Towards enhanced PET quantification in clinical oncology.

Background: Positron emission tomography (PET) imaging in epilepsy is an in vivo technique that allows the localization of a possible seizure onset zone (SOZ) during the interictal period. Stereo-electro-encephalography (SEEG) is the gold standard to define the SOZ. The objective of this research was to evaluate the accuracy of PET imaging in localizing the site of SOZ compared with SEEG. Methods: Seven patients with refractory temporal lobe epilepsy (Ep) and 2 healthy controls (HC) underwent 2 PET scans, one with 2-[¹⁸F]-fluoro-2-deoxy-D-glucose (FDG) and another with 2’-[¹⁸F]fluoroflumazenil (FFMZ), acquired 1 day apart. FDG was acquired for 10 min (static scan) 1 h after administration. An FFMZ scan was acquired for 60 min from radiopharmaceutical administration in a dynamic mode. Each brain PET image was segmented using a standard template implemented in PMOD 3.8. The pons was used as the reference region for modeling of the nondisplaceable binding potential (BP_ND)for FFMZ, and to obtain uptake ratios for FDG. SEEG studies of patients were performed as a part of their surgical evaluation to define the SOZ. Results: Well-defined differences between HC and Ep were found with both radiopharmaceuticals, showing the utility to identify abnormal brain regions using quantitative PET imaging. Lateralization of the SOZ findings by PET (lower uptake/binding in a specific brain hemisphere) matched in 86% for FFMZ and 71% for FDG with SEEG data. Conclusion: Quantitative PET imaging is an excellent complementary tool that matches reasonably well with SEEG to define SOZ in presurgical evaluation.

Small-animal positron emission tomography as a tool for neuropharmacology

Purpose: Positron Emission Tomography (PET) images show physiological and biological information through the in vivo distribution of radioactive, positron‐emitting agents. PET imaging shows focal and distributed regions of cancer and its metastases. Initial PET uses in oncology include diagnosis and staging, which are important for determining treatment decisions. Current PET uses now include target definition for radiation planning followed by PET‐based assessment of treatment. Hybrid PET‐CT devices are beginning to be used as radiation treatment simulators. Method and Materials: F‐18‐labled Fluoro‐deoxyglucose (F‐18 FDG) is the most commonly used PET imaging agent. FDG shows regions of active glucose metabolism, such as local cancer, metastases, non‐cancer inflammation, and normal glucose use. Non‐FDG PET agents can be more specific in cell targeting (binding), and can image different aspects of tumor biology, like hypoxia (FMISO, CuATSM) and cell proliferation (FLT). Results: PET imaging has coarse spatial resolution compared to CT and MR. PET's clinical use is valued because of its great sensitivity for cancer detection. Voxel intensity and image fidelity depend on equipment design, patient size, anatomic site, and imaging study parameters. PET‐CT units enable CT‐based attenuation corrections and inclusion of CT information in a registered PET‐CT dataset. The Standardized Uptake Value (SUV) is a normalized intensity measure for quantitative indication of disease, and can be used to identify disease or possibly for target delineation, with certain limitations. While FDG remains the most promising agent for tumor detection, other, biologically more specific agents (e.g., FMISO, CuATSM for hypoxia imaging or FLT for cell proliferation imaging) might be more appropriate for target delineation and treatment assessment. Conclusion: This course reviews PET‐CT hybrid scanning devices, uses of FDG and non‐FDG PET for oncology imaging, and quantitative aspects for PET‐based radiation target definition and treatment assessment. Example images demonstrate the potential contributions and limitations of FDG and non‐FDG PET oncology imaging. This review course is intended for both imaging and radiation oncology physicists.Educational Objectives:1. Describe FDG PET imaging and oncologic indications.2. Review the uses and limitations of PET images in radiation treatment.3. Describe the SUV and other threshold parameters for target delineation.4. Review non‐FDG PET imaging of tumor biology.5. Discuss quantitative aspects of PET imaging for treatment assessment.

