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Küppers F, Kassem M, Yun SD, Stoffels G, Filß C, Galldiks N, Mottaghy FM, Kooi ME, Langen KJ, Lohmann P, Shah NJ. Brain Tumor Characterization Using Multiple MR Parameters From Multi-Contrast EPI With Keyhole (GE-SE EPIK) Including Oxygen Extraction Fraction: A Comparison to O-(2-[18F]Fluoroethyl)-L-Tyrosine (FET) Positron Emission Tomography. J Magn Reson Imaging 2025. [PMID: 40243088 DOI: 10.1002/jmri.29795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 04/01/2025] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Tumor characterization and treatment efficacy are associated with tissue hypoxia. MR-derived oxygen extraction fraction (OEF) may offer valuable tumor insights but depends on multiple measurement parameters, often requiring multiple sequence acquisitions. Specific multi-parametric sequences offer direct access to MR parameter sets within short acquisition times. PURPOSE To evaluate the potential of gradient-echo spin-echo echo-planar imaging with keyhole (GE-SE EPIK)-derived parameters (OEF/T2/T2*/venous cerebral blood volume (vCBV)) to characterize increased metabolic activity tissue identified in [18F]fluoroethyl-L-tyrosine (FET) PET, serving as a surrogate for neoplastic tissue. STUDY TYPE Retrospective. POPULATION Fifty-seven brain tumor patients (female/male:31/26; age 27-73 years) with 66 histologically confirmed lesions (suspected glioblastoma (16), glioblastoma (28), astrocytoma (11), metastasis (6), oligodendroglioma (5)). FIELD STRENGTH/SEQUENCE 10-echo GE-SE EPIK sequence at 3 T. ASSESSMENT GE-SE EPIK data were acquired in a hybrid MR PET scanner during FET PET acquisitions. Two tumor segmentations based on FET-PET uptake and FLAIR hyperintensities were manually created. Mean GE-SE EPIK-derived parameters were calculated within tumor regions and compared to contralateral reference values. Relative tumor-to-reference parameters were compared across tumor types. STATISTICAL TESTS One/two-sampled, two-tailed t-tests of mean relative MR-derived parameters. p-value < 0.05 was considered significant. RESULTS Significantly increased T2/T2* and decreased vCBV/OEF were found in FET-PET and FLAIR-derived VOIs. Latter showed decreased R2'. Significant correlation between FET uptake and T2/T2* was found in FET-VOIs (Pearson correlation: 0.26/0.31, respectively). Oligodendrogliomas showed significant differences to glioblastomas (rR2', rOEF) and astrocytomas (rR2'). Metastasis showed different rT2 values than suspected gliomas. Astrocytoma differed from gliomas in FET-TBR. Susceptibility artifacts in T2* maps from air-tissue interfaces limited qualitative data interpretation. DATA CONCLUSION GE-SE EPIK provides multiple MR parameters that are sensitive to expected changes in tumor regions obtained from FET and FLAIR thresholds. Susceptibility artifacts in T2*/OEF maps made the differentiation between tumor relapse and treatment-related changes challenging. However, certain MR-derived parameters showed the ability to distinguish tumor types. EVIDENCE LEVEL 3. TECHNICAL EFFICACY Stage 2.
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Affiliation(s)
- Fabian Küppers
- Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich, Jülich, Germany
| | - Mohamed Kassem
- Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich, Jülich, Germany
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
| | - Seong Dae Yun
- Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich, Jülich, Germany
| | - Gabriele Stoffels
- Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich, Jülich, Germany
| | - Christian Filß
- Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich, Jülich, Germany
- Department of Nuclear Medicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Norbert Galldiks
- Department of Neurology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Institute of Neuroscience and Medicine 3, Forschungszentrum Jülich, Jülich, Germany
- Center of Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Bonn, Germany
| | - Felix M Mottaghy
- Department of Nuclear Medicine, RWTH Aachen University Hospital, Aachen, Germany
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center (MUMC+), Maastricht, the Netherlands
| | - M Eline Kooi
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center (MUMC+), Maastricht, the Netherlands
| | - Karl-Josef Langen
- Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich, Jülich, Germany
- Department of Nuclear Medicine, RWTH Aachen University Hospital, Aachen, Germany
| | - Philipp Lohmann
- Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich, Jülich, Germany
| | - N Jon Shah
- Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich, Jülich, Germany
- Institute of Neuroscience and Medicine 11, Forschungszentrum Jülich, Jülich, Germany
- JARA-BRAIN-Translational Medicine, Aachen, Germany
- Department of Neurology, RWTH Aachen University Hospital, Aachen, Germany
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Zhu J, Pan F, Cai H, Pan L, Li Y, Li L, Li Y, Wu X, Fan H. Positron emission tomography imaging of lung cancer: An overview of alternative positron emission tomography tracers beyond F18 fluorodeoxyglucose. Front Med (Lausanne) 2022; 9:945602. [PMID: 36275809 PMCID: PMC9581209 DOI: 10.3389/fmed.2022.945602] [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: 05/16/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
Lung cancer has been the leading cause of cancer-related mortality in China in recent decades. Positron emission tomography-computer tomography (PET/CT) has been established in the diagnosis of lung cancer. 18F-FDG is the most widely used PET tracer in foci diagnosis, tumor staging, treatment planning, and prognosis assessment by monitoring abnormally exuberant glucose metabolism in tumors. However, with the increasing knowledge on tumor heterogeneity and biological characteristics in lung cancer, a variety of novel radiotracers beyond 18F-FDG for PET imaging have been developed. For example, PET tracers that target cellular proliferation, amino acid metabolism and transportation, tumor hypoxia, angiogenesis, pulmonary NETs and other targets, such as tyrosine kinases and cancer-associated fibroblasts, have been reported, evaluated in animal models or under clinical investigations in recent years and play increasing roles in lung cancer diagnosis. Thus, we perform a comprehensive literature review of the radiopharmaceuticals and recent progress in PET tracers for the study of lung cancer biological characteristics beyond glucose metabolism.
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Affiliation(s)
- Jing Zhu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China,Respiratory and Critical Care Medicine, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China,NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Fei Pan
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Huawei Cai
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lili Pan
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yalun Li
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Li
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - YunChun Li
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China,Department of Nuclear Medicine, The Second People’s Hospital of Yibin, Yibin, China
| | - Xiaoai Wu
- Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, China,Xiaoai Wu,
| | - Hong Fan
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Hong Fan,
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Horsman MR, Wittenborn TR, Nielsen PS, Elming PB. Tumors Resistant to Checkpoint Inhibitors Can Become Sensitive after Treatment with Vascular Disrupting Agents. Int J Mol Sci 2020; 21:ijms21134778. [PMID: 32640548 PMCID: PMC7370297 DOI: 10.3390/ijms21134778] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/29/2020] [Accepted: 07/03/2020] [Indexed: 12/17/2022] Open
Abstract
Immune therapy improves cancer outcomes, yet many patients do not respond. This pre-clinical study investigated whether vascular disrupting agents (VDAs) could convert an immune unresponsive tumor into a responder. CDF1 mice, with 200 mm3 C3H mammary carcinomas in the right rear foot, were intraperitoneally injected with combretastatin A-4 phosphate (CA4P), its A-1 analogue OXi4503, and/or checkpoint inhibitors (anti-PD-1, PD-L1, or CTLA-4 antibodies), administered twice weekly for two weeks. Using the endpoint of tumor growth time (TGT5; time to reach five times the starting volume), we found that none of the checkpoint inhibitors (10 mg/kg) had any effect on TGT5 compared to untreated controls. However, CA4P (100 mg/kg) or OXi4503 (5–50 mg/kg) did significantly increase TGT5. This further significantly increased by combining the VDAs with checkpoint inhibitors, but was dependent on the VDA, drug dose, and inhibitor. For CA4P, a significant increase was found when CA4P (100 mg/kg) was combined with anti-PD-L1, but not with the other two checkpoint inhibitors. With OXi4503 (50 mg/kg), a significant enhancement occurred when combined with anti-PD-L1 or anti-CTLA-4, but not anti-PD-1. We observed no significant improvement with lower OXi4503 doses (5–25 mg/kg) and anti-CTLA-4, although 30% of tumors were controlled at the 25 mg/kg dose. Histological assessment of CD4/CD8 expression actually showed decreased levels up to 10 days after treatment with OXi4503 (50 mg/kg). Thus, the non-immunogenic C3H mammary carcinoma was unresponsive to checkpoint inhibitors, but became responsive in mice treated with VDAs, although the mechanism remains unclear.
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Affiliation(s)
- Michael R. Horsman
- Experimental Clinical Oncology-Department of Oncology, Aarhus University Hospital, DK-8200 Aarhus, Denmark; (T.R.W.); (P.B.E.)
- Correspondence: ; Tel.: +45-78454973
| | - Thomas R. Wittenborn
- Experimental Clinical Oncology-Department of Oncology, Aarhus University Hospital, DK-8200 Aarhus, Denmark; (T.R.W.); (P.B.E.)
| | - Patricia S. Nielsen
- Department of Pathology, Aarhus University Hospital, DK-8200 Aarhus, Denmark;
| | - Pernille B. Elming
- Experimental Clinical Oncology-Department of Oncology, Aarhus University Hospital, DK-8200 Aarhus, Denmark; (T.R.W.); (P.B.E.)
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Müller J, Schürer M, Neubert C, Tillner F, Beyreuther E, Suckert T, Peters N, von Neubeck C, Lühr A, Krause M, Bütof R, Dietrich A. Multi-modality bedding platform for combined imaging and irradiation of mice. Biomed Phys Eng Express 2020; 6:037003. [PMID: 33438682 DOI: 10.1088/2057-1976/ab79f1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Preclinical imaging and irradiation yields valuable insights into clinically relevant research topics. While complementary imaging methods such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) can be combined within single devices, this is technically demanding and cost-intensive. Similarly, bedding and setup solutions are often specific to certain devices and research questions. We present a bedding platform for mice that is compatible with various preclinical imaging modalities (combined PET/MRI, cone beam CT) and irradiation with photons and protons. It consists of a 3D-printed bedding unit (acrylonitrile butadiene styrene, ABS) holding the animal and features an inhalation anesthesia mask, jaw fixation, ear pins, and immobilization for the hind leg. It can be embedded on mounting adaptors for multi-modal imaging and into a transport box (polymethyl methacrylate, PMMA) for experiments outside dedicated animal facilities while maintaining the animal's hygiene status. A vital support unit provides heating, inhalation anesthesia, and a respiration monitor. We dosimetrically evaluated used materials in order to assess their interaction with incident irradiation. Proof-of-concept multi-modal imaging protocols were used on phantoms and mice. The measured attenuation of the bedding unit for 40/60/80/200 kV X-rays was less than 3%. The measured stopping-power-ratio of ABS was 0.951, the combined water-equivalent thickness of bedding unit and transport box was 4.2 mm for proton energies of 150 MeV and 200 MeV. Proof-of-concept imaging showed no loss of image quality. Imaging data of individual mice from different imaging modalities could be aligned rigidly. The presented bed aims to provide a platform for experiments related to both multi-modal imaging and irradiation, thus offering the possibility for image-guided irradiation which relies on precise imaging and positioning. The usage as a self-contained, stand-alone unit outside dedicated animal facilities represents an advantage over setups designed for specific devices.
