Positron Emission Tomography Imaging In Oncology Research Articles

Personalised PET imaging in oncology: an umbrella review of meta-analyses to guide the appropriate radiopharmaceutical choice and indication.

For several years, oncological positron emission tomography (PET) has developed beyond 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). This umbrella review of meta-analyses aims to provide up-to-date, comprehensive, high-level evidence to support appropriate referral for a specific radiopharmaceutical PET/computed tomography (CT) or PET/magnetic resonance (MR) in the diagnosis and staging of solid cancers other than brain malignancies. We performed a systematic literature search on the PubMed/MEDLINE and EMBASE databases for meta-analyses assessing the accuracy of PET/CT and/or PET/MRI with [18F]FDG, somatostatin- receptor-targeting 68Ga-DOTA-peptides, 18F-labelled dihydroxyphenylalanine ([18F]DOPA), prostate-specific membrane antigen (PSMA)-targeted radioligands, and fibroblast activation protein inhibitors (FAPI) in the diagnosis/disease characterisation and staging of solid cancers other than brain tumours. The literature search yielded 449 scientific articles. After screening titles and abstracts and applying inclusion and exclusion criteria, we selected 173 meta-analyses to assess the strength of evidence. One article was selected from references. Sixty-four meta-analyses were finally considered. The current evidence corroborates the role of [18F]FDG as the main player in molecular imaging; PSMA tracers are useful in staging and re-staging prostate cancer; somatostatin-targeting peptides (e.g. [68Ga]Ga- DOTA-TOC and -TATE) or [18F]DOPA are valuable in neuroendocrine tumours (NETs). FAPI has emerged in gastric cancer assessment. According to search and selection criteria, no satisfactory meta-analysis was selected for the diagnosis/detection of oesophageal cancer, the diagnosis/detection and N staging of small cell lung cancer and hepatic cell carcinoma, the diagnosis/detection and M staging of melanoma and Merkel cell carcinoma, cervical, vulvar and penis cancers, the N and M staging of lung and gastroenteropancreatic NET, testicular cancer, and chondrosarcoma, and the M staging of differentiated thyroid, bladder and anal cancers. The comprehensive high-level evidence synthesised in the present umbrella review serves as a guiding compass for clinicians and imagers, aiding them in navigating the increasingly intricate seascape of PET examinations.

Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging.

Positron emission tomography (PET) imaging of the translocator 18 kDa protein (TSPO) with radioligands has become an effective means of research in peripheral inflammatory conditions that occur in many diseases and cancers. The peripheral sterile inflammatory diseases (PSIDs) are associated with a diverse group of disorders that comprises numerous enduring insults including the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system. TSPO has recently been introduced as a potential biomarker for peripheral sterile inflammatory diseases (PSIDs). The major critical issue related to PSIDs is its timely characterization and localization of inflammatory foci for proper therapy of patients. As an alternative to metabolic imaging, protein imaging expressed on immune cells after activation is of great importance. The five transmembrane domain translocator protein-18 kDa (TSPO) is upregulated on the mitochondrial cell surface of macrophages during inflammation, serving as a potential ligand for PET tracers. Additionally, the overexpressed TSPO protein has been positively correlated with various tumor malignancies. In view of the association of escalated TSPO expression in both disease conditions, it is an immensely important biomarker for PET imaging in oncology and PSIDs. In this review, we summarize the most outstanding advances on TSPO-targeted PSIDs and cancer in the development of TSPO ligands as a potential diagnostic tool, specifically discussing the last five years.