Respiratory motion blurs positron emission tomography (PET) images in thorax and abdominal regions, and can cause attenuation-related errors in quantitative parameters. In addition, this motion can cause localization error and disappearance of tumor(s) near the diaphragm. Respiratory gated PET imaging, or 4D PET imaging, is an attractive solution. For 4D PET, a surrogate measurement of the patient's breathing is made during the scan, and based on this measurement the list-mode PET data are sorted and reconstructed into multiple images. In several studies, it has been reported that 4D PET imaging recovers tumor volume more accurately than 3D PET imaging, and yields more accurate standard uptake values. In spite of its promise, 4D PET images suffer from statistical noise because only a fraction of the acquired data can be used in each image. Moreover, they also suffer from inconsistent attenuation correction due to mismatches between PET and CT images. In this paper, we propose a novel framework for phased attenuation correction and respiratory motion compensation for a 3D PET image by using a 3D CT image and multiple respiratory-phase 3D MR images. For phased attenuation correction, we generate and utilize 4D CT image obtained via non-rigid registrations among a 3D CT image and multiple respiratory-phase 3D MR images. A 3D PET image at a selected respiratory phase is then obtained by adding attenuation corrected multiple 3D PET images through non-rigid transformation. Experimental result for a clinical dataset shows that the proposed algorithm can provide much clearer organ boundary with improved quality than the conventional method in a 3D PET image.

Whole-body positron emission tomography (PET) with F-fluorodeoxyglucose (FDG) has proven to be a very effective staging imaging modality in manymalignant tumours, particularly in lung cancer, malignant melanoma, lymphoma, colorectal cancer and head and neck tumours [1–7]. Since PET images have a fairly high resolution (,6 mm), even small lesions with an increased FDG uptake can be detected. This represents a critical advantage of PET over the conventional cross-sectional imaging modalities CT and MRI. PET can be used to identify tumour tissue on the basis of FDG uptake, rather than on the basis of morphological appearance or size, and thus also in lesions with a size less than 1 cm. Unfortunately, FDG–PET provides little anatomical information, and therefore it is sometimes difficult to determine where the lesions detected are located and what they represent. It is important for the surgeon to know precisely where lesions are located, especially for small tumours. Currently, comparison and juxtaposition of PET images and CT images serves to define the localization of the lesions. Owing to the different image slice thickness, the different positioning of the patient during the two examinations and the different states of nutrition, i.e. fasting for 4 h prior to FDG–PET, it is often very difficult and time consuming to match the images for exact anatomical localization. Image co-registration has been used to overcome these problems [8]. It has been recognized that proper image co-registration is rather difficult for whole-body examinations with separate scanners. For identical patient positioning during PET and CT scanning, special ‘‘cast forming’’ vacuum mattresses or other immobilization methods should be used. However, patients frequently find these methods of immobilization uncomfortable. Logistic problems also limit the use of image co-registration of PET and CT with separate scanners. Scheduling problems arise when performing the two examinations one after the other. These limitations restrict image co-registration with separate scanners to individual cases. In our experience, the exact localization of lesions is often not possible when juxtaposing PET and CT images. Examinations had to be repeated for exact image co-registration. As a result, image co-registration with separate scanners has never become routine in our practice. To overcome the problems related to software fusion, various prototype systems combining molecular and morphologic imaging have been developed. Hasegawa and colleagues proposed an integrated SPECT/CT scanner [9], and in 1999 Townsend and his colleagues at the University of Pittsburgh presented a prototype integrated PET/CT scanner by combining a CT scanner and a partial ring, rotating PET scanner in a single gantry [10, 11]. Such systems are attractive not only because of the ‘‘hardware’’ image coregistration capabilities but also because the CT data can be used to correct PET scans for patient self-absorption of the PET emission rays. This decreases the acquisition time for the correcting attenuation scans by an order of magnitude compared with the conventional techniques used in PET for this purpose, and decreases the overall imaging time by up to 30% depending on the CT system used. In March 2001, the first clinical integrated PET/ CT device (Discovery LS, GE Medical Systems, Milwaukee, USA) was installed at the University Hospital of Zurich in Switzerland. This novel inline system consists of a dedicated high resolution/ high sensitivity full-ring PET scanner (Advance Nxi) and a very fast high-end multi-detector spiral CT scanner (Light Speed Plus). The axes of both systems are mechanically aligned so that simple translation of the patient table by 60 cm moves the patient from the CT into the PET gantry. The resulting PET and CT images are ‘‘hardware’’ coregistered to an accuracy in the range of 1 mm. Data acquisition in the combined system is as follows. At 45–55 min post-injection of FDG and after bladder emptying a multidetector computed tomography scan is performed from the pelvic floor to the head (scan length, 86.7 cm) and normal end-expiration. Immediately after CT scanning, a PET emission scan is obtained covering the identical axial field of view using six PET fields of view. The acquisition time is 4 min at each table position. With this protocol it is The British Journal of Radiology, 75 (2002), S36–S38 E 2002 The British Institute of Radiology