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Affiliation(s)
- Johannes Müller
- OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany. Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Institute of Radiooncology-OncoRay, Germany
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The Effect of Carbogen Breathing on 18F-FDG Uptake in Non-Small-Cell Lung Cancer. BIOMED RESEARCH INTERNATIONAL 2019; 2019:2920169. [PMID: 31886195 PMCID: PMC6893244 DOI: 10.1155/2019/2920169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 03/20/2019] [Accepted: 11/04/2019] [Indexed: 12/19/2022]
Abstract
It has been reported that 18F-FDG uptake is higher in hypoxic cancer cells than in well-oxygenated cells. We demonstrated that 18F-FDG uptake in lung cancer would be affected by high concentration oxygen breathing. Methods. Overnight fasted non-small-cell lung cancer A549 subcutaneous (s.c.) xenografts bearing mice (n = 10) underwent 18F-FDG micro-PET scans, animals breathed room air on day 1, and same animals breathed carbogen (95% O2 + 5% CO2) on the subsequent day. In separated studies, autoradiography and immunohistochemical staining visualization of frozen section of A549 s.c. tumors were applied, and to compare between carbogen-breathing mice and those with air breathing, a combination of 18F-FDG and hypoxia marker pimonidazole was injected 1 h before animal sacrifice, and 18F-FDG accumulation was compared with pimonidazole binding and glucose transporter 1 (GLUT-1) expression. Results. PET studies revealed that tumor 18F-FDG uptake was significantly decreased in carbogen-breathing mice than those with air breathing (P < 0.05). Ex vivo studies confirmed that carbogen breathing significantly decreased hypoxic fraction detected by pimonidazole staining, referring to GLUT-1 expression, and significantly decreased 18F-FDG accumulation in tumors. Conclusions. High concentration of O2 breathing during 18F-FDG uptake phase significantly decreases 18F-FDG uptake in non-small-cell lung cancer A549 xenografts growing in mice.
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How to Modulate Tumor Hypoxia for Preclinical In Vivo Imaging Research. CONTRAST MEDIA & MOLECULAR IMAGING 2018; 2018:4608186. [PMID: 30420794 PMCID: PMC6211155 DOI: 10.1155/2018/4608186] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/24/2018] [Accepted: 08/13/2018] [Indexed: 01/20/2023]
Abstract
Tumor hypoxia is related with tumor aggressiveness, chemo- and radiotherapy resistance, and thus a poor clinical outcome. Therefore, over the past decades, every effort has been made to develop strategies to battle the negative prognostic influence of tumor hypoxia. For appropriate patient selection and follow-up, noninvasive imaging biomarkers such as positron emission tomography (PET) radiolabeled ligands are unprecedentedly needed. Importantly, before being able to implement these new therapies and potential biomarkers into the clinical setting, preclinical in vivo validation in adequate animal models is indispensable. In this review, we provide an overview of the different attempts that have been made to create differential hypoxic in vivo cancer models with a particular focus on their applicability in PET imaging studies.
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Horsman MR. Enhancing the radiation response of tumors but not early or late responding normal tissues using a vascular disrupting agent. Acta Oncol 2017; 56:1634-1638. [PMID: 28838284 DOI: 10.1080/0284186x.2017.1348629] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Vascular disrupting agents (VDAs) damage tumor vasculature and enhance tumor radiation response. In this pre-clinical study, we combined radiation with the leading VDA in clinical development, combretastatin A-4 phosphate (CA4P), and compared the effects seen in tumors and relevant normal tissues. MATERIAL AND METHODS Radiation was applied locally to tissues in CDF1 mice to produce full radiation dose-response curves. CA4P (250 mg/kg) was intraperitoneally (i.p.) injected within 30 minutes after irradiating. Response of 200 mm3 foot implanted C3H mammary carcinomas was assessed using percent tumor control at 90 days. Normal tissue effects were evaluated using early responding skin (development of moist desquamation in the foot at 11-30 days), and late responding bladder (50% reduction in reservoir function estimated by cystometry up to 9 months after treatment), and lung (20% increase in ventilation rate measured by plethysmography within 9 months). A Chi-squared test was used for statistical comparisons (significance level of p < .05). RESULTS The radiation dose controlling 50% of irradiated tumors was 52 Gy. This significantly decreased to 45 Gy with CA4P. The radiation doses inducing a change in skin, bladder and lung response in 50% of mice were 31 Gy, 14 Gy and 12 Gy, respectively. CA4P had no significant effect on the radiation response of any of these normal tissues. CONCLUSIONS VDAs significantly enhance tumor radiation response, but had absolutely no effect on the radiation response of early or late responding normal tissues.
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Affiliation(s)
- Michael R. Horsman
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
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De Bruycker S, Vangestel C, Van den Wyngaert T, Wyffels L, Wouters A, Pauwels P, Staelens S, Stroobants S. Baseline [(18)F]FMISO μPET as a Predictive Biomarker for Response to HIF-1α Inhibition Combined with 5-FU Chemotherapy in a Human Colorectal Cancer Xenograft Model. Mol Imaging Biol 2017; 18:606-16. [PMID: 26728163 DOI: 10.1007/s11307-015-0926-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE The purpose of this study was to characterize imaging biomarkers for the potential benefit of hypoxia-inducible factor-1 (HIF-1)α inhibition (by PX-12) during 5-fluorouracil (5-FU) chemotherapy in the treatment of colorectal cancer (CRC). PROCEDURES Therapy response to 5-FU ± PX-12 was assessed with baseline [(18)F]fluoromisonidazole ([(18)F]FMISO) and longitudinal 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission computed tomography (μPET/CT) in CRC xenograft model (n = 36) during breathing of a hypoxic (10 % O2) or normoxic (21 % O2) atmosphere. Ex vivo, immunohistochemistry was performed. RESULTS Baseline [(18)F]FMISO uptake and relative tumor volume (RTV) 2 days after 5-FU or 5-FU + PX-12 administration correlated significantly (p ≤ 0.01). Under hypoxic breathing conditions, [(18)F]FDG uptake (-53.1 ± 8.4 %) and Ki67 expression (-16 %) decreased and RTV stagnated in the 5-FU + PX-12 treatment group, but not in 5-FU alone-treated tumors. Under normoxic breathing, [(18)F]FDG uptake (-23.5 ± 15.2 % and -72.8 ± 7.1 %) and Ki67 expression (-5 % and -19 %) decreased and RTV stagnated in both the 5-FU and the combination treatment group, respectively. CONCLUSION Baseline [(18)F]FMISO μPET may predict the beneficial effect of HIF-1α inhibition during 5-FU chemotherapy in CRC.
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Affiliation(s)
- Sven De Bruycker
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium
| | - Christel Vangestel
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium.,Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium
| | - Tim Van den Wyngaert
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium.,Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium
| | - Leonie Wyffels
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium.,Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium
| | - An Wouters
- Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium
| | - Patrick Pauwels
- Center for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium
| | - Steven Staelens
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium
| | - Sigrid Stroobants
- Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, Belgium. .,Department of Nuclear Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.
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Verwer EE, Boellaard R, Veldt AAMVD. Positron emission tomography to assess hypoxia and perfusion in lung cancer. World J Clin Oncol 2014; 5:824-844. [PMID: 25493221 PMCID: PMC4259945 DOI: 10.5306/wjco.v5.i5.824] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 04/29/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023] Open
Abstract
In lung cancer, tumor hypoxia is a characteristic feature, which is associated with a poor prognosis and resistance to both radiation therapy and chemotherapy. As the development of tumor hypoxia is associated with decreased perfusion, perfusion measurements provide more insight into the relation between hypoxia and perfusion in malignant tumors. Positron emission tomography (PET) is a highly sensitive nuclear imaging technique that is suited for non-invasive in vivo monitoring of dynamic processes including hypoxia and its associated parameter perfusion. The PET technique enables quantitative assessment of hypoxia and perfusion in tumors. To this end, consecutive PET scans can be performed in one scan session. Using different hypoxia tracers, PET imaging may provide insight into the prognostic significance of hypoxia and perfusion in lung cancer. In addition, PET studies may play an important role in various stages of personalized medicine, as these may help to select patients for specific treatments including radiation therapy, hypoxia modifying therapies, and antiangiogenic strategies. In addition, specific PET tracers can be applied for monitoring therapy. The present review provides an overview of the clinical applications of PET to measure hypoxia and perfusion in lung cancer. Available PET tracers and their characteristics as well as the applications of combined hypoxia and perfusion PET imaging are discussed.
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Adachi M, Thomas L. Molecular-targeted therapy hypoxia in head and neck squamous cell carcinoma patients. Mol Clin Oncol 2013; 1:12-14. [PMID: 24649115 DOI: 10.3892/mco.2012.17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Accepted: 08/21/2012] [Indexed: 11/05/2022] Open
Abstract
Despite advances in surgical techniques, radiotherapy, and chemotherapy, 5-year survival in patients with late-stage head and neck squamous cell carcinoma (HNSCC) have not improved significantly over the past decades. HNSCC tumors are commonly associated with hypoxia, which is characterized by an acute and/or chronic decline in oxygen tension. Hypoxia is an important cancer-aggravating microenvironmental factor that contributes to malignant behaviors such as acquisition of antiapoptotic ability by cancer cells and tumor progression, invasion, metastasis, and resistance to chemotherapy and radiotherapy. Numerous studies have assessed tumor hypoxia and identified molecular markers that are promising therapeutic targets in HNSCC cases. Moreover, investigators have suggested a number of molecular strategies to target cell processes critical to hypoxia development in HNSCC patients via the direct or indirect regulation of hypoxia-inducible factor-1α expression in cancer cells. In this review, we described recent advances in the identification and development of molecular-targeted therapy targeting hypoxia in HNSCC patients.