Excitatory glutamate transporter EAAC1 as an important transporter of N-(2-[18F]fluoropropionyl)-L-glutamate in oncology PET imaging

IntroductionWe have reported that N-(2-[18F]fluoropropionyl)-L-glutamate ([18F]FPGLU) was a potential amino acid tracer for tumor imaging with positron emission tomography (PET). In this study, the relationship between glutamate transporter excitatory amino acid carrier 1 (EAAC1) expression and [18F]FPGLU uptake in rat C6 glioma cell lines and human SPC-A-1 lung adenocarcinoma cell lines was investigated. MethodsThe uptake of [18F]FPGLU was assessed in ATRA-treated and untreated C6 cell lines, and also in EAAC1 knock-down SPC-A-1(shRNA) cells and SPC-A-1(NT) control cells. PET imaging of [18F]FPGLU was performed on the SPC-A-1 and SPC-A-1 (shRNA)-bearing mice models. ResultsThe uptake of [18F]FPGLU in C6 cells increased significantly after induced by ATRA for 24, 48, and 72 h, which was closely related to expression of EAAC1 in C6 cells (R2 = 0.939). Compared with the SPC-A-1(NT) control cells, the uptake of [18F]FPGLU on EAAC1 knock-down SPC-A-1(shRNA) cells significantly decreased to 64.0%. Moreover, the uptake of [18F]FPGLU in EAAC1 knock-down SPC-A-1(shRNA) xenografts was significantly lower than that in SPC-A-1 xenografts, with tumor/muscle ratios of 3.01 vs. 1.67 at 60 min post-injection of [18F]FPGLU. ConclusionThe transport mechanism of [18F]FPGLU in glioma C6 and lung adenocarcinoma SPC-A-1 cell lines mainly involves in glutamate transporter EAAC1. EAAC1 is an important transporter of N-(2-[18F]fluoropropionyl)-L-glutamate in oncologic PET imaging.

The Landscape of Clinical Trials Evaluating the Theranostic Role of PET Imaging in Oncology: Insights from an Analysis of ClinicalTrials.gov Database.

In the war on cancer marked by personalized medicine, positron emission tomography (PET)-based theranostic strategy is playing an increasingly important role. Well-designed clinical trials are of great significance for validating the PET applications and ensuring evidence-based cancer care. This study aimed to provide a comprehensive landscape of the characteristics of PET clinical trials using the substantial resource of ClinicalTrials.gov database. We identified 25,599 oncology trials registered with ClinicalTrials.gov in the last ten-year period (October 2005-September 2015). They were systematically reviewed to validate classification into 519 PET trials and 25,080 other oncology trials used for comparison. We found that PET trials were predominantly phase 1-2 studies (86.2%) and were more likely to be single-arm (78.9% vs. 57.9%, P <0.001) using non-randomized assignment (90.1% vs. 66.7%, P <0.001) than other oncology trials. Furthermore, PET trials were small in scale, generally enrolling fewer than 100 participants (20.3% vs. 25.7% for other oncology trials, P = 0.014), which might be too small to detect a significant theranostic effect. The funding support from industry or National Institutes of Health shrunk over time (both decreased by about 5%), and PET trials were more likely to be conducted in only one region lacking international collaboration (97.0% vs. 89.3% for other oncology trials, P <0.001). These findings raise concerns that clinical trials evaluating PET imaging in oncology are not receiving the attention or efforts necessary to generate high-quality evidence. Advancing the clinical application of PET imaging will require a concerted effort to improve the quality of trials.

A novel respiratory gating method for oncologic positron emission tomography based on bioimpedance approach.

Respiratory motion causes loss of image quality and inaccuracy of quantification in oncologic positron emission tomography (PET) imaging. This study introduces a bioimpedance-based gating method for compensation of respiratory motion artefacts. The bioimpedance-based respiratory gating method was studied parallel to a clinically used respiratory gating method [Real-time Position Management by Varian Medical Systems] in 4D PET/CT acquisition of 9 oncologic patients. The quantitative analysis consisted of the evaluation of tumour SUVpeak, SUVmax and volume. Additionally, target-to-background ratios as well as motion in cranial-caudal and anterior-posterior directions were measured. The evaluation was performed with amplitude- and time-based gating using averaged attenuation correction maps. Bioimpedance gating resulted in 17.7-18.9% increase in mean SUVpeak and 20.0-21.4% decrease in mean volume compared to non-gated images. The maximum motion measured from the bioimpedance-gated images was 19mm in cranial-caudal direction and 9mm in anterior-posterior direction. Bioimpedance-based respiratory gating compensates the adverse effects of motion in oncologic PET imaging.