Since its inception, positron emission tomography (PET) has emerged as a non-invasive imaging modality that allows, in different fields (neurology, cardiology and oncology), in vivo quantitative assessment of molecular and physiological biomarkers in healthy and disease states [1–4]. Quantitative analysis makes it possible to establish a direct relationship between the time-varying activity concentration in organs/tissues of interest and the functional parameters representing the underlying biological processes at the cellular level [5–8]. It should, however, be emphasized that the term quantification has often been used inappropriately in the medical imaging literature to indicate different measurement approaches such as [5]: (1) semi-quantification (a contradiction in terms) or relative quantification (e.g., measurement of SUV), (2) absolute quantification of activity concentration, usually incorporating careful corrections for physical degrading factors (e.g., measurement of tracer uptake in MBq), and (3) proper physiological quantification, where the absolute activity concentration [obtained in (2)] is converted into molecular parameters of interest [e.g., glucose metabolic rate (rGMCglc) expressed as mol/100 g/min]. The concentration of tracers in organs/tissues of interest depends on their specific kinetic properties, i.e., various factors including, but not limited to, the rate of delivery through circulation, the biochemical reactions involved in the specific biological process under examination, biological clearance, and so on. Furthermore, the measurement of radioactivity in volumes of interest must take into account the physical half-life of the radionuclide employed for the pharmaceutical labeling. These physiological and physical factors must be fully taken into consideration if quantitative PET is to realize its full potential, and thus allow assessment of the physiological and molecular characteristics of the cells and organs/tissues under examination. Using these approaches, it is possible to quantify a number of processes, including the rate of glucose utilization, receptor binding, receptor occupancy, and so on. The resulting estimates can then be linked to clinical outcomes (e.g., disease evolution, response to treatment, survival) so that disease activity can be assessed and related to the underlying pathological states. Moreover, these quantitative measures can provide surrogate endpoints in therapy trials. The major challenges to quantitative preclinical PET imaging, when the aim is to quantify biological or pharmacokinetic processes, can be categorized in five classes [9, 10]:

Lung cancer is responsible for 32% of all cancer deaths in men and 25% in women in the United States It also ranked first in women(17.3%)and ranked second in men(23.2%)of cancer death here in Taiwan. The incidence of lung cancer is still increasing globally. In United States, despite the curative intention to treat the disease, about 6% of patients are unresectable at surgery and 14% die in one year. Improvement of the diagnostic strategy in lung cancer is thus needed. Positron emission tomography(PET)imaging can reflect the biochemical processes in cancers. Due to the high cancer-to-background ratio in lung parenchyma, 2-[18F]fluoro-2-deoxy-D-glucose(FDG)has become the most commonly used radiopharmaceutical in the clinical oncology. The clinical applications of FDG PET imaging has moved beyond the clinical diagnosis and initial staging for lung cancer. The current applications of PET and especially PET-CT focus on the treatment planning for lung cancer. Continued advances in computer, electronic and crystal technology and development of new biotracers have resulted in improved management of lung cancer by functional PET imaging in the diagnosis, staging, treatment planning and evaluation of therapeutic responses. PET and PET-CT has moved into the main stream of clinical applications, which may prove to impact greatly on the patient survival in the years to come.