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Affiliation(s)
- Makoto Adachi
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ligy Thomas
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Axente M, Lin PS, Pugachev A. Single-fraction simulation of relative cell survival in response to uniform versus hypoxia-targeted dose escalation. Phys Med Biol 2012; 57:2757-74. [DOI: 10.1088/0031-9155/57/9/2757] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Mortensen LS, Buus S, Nordsmark M, Bentzen L, Munk OL, Keiding S, Overgaard J. Identifying hypoxia in human tumors: A correlation study between 18F-FMISO PET and the Eppendorf oxygen-sensitive electrode. Acta Oncol 2010; 49:934-40. [PMID: 20831480 DOI: 10.3109/0284186x.2010.516274] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Polarographic oxygen-sensitive electrodes have demonstrated prognostic significance of hypoxia. However, its routine application is limited. (18)F-FMISO PET scans are a noninvasive approach, able to measure spatial and temporal changes in hypoxia. The aim of this study was to examine the association between measures of hypoxia defined by functional imaging and Eppendorf pO(2) electrodes. MATERIALS AND METHODS A total of 18 patients were included, nine squamous cell carcinoma of the head and neck and nine soft tissue tumors. The tumor volume was defined by CT, MRI, (18)FDG-PET or by clinical examination. The oxygenation status of the tumors was assessed using (18)F-FMISO PET imaging followed by Eppendorf pO(2) electrode measurements. Data were compared in a 'virtual voxel', resulting in individual histograms from each tumor. RESULTS The percentages of pO(2) ≤ 5 mmHg ranged from 9 to 94% (median 43%) for all 18 tumors. For (18)F-FMISO PET the T/M ratio ranged from 0.70 to 2.38 (median 1.13). Analyzing the virtual voxel histograms tumors could be categorized in three groups: Well oxygenated tumors with no hypoxia and concordance between the (18)F-FMISO data and the Eppendorf measurements, hypoxic tumors likewise with concordance between the two assays and inconclusive tumors with no concordance between the assays. CONCLUSION This study analyzed the relationship between (18)F-FMISO PET and Eppendorf pO(2) electrode measurements by use of a virtual voxel model. There was a spectrum of hypoxia among tumors that can be detected by both assays. However no correlation was observed, and in general tumors were more hypoxic based on Eppendorf pO(2) measurements as compared to (18)F-FMISO PET.
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Affiliation(s)
- Lise Saksø Mortensen
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
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Li XF, Ma Y, Sun X, Humm JL, Ling CC, O'Donoghue JA. High 18F-FDG uptake in microscopic peritoneal tumors requires physiologic hypoxia. J Nucl Med 2010; 51:632-8. [PMID: 20351353 DOI: 10.2967/jnumed.109.071233] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
UNLABELLED The objective of this study was to examine (18)F-FDG uptake in microscopic tumors grown intraperitoneally in nude mice and to relate this to physiologic hypoxia and glucose transporter-1 (GLUT-1) expression. METHODS Human colon cancer HT29 and HCT-8 cells were injected intraperitoneally into nude mice to generate disseminated tumors of varying sizes. After overnight fasting, animals, breathing either air or carbogen (95% O(2) + 5% CO(2)), were intravenously administered (18)F-FDG together with the hypoxia marker pimonidazole and cellular proliferation marker bromodeoxyuridine 1 h before sacrifice. Hoechst 33342, a perfusion marker, was administered 1 min before sacrifice. After sacrifice, the intratumoral distribution of (18)F-FDG was assessed by digital autoradiography of frozen tissue sections. Intratumoral distribution was compared with the distributions of pimonidazole, GLUT-1 expression, bromodeoxyuridine, and Hoechst 33342 as visualized by immunofluorescent microscopy. RESULTS Small tumors (diameter, <1 mm) had high (18)F-FDG accumulation and were severely hypoxic, with high GLUT-1 expression. Larger tumors (diameter, 1-4 mm) generally had low (18)F-FDG accumulation and were not significantly hypoxic, with low GLUT-1 expression. Carbogen breathing significantly decreased (18)F-FDG accumulation and tumor hypoxia in microscopic tumors but had little effect on GLUT-1 expression. CONCLUSION There was high (18)F-FDG uptake in microscopic tumors that was spatially associated with physiologic hypoxia and high GLUT-1 expression. This enhanced uptake was abrogated by carbogen breathing, indicating that in the absence of physiologic hypoxia, high GLUT-1 expression, by itself, was insufficient to ensure high (18)F-FDG uptake.
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Affiliation(s)
- Xiao-Feng Li
- Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
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Huchet A, Fernandez P, Allard M, Belkacémi Y, Maire JP, Trouette R, Eimer S, Tourdias T, Loiseau H. Imagerie moléculaire de l’hypoxie tumorale. Cancer Radiother 2009; 13:747-57. [DOI: 10.1016/j.canrad.2009.07.038] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2008] [Revised: 06/05/2009] [Accepted: 07/08/2009] [Indexed: 12/28/2022]
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Li XF, Sun X, Ma Y, Suehiro M, Zhang M, Russell J, Humm JL, Ling CC, O'Donoghue JA. Detection of hypoxia in microscopic tumors using 131I-labeled iodo-azomycin galactopyranoside (131I-IAZGP) digital autoradiography. Eur J Nucl Med Mol Imaging 2009; 37:339-48. [PMID: 19921184 DOI: 10.1007/s00259-009-1310-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2009] [Accepted: 10/21/2009] [Indexed: 12/17/2022]
Abstract
PURPOSE Previous studies have shown that tumors less than 1 mm diameter derived from HT29 colorectal cancer cells are extremely hypoxic when grown intraperitoneally or intradermally in nude mice, whereas those of greater size (approximately 1-4 mm diameter) are not significantly hypoxic. The object of this study was to determine if digital autoradiography using the radiolabeled hypoxia imaging tracer iodo-azomycin galactopyranoside ((131)I-IAZGP) could detect hypoxia in this model. METHODS Microscopic HT29 tumors were grown as disseminated peritoneal disease and intradermally in nude mice. Tumors ranged in size from a few hundred microns to several millimeters in diameter. Animals were intravenously administered (131)I-IAZGP and pimonidazole 2 h before sacrifice. Following sacrifice, the intratumoral distribution of (131)I-IAZGP was assessed by digital autoradiography and compared with immunofluorescence microscopic images of pimonidazole binding and carbonic anhydrase IX (CAIX) expression. RESULTS The distributions of (131)I-IAZGP, pimonidazole, and CAIX expression were similar. Tumors less than 1 mm diameter displayed high (131)I-IAZGP uptake; these tumors also stained strongly for pimonidazole and CAIX. Larger tumors (approximately 1-4 mm diameter) were not significantly hypoxic and had low (131)I-IAZGP accumulation. CONCLUSION (131)I-IAZGP can detect hypoxia in microscopic tumors. Microscopic tumors are useful models for the validation of hypoxia radiotracers, and digital autoradiography is an appropriate technique for studying the distribution of hypoxia radiotracers in microscopic tumors.
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Affiliation(s)
- Xiao-Feng Li
- Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Bruechner K, Bergmann R, Santiago A, Mosch B, Yaromina A, Hessel F, Hofheinz F, van den Hoff J, Baumann M, Beuthien-Baumann B. Comparison of [18F]FDG uptake and distribution with hypoxia and proliferation in FaDu human squamous cell carcinoma (hSCC) xenografts after single dose irradiation. Int J Radiat Biol 2009; 85:772-80. [PMID: 19657862 DOI: 10.1080/09553000903043067] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE This study investigated the uptake of [(18)F]2-fluoro-2-deoxy-glucose ([(18)F]FDG) in the human tumour xenograft FaDu at early time points after single dose irradiation with Positron-Emission-Tomography (PET), autoradiography and functional histology. MATERIALS AND METHODS [(18)F]FDG-PET of FaDu hSCC xenografts on nude mice was performed before 25 Gy or 35 Gy single dose irradiation and one, seven or 11 days post irradiation (p.irr.). Before the second PET, mice were injected with pimonidazole (pimo) and bromodeoxyuridine (BrdU). After the PET tumours were excised, sliced and subjected to autoradiography and functional histology staining (pimo, BrdU, Ki67). [(18)F]FDG tumour uptake was quantified in the PET scans by maximal standard uptake value (SUV(max)) and in the autoradiography after co-registration to the histology slices. RESULTS No differences in the overall [(18)F]FDG uptake between the two dose groups and time points were found with PET or autoradiography. Comparing autoradiography and histology, the [(18)F]FDG uptake was constant in tumour necrosis over time, while it decreased in vital tumour areas and particularly in hypoxic regions. No differences in the [(18)F]FDG uptake between positive and negative areas of Ki67 and BrdU were found. CONCLUSIONS The decline of [(18)F]FDG uptake in vital tumour and in pimopositive areas as seen in autoradiography, was not reflected by evaluation of SUV(max) determined by PET. These findings suggest that the SUV(max) does not necessarily reflect changes in tumour biology after irradiation.
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Affiliation(s)
- Kerstin Bruechner
- Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, University of Technology-Dresden, Fetscherstrasse 74, Dresden,Germany
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Molecular imaging of hypoxia with radiolabelled agents. Eur J Nucl Med Mol Imaging 2009; 36:1674-86. [PMID: 19565239 PMCID: PMC2758191 DOI: 10.1007/s00259-009-1195-9] [Citation(s) in RCA: 145] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2009] [Accepted: 06/07/2009] [Indexed: 01/29/2023]
Abstract
Tissue hypoxia results from an inadequate supply of oxygen (O2) that compromises biological functions. Structural and functional abnormalities of the tumour vasculature together with altered diffusion conditions inside the tumour seem to be the main causes of tumour hypoxia. Evidence from experimental and clinical studies points to a role for tumour hypoxia in tumour propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and non-invasive approaches have been developed to measure tumour oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), autoradiography and immunohistochemistry. This review aims to give a detailed overview of non-invasive molecular imaging modalities with radiolabelled PET and SPECT tracers that are available to measure tumour hypoxia.
