Synergistic value of single-photon emission computed tomography/computed tomography fusion to radioimmunoscintigraphic imaging of prostate cancer

The rationale on which positron emission tomography/computed tomography (PET/CT) imaging is based, combining the functional features of PET with the anatomic detail of CT, provides many advantages that are easily transferable to single-photon emission computed tomography (SPECT)/CT imaging. Our efforts have focused on applying fused SPECT/CT imaging to identify prostate cancer and its metastasis and recurrence through radioimmunoscintigraphy (RIS). This application of RIS to imaging prostate cancer requires 2 key components: (1) a well-defined target associated with the cancer and (2) a "magic bullet" to seek that target. A well-characterized RIS target for prostate cancer is prostate-specific membrane antigen, or PSMA, and finding the bullet to seek this target with high sensitivity and specificity has been the focus of intensive study for nearly two decades. One of the candidate bullets developed is capromab pendetide, which is a monoclonal antibody that seeks PSMA. This antibody is commercially available as ProstaScint, which can be labeled with indium-111 to localize prostate cancer via SPECT imaging. In the course of applying fused SPECT/CT ProstaScint imaging to more than 800 prostate cancer cases, numerous refinements to our protocol have evolved that are aimed at staging the cancer with utmost accuracy. In addition to optimizing the localization of prostate cancer and its metastasis, these refinements also have been extended toward guiding both the implantation of radioactive seeds in brachytherapy and in other types of radiation therapy which is illustrated through 5 case reports. Progress in the therapeutic targeting of PSMA is also being actively explored, which has more universal ramifications because PSMA is found in the neovasculature of other types of cancers.     

Prosthetic joint infections: radionuclide state-of-the-art imaging

Prosthetic joint replacement surgery is performed with increasing frequency. Overall the incidence of prosthetic joint infection (PJI) and subsequently prosthesis revision failure is estimated to be between 1 and 3%. Differentiating infection from aseptic mechanical loosening, which is the most common cause of prosthetic failure, is especially important because of different types of therapeutic management. Despite a thorough patient history, physical examination, multiple diagnostic tests and complex algorithms, differentiating PJI from aseptic loosening remains challenging. Among imaging modalities, radiographs are neither sensitive nor specific and cross-sectional imaging techniques, such as computed tomography and magnetic resonance imaging, are limited by hardware-induced artefacts. Radionuclide imaging reflects functional rather than anatomical changes and is not hampered by the presence of a metallic joint prosthesis. As a result scintigraphy is currently the modality of choice in the investigation of suspected PJI. Unfortunately, there is no true consensus about the gold standard technique since there are several drawbacks and limitations inherent to each modality. Bone scintigraphy (BS) is sensitive for identifying the failed joint replacement, but cannot differentiate between infection and aseptic loosening. Combined bone/gallium scintigraphy (BS/GS) offers modest improvement over BS alone for diagnosing PJI. However, due to a number of drawbacks, BS/GS has generally been superseded by other techniques but it still may have a role in neutropenic patients. Radiolabelled leucocyte scintigraphy remains the gold standard technique for diagnosing neutrophil-mediated processes. It seems to be that combined in vitro labelled leucocyte/bone marrow scintigraphy (LS/BMS), with an accuracy of about 90%, is currently the imaging modality of choice for diagnosing PJI. There are, however, significant limitations using in vitro labelled leucocytes and considerable effort has been devoted to developing alternative radiotracers, such as radiolabelled HIGs, liposomes, antigranulocyte antibodies and fragments, as well as more investigational tracers such as radiolabelled antibiotics, antimicrobial peptides, bacteriophages and thymidine kinase. On the other hand, positron emission tomography (PET) is still growing in the field of PJI imaging with radiotracers such as ¹⁸F-fluorodeoxyglucose (FDG), ¹⁸F-FDG white blood cells and ¹⁸F-fluoride. But unfortunately this superb tomographic technique will only receive full acceptance when specific PET uptake patterns can be successfully developed. The emergence of hybrid modality imaging using integrated single photon emission computed tomography (SPECT) and PET with computed tomography (SPECT/CT and PET/CT) may also have a contributing role for more accurate assessment of joint replacement complications, especially combined with new radiotracers such as ⁶⁸Ga and ⁶⁴Cu. Finally, in searching for infection-specific tracers, currently there is no such diagnostic agent available.     