Medical imaging has undergone a revolution in the past decade. This is largely due to improved technology involving all the major imaging modalities: MRI, computed tomography (CT), positron emission tomography (PET), ultrasound, and optical imaging. These advances and improvements in technology are being rapidly translated into the clinic and have established new standards of medical practice. Cancer imaging was identified as one of six “extraordinary scientific opportunities” by the National Cancer Institute in 1997–1998, and the institute’s subsequent funding initiatives have provided a major stimulus for further developments. A major target of these initiatives has been development of and support for molecular imaging. Molecular-genetic imaging provides visualization in space and time of normal as well as abnormal cellular processes at a molecular or genetic level. Needless to say, current gamma camera, PET, MRI, and optical technologies do not visualize individual cells, much less molecules. Perhaps the most exciting aspect of this emerging new field are the novel imaging paradigms being developed — paradigms that image molecular-genetic processes rather than anatomy. These paradigms can be successful within the inherent spatial-resolution limits of existing imaging systems, provided that the volume element, or voxel, of the tissue (cells) is relatively homogenous. This review will focus primarily on radionuclide imaging, although many of the principles described are directly applicable to optical and MRI technology as well. A more extensive discussion of these issues was recently published (1). Molecular imaging has its roots in molecular biology and cell biology as well as in imaging technology. Three different noninvasive, in vivo imaging technologies have developed more or less in parallel: (a) MRI (2–6); (b) nuclear imaging (quantitative autoradiography, gamma camera, and PET) (7–11); and (c) optical imaging of small animals (12–14). The convergence of these disciplines is at the heart of the molecular imaging success story and constitutes the wellspring for further advances in the field. The development of versatile and sensitive assays that do not require tissue samples will be of considerable value for monitoring of molecular-genetic and cellular processes in animal models of human disease, as well as for studies in human subjects. Noninvasive imaging of molecular-genetic and cellular processes will complement established ex vivo molecular-biological assays that require tissue sampling; it also provides a spatial as well as a temporal dimension to our understanding of various diseases.

Cardiac positron emission tomography imaging

Positive Positron Emission Tomography (PET) Scan in Non-Hodgkin Lymphoma Pre-Transplant Had No Impact On Relapse and Survival After Allogenenic Transplantation

To assess and account for the impact of respiratory motion on the variability of activity and volume determination of liver tumor in positron emission tomography (PET) through a comparison between free-breathing (FB) and respiration-suspended (RS) PET images. As part of a PET/computed tomography (CT) guided percutaneous liver ablation procedure performed on a PET/CT scanner, a patient's breathing is suspended on a ventilator, allowing the acquisition of a near-motionless PET and CT reference images of the liver. In this study, baseline RS and FB PET/CT images of 20 patients undergoing thermal ablation were acquired. The RS PET provides near-motionless reference in a human study, and thereby allows a quantitative evaluation of the effect of respiratory motion on PET images obtained under FB conditions. Two methods were applied to calculate tumor activity and volume: (1) threshold-based segmentation (TBS), estimating the total lesion glycolysis (TLG) and the segmented volume and (2) histogram-based estimation (HBE), yielding the background-subtracted lesion (BSL) activity and associated volume. The TBS method employs 50% of the maximum standardized uptake value (SUVmax) as the threshold for tumors with SUVmax≥2× SUVliver-bkg, and tumor activity above this threshold yields TLG50%. The HBE method determines local PET background based on a Gaussian fit of the low SUV peak in a SUV-volume histogram, which is generated within a user-defined and optimized volume of interest containing both local background and lesion uptakes. Voxels with PET intensity above the fitted background were considered to have originated from the tumor and used to calculate the BSL activity and its associated lesion volume. Respiratory motion caused SUVmax to decrease from RS to FB by -15%±11% (p=0.01). Using TBS method, there was also a decrease in SUVmean (-18%±9%, p=0.01), but an increase in TLG50% (18%±36%) and in the segmented volume (47%±52%, p=0.01) from RS to FB PET images. The background uptake in normal liver was stable, 1%±9%. In contrast, using the HBE method, the differences in both BSL activity and BSL volume from RS to FB were -8%±10% (p=0.005) and 0%±16% (p=0.94), respectively. This is the first time that almost motion-free PET images of the human liver were acquired and compared to free-breathing PET. The BSL method's results are more consistent, for the calculation of both tumor activity and volume in RS and FB PET images, than those using conventional TBS. This suggests that the BSL method might be less sensitive to motion blurring and provides an improved estimation of tumor activity and volume in the presence of respiratory motion.

