also, PET/CT identified significantly more PC lesions than CE-CT (78 and 38%, p = 0.004, respectively). Conclusion PET/CT detected more PT and PC lesions than CE-CT. Some PTs and PC lesions were only detected by one of the modalities, and CT performed in conjunction with PET/CT should therefore be performed as a fully diagnostic CE-CT for optimal results. Palpation of the small bowel remains crucial during surgery in these patients because several PTs escaped detection by both PET/CT and CE-CT.
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Affiliation(s)
- Olov Norlén
- Department of Surgery, Institute of Surgical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Harald Montan
- Department of Radiology and Molecular Imaging, Institute of Surgical Sciences, Uppsala University Hospital, Uppsala University, 751 85, Uppsala, Sweden
| | - Per Hellman
- Department of Surgery, Institute of Surgical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Peter Stålberg
- Department of Surgery, Institute of Surgical Sciences, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Anders Sundin
- Department of Radiology and Molecular Imaging, Institute of Surgical Sciences, Uppsala University Hospital, Uppsala University, 751 85, Uppsala, Sweden.
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Amair-Pinedo F, Matos I, Saurí T, Hernando J, Capdevila J. The Treatment Landscape and New Opportunities of Molecular Targeted Therapies in Gastroenteropancreatic Neuroendocrine Tumors. Target Oncol 2018; 12:757-774. [PMID: 29143176 DOI: 10.1007/s11523-017-0532-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that originate from neuroendocrine stem cells and express both neural and endocrine markers. They are found in almost every organ, and while NENs are mostly associated with slow growth, complications due to the uncontrolled secretion of active peptides, and metastatic disease, may significantly impair the quality of life and can ultimately lead to the death of affected individuals. Expanding knowledge of the genetic, epigenetic, and proteomic landscapes of NENs has led to a better understanding of their molecular pathology and consequently increased treatment options for patients. Here, we review the principal breakthroughs in NEN treatment management, owing largely to omics technologies over the last few years, current recommendations of systemic treatment, and ongoing research into the identification of predictive and response biomarkers based on molecular targeted therapies.
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Affiliation(s)
| | - Ignacio Matos
- Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Tamara Saurí
- Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Jorge Hernando
- Vall d'Hebron University Hospital, Barcelona, Spain.,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Jaume Capdevila
- Vall d'Hebron University Hospital, Barcelona, Spain. .,Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
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Evaluation of HER2-specific peptide ligand for its employment as radiolabeled imaging probe. Sci Rep 2018; 8:2998. [PMID: 29445216 PMCID: PMC5812989 DOI: 10.1038/s41598-018-21283-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 02/01/2018] [Indexed: 01/19/2023] Open
Abstract
HER2 transmembrane receptor is an important target in immunotherapy treatment of breast and gastroesophageal cancer. Molecular imaging of HER2 expression may provide essential prognostic and predictive information concerning disseminated cancer and aid in selection of an optimal therapy. Radiolabeled low molecular weight peptide ligands are particularly attractive as probes for molecular imaging, since they reach and bind to the target and clear from non-target organs and blood stream faster than bulky antibodies. In this study, we evaluated a potential HER2-imaging probe, an A9 nonapeptide, derived from the trastuzumab-Fab portion. Its cellular uptake was investigated by mass spectrometry analysis of the cytoplasmic cellular extracts. Moreover, based on in-silico modeling, DTPA chelator was conjugated to N-terminus of A9. 111In-labeled A9 demonstrated nanomolar affinity to HER2-expressing BT474 cells and favorable biodistribution profile in NMRI mice. This study suggests that the peptide A9 represents a good lead candidate for development of molecular probe, to be used for imaging purposes and for the delivery of cytotoxic agents.