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Initial results of hypoxia imaging using 1-alpha-D: -(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole ( 18F-FAZA). Eur J Nucl Med Mol Imaging 2009; 36:1565-73. [PMID: 19430784 DOI: 10.1007/s00259-009-1154-5] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2009] [Accepted: 04/17/2009] [Indexed: 12/12/2022]
Abstract
PURPOSE Tumour hypoxia is thought to play a significant role in the outcome of solid tumour therapy. Positron emission tomography (PET) is the best-validated noninvasive technique able to demonstrate the presence of hypoxia in vivo. The locally developed PET tracer for imaging hypoxia, 1-alpha-D: -(5-deoxy-5-[(18)F]-fluoroarabinofuranosyl)-2-nitroimidazole ((18)F-FAZA), has been shown to accumulate in experimental models of tumour hypoxia and to clear rapidly from the circulation and nonhypoxic tissues. The safety and general biodistribution patterns of this radiopharmaceutical in patients with squamous cell carcinoma of the head and neck (HNSCC), small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC), malignant lymphoma, and high-grade gliomas, were demonstrated in this study. METHODS Patients with known primary or suspected metastatic HNSCC, SCLC or NSCLC, malignant lymphoma or high-grade gliomas were dosed with 5.2 MBq/kg of (18)F-FAZA, then scanned 2-3 h after injection using a PET or PET/CT scanner. Images were interpreted by three experienced nuclear medicine physicians. The location and relative uptake scores (graded 0 to 4) of normal and abnormal (18)F-FAZA biodistribution patterns, the calculated tumour-to-background (T/B) ratio, and the maximum standardized uptake value were recorded. RESULTS Included in the study were 50 patients (32 men, 18 women). All seven patients with high-grade gliomas showed very high uptake of (18)F-FAZA in the primary tumour. In six out of nine patients with HNSCC, clear uptake of (18)F-FAZA was observed in the primary tumour and/or the lymph nodes in the neck. Of the 21 lymphoma patients (15 with non-Hodgkin's lymphoma and 6 with Hodgkin's disease), 3 demonstrated moderate lymphoma-related uptake. Of the 13 lung cancer patients (12 NSCLC, 1 SCLC), 7 had increased (18)F-FAZA uptake in the primary lung tumour. No side effects of the administration of (18)F-FAZA were observed. CONCLUSION This study suggests that (18)F-FAZA may be a very useful radiopharmaceutical to image hypoxia in the tumour types selected. Especially the high uptake by gliomas was encouraging. Given the good imaging properties, including acceptable T/B ratios in the tumour categories studied, (18)F-FAZA could be considered as a very promising agent for assessing the hypoxic fraction of these tumour types.
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Lee BF, Chiu NT, Hsia CC, Shen LH. Accumulation of Tc-99m HL91 in tumor hypoxia: in vitro cell culture and in vivo tumor model. Kaohsiung J Med Sci 2009; 24:461-72. [PMID: 19073378 DOI: 10.1016/s1607-551x(09)70003-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Hypoxic cells within a tumor can account, in part, for resistance to radiotherapy and chemotherapy. Indeed, the oxygenation status has been shown to be a prognostic marker for the outcome of therapy. The purpose of this study was to determine whether Tc-99m HL91 (HL91), a noninvasive imaging tracer, detects tumor hypoxia in vitro in cell culture and in vivo in a tumor model. Uptake of HL91 in vitro into human lung cancer cells (A549) and murine Lewis lung cancer cells (LL2) was investigated at oxygen concentrations of 20% O2 (normoxia), and 1% O2 (hypoxia). HL91 biodistribution was studied in four groups: severe combined immune deficiency (SCID) mice bearing A549 tumors, C57BL/6NCrj (B6) mice bearing LL2 tumors, SCID controls, and B6 controls. Accumulation of the tracer was compared between tumors treated with hydralazine or phosphate-buffered saline (PBS). Scintigraphic images were obtained for hydralazine-treated mice and PBS-treated mice in each of the four study groups. Autoradiography of tumor slices was also acquired. In vitro studies identified hypoxia-selective uptake of HL91, with significantly increased uptake in the hypoxic state than in the normoxic state. Biodistribution and scintigraphy showed increased HL91 uptake during tumor hypoxia at 0.5 hours, and there was progressively increased activity for up to 4 hours after tracer administration. HL91 accumulation in tumor hypoxia was markedly increased in mice treated with hydralazine compared with those treated with PBS. Autoradiography revealed high HL91 uptake in the peripheral areas around the necrotic regions of the tumor, which were identified by histologic examination. HL91 exhibits selectivity for tumor hypoxia both in vitro and in vivo and provides a successful imaging modality for the detection of tumor hypoxia in vivo.
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Affiliation(s)
- Bi-Fang Lee
- Department of Nuclear Medicine, National Cheng Kung University, Tainan, Taiwan.
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Dubois L, Landuyt W, Cloetens L, Bol A, Bormans G, Haustermans K, Labar D, Nuyts J, Grégoire V, Mortelmans L. [18F]EF3 is not superior to [18F]FMISO for PET-based hypoxia evaluation as measured in a rat rhabdomyosarcoma tumour model. Eur J Nucl Med Mol Imaging 2008; 36:209-18. [PMID: 18690432 DOI: 10.1007/s00259-008-0907-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2007] [Accepted: 07/20/2008] [Indexed: 12/12/2022]
Abstract
PURPOSE The aim of this investigation was to quantitatively compare the novel positron emission tomography (PET) hypoxia marker 2-(2-nitroimidazol-1-yl)-N-(3[(18)F],3,3-trifluoropropyl)acetamide ([(18)F]EF3) with the reference hypoxia tracer [(18)F]fluoromisonidazole ([(18)F]FMISO). METHODS [(18)F]EF3 or [(18)F]FMISO was injected every 2 days into two separate groups of rats bearing syngeneic rhabdomyosarcoma tumours. In vivo PET analysis was done by drawing regions of interest on the images of selected tissues. The resulting activity data were quantified by the percentage of injected radioactivity per gram tissue (%ID/g) and tumour to blood (T/B) ratio. The spatial distribution of radioactivity was defined by autoradiography on frozen tumour sections. RESULTS The blood clearance of [(18)F]EF3 was faster than that of [(18)F]FMISO. The clearance of both tracers was slower in tumour tissue compared with other tissues. This results in increasing T/B ratios as a function of time post tracer injection (p.i.). The maximal [(18)F]EF3 tumour uptake, compared to the maximum [(18)F]FMISO uptake, was significantly lower at 2 h p.i. but reached similar levels at 4 h p.i. The tumour uptake for both tracers was independent of the tumour volume for all investigated time points. Both tracers showed heterogeneous intra-tumoural distribution. CONCLUSIONS [(18)F]EF3 tumour uptake reached similar levels at 4 h p.i. compared with tumour retention observed after injection of [(18)F]FMISO at 2 h p.i. Although [(18)F]EF3 is a promising non-invasive tracer, it is not superior over [(18)F]FMISO for the visualisation of tumour hypoxia. No significant differences between [(18)F]EF3 and [(18)F]FMISO were observed with regard to the intra-tumoural distribution and the extra-tumoural tissue retention.
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Affiliation(s)
- Ludwig Dubois
- Department of Nuclear Medicine, University Hospital Gasthuisberg and KU Leuven, 3000, Leuven, Belgium.
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Busk M, Horsman MR, Jakobsen S, Bussink J, van der Kogel A, Overgaard J. Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage. Eur J Nucl Med Mol Imaging 2008; 35:2294-303. [PMID: 18682937 DOI: 10.1007/s00259-008-0888-9] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2008] [Accepted: 07/02/2008] [Indexed: 11/26/2022]
Abstract
PURPOSE Tumour hypoxia and elevated glycolysis (Warburg effect) predict poor prognosis. Each parameter is assessable separately with positron emission tomography, but they are linked through anaerobic glycolysis (Pasteur effect). Here, we compare the oxygenation-dependent retention of fluoroazomycin arabinoside ([(18)F]FAZA), a promising but not well-characterised hypoxia-specific tracer, and fluorodeoxyglucose ([(18)F]FDG) in four carcinoma cell lines. METHODS Cells seeded on coverslips were positioned in modified Petri dishes that allow physically separated cells to share the same tracer-containing medium pool. Following oxic, hypoxic or anoxic tracer incubation, coverslips were analysed for radioactivity ([(18)F]FDG + [(18)F]FAZA) or re-incubated in tracer-free oxygenated medium and then measured ([(18)F]FAZA). Next, we tested the reliability of [(18)F]FDG as a relative measure of glucose metabolic rate. Finally, from two cell lines, xenografts were established in mice, and the tracer distribution between hypoxic and well-oxygenated areas were deduced from tissue sections. RESULTS Three hours of anoxia strongly stimulated [(18)F]FAZA retention with anoxic-to-oxic uptake ratios typically above 30. Three out of four cell lines displayed similar selectivity of [(18)F]FDG versus glucose, but oxic uptake and anoxic-to-oxic uptake ratio of [(18)F]FDG varied considerably. Although less pronounced, [(18)F]FAZA also showed superior in vivo hypoxia specificity compared with [(18)F]FDG. CONCLUSIONS [(18)F]FAZA displays excellent in vitro characteristics for hypoxia imaging including modest cell-to-cell line variability and no binding in oxic cells. In contrast, the usability of [(18)F]FDG as a surrogate marker for hypoxia is questionable due to large variations in baseline (oxic) glucose metabolism and magnitudes of the Pasteur effects.
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Affiliation(s)
- Morten Busk
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus C, Denmark.
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Busk M, Horsman MR, Kristjansen PEG, van der Kogel AJ, Bussink J, Overgaard J. Aerobic glycolysis in cancers: implications for the usability of oxygen-responsive genes and fluorodeoxyglucose-PET as markers of tissue hypoxia. Int J Cancer 2008; 122:2726-34. [PMID: 18351643 DOI: 10.1002/ijc.23449] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The hypoxia-responsiveness of the glycolytic machinery may allow pretreatment identification of hypoxic tumors from HIF-1 targets (e.g., Glut-1) or [18F]-fluorodeoxyglucose positron emission tomography but results have been mixed. We hypothesized that this discrepancy is an inevitable consequence of elevated aerobic glycolysis in tumors (Warburg effect) as energetics in predominantly glycolytic cells is little affected by hypoxia. Accordingly, we characterized glycolytic and mitochondrial ATP generation in normoxic and anoxic cell lines. Measurements demonstrated that most cancer cells rely largely on aerobic glycolysis as it accounts for 56-63% of their ATP budget, but in the cervical carcinoma SiHa, ATP synthesis was mainly mitochondrial. Moreover, the stimulatory effect of anoxia on glycolytic flux was inversely correlated to the relative reliance on aerobic glycolysis. Next, tumor cells representing a Warburg or a nonglycolytic phenotype were grown in mice and spatial patterns of hypoxia (pimonidazole-stained), Glut-1 expression and (18)F-FDG uptake were analysed on sectioned tumors. Only in SiHa tumors did foci of elevated glucose metabolism consistently colocalize with regions of hypoxia and elevated Glut-1 expression. In contrast, spatial patterns of Glut-1 and pimonidazole staining correlated reasonably well in all tumors. In conclusion, Glut-1's value as a hypoxia marker is not severely restricted by aerobic glycolysis. In contrast, the specificity of (18)F-FDG uptake and Glut-1 expression as markers of regional hypoxia and glucose metabolism, respectively, scales inversely with the intensity of the Warburg effect. This linkage suggests that multi-tracer imaging combining FDG and hypoxia-specific markers may provide therapeutically relevant information on tumor energetic phenotypes.