PET/CT Imaging and Radioimmunotherapy of Prostate Cancer

Prostate cancer is a common cancer in men and continues to be a major health problem. Imaging plays an important role in the clinical management of patients with prostate cancer. An important goal for prostate cancer imaging is more accurate disease characterization through the synthesis of anatomic, functional, and molecular imaging information. Positron emission tomography (PET)/computed tomography (CT) in oncology is emerging as an important imaging tool. The most common radiotracer for PET/CT in oncology, (18)F-fluorodeoxyglucose (FDG), is not very useful in the imaging of prostate cancer. However, in recent years other PET tracers have improved the accuracy of PET/CT imaging of prostate cancer. Among these, choline labeled with (18)F or (11)C, (11)C-acetate, and (18)F-fluoride has demonstrated promising results, and other new radiopharmaceuticals are under development and evaluation in preclinical and clinical studies. Large prospective clinical PET/CT trials are needed to establish the role of PET/CT in prostate cancer patients. Because there are only limited available therapeutic options for patients with advanced metastatic prostate cancer, there is an urgent need for the development of more effective treatment modalities that could improve outcome. Prostate cancer represents an attractive target for radioimmunotherapy (RIT) for several reasons, including pattern of metastatic spread (lymph nodes and bone marrow, sites with good access to circulating antibodies) and small volume disease (ideal for antigen access and antibody delivery). Furthermore, prostate cancer is also radiation sensitive. Prostate-specific membrane antigen is expressed by virtually all prostate cancers, and represents an attractive target for RIT. Antiprostate-specific membrane antigen RIT demonstrates antitumor activity and is well tolerated. Clinical trials are underway to further improve upon treatment efficacy and patient selection. This review focuses on the recent advances of clinical PET/CT imaging and RIT of prostate cancer.     

Advances in PET myocardial perfusion imaging: F-18 labeled tracers

Coronary artery disease and its related cardiac disorders represent the most common cause of death in the USA and Western world. Despite advancements in treatment and accompanying improvements in outcome with current diagnostic and therapeutic modalities, it is the correct assignment of these diagnostic techniques and treatment options which are crucial. From a diagnostic standpoint, SPECT myocardial perfusion imaging (MPI) using traditional radiotracers like thallium-201 chloride, Tc-99m sestamibi or Tc-99m tetrofosmin is the most utilized imaging technique. However, PET MPI using N-13 ammonia, rubidium-82 chloride or O-15 water is increasing in availability and usage as a result of the growing number of medical centers with new-generation PET/CT systems taking advantage of the superior imaging properties of PET over SPECT. The routine clinical use of PET MPI is still limited, in part because of the short half-life of conventional PET MPI tracers. The disadvantages of these conventional PET tracers include expensive onsite production and inconvenient on-scanner tracer administration making them unsuitable for physical exercise stress imaging. Recently, two F-18 labeled radiotracers with longer radioactive half-lives than conventional PET imaging agents have been introduced. These are flurpiridaz F 18 (formerly known as F-18 BMS747158-02) and F-18 fluorobenzyltriphenylphosphonium. These longer half-life F-18 labeled perfusion tracers can overcome the production and protocol limitations of currently used radiotracers for PET MPI.     

Role of fusion in radiotherapy treatment planning

The fusion of functional imaging to traditional imaging modalities, such as computed tomography (CT) and magnetic resonance imaging (MRI), is currently being investigated in radiotherapy treatment planning. Most studies that have been reported are in patients with lung, brain, or head and neck neoplasms. There is a potential role for either positron emission tomography (PET) or single photon emission computed tomography (SPECT) to delineate biologically active or tumor-bearing areas that otherwise would not be detected by CT or MRI. Furthermore, target volumes may be modified by using functional imaging, which can have a significant impact in the modern era of three-dimensional radiotherapy. SPECT may also be able to identify "nonfunctional" surrounding tissue and may influence radiotherapy beam arrangement.     