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Limited Value of Ga-68-DOTATOC-PET-CT in Routine Screening of Patients with Multiple Endocrine Neoplasia Type 1. World J Surg 2018; 41:1521-1527. [PMID: 28138732 DOI: 10.1007/s00268-017-3907-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Routine screening is recommended for patients with multiple endocrine neoplasia type 1 (MEN1) to enable early detection and treatment of associated neuroendocrine neoplasms (NEN). Gallium68-DOTATOC-Positron emission tomography combined with computed tomography (Ga-68-DOTATOC-PET-CT) is a very sensitive and specific imaging technique for the detection of sporadic neuroendocrine tumors. The present study evaluated the value of Ga-68-DOTATOC-PET-CT in routine screening of patients with MEN1. METHODS Between January 2014 and March 2016, all MEN1 patients underwent Ga-68-DOTATOC-PET-CT in addition to conventional imaging (computed tomography of the thorax, magnetic resonance imaging of the abdomen and pituitary, endoscopic ultrasonography). The diagnostic yield of conventional imaging and Ga-68-DOTATOC-PET-CT was prospectively documented and compared, and treatment changes caused by the addition of Ga-68-DOTATOC-PET-CT were recorded. RESULTS Conventional imaging detected 145 NENs, mainly pancreaticoduodenal NENs (n = 117, 81%), in 31 of 33 MEN1 patients. Ga-68-DOTATOC-PET-CT detected 55 NENs in 23 of the 33 patients (p = 0.0001). Ninety (62%) NENs detected by conventional imaging were missed by DOTATOC-PET-CT. The majority of missed lesions were pNEN (n = 68; 74%). The sensitivity of Ga-68-DOTATOC-PET-CT for NENs <5, 5-9, 10-19 and ≥20 mm was 0, 29, 81 and 100%, respectively. However, Ga-68-DOTATOC-PET-CT detected more liver and lymph node metastases in patients with known metastatic disease, which did not lead to a change of patients' management. In one patient (3%), Ga-68-DOTATOC-PET-CT was the only imaging modality that detected a small intestine NEN and led to potentially curative surgery. CONCLUSION Ga-68-DOTATOC-PET-CT cannot be recommended for routine screening of MEN1 patients. It might provide important additional information in patients with suspected or known metastatic disease.
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47
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Raphael MJ, Chan DL, Law C, Singh S. Principles of diagnosis and management of neuroendocrine tumours. CMAJ 2017; 189:E398-E404. [PMID: 28385820 DOI: 10.1503/cmaj.160771] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Michael J Raphael
- Departments of Medicine (Raphael, Chan, Singh) and Surgery (Law), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont
| | - David L Chan
- Departments of Medicine (Raphael, Chan, Singh) and Surgery (Law), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont
| | - Calvin Law
- Departments of Medicine (Raphael, Chan, Singh) and Surgery (Law), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont
| | - Simron Singh
- Departments of Medicine (Raphael, Chan, Singh) and Surgery (Law), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ont.
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Manoharan J, Albers MB, Bartsch DK. The future: diagnostic and imaging advances in MEN1 therapeutic approaches and management strategies. Endocr Relat Cancer 2017; 24:T209-T225. [PMID: 28790162 DOI: 10.1530/erc-17-0231] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 08/08/2017] [Indexed: 12/13/2022]
Abstract
Prospective randomized data are lacking, but current clinical expert guidelines recommend annual screening examinations, including laboratory assessments and various imaging modalities (e.g. CT, MRI, scintigraphy and EUS) for patients with multiple endocrine neoplasia type 1 (MEN1). Routine screening is proposed to detect and localize neuroendocrine manifestations as early as possible. The goal is timely intervention to improve quality of life and to increase life expectancy by preventing the development of life-threatening hormonal syndromes and/or metastatic disease. In recent years, some studies compared different and new imaging methods regarding their sensitivity and utility in MEN1 patients. This present article reviews the proposed diagnostic tools for MEN1 screening as well as potential future perspectives.
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Affiliation(s)
- Jerena Manoharan
- Department of VisceralThoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Max B Albers
- Department of VisceralThoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Detlef K Bartsch
- Department of VisceralThoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
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Thuillier P, Bourhis D, Robin P, Keromnes N, Schick U, Le Roux PY, Kerlan V, Chaumet-Riffaud P, Salaün PY, Abgral R. Clinical Validation of a Pixon-Based Reconstruction Method Allowing a Twofold Reduction in Planar Images Time of 111In-Pentetreotide Somatostatin Receptor Scintigraphy. Front Med (Lausanne) 2017; 4:143. [PMID: 28913338 PMCID: PMC5583596 DOI: 10.3389/fmed.2017.00143] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 08/11/2017] [Indexed: 12/24/2022] Open