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Affiliation(s)
- Morten Busk
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
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Riesterer O, Honer M, Jochum W, Oehler C, Ametamey S, Pruschy M. Ionizing radiation antagonizes tumor hypoxia induced by antiangiogenic treatment. Clin Cancer Res 2007; 12:3518-24. [PMID: 16740778 DOI: 10.1158/1078-0432.ccr-05-2816] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE The combined treatment modality of ionizing radiation with inhibitors of angiogenesis is effective despite the supposition that inhibition of angiogenesis might increase tumor hypoxia and thereby negatively affect radiation sensitivity. To directly assess this still controversial issue, we analyzed treatment-dependent alterations of tumor oxygenation in response to inhibition of angiogenesis alone, ionizing radiation, and combined treatment. EXPERIMENTAL DESIGN Serial measurements with high-resolution [18F]fluoromisonidazole positron emission tomography and immunohistochemical detection of the endogenous hypoxia marker glucose transporter-1 were done to determine tumor hypoxia in a murine mammary carcinoma allograft model. RESULTS Inhibition of angiogenesis with the clinically relevant vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 reduced microvessel density but had only minimal effects on tumor growth, tumor cell apoptosis, and proliferation. However, PTK787/ZK222584 treatment increased overall and local tumor hypoxia as revealed by extended expression of the hypoxia marker glucose transporter-1 and increased uptake of [18F]fluoromisonidazole. Fractionated irradiation induced a strong growth delay, which was associated with enhanced apoptosis and reduced proliferation of tumor cells but only minor effects on microvessel density and allograft oxygenation. Combined treatment with fractionated irradiation resulted in extended tumor growth delay and tumor cell apoptosis but no increase in tumor hypoxia. CONCLUSIONS These results show that irradiation antagonizes the increase of hypoxia by vascular endothelial growth factor receptor tyrosine kinase inhibition and abrogates the potential negative effect on tumor hypoxia. Thus, the risk of treatment-induced hypoxia by inhibitors of angiogenesis exists but is kept minimal when combined with a cytotoxic treatment modality.
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Affiliation(s)
- Oliver Riesterer
- Department of Radiation Oncology, University Hospital Zurich, Zürich, Switzerland
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Champion C, Le Loirec C. Positron follow-up in liquid water: II. Spatial and energetic study for the most important radioisotopes used in PET. Phys Med Biol 2007; 52:6605-25. [DOI: 10.1088/0031-9155/52/22/004] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Airley RE, Mobasheri A. Hypoxic regulation of glucose transport, anaerobic metabolism and angiogenesis in cancer: novel pathways and targets for anticancer therapeutics. Chemotherapy 2007; 53:233-56. [PMID: 17595539 DOI: 10.1159/000104457] [Citation(s) in RCA: 254] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2005] [Accepted: 05/09/2006] [Indexed: 12/15/2022]
Abstract
Cancer cells require a steady source of metabolic energy in order to continue their uncontrolled growth and proliferation. Accelerated glycolysis is one of the biochemical characteristics of cancer cells. Recent work indicates that glucose transport and metabolism are essential for the posttreatment survival of tumor cells, leading to poor prognosis. Glycolytic breakdown of glucose is preceded by the transport of glucose across the cell membrane, a rate-limiting process mediated by facilitative glucose transporter proteins belonging to the facilitative glucose transporter/solute carrier GLUT/SLC2A family. Tumors frequently show overexpression of GLUTs, especially the hypoxia-responsive GLUT1 and GLUT3 proteins. There are also studies that have reported associations between GLUT expression and proliferative indices, whilst others suggest that GLUT expression may be of prognostic significance. In this article we revisit Warburg's original hypothesis and review the recent clinical and basic research on the expression of GLUT family members in human cancers and in cell lines derived from human tumors. We also explore the links between hypoxia-induced genes, glucose transporters and angiogenic factors. Hypoxic tumors are significantly more malignant, metastatic, radio- and chemoresistant and have a poor prognosis. With the discovery the oxygen-sensitive transcription factor hypoxia-inducible factor (HIF-1) has come a new understanding of the molecular link between hypoxia and deregulated glucose metabolism. HIF-1 induces a number of genes integral to angiogenesis, e.g. vascular endothelial growth factor (VEGF), a process intimately involved with metastatic spread. This knowledge may enhance existing chemotherapeutic strategies so that treatment can be more rationally applied and personalized for cancer patients.
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Affiliation(s)
- Rachel E Airley
- Department of Developmental and Molecular Biology, Chanin Institute, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA
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Belkacémi Y, Tsoutsou P, Magné N, Castadot P, Azria D. Metabolic functional imaging for tumor radiosensitivity monitoring. Crit Rev Oncol Hematol 2007; 62:227-39. [PMID: 17241788 DOI: 10.1016/j.critrevonc.2006.12.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2006] [Revised: 12/05/2006] [Accepted: 12/08/2006] [Indexed: 11/17/2022] Open
Abstract
Assessing tumor radiosensitivity before and during radiation therapy can be a crucial element in decision-making with regard to treatment. However, no known non-invasive test is available at present, which allows for a reliable evaluation of the radiosensitivity of a tissue subjected to radiotherapy. Among tests being evaluated, positron emission tomography (PET) is considered to be a promising method. The purpose of this review is to identify the tests and research paths that have recently been explored for the evaluation of tumor response to treatment after isotopic labeling revealed by nuclear imaging. The majority of the explored methodologies are based on the indirect evaluation of the radiosensitivity by cell proliferation or apoptosis, tissue oxygenation or hypoxia, intrinsic radiosensitivity of clonogenic cells, tumor metabolism and angiogenesis. The development of such methods would permit the adoption of a therapeutic regimen with respect to a given radiosensitivity of a tissue. Therefore, a given therapeutic strategy could be readjusted (by associating, for instance, a radiosensitizer of hypoxic cells) or even modified if it proved to be inadequate or when it presents an unfavorable cost-effectiveness ratio. We present here a critical review of the radiotracers revealed by nuclear imaging that are developed for radiosensitivity monitoring.
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Affiliation(s)
- Yazid Belkacémi
- Department of Radiation Oncology, Oscar Lambret Anti-Cancer Center and University of Lille II, Lille, France.
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Chen Q, Huang Z, Chen H, Shapiro H, Beckers J, Hetzel FW. Improvement of Tumor Response by Manipulation of Tumor Oxygenation During Photodynamic Therapy¶. Photochem Photobiol 2007. [DOI: 10.1562/0031-8655(2002)0760197iotrbm2.0.co2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Davda S, Bezabeh T. Advances in methods for assessing tumor hypoxia in vivo: implications for treatment planning. Cancer Metastasis Rev 2007; 25:469-80. [PMID: 17029029 DOI: 10.1007/s10555-006-9009-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Tumor hypoxia and its downstream effects have remained of considerable interest for decades due to its negative impact on response to various cancer therapies and promotion of metastasis. Diagnosing hypoxia non-invasively can provide a significant advancement in cancer treatment and is the dire necessity for implementing specific targeted therapies now emerging to treat different aspects of cancer. A variety of techniques are being proposed to do so. However, none of them has yet been established in the clinical arena. This review summarizes the methods currently available to assess tumor hypoxia in vivo and their respective advantages and shortcomings. It also points out the impedances that need to be overcome to establish any particular method in the clinic, along with a broad overview of requirements for further advancement in this sphere of cancer research.
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Affiliation(s)
- Sonal Davda
- Institute for Biodiagnostics, National Research Council, 435 Ellice Avenue, Winnipeg, Manitoba, Canada, R3B 1Y6
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Affiliation(s)
- Inna Serganova
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
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Yin FF, Das S, Kirkpatrick J, Oldham M, Wang Z, Zhou SM. Physics and imaging for targeting of oligometastases. Semin Radiat Oncol 2006; 16:85-101. [PMID: 16564444 DOI: 10.1016/j.semradonc.2005.12.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Oligometastases refer to metastases that are limited in number and location and are amenable to regional treatment. The majority of these metastases appear in the brain, lung, liver, and bone. Although the focus of interest in the past within radiation oncology has been on the treatment of intracranial metastases, there has been growing interest in extracranial sites such as the liver and lung. This is largely because of the rapid development of targeting techniques for oligometastases such as intensity-modulated and image-guided radiation therapy, which has made it possible to deliver single or a few fractions of high-dose radiation treatments, highly conformal to the target. The clinical decision to use radiation to treat oligometastases is based on both radiobiological and physics considerations. The radiobiological considerations involve improvement of treatment schema for time, dose, and volume. Areas of interests are hypofractionation, tumor and normal tissue tolerance, and hypoxia. The physics considerations for oligometastases treatment are focused mainly on ensuring treatment accuracy and precision. This article discusses the physics and imaging aspects involved in each step of the radiation treatment process for oligometastases, including target definition, treatment simulation, treatment planning, pretreatment target localization, radiation delivery, treatment verification, and treatment evaluation.
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Affiliation(s)
- Fang-Fang Yin
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
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Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors. Radiother Oncol 2006; 80:157-64. [PMID: 16905213 DOI: 10.1016/j.radonc.2006.07.023] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2006] [Revised: 07/12/2006] [Accepted: 07/14/2006] [Indexed: 12/12/2022]
Abstract
PURPOSE Hypoxia is one of the reasons for radiation therapy resistance. Positron emission tomography using (18)F-labeled misonidazole ([(18)F]FMISO) is a non-invasive method of imaging tumor hypoxia. Aim of this study was to validate [(18)F]FMISO against the clinically most widely used hypoxic cell marker pimonidazole under different oxygenation conditions. MATERIALS AND METHODS One human head and neck squamous cell carcinoma (SCCNij3) and two human glioblastoma (E102 and E106) xenograft tumor lines were studied after injection of [(18)F]FMISO and pimonidazole. Control mice were compared with a second group breathing carbogen to reduce tumor hypoxia and with a third group with clamped tumors to increase hypoxia. Tumor sections were analyzed on a phosphor imaging system and consecutively stained immunohistochemically (IHC) for visualization of pimonidazole. Pixel-by-pixel analysis was performed and the hypoxic fraction, obtained after segmentation of the pimonidazole signal, was related to the mean optical density of [(18)F]FMISO and pimonidazole. RESULTS A moderate pixel-by-pixel correlation between [(18)F]FMISO autoradiography and pimonidazole IHC was found for the control tumors, after carbogen breathing and after clamping for SCCNij3. For E102 and E106, mean signal intensities for pimonidazole significantly decreased after carbogen breathing and increased after clamping, mean [(18)F]FMISO signal intensities increased significantly after clamping and a significant correlation between the hypoxic fractions and the mean [(18)F]FMISO signal intensities was found. CONCLUSIONS [(18)F]FMISO autoradiography and pimonidazole immunohistochemistry can both be used to visualize treatment induced changes in tumor hypoxia. However, the response to these modifications differs widely between xenograft tumor lines.