Review of functional/anatomical imaging in oncology

Patient management in oncology increasingly relies on imaging for diagnosis, response assessment, and follow-up. The clinical availability of combined functional/anatomical imaging modalities, which integrate the benefits of visualizing tumor biology with those of high-resolution structural imaging, revolutionized clinical management of oncologic patients. Conventional high-resolution anatomical imaging modalities such as computed tomography (CT) and MRI excel at providing details on lesion location, size, morphology, and structural changes to adjacent tissues; however, these modalities provide little insight into tumor physiology. With the increasing focus on molecularly targeted therapies, imaging radiolabeled compounds with PET and single-photon emission tomography (SPECT) is often carried out to provide insight into a tumor's biological functions and its surrounding microenvironment. Despite their high sensitivity and specificity, PET and SPECT alone are substantially limited by low spatial resolution and inability to provide anatomical detail. Integrating SPECT or PET with a modality capable of providing these (i.e. CT or MR) maximizes their separate strengths and provides anatomical localization of physiological processes with detailed visualization of a tumor's structure. The availability of multimodality (hybrid) imaging with PET/CT, SPECT/CT, and PET/MR improves our ability to characterize lesions and affect treatment decisions and patient management. We have just begun to exploit the truly synergistic capabilities of multimodality imaging. Continued advances in the development of instrumentation and imaging agents will improve our ability to noninvasively characterize disease processes. This review will discuss the evolution of hybrid imaging technology and provide examples of its current and potential future clinical uses.     

The Current Status of SPECT or SPECT/CT in South Korea

The first step to nuclear medicine in Korea started with introduction of the gamma camera in 1969. Although planar images with the gamma camera give important functional information, they have the limitations that result from 2-dimensional images. Single-photon emission computed tomography (SPECT) due to its 3-dimensional image acquisition is superior to earlier planar gamma imaging in image resolution and diagnostic accuracy. As demand for a hybrid functional and anatomical imaging device has increased, integrated SPECT/CT systems have been used. In Korea, SPECT/CT was for the first time installed in 2003. SPECT/CT can eliminate many possible pitfalls on SPECT-alone images, making better attenuation correction and thereby improving image quality. Therefore, SPECT/CT is clinically preferred in many hospitals in various aspects. More recently, additional SPECT/CT images taken from the region with equivocal uptake on planar images have been helpful in making precise interpretation as part of their clinical workup in postoperative thyroid cancer patients. SPECT and SPECT/CT have various advantages, but its clinical application has gradually decreased in recent few years. While some researchers investigated the myocardial blood flow with cardiac PET using F-18 FDG or N-13 ammonia, myocardial perfusion SPECT is, at present, the radionuclide imaging study of choice for the risk stratification and guiding therapy in the coronary artery disease patients in Korea. New diagnostic radiopharmaceuticals for AD have received increasing attention; nevertheless, brain SPECT will remain the most reliable modality evaluating cerebral perfusion.     

Targeted molecular imaging in oncology

Improvement of scintigraphic tumor imaging is extensively determined by the development of more tumor specific radiopharmaceuticals. Thus, to improve the differential diagnosis, prognosis, planning and monitoring of cancer treatment, several functional pharmaceuticals have been developed. Application of molecular targets for cancer imaging, therapy and prevention using generator-produced isotopes is the major focus of ongoing research projects. Radionuclide imaging modalities (positron emission tomography, PET; single photon emission computed tomography, SPECT) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclide-labeled radiotracers. 99mTc- and 68Ga-labeled agents using ethylenedicysteine (EC) as a chelator were synthesized and their potential uses to assess tumor targets were evaluated. 99mTc (t1/2 = 6 hr, 140 keV) is used for SPECT and 68Ga (t1/2 = 68 min, 511 keV) for PET. Molecular targets labeled with Tc-99m and Ga-68 can be utilized for prediction of therapeutic response, monitoring tumor response to treatment and differential diagnosis. Molecular targets for oncological research in (1) cell apoptosis, (2) gene and nucleic acid-based approach, (3) angiogenesis (4) tumor hypoxia, and (5) metabolic imaging are discussed. Numerous imaging ligands in these categories have been developed and evaluated in animals and humans. Molecular targets were imaged and their potential to redirect optimal cancer diagnosis and therapeutics were demonstrated.     