Abstract
Objective Methods Results Conclusion
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Affiliation(s)
- Philippe Thuillier
- Department of Endocrinology, University Hospital of Brest, Brest, France
| | - David Bourhis
- Department of Nuclear Medicine, University Hospital of Brest, Brest, France
- EA GETBO 3878, IFR 148, University Hospital of Brest, Brest, France
| | - Philippe Robin
- Department of Nuclear Medicine, University Hospital of Brest, Brest, France
- EA GETBO 3878, IFR 148, University Hospital of Brest, Brest, France
| | - Nathalie Keromnes
- Department of Nuclear Medicine, University Hospital of Brest, Brest, France
- EA GETBO 3878, IFR 148, University Hospital of Brest, Brest, France
| | - Ulrike Schick
- Department of Oncology-Radiotherapy, University Hospital of Brest, Brest, France
| | - Pierre-Yves Le Roux
- Department of Nuclear Medicine, University Hospital of Brest, Brest, France
- EA GETBO 3878, IFR 148, University Hospital of Brest, Brest, France
| | - Véronique Kerlan
- Department of Endocrinology, University Hospital of Brest, Brest, France
- EA GETBO 3878, IFR 148, University Hospital of Brest, Brest, France
| | - Philippe Chaumet-Riffaud
- Department of Nuclear Medicine, University Hospital of Paris-Sud Bicêtre, Le Kremlin-Bicêtre, France
| | - Pierre-Yves Salaün
- Department of Nuclear Medicine, University Hospital of Brest, Brest, France
- EA GETBO 3878, IFR 148, University Hospital of Brest, Brest, France
| | - Ronan Abgral
- Department of Nuclear Medicine, University Hospital of Brest, Brest, France
- EA GETBO 3878, IFR 148, University Hospital of Brest, Brest, France
- *Correspondence: Ronan Abgral,
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Bailly C, Bodet-Milin C, Rousseau C, Faivre-Chauvet A, Kraeber-Bodéré F, Barbet J. Pretargeting for imaging and therapy in oncological nuclear medicine. EJNMMI Radiopharm Chem 2017; 2:6. [PMID: 29503847 PMCID: PMC5824696 DOI: 10.1186/s41181-017-0026-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 05/24/2017] [Indexed: 12/27/2022] Open
Abstract
Background Oncological pretargeting has been implemented and tested in several different ways in preclinical models and clinical trials over more than 30 years. Despite highly promising results, pretargeting has not achieved market approval even though it could be considered the ultimate theranostic, combining PET imaging with short-lived positron emitters and therapy with radionuclides emitting beta or alpha particles. Results We have reviewed the pretargeting approaches proposed over the years, discussing their suitability for imaging, particularly PET imaging, and therapy, as well as their limitations. The reviewed pretargeting modalities are the avidin-biotin system, bispecific anti-tumour x anti-hapten antibodies and bivalent haptens, antibody-oligonucleotide conjugates and radiolabelled complementary oligonucleotides, and approaches using click chemistry. Finally, we discuss recent developments, such as the use of small binding proteins for pretargeting that may offer new perspectives to cancer pretargeting. Conclusions While pretargeting has shown promise and demonstrated preclinical and clinical proof of principle, full-scale clinical development programs are needed to translate pretargeting into a clinical reality that could ideally fit into current theranostic and precision medicine perspectives.
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Affiliation(s)
- Clément Bailly
- 1Service de Médecine Nucléaire, CHU de Nantes, Nantes, France.,3Centre de Recherche en Cancérologie Nantes/Angers (CRCNA), Nantes, France.,6299 CNRS, Nantes, France.,UMR892 Inserm, Nantes, France.,6Université de Nantes, Nantes, France
| | - Caroline Bodet-Milin
- 1Service de Médecine Nucléaire, CHU de Nantes, Nantes, France.,3Centre de Recherche en Cancérologie Nantes/Angers (CRCNA), Nantes, France.,6299 CNRS, Nantes, France.,UMR892 Inserm, Nantes, France.,6Université de Nantes, Nantes, France
| | - Caroline Rousseau
- 2Service de Médecine Nucléaire, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.,3Centre de Recherche en Cancérologie Nantes/Angers (CRCNA), Nantes, France.,6299 CNRS, Nantes, France.,UMR892 Inserm, Nantes, France.,6Université de Nantes, Nantes, France
| | - Alain Faivre-Chauvet
- 1Service de Médecine Nucléaire, CHU de Nantes, Nantes, France.,3Centre de Recherche en Cancérologie Nantes/Angers (CRCNA), Nantes, France.,6299 CNRS, Nantes, France.,UMR892 Inserm, Nantes, France.,6Université de Nantes, Nantes, France
| | - Françoise Kraeber-Bodéré
- 1Service de Médecine Nucléaire, CHU de Nantes, Nantes, France.,2Service de Médecine Nucléaire, Institut de Cancérologie de l'Ouest, Saint-Herblain, France.,3Centre de Recherche en Cancérologie Nantes/Angers (CRCNA), Nantes, France.,6299 CNRS, Nantes, France.,UMR892 Inserm, Nantes, France.,6Université de Nantes, Nantes, France
| | - Jacques Barbet
- 6Université de Nantes, Nantes, France.,GIP Arronax, 1, rue Arronax, 44187 Saint-Herblain cedex, France
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