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Abstract
A high level of hypoxia in solid tumours is an adverse prognostic factor for the poor outcome of cancer patients following treatment. This review describes the status of research into finding a practical method for measuring hypoxia and treating hypoxic tumours. The application of such methodology would enable the selection of head and neck cancer treatment based on an individual's tumour oxygenation status. This individualization would include the selection not only of surgery or radiotherapy, but also of novel hypoxia-modification strategies.
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Affiliation(s)
- A Y Isa
- Department of Surgery, Christie Hospital, Manchester, UK
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Zimny M, Gagel B, DiMartino E, Hamacher K, Coenen HH, Westhofen M, Eble M, Buell U, Reinartz P. FDG--a marker of tumour hypoxia? A comparison with [18F]fluoromisonidazole and pO2-polarography in metastatic head and neck cancer. Eur J Nucl Med Mol Imaging 2006; 33:1426-31. [PMID: 16841141 DOI: 10.1007/s00259-006-0175-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2006] [Accepted: 05/11/2006] [Indexed: 02/08/2023]
Abstract
PURPOSE Experimental data suggest that the accumulation of [(18)F]fluorodeoxyglucose (FDG) in malignant tumours is related to regional hypoxia. The aim of this study was to evaluate the clinical potential of FDG positron emission tomography (PET) to assess tumour hypoxia in comparison with [(18)F]fluoromisonidazole (FMISO) PET and pO(2)-polarography. METHODS Twenty-four patients with head and neck malignancies underwent FDG PET, FMISO PET, and pO(2)-polarography within 1 week. Parameters of pO(2)-polarography were the relative frequency of pO(2) readings <or=2.5 mmHg, <or=5 mmHg and <or=10 mmHg, respectively, as well as the mean and median pO(2). RESULTS We observed a moderate correlation of the maximum standardised uptake value (SUV) of FDG with the tumour to blood ratio of FMISO at 2 h (R=0.53, p<0.05). However, SUV of FDG was similar in hypoxic and normoxic tumours as defined by pO(2)-polarography (6.9+/-3.2 vs 6.2+/-3.0, NS), and the FDG uptake was not correlated with the results of pO(2)-polarography. The retention of FMISO was significantly higher in hypoxic tumours than in normoxic tumours (tumour to muscle ratio at 2 h: 1.8+/-0.4 vs 1.4+/-0.1, p<0.05), and the FMISO tumour to muscle ratio showed a strong correlation with the frequency of pO(2) readings <or=5 mmHg (R=0.80, p<0.001). CONCLUSION These results support the hypothesis that tumour hypoxia has an effect on glucose metabolism. However, other factors affecting FDG uptake may be more predominant in chronic hypoxia, and thus FDG PET cannot reliably differentiate hypoxic from normoxic tumours.
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Affiliation(s)
- Michael Zimny
- Department of Nuclear Medicine, University Hospital Aachen, Aachen, Germany.
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de Geus-Oei LF, Kaanders JHAM, Pop LAM, Corstens FHM, Oyen WJG. Effects of hyperoxygenation on FDG-uptake in head-and-neck cancer. Radiother Oncol 2006; 80:51-6. [PMID: 16820237 DOI: 10.1016/j.radonc.2006.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2005] [Revised: 05/18/2006] [Accepted: 06/08/2006] [Indexed: 10/24/2022]
Abstract
PURPOSE Tumor hyperoxygenation results in high response rates to ARCON (accelerated radiotherapy with carbogen and nicotinamide). The effect of hyperoxygenation on tumor metabolism using [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) was investigated. METHODS Within one week, FDG-PET was performed without and with hyperoxygenation by carbogen breathing and/or nicotinamide administration in 22 patients, eligible for ARCON for head-and-neck cancer. Maximum standardized uptake values (SUV(max)) in both scans and the relative change were calculated in the primary tumor and in normal muscle. RESULTS Alteration of the tumor oxygenation state induced profound, but variable, metabolic changes (median DeltaSUV(max) -4%; range -61% to +30%). Metabolism in normal muscle was not affected. In three patients who did not achieve local tumor control, the SUV(max) after hyperoxygenation differed less than 5% change as compared to baseline, whereas 13 of the 16 patients with local tumor control showed a larger difference (p<0.05). CONCLUSION Given the heterogeneous response pattern of nicotinamide and carbogen on FDG-uptake in head-and-neck carcinoma, the prognostic significance of semiquantitative FDG-PET before and after hyperoxygenation remains uncertain and requires confirmation in larger clinical studies before introducing the procedure as a predictive tool for oxygenation modifying treatments.
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Affiliation(s)
- Lioe-Fee de Geus-Oei
- Department of Nuclear Medicine, Radbound University Nijmegen Medical Center, The Netherlands.
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Zanzonico P, Campa J, Polycarpe-Holman D, Forster G, Finn R, Larson S, Humm J, Ling C. Animal-specific positioning molds for registration of repeat imaging studies: comparative microPET imaging of F18-labeled fluoro-deoxyglucose and fluoro-misonidazole in rodent tumors. Nucl Med Biol 2006; 33:65-70. [PMID: 16459260 DOI: 10.1016/j.nucmedbio.2005.07.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2005] [Revised: 07/28/2005] [Accepted: 07/30/2005] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Comparative imaging of multiple radiotracers in the same animal can be invaluable in elucidating and validating their respective mechanisms of localization. Comparative imaging of PET tracers, particularly in small animals, is problematic, however: such tracers must be administered and imaged separately because simultaneously imaged positron emitters cannot be separated based on energy discrimination. OBJECTIVE As part of our ongoing development of hypoxia imaging radiotracers, the intratumoral distributions of sequentially administered F18-fluoro-deoxyglucose (FDG) and the hypoxia tracer F18-fluoromisonidazole (FMiso) were compared in rats by registered microPET imaging with positioning of each animal in a custom-fabricated whole-body mold. METHODS Nude rats with a hindlimb R3327-AT anaplastic rat prostate tumor xenograft and a hindlimb FaDu human squamous cell carcinoma (each up to 20 x 20 x 30 mm in size) were studied. Rapid-Foam (Soule Medical, Lutz, FL) was used to fabricate animal-specific molds for immobilization and reproducible positioning. Each rat was injected via the tail vein with approximately 33 MBq (900 microCi) of FDG and imaged in its mold at 1 h postinjection (pi) on the microPET. The next day, each rat was injected with approximately 22 MBq (600 microCi) of FMiso and positioned and imaged in its mold at approximately 2 h pi. Custom-manufactured germanium-68 rods (10 microCi each, 1 x 10 mm) were reproducibly positioned in the mold as fiduciary markers. RESULTS The registered microPET images unambiguously demonstrated grossly similar though not identical distributions of FDG and FMiso in the tumors - a high-activity rim surrounding a lower-activity core. There were subtle but possibly significant differences in the intratumoral distributions of FDG and FMiso, however. These may not have been discerned without careful image registration. CONCLUSION Animal-specific molds are inexpensive and straightforward to fabricate and use for registration (+/-1 to 2 mm) of sequential PET images and may aid image interpretation.
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Affiliation(s)
- Pat Zanzonico
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
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Rajendran JG, Hendrickson KRG, Spence AM, Muzi M, Krohn KA, Mankoff DA. Hypoxia imaging-directed radiation treatment planning. Eur J Nucl Med Mol Imaging 2006; 33 Suppl 1:44-53. [PMID: 16763816 DOI: 10.1007/s00259-006-0135-1] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Increasing evidence supports the role of the tumor microenvironment in modulating cancer behavior. Tissue hypoxia, an important and common condition affecting the tumor microenvironment, is well established as a resistance factor in radiotherapy. Increasing evidence points to the ability of hypoxia to induce the expression of gene products, which confer aggressive tumor behavior and promote broad resistance to therapy. These factors suggest that determining the presence or absence of tumor hypoxia is important in planning cancer therapy. Recent advances in PET hypoxia imaging, conformal radiotherapy, and imaging-directed radiotherapy treatment planning now make it possible to perform hypoxia-directed radiotherapy. We review the biological aspects of tumor hypoxia and PET imaging approaches for measuring tumor hypoxia, along with methods for conformal radiotherapy and image-guided treatment, all of which provide the underpinnings for hypoxia-directed therapy. As a case example, we review emerging data on PET imaging of hypoxia to direct radiotherapy.
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Affiliation(s)
- J G Rajendran
- Department of Radiology, University of Washington, Seattle, WA 98195, USA.
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Belkacémi Y, Tsoutsou PG, Comet B, Kerrou K, Lartigau E. Évaluation de la radiosensibilité tumorale par l'imagerie fonctionnelle et métabolique : de la recherche à l'application clinique. Revue de la littérature. Cancer Radiother 2006; 10:124-33. [PMID: 16310397 DOI: 10.1016/j.canrad.2005.09.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2005] [Revised: 09/06/2005] [Accepted: 09/22/2005] [Indexed: 11/16/2022]
Abstract
During the last half of century considerable research on radiosensitivity biomarkers has been published. However, to date there is no non-invasive marker of cellular radiosensitivity identified for clinical routinely use. In this review, the main functional and metabolic imaging isotopic techniques for tumor radiosensitivity that have been explored over the last years are being described. This indirect evaluation fall into 3 topics associated with tumor proliferation rate or apoptosis, tumor hypoxic fraction, neoangiogenesis and the intrinsic radiosensitivity of clonogenic tumor cells. The final objective of the radiosensitivity monitoring during radiotherapy would be to adapt treatment strategy for overcoming the identified radioresistance mechanism such as hypoxia by the addition of radiosensitisers for example. This would allow better tumor control rather than continue inefficient and costly treatment delivery, which in addition could compromise outcome.