Evolution of brain imaging instrumentation

Computed tomography (CT) and static magnetic resonance imaging (MRI) are now the most common imaging modalities used for anatomic evaluation of pathologic processes affecting the brain. By contrast, radionuclide-based methods, including planar imaging, single-photon emission computed tomography (SPECT), and positron emission tomography (PET), are the most widely used methods for evaluating brain function. SPECT and PET have been evolving for a longer time than CT and MRI and have made significant contributions to understanding brain function. The pioneering work on cerebral flow early in the last century laid the foundation of measurement with radioactive gases. This was initially performed with scintillation counters, which gave way to single, then multiple scintillation and multiprobe detectors. The invention of rectilinear scanners, MARK series, Anger cameras, and SPECT imaging further advanced nuclear medicine's role in brain imaging. Measurement of regional cerebral blood flow by SPECT provides pathophysiologic information that directs patient management in a variety of central nervous disorders (CNS), with the greatest clinical impact found in cerebrovascular disease and seizure disorder. In the former, SPECT not only provides means of early detection and localization of acute strokes but can also direct thrombolysis and determine prognosis in the postcerebrovascular accident period. With respect to the latter, ictal SPECT can localize seizure foci so that patients with refractory disease can potentially undergo surgical resection of the affected area. In contrast to brain SPECT, brain PET images reflect regional cerebral metabolism. Because of neurovascular coupling, findings on SPECT and PET images are often comparable. PET, however, still has improved spatial resolution and is therefore more sensitive than SPECT, particularly in the evaluation of dementias. Brain PET instrumentation has greatly evolved from its infancy, when it was used in regional localization, to currently providing excellent resolution with imaging characteristics that can greatly impact clinical management. In addition, although ictal SPECT remains more sensitive than interictal PET for detection of seizure foci, the stringent conditions required for SPECT can be difficult to achieve, making interictal PET a very reasonable alternative. The clinical utility of PET and SPECT in neuropsychiatric and addictive disorders has not yet been defined, though a plethora of data exits. This arena of CNS disease has been the impetus for development of neurotransmitter-receptor-specific radioligands, which have already led to better understanding of dopaminergic, GABAergic, and serotonergic pathways. Another functional brain imaging technique that has gained broad acceptance since its invention in the early 1990 s, is functional MRI, which indirectly measures CNS neuronal activity by evaluating oxygenation levels of cerebral vessels. Despite other recent related developments, such as MR spectroscopy, arterial spin labeling, and diffusion tensor imaging, nuclear medicine-based techniques remain clinically relevant and robust modalities, especially with the ever-expanding armamentarium of radiotracers and radioligands in conjunction with industry-driven improvements in image-analysis hardware and software.     

Emerging Tracers for Nuclear Cardiac PET Imaging

Myocardial perfusion imaging using positron emission tomography (PET) has several advantages over single photon emission computed tomography (SPECT). The recent advances in SPECT technology have shown promise, but there is still a large need for PET in the clinical management of coronary artery disease (CAD). Especially, absolute quantification of myocardial blood flow (MBF) using PET is extremely important. In spite of considerable advances in the diagnosis of CAD, novel PET radiopharmaceuticals remain necessary for the diagnosis of CAD because clinical use of current cardiac radiotracers is limited by their physical characteristics, such as decay mode, emission energy, and half-life. Thus, the use of a radioisotope that has proper characteristics and a proper half-life to develop myocardial perfusion agents could overcome these limitations. In this review, the current state of cardiac PET and a general overview of novel ¹⁸F or ⁶⁸Ga-labeled radiotracers, including their radiosynthesis, in vivo characterization, and evaluation, are provided. The future perspectives are discussed in terms of their potential usefulness based on new image analysis methods and hybrid imaging.     