5-Fluoro-[β-11C]-L-tryptophan is a functional analogue of 5-hydroxy-[β-11C]-L-tryptophan in vitro but not in vivo

5-Hydroxy-[β-(11)C]-L-tryptophan ([(11)C]HTP) is an established positron emission tomography (PET) imaging agent for neuroendocrine tumors (NETs). It has also been used for other clinical research purposes in neurology and diabetes. However, its widespread use is limited by the short physical half-life of the radionuclide and a difficult radiosynthesis. Therefore, a Fluorine-18 labeled analogue, 5-[(18)F]Fluoro-L-tryptophan ([(18)F]FTRP), has been proposed as a functional analogue. There is no published method for the synthesis of L-[(18)F]FTRP. We have therefore developed a synthesis of 5-fluoro-[β-(11)C]-L-tryptophan ([(11)C]FTRP), based on the existing chemo-enzymatic method for [(11)C]HTP and evaluated the potential usefulness of radiolabeled FTRP as a substitute for [(11)C]HTP. The in vitro and in vivo behavior of [(11)C]FTRP, including the dependence of key enzymes in the serotonergic metabolic pathway, was investigated in NET cell lines, NET xenograft carrying immunodeficient mice, normal rats and in non-human primate. [(11)C]HTP was used for direct comparison. Uptake of [(11)C]FTRP in NET cell lines in vitro was mediated by enzymes involved in serotonin synthesis and metabolism, similar to [(11)C]HTP. In vivo biodistribution, either in rodent or non-human primate, was not affected by selectively inhibiting enzymatic steps in the serotonergic metabolic pathway. [(11)C]FTRP has in vitro biological function similar to that of [(11)C]HTP. However, this function is not retained in vivo as shown by biodistribution and PET/CT studies. Radiolabeled FTRP is thus not likely to provide an advantage over [(11)C]HTP in PET imaging in oncology, neurology or diabetes.

Methodology for Quantitative Rapid Multi-Tracer PET Tumor Characterizations

Positron emission tomography (PET) can image a wide variety of functional and physiological parameters in vivo using different radiotracers. As more is learned about the molecular basis for disease and treatment, the potential value of molecular imaging for characterizing and monitoring disease status has increased. Characterizing multiple aspects of tumor physiology by imaging multiple PET tracers in a single patient provides additional complementary information, and there is a significant body of literature supporting the potential value of multi-tracer PET imaging in oncology. However, imaging multiple PET tracers in a single patient presents a number of challenges. A number of techniques are under development for rapidly imaging multiple PET tracers in a single scan, where signal-recovery processing algorithms are employed to recover various imaging endpoints for each tracer. Dynamic imaging is generally used with tracer injections staggered in time, and kinetic constraints are utilized to estimate each tracers' contribution to the multi-tracer imaging signal. This article summarizes past and ongoing work in multi-tracer PET tumor imaging, and then organizes and describes the main algorithmic approaches for achieving multi-tracer PET signal-recovery. While significant advances have been made, the complexity of the approach necessitates protocol design, optimization, and testing for each particular tracer combination and application. Rapid multi-tracer PET techniques have great potential for both research and clinical cancer imaging applications, and continued research in this area is warranted.

Amino Acid Transporter-Targeted Radiotracers for Molecular Imaging in Oncology

Amino acids are required for sustenance of continuous uncontrolled growth of tumor cells, and upregulation of amino acid transporter expression has often been observed in tumor cells to facilitate their accelerated rates of amino acid uptake. Therefore, amino acid transporters have promise as ideal targets for tumor imaging. In fact, many natural and artificial amino acids have been radiolabeled for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging of tumor. In this article, we review the classification, molecular biology, and pharmacological relevance of amino acid transport systems. In addition, we discuss the chemistry, radiochemistry, current clinical applications, and future prospects for the use of radiolabeled amino acid-based probes for PET and SPECT imaging in oncology for each category of radionuclide.