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Affiliation(s)
- Y Belkacémi
- Département universitaire de radiothérapie, centre Oscar-Lambret, 3, rue Frédéric-Combemale, 59020, Lille, France.
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Chan LW, Hapdey S, English S, Seidel J, Carson J, Sowers AL, Krishna MC, Green MV, Mitchell JB, Bacharach SL. The influence of tumor oxygenation on (18)F-FDG (fluorine-18 deoxyglucose) uptake: a mouse study using positron emission tomography (PET). Radiat Oncol 2006; 1:3. [PMID: 16722588 PMCID: PMC1436004 DOI: 10.1186/1748-717x-1-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2005] [Accepted: 02/28/2006] [Indexed: 11/29/2022] Open
Abstract
Background This study investigated whether changing a tumor's oxygenation would alter tumor metabolism, and thus uptake of 18F-FDG (fluorine-18 deoxyglucose), a marker for glucose metabolism using positron emission tomography (PET). Results Tumor-bearing mice (squamous cell carcinoma) maintained at 37°C were studied while breathing either normal air or carbogen (95% O2, 5% CO2), known to significantly oxygenate tumors. Tumor activity was measured within an automatically determined volume of interest (VOI). Activity was corrected for the arterial input function as estimated from image and blood-derived data. Tumor FDG uptake was initially evaluated for tumor-bearing animals breathing only air (2 animals) or only carbogen (2 animals). Subsequently, 5 animals were studied using two sequential 18F-FDG injections administered to the same tumor-bearing mouse, 60 min apart; the first injection on one gas (air or carbogen) and the second on the other gas. When examining the entire tumor VOI, there was no significant difference of 18F-FDG uptake between mice breathing either air or carbogen (i.e. air/carbogen ratio near unity). However, when only the highest 18F-FDG uptake regions of the tumor were considered (small VOIs), there was a modest (21%), but significant increase in the air/carbogen ratio suggesting that in these potentially most hypoxic regions of the tumor, 18F-FDG uptake and hence glucose metabolism, may be reduced by increasing tumor oxygenation. Conclusion Tumor 18F-FDG uptake may be reduced by increases in tumor oxygenation and thus may provide a means to further enhance 18F-FDG functional imaging.
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Affiliation(s)
- Linda W Chan
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Sebastien Hapdey
- Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Sean English
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Jurgen Seidel
- Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Joann Carson
- Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Anastasia L Sowers
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Murali C Krishna
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Michael V Green
- Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - James B Mitchell
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Stephen L Bacharach
- Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
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Wyss MT, Honer M, Schubiger PA, Ametamey SM. NanoPET imaging of [(18)F]fluoromisonidazole uptake in experimental mouse tumours. Eur J Nucl Med Mol Imaging 2005; 33:311-8. [PMID: 16258762 DOI: 10.1007/s00259-005-1951-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2005] [Accepted: 08/11/2005] [Indexed: 02/08/2023]
Abstract
PURPOSE The purpose of this study was to assess the potential and utility of ultra-high-resolution hypoxia imaging in various murine tumour models using the established hypoxia PET tracer [(18)F]fluoromisonidazole ([(18)F]FMISO). METHODS [(18)F]FMISO PET imaging was performed with the dedicated small-animal PET scanner NanoPET (Oxford Positron Systems) and ten different human tumour xenografts in nude mice as well as B16 melanoma tumours in syngeneic Balb/c mice. For comparison, [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET scans were also performed in the mice bearing human tumour xenografts. RESULTS In 10 out of 11 experimental tumour models, [(18)F]FMISO PET imaging allowed clear-cut visualisation of the tumours. Inter- and intratumoural heterogeneity of tracer uptake was evident. In addition to average TMRR (tumour-to-muscle retention ratio including all voxels in a volume of interest (VOI)), the parameters TMRR(75%) and TMRR(5) (tumour-to-muscle retention ratio including voxels of 75% or more of the maximum radioactivity in a VOI and the five hottest pixels, respectively) also served as measures for quantifying the heterogeneous [(18)F]FMISO uptake in the tumours. The variability observed in [(18)F]FMISO uptake was related neither to tumour size nor to the injected mass of the radiotracer. The pattern of normoxic and hypoxic regions within the human tumour xenografts, however, correlated with glucose metabolism as revealed by comparison of [(18)F]FDG and [(18)F]FMISO images. CONCLUSION This study demonstrates the feasibility and utility of [(18)F]FMISO for imaging murine tumour models using NanoPET.
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Affiliation(s)
- Matthias T Wyss
- Center for Radiopharmaceutical Science of ETH, PSI and USZ, Paul Scherrer Institute, Villigen, Switzerland.
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Sørensen M, Horsman MR, Cumming P, Munk OL, Keiding S. Effect of intratumoral heterogeneity in oxygenation status on FMISO PET, autoradiography, and electrode Po2 measurements in murine tumors. Int J Radiat Oncol Biol Phys 2005; 62:854-61. [PMID: 15936570 DOI: 10.1016/j.ijrobp.2005.02.044] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2004] [Revised: 02/15/2005] [Accepted: 02/21/2005] [Indexed: 01/06/2023]
Abstract
PURPOSE To explore conflicting results obtained when tumor hypoxia is assessed with Eppendorf electrode Po(2) measurements and with positron emission tomography (PET) by use of [(18)F]fluoromisonidazole (FMISO). METHODS AND MATERIALS We compared the 2 methods in conjunction with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) PET, dual-tracer ex vivo autoradiography (FMISO and 2-deoxy-D-[1-(14)C]glucose (2DG)), and histology in 2 murine tumor models, the C3H mammary carcinoma and the SCCVII squamous cell carcinoma. RESULTS 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-PET showed tumor-to-reference tissue ratios of 3.5 in both tumor models after 2 hours. C3H mammary carcinoma reached an FMISO PET ratio of 11 after 3.5 hours. Autoradiography showed large confluent areas of FMISO and 2DG uptake. Median Po(2) was 7 mm Hg and necrotic fraction was 10% to 30%. SCCVII squamous-cell carcinoma reached an FMISO PET tumor-to-reference tissue ratio of 2 after 2.5 hours. Autoradiography showed homogeneous 2DG uptake and scattered foci of high FMISO uptake. Median Po(2) was 1 mm Hg and necrotic fraction was below 5%. CONCLUSIONS Ex vivo dual-tracer autoradiography documented the ability of in vivo FMISO PET to distinguish between confluent areas of either viable tissue or necrosis. Electrode Po(2) measurements could not be ascribed to specific areas in the tumors. Less uptake of FMISO in SCCVII squamous-cell carcinoma than in C3H mammary carcinoma could be caused by scattered foci versus confluent areas of viable hypoxic tissue in the 2 tumors, respectively.
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Buus S, Grau C, Munk OL, Bender D, Jensen K, Keiding S. 11C-methionine PET, a novel method for measuring regional salivary gland function after radiotherapy of head and neck cancer. Radiother Oncol 2005; 73:289-96. [PMID: 15588873 DOI: 10.1016/j.radonc.2004.09.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2004] [Revised: 09/15/2004] [Accepted: 09/17/2004] [Indexed: 10/26/2022]
Abstract
BACKGROUND AND PURPOSE Loss of salivary gland function is a distressing side-effect of radiotherapy (RT) for head and neck cancer. The aim of this study was to develop a positron emission tomography (PET) method for measuring regional salivary gland function in the major salivary glands irradiated during RT. PATIENTS AND METHODS Eight head and neck cancer patients were included; two were examined before RT and six after parotid sparing RT. Patients were examined by dynamic 11C-methionine PET of the major salivary glands and parotid gland salivary flow measurements. PET data were analysed using a kinetic model of salivary gland 11C-methionine metabolism, in which salivary gland function was quantified by the net metabolic clearance of 11C-methionine, K. Functional voxel-wise images of K were calculated and matched with the CT-dose-plan for comparing regional salivary gland function with the regional radiation dose. RESULTS Parotid gland K correlated positively with parotid gland salivary flow, indicating that K can be used as an index of salivary gland function. K of parotid and submandibular glands was reduced dependent on the median radiation dose. In one patient, receiving a heterogeneous radiation dose to the parotid glands, regional salivary gland function was inversely correlated to the regional radiation dose. CONCLUSIONS Salivary gland function can be measured by dynamic 11C-methionine PET. The net metabolic clearance of 11C-methionine of salivary glands was reduced dependent on the radiation dose. Dynamic 11C-methionine PET offers a method for studying the individual response of the major salivary glands to irradiation.
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Affiliation(s)
- Simon Buus
- PET Centre, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark
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Abstract
There is a clear need in cancer treatment for a noninvasive imaging assay that evaluates the oxygenation status and heterogeneity of hypoxia and angiogenesis in individual patients. Such an assay could be used to select alternative treatments and to monitor the effects of treatment. Of the several methods available, each imaging procedure has at least one disadvantage. The limited quantitative potential of single-photon emission CT and MR imaging always limits tracer imaging based on these detection systems. PET imaging with FMISO and Cu-ATSM is ready for coordinated multicenter trials, however, that should move aggressively forward to resolve the debate over the importance of hypoxia in limiting response to cancer therapy. Advances in radiation treatment planning, such as intensity-modulated radiotherapy, provide the ability to customize radiation delivery based on physical conformity. With incorporation of regional biologic information, such as hypoxia and proliferating vascular density in treatment planning, imaging can create a biologic profile of the tumor to direct radiation therapy. Presence of widespread hypoxia in the tumor benefits from a systemic hypoxic cell cytotoxin. Angiogenesis is also an important therapeutic target. Imaging hypoxia and angiogenesis complements the efforts in development of antiangiogenesis and hypoxia-targeted drugs. The complementary use of hypoxia and angiogenesis imaging methods should provide the impetus for development and clinical evaluation of novel drugs targeted at angiogenesis and hypoxia. Hypoxia imaging brings in information different from that of FDG-PET but it will play an important niche role in oncologic imaging in the near future. FMISO, radioiodinated azamycin arabinosides, and Cu-ATSM are all being evaluated in patients. The Cu-ATSM images show the best contrast early after injection but these images are confounded by blood flow and their mechanism of localization is one step removed from the intracellular O2 concentration. FMISO has been criticized as inadequate because of its clearance characteristics, but its uptake after 2 hours is probably the most purely reflective of regional PO2 at the time the radiopharmaceutical is used. The FMISO images show less contrast than those of Cu-ATSM because of the lipophilicity and slower clearance of FMISO but attempts to increase the rate of clearance led to tracers whose distribution is contaminated by blood flow effects. For single-photon emission CT the only option is radioiodinated azamycin arabinosides, because the technetium agents are not yet ready for clinical evaluation. Rather than develop new and improved hypoxia agents, or even quibbling about the pros and cons of alternative agents, the nuclear medicine community needs to convince the oncology community that imaging hypoxia is an important procedure that can lead to improved treatment outcome.