Technological development and advances in single-photon emission computed tomography/computed tomography

Single-photon emission computed tomography/computed tomography (SPECT/CT) has emerged during the past decade as a means of correlating anatomical information from CT with functional information from SPECT. The integration of SPECT and CT in a single imaging device facilitates anatomical localization of the radiopharmaceutical to differentiate physiological uptake from that associated with disease and patient-specific attenuation correction to improve the visual quality and quantitative accuracy of the SPECT image. The first clinically available SPECT/CT systems performed emission-transmission imaging using a dual-headed SPECT camera and a low-power x-ray CT subsystem. Newer SPECT/CT systems are available with high-power CT subsystems suitable for detailed anatomical diagnosis, including CT coronary angiography and coronary calcification that can be correlated with myocardial perfusion measurements. The high-performance CT capabilities also offer the potential to improve compensation of partial volume errors for more accurate quantitation of radionuclide measurement of myocardial blood flow and other physiological processes and for radiation dosimetry for radionuclide therapy. In addition, new SPECT technologies are being developed that significantly improve the detection efficiency and spatial resolution for radionuclide imaging of small organs including the heart, brain, and breast, and therefore may provide new capabilities for SPECT/CT imaging in these important clinical applications.     

Hybrid cardiac imaging: SPECT/CT and PET/CT. A joint position statement by the European Association of Nuclear Medicine (EANM), the European Society of Cardiac Radiology (ESCR) and the European Council of Nuclear Cardiology (ECNC)

Improvements in software and hardware have enabled the integration of dual imaging modalities into hybrid systems, which allow combined acquisition of the different data sets. Integration of positron emission tomography (PET) and computed tomography (CT) scanners into PET/CT systems has shown improvement in the management of patients with cancer over stand-alone acquired CT and PET images. Hybrid cardiac imaging either with single photon emission computed tomography (SPECT) or PET combined with CT depicts cardiac and vascular anatomical abnormalities and their physiologic consequences in a single setting and appears to offer superior information compared with either stand-alone or side-by-side interpretation of the data sets in patients with known or suspected coronary artery disease (CAD). Hybrid systems are also advantageous for the patient because of the single short dual data acquisition. However, hybrid cardiac imaging has also generated controversy with regard to which patients should undergo such integrated examination for clinical effectiveness and minimization of costs and radiation dose, and if software-based fusion of images obtained separately would be a useful alternative. The European Association of Nuclear Medicine (EANM), the European Society of Cardiac Radiology (ESCR) and the European Council of Nuclear Cardiology (ECNC) in this paper want to present a position statement of the institutions on the current roles of SPECT/CT and PET/CT hybrid cardiac imaging in patients with known or suspected CAD.     

SPECT/CT in the Treatment of Differentiated Thyroid Cancer

Single-photon emission computed tomography with integrated computed tomography (SPECT/CT) systems has been applied in a wide range of clinical circumstances, and differentiated thyroid cancer (DTC) is one of the most important indications of SPECT/CT imaging. In the treatment of DTC, SPECT/CT images have been reported to have many advantages over conventional planar whole-body scintigraphy based on its precise localization and characterization of abnormal foci of radioactive iodine (RAI) accumulation, influencing the staging, risk stratification, and clinical management as well as reader confidence. On the other hand, SPECT/CT has limitations including additional radiation exposure from the CT component, additional imaging time, and cost-related issues. Each SPECT/CT image acquired at different time points throughout the management of DTC may have a different clinical meaning and significance. This review article addresses the clinical usefulness of RAI SPECT/CT images acquired during the pre-ablation period, post-therapy period, and long-term follow-up period, respectively.     

Bildgebende Methoden in der onkologischen Diagnostik

Cross-sectional imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) CT are an integral part of the modern oncological workup. They are used for tumor detection and staging as well as for treatment evaluation and monitoring. Due to pathophysiological and histological differences there is no universal imaging protocol for the assessment of different forms of cancer. For instance, CT is still the standard technique for the detection and staging of lung cancer supplemented by PET which aids the exclusion of nodal involvement and the detection of distant metastases. For hepatocellular carcinoma on the other hand, MRI is the preferred imaging technique, particularly when used in conjunction with liver-specific contrast media - PET/CT is only of limited value. Finally, for neuroendocrine tumors there is a focus on special radiotracers, which, in the context of PET/CT, enable a highly specific whole-body assessment. Thus, knowledge of the pathophysiological and imaging characteristics of different tumors is essential for a personalized, state-of-the art management of oncology patients.     