Application of Metabolic PET Imaging in Radiation Oncology

Positron emission tomography (PET) is a noninvasive imaging technique that provides functional or metabolic assessment of normal tissue or disease conditions and is playing an increasing role in cancer radiotherapy planning. (18)F-Fluorodeoxyglucose PET imaging (FDG-PET) is widely used in the clinic for tumor imaging due to increased glucose metabolism in most types of tumors; its role in radiotherapy management of various cancers is reviewed. In addition, other metabolic PET imaging agents at various stages of preclinical and clinical development are reviewed. These agents include radiolabeled amino acids such as methionine for detecting increased protein synthesis, radiolabeled choline for detecting increased membrane lipid synthesis, and radiolabeled acetate for detecting increased cytoplasmic lipid synthesis. The amino acid analogs choline and acetate are often more specific to tumor cells than FDG, so they may play an important role in differentiating cancers from benign conditions and in the diagnosis of cancers with either low FDG uptake or high background FDG uptake. PET imaging with FDG and other metabolic PET imaging agents is playing an increasing role in complementary radiotherapy planning.

Novel F-18–Labeled PET Myocardial Perfusion Tracers: Bench to Bedside

Myocardial perfusion imaging is a widely used approach to noninvasively identify myocardial ischemia and guide therapies. It is typically performed using single photon emission computed tomography. The competing technology positron emission tomography (PET) offers higher diagnostic accuracies but suffers from logistical limitations due to the use of short-lived radioisotopes. New (18)F-labeled perfusion markers were introduced in the past years and offer simplified supply approaches, as known from oncologic PET imaging. This review summarizes the available literature especially from preclinical studies, but also very recent findings from early clinical trials. We discuss the consequences of long-lived radioisotopes in myocardial PET and the potential role of absolute blood flow quantification to establish efficient clinical protocols.

OPERATIONAL RADIATION SAFETY FOR PET-CT, SPECT-CT, AND CYCLOTRON FACILITIES

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are well- established and indispensable imaging modalities in modern medicine. State-of-the-art computed tomography (CT) scanners have now been integrated into multi-modality PET-CT and SPECT-CT devices, and these devices, particularly PET-CT scanners, are dramatically impacting clinical practice. 18F-fluorodeoxyglucose (FDG), by far the most widely used radiopharmaceutical for clinical PET imaging in general and oncologic PET imaging in particular, is highly accurate in detecting (approximately 90%) and staging many types of tumors, monitoring therapy response, and differentiating benign from malignant lesions. Several factors, including the relatively high administered activities [e.g., 370-740 MBq (10-20 mCi) of FDG], the high patient throughput (up to 30 patients per d), and in particular, the uniquely high energies (for a diagnostic setting) of the 511-keV positron-negatron annihilation photons, make shielding requirements, workflow, and other radiation protection issues important considerations in the design of a PET or PET-CT facility. The Report of Task Group 108 of the American Association of Physicists in Medicine (AAPM) provides a comprehensive summary of shielding design and related considerations, along with illustrative calculations. Whether in the form of a PET-CT or a SPECT-CT device, the introduction of CT scanners into a nuclear medicine setting has created new and complex radiation protection issues concerning the radiation burden and attendant risks accrued by patients undergoing such multi-modality procedures (especially in those instances in which higher-dose, diagnostic-quality CT studies are done as part of the PET-CT or SPECT-CT exam). In addition, because PET is dependent on the availability of short-lived 18F (Tp = 110 min) primarily in the form of FDG, and other short-lived positron emitters such as 11C (20 min), 13N (10 min), and 15O (2 min), cyclotrons for production of medically applied radionuclides and associated radiochemistry facilities are now widespread (well over 100 worldwide) and present their own radiation safety issues. In addition to the radioactive product, sources of exposure include neutrons and radioactive activation products in the various cyclotron components and surrounding shielding. Nonetheless, published studies have shown that the radiation doses to personnel working in cyclotron and associated radiochemistry facilities, as well as in PET or PET-CT and SPECT or SPECT-CT facilities, can be maintained below, and generally well below, the pertinent regulatory limits. This presentation will review the basic radiation safety aspects, including shielding and workflow, of these increasingly important and increasingly numerous facilities. The radiation burden accrued by the patients undergoing PET-CT or SPECT-CT exams will be considered as well.