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Affiliation(s)
- Joseph G Rajendran
- Division of Nuclear Medicine, Department of Radiology, Box 356113, University of Washington, Seattle, WA 98195, USA.
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Dubois L, Landuyt W, Haustermans K, Dupont P, Bormans G, Vermaelen P, Flamen P, Verbeken E, Mortelmans L. Evaluation of hypoxia in an experimental rat tumour model by [(18)F]fluoromisonidazole PET and immunohistochemistry. Br J Cancer 2005; 91:1947-54. [PMID: 15520822 PMCID: PMC2409764 DOI: 10.1038/sj.bjc.6602219] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This study aimed to evaluate tumour hypoxia by comparing [18F]Fluoromisonidazole uptake measured using positron emission tomography ([18F]FMISO-PET) with immunohistochemical (IHC) staining techniques. Syngeneic rhabdomyosarcoma (R1) tumour pieces were transplanted subcutaneously in the flanks of WAG/Rij rats. Tumours were analysed at volumes between 0.9 and 7.3 cm3. Hypoxic volumes were defined using a 3D region of interest on 2 h postinjection [18F]FMISO-PET images, applying different thresholds (1.2–3.0). Monoclonal antibodies to pimonidazole (PIMO) and carbonic anhydrase IX (CA IX), exogenous and endogenous markers of hypoxia, respectively, were used for IHC staining. Marker-positive fractions were microscopically measured for each tumour, and hypoxic volumes were calculated. A heterogeneous distribution of hypoxia was observed both with histology and [18F]FMISO autoradiography. A statistically significant correlation (P<0.05) was obtained between the hypoxic volumes defined with [18F]FMISO-PET and the volumes derived from the PIMO-stained tumour sections (r=0.9066; P=0.0001), regardless of the selected threshold between 1.4 and 2.2. A similar observation was made with the CA IX staining (r=0.8636; P=0.0006). The relationship found between [18F]FMISO-PET and PIMO- and additionally CA IX-derived hypoxic volumes in rat rhabdomyosarcomas indicates the value of the noninvasive imaging method to measure hypoxia in whole tumours.
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Affiliation(s)
- L Dubois
- Department of Nuclear Medicine, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - W Landuyt
- Lab Experimental Radiobiology/LEO, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium
- Experimental Radiobiology/LEO, KU Leuven, Gasthuisberg-CDG 8th floor, Herestraat 49, B-3000 Leuven, Belgium. Lab Experimental Radiobiology/LEO, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail:
| | - K Haustermans
- Lab Experimental Radiobiology/LEO, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - P Dupont
- Department of Nuclear Medicine, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - G Bormans
- Lab Radiopharmaceutical Chemistry, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - P Vermaelen
- Department of Nuclear Medicine, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - P Flamen
- Department of Nuclear Medicine, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - E Verbeken
- Morphology and Molecular Pathology, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - L Mortelmans
- Department of Nuclear Medicine, University Hospital Gasthuisberg and KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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Abstract
Positron emission tomography (PET) imaging of small animals enables researchers to bridge the gap between in vitro science and in vivo human studies. The imaging paradigm can be established and refined in animals before implementation in humans and image data related to ex vivo assays of biological activity. Small animal PET (saPET) imaging enables assessment of baseline focal pathophysiology, pharmacokinetics, biological target modulation and the efficacy of novel drugs. The potential and challenge of this technology as applied to anticancer drug development is discussed here.
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Affiliation(s)
- Eric O Aboagye
- Molecular Therapy and PET Oncology Research group, The Clinical Sciences Centre, Faculty of Medicine, Hammersmith Hospital Campus, Imperial College London, Rm. 242 MRC Cyclotron Building, London, W12 0NN, UK.
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Rajendran JG, Mankoff DA, O'Sullivan F, Peterson LM, Schwartz DL, Conrad EU, Spence AM, Muzi M, Farwell DG, Krohn KA. Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res 2004; 10:2245-52. [PMID: 15073099 DOI: 10.1158/1078-0432.ccr-0688-3] [Citation(s) in RCA: 288] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). (18)F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of (18)F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake. EXPERIMENTAL DESIGN Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue:blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane. RESULTS Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r = 0.24), with highly significant differences among the different tumor types (P < 0.005). CONCLUSIONS Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.
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West CML, Jones T, Price P. The potential of positron-emission tomography to study anticancer-drug resistance. Nat Rev Cancer 2004; 4:457-69. [PMID: 15170448 DOI: 10.1038/nrc1368] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Catharine M L West
- Academic Department of Radiation Oncology and Manchester Molecular Imaging Centre, University of Manchester, Christie NHS Trust Hospital, Wilmslow Road, Manchester, M20 4BX, United Kingdom.
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Grönroos T, Bentzen L, Marjamäki P, Murata R, Horsman MR, Keiding S, Eskola O, Haaparanta M, Minn H, Solin O. Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma. Eur J Nucl Med Mol Imaging 2004; 31:513-20. [PMID: 14722675 DOI: 10.1007/s00259-003-1404-x] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2003] [Accepted: 10/30/2003] [Indexed: 12/12/2022]
Abstract
The first aim of this study was to compare the hypoxia imaging ability of fluorine-18 fluoroerythronitroimidazole ([18F]FETNIM) with that of fluorine-18 fluoromisonimidazole ([18F]FMISO) in murine tumours of different sizes under two different oxygenation conditions. Secondly, we wanted to assess the biodistribution of the markers in normal tissues under similar conditions. Female CDF1 mice with a C3H mammary carcinoma grown on their backs were used. Tumours were size matched and animals breathed either normal air (21% O(2)) or carbogen gas (95% O(2) + 5% CO(2)). The gassing procedure was begun 5 min before the intravenous injection of either [18F]FETNIM or [18F]FMISO and continued until the mice were sacrificed at 120 min. Blood, tumour, muscle, heart, lung, liver, kidney and fat were removed, counted for radioactivity and weighed. The tumour and muscle were frozen and cut with a cryomicrotome into sections. The spatial distribution of radioactivity from the tissue sections was determined with digital autoradiography. Estimation of the necrotic fraction was made on sections from formalin-fixed tumours. Digital autoradiography showed that the whole tumour-to-muscle radioactivity uptake ratios were significantly higher in normal air-breathing mice than in carbogen-treated mice for both [18F]FETNIM (4.9+/-2.6 vs 1.8+/-0.5; P<0.01) and [18F]FMISO (4.4+/-1.0 vs 1.5+/-0.4; P<0.01). The carbogen treatment had only slight effects on the biodistribution of either marker in normal tissues. The necrotic fraction determined in tumours did not correlate with the tumour volume or with the tumour-to-muscle radioactivity uptake ratio. This study shows that the uptake of both [18F]FETNIM and [18F]FMISO correlates with the oxygenation status in tumours. In addition, our data show no significant difference in the intratumoral uptake between the two markers. However, significantly higher radioactivity uptake values were measured for [18F]FMISO than for [18F]FETNIM in normal tissues.
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Affiliation(s)
- Tove Grönroos
- Medicity Research Laboratory, Turku PET Centre, Tykistökatu 6 A, 20520 Turku, Finland.
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Hammond LA, Denis L, Salman U, Jerabek P, Thomas CR, Kuhn JG. Positron emission tomography (PET): expanding the horizons of oncology drug development. Invest New Drugs 2003; 21:309-40. [PMID: 14578681 DOI: 10.1023/a:1025468611547] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Positron emission tomography (PET) allows three-dimensional quantitative determination of the distribution of radioactivity permitting measurement of physiological, biochemical, and pharmacological functions at the molecular level. Until recently, no method existed to directly and noninvasively assess transport and metabolism of neoplastic agents as a function of time in various organs as well as in the tumor. Standard preclinical evaluation of potential anticancer agents entails radiolabeling the agent, usually with tritium or 14C, sacrifice experiments, and high-performance liquid chromatography (HPLC) analysis to determine the biodistribution and metabolism in animals. Radiolabeling agents with positron-emitting radionuclides allows the same information to be obtained as well as in vivo pharmacokinetic (PK) data by animal tissue and plasma sampling in combination with PET scanning. In phase I/II human studies, classic PK measurements can be coupled with imaging measurements to define an optimal dosing schedule and help formulate the design of phase III studies that are essential for drug licensure [1]. Many of the novel agents currently in development are cytostatic rather than cytotoxic and therefore, the traditional standard endpoints in phase I and II studies may no longer be relevant. The use of a specialized imaging modality that allows PK and pharmacodynamic (PD) evaluation of a drug of interest has been proposed to permit rapid and sensitive assessment of the biological effects of novel anticancer agents. The progress to date and the challenges of incorporating PET technology into oncology drug development from the preclinical to clinical setting are reviewed in this article.
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Affiliation(s)
- Lisa A Hammond
- Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78229, USA.
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Bentzen L, Keiding S, Nordsmark M, Falborg L, Hansen SB, Keller J, Nielsen OS, Overgaard J. Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours. Radiother Oncol 2003; 67:339-44. [PMID: 12865184 DOI: 10.1016/s0167-8140(03)00081-1] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND PURPOSE The aim of the study was to identify hypoxia in human soft tissue sarcomas (STS) by PET scanning using the hypoxia marker [18F]-fluoromisonidazole ([18F]FMISO) and invasive oxygen sensitive probes (Eppendorf pO2 Histograph, Germany). MATERIALS AND METHODS Thirteen patients with tumours suspected to be STS were examined by [18F]FMISO PET scanning, and eleven of these patients completed a set of Eppendorf pO2 Histograph measurements following the scanning. RESULTS AND DISCUSSION By histopathological diagnosis, seven tumours were shown to be STS and six tumours were benign. Ratios between tumour and muscle radioactivity and time activity curves for tumours and muscle tissue were examined in defined regions of interest. Only two malignant tumours showed [18F]FMISO uptake in higher amounts than muscle tissue over time. Hypoxia was present in both benign and malignant tumours as measured by the oxygen electrode method. CONCLUSIONS [18F]FMISO PET in our setting seemed not to be feasible for the detection of tumour hypoxia in human soft tissue tumours. Neither did it reflect the extent of hypoxia as determined with the oxygen electrode measurements.
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Affiliation(s)
- Lise Bentzen
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Noerrebrogade 4, DK-8000 Aarhus C, Denmark
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