New horizons in cardiac innervation imaging: introduction of novel <Superscript>18</Superscript>F-labeled PET tracers

Cardiac sympathetic nervous activity can be uniquely visualized by non-invasive radionuclide imaging techniques due to the fast growing and widespread application of nuclear cardiology in the last few years. The norepinephrine analogue ¹²³I–meta-iodobenzylguanidine (¹²³I–MIBG) is a single photon emission computed tomography (SPECT) tracer for the clinical implementation of sympathetic nervous imaging for both diagnosis and prognosis of heart failure. Meanwhile, positron emission tomography (PET) imaging has become increasingly attractive because of its higher spatial and temporal resolution compared to SPECT, which allows regional functional and dynamic kinetic analysis. Nevertheless, wider use of cardiac sympathetic nervous PET imaging is still limited mainly due to the demand of costly on-site cyclotrons, which are required for the production of conventional ¹¹C-labeled (radiological half-life, 20 min) PET tracers. Most recently, more promising ¹⁸F-labeled (half-life, 110 min) PET radiopharmaceuticals targeting sympathetic nervous system have been introduced. These tracers optimize PET imaging and, by using delivery networks, cost less to produce. In this article, the latest advances of sympathetic nervous imaging using ¹⁸F-labeled radiotracers along with their possible applications are reviewed.     

<Superscript>68</Superscript>Ga-PSMA-PET: added value and future applications in comparison to the current use of choline-PET and mpMRI in the workup of prostate cancer

Positron emission tomography (PET) has been commonly and successfully used, in combination with computed tomography (CT) and more recently magnetic resonance (MRI), in the workup of intermediate or high-risk prostate cancer (PCa). Nowadays, new specific receptor targeted PET tracers in prostate cancer imaging have been introduced; one of the most used is ⁶⁸Ga-PSMA, that evaluates the expression of prostate-specific membrane antigen (PSMA). This tracer has been rapidly taken into account for its better sensitivity and specificity compared to lipid metabolism tracers, such as ¹¹C/¹⁸F labelled fluorocholine. Besides, in the era of theranostics, this tracer is having a useful application not only for imaging but also for therapeutic purposes. The aim of this review article is, in the first part, to give an overview of the main indications and future development of ⁶⁸Ga-PSMA imaging, using PET/CT or PET/MRI, according to the clinical course of the disease and in view of the current use of multiparametric MRI (mpMRI) and choline PET in the management of PCa. In the second part, a brief overview of the promising ¹⁸F-labelled PSMA tracers and the current use of PSMA radionuclide therapy will be provided.     

Fusion images of Tl-201 SPECT and FDG PET with CT in detection of cervical carcinoma with bladder invasion

Thallium-201 single-photon emission computed tomography (Tl-201 SPECT) and F-18 fluorodeoxyglucose positron emission tomography (FDG PET) are accurate and excellent methods for detecting malignant tumors and related metabolic abnormalities. However, there are still some limitations in clinical application. The major limitation of SPECT is poor image resolution. PET is less sensitive for detecting lesions of the urinary system adjacent to the bladder because of bladder radioactivity. Both T1-201 and F-18 FDG PET often provide less information than x-ray computed tomography (CT) about the anatomic landmarks needed to precisely locate lesions. Recent development of multimodality image registration and fusion has been shown to be an excellent tool to resolve these drawbacks. The authors present a rare case of residual cervical carcinoma with bladder invasion, which was detected by fusion imaging of Tl-201 SPECT and FDG PET with CT. This noninvasive image technique may become a valuable alternative to identify bladder invasion in cervical cancer.     

Two more cases of evaluation of POEMS syndrome using 18-FDG PET/CT

Following the article of Alberti et al., we would like to provide our own experience with two more cases in evaluation of POEMS syndrome using morphological and functional imaging modalities, including plain X-rays, computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy and positrons emission tomography with computed tomography (PET/CT). Among them, 18-FDG PET/CT proved its usefulness allowing extensive screening of the bony lesions involved.