RT_Image: An Open-Source Tool for Investigating PET in Radiation Oncology

Positron emission tomography (PET) has emerged as a valuable imaging modality for the diagnosis and staging of cancer. However, despite evidence that PET may be useful for defining target volumes for radiation therapy, no standardized methodology for accomplishing this task exists. To facilitate the investigation of the utility of PET imaging in radiotherapy treatment planning and accelerate its integration into clinical radiation oncology, we have developed software for exploratory analysis and segmentation of functional imaging datasets. The application, RT_Image, allows display of multiple imaging datasets and associated three-dimensional regions-of-interest (ROIs) at arbitrary view angles and fields of view. It also includes semi-automated image segmentation tools for defining metabolically active tumor volumes that may aid creation of target volumes for treatment planning. RT_Image is DICOM compliant, permitting the transfer of imaging data and DICOM-RT structure sets between the application and treatment planning software. RT_Image has been used by radiation oncologists, nuclear medicine physicians, and radiation physicists to analyze over 200 PET datasets. Novel segmentation techniques have been implemented within this programming framework for therapy planning and for evaluation of molecular imaging-derived parameters as prognostic indicators. RT_Image represents a freely-available software base on which further investigations of the utlity of PET and molecular imaging in radiation oncology may be built. The development of tools such as this is critical in order to realize the potential of molecular imaging-guided radiation therapy.

Staging and follow-up of gastrointestinal tumors with PET/CT

Positron emission tomography (PET) is a functional imaging modality that has been documented to be useful in patient care. Oncologic PET imaging is used for a wide variety of neoplasms, mainly for staging and follow-up, differentiation of equivocal morphologic findings, therapy stratification, and monitoring. Because PET imaging is based on the physiologically mediated distribution of the administered tracer but not on anatomic information, the addition of computed tomography (CT) to PET may improve the interpretation of PET. Combined PET and CT offers several potential advantages over PET alone that may influence the clinical routine. PET/CT was introduced into clinical use only 3 years ago and has found widespread application within only 1 to 2 years. This article summarizes preliminary data of clinical applications for PET/CT in gastrointestinal tumors.

Positron emission tomography imaging in oncology

Clinical positron emission tomography (PET) is a molecular imaging method that has recently emerged from being a research tool to a mainstream imaging modality. PET uses a glucose analogue (fluoro-2-deoxy-D-glucose or FDG) tagged with a positron-emitting isotope (radioactive fluorine or 18F), to produce 18F-FDG. 18F-FDG follows the metabolic pathway of glucose throughout the body, with rapid and increased selective uptake in: • pathological tissues (particularly tumours) • inflammatory cells (e.g. granulocytes, macrophages). Whereas other radiopharmaceutical agents usually pass dynamically through the body, 18F-FDG is trapped in these particular cells, allowing the ‘annihilation radiation’ emanating from these sites to be detected. This contribution will discuss the current status of PET imaging in oncology and cardiology.

PET imaging in oncology

The role of positron emission tomography (PET) during the past decade has evolved rapidly from a pure research tool to a methodology of enormous clinical potential. Perhaps the most striking development is the use of PET in oncology. PET imaging is approved in the United States for lung, lymphoma, colon, and melanoma cancer imaging. Data are accumulating rapidly to attest the efficacy of Fluorine-18 fluorodeoxyglucose (FDG) imaging in a wide variety of malignant tumors with sensitivities and specificities often in the high 90s. FDG uptake has been shown in tumors of the head and neck, ovary, breast, musculoskeletal system, and neuroendocrine system as well. The major role of PET has emerged as a reliable method for evaluating and staging recurrent disease. But it also has an important role in differentiating benign and malignant primary tumors. This has been shown particularly well in the differential diagnosis of solitary lung nodules. Although FDG has emerged as the dominant radiopharmaceutical for PET imaging in oncology, numerous other compounds are being evaluated. It is likely that more specific and efficacious compounds will be introduced during the next decade. F-18, because of its highly favorable physical characteristics, is likely to become the technetium of PET imaging. The next decade will witness an explosive growth of PET technology in oncologic imaging.