An important aspect of positron emission tomography (PET) imaging in a clinical application is the localization and detection of tumors and lesions by administering a predetermined amount of radiotracer. This allows detailed 3D imaging of a wide range of molecular processes in the human body. The quality of the PET image is dependent on the amount of radiotracer administrated and the patient’s body parameters. As the amount of injected radiotracer increases, an overall improvement in the quality of the reconstructed PET images and lesion detectability is expected, but it is accepted that any radiotracer doses are associated with the risk of radiation and it could be harmful to the patient if essential PET imaging is not performed because of the fear of radiation risk. To ensure the highest-quality diagnosis and the smallest radiation risk, the patient should receive the smallest amount of radiotracer that provides an image of sufficient quality. Our study proposed a PET simulation tool to predict the smallest amount of radiotracer that allows for a reliable diagnosis based on patients’ significant body parameters (weight, age) within a fixed total scan time to improve diagnostic processes for detecting and localizing tumors. We built a model of a particular PET scanner and patient, based on real MRI images and a digital anthropomorphic phantom of the brain. We performed Monte Carlo simulations of PET data acquisitions. A dataset of 60 patients was used, and 11 independent dose prediction simulations were performed for each patient. We concluded that our simulator estimated injected radiotracer doses 28% smaller than the standard clinical doses that yielded PET images of clinically acceptable quality. We also found that the total injected radiotracer dose for adult patients was affected by considering the patient’s weight rather than age.

The oncogene c-Met is a clinically validated target having been shown to be involved in tumorigenesis. Imaging agents capable of quantifying c-Met expression in human tumors would be a valuable tool for aiding diagnosis, drug scheduling and monitoring the response to targeted therapies. Anticalins are a novel class of biopharmaceuticals based on the human lipocalin scaffold with many properties which make them desirable imaging agents including their smaller size and ease of manufacturing when compared to antibodies. PRS-110 is a c-Met specific anticalin which is being developed as a therapeutic and imaging modality. The aim of this study was to evaluate the utility of the c-Met anticalin as a positron emission tomography (PET) imaging agent and analyze its biodistribution in human tumor bearing mice. Methods: A zirconium-89 (89Zr) labeled version of PRS-110 was generated and biodistribution studies were performed 96 h after single dose injection of the tracer (10 to 500 μg) into Balb/c mice bearing subcutaneous c-Met expressing human H441 non-small cell lung cancer tumors. PET imaging was executed at 6, 24, 48 and 96 h after injection of 50 μg 89Zr-PRS-110 to mice bearing H441 (c-Met ++), primary glioblastoma U87-MG (c-Met +) or ovarian cancer A2780 (c-Met -) xenografts. After the final scan, biodistribution analysis was performed. The excised tumors were analyzed for c-Met expression by immunohistochemistry and fluorescent PRS-110-800CW distribution by fluorescence microscopy. Results: Biodistribution analyses showed a PRS-110 dose-dependent 89Zr-PRS-110 H441-tumor uptake, with the highest tumor uptake at 10 μg PRS-110 resulting in 7.5 %ID/g at 96 h after tracer injection. MicroPET imaging revealed specific tumor uptake of 89Zr-PRS-110 in the c-Met expressing H441 and U87 tumors while imaging of the c-Met negative A2780 tumor model showed background level similar to a non-specific anticalin control. Biodistribution data supported the microPET findings, showing ex vivo tumor uptake of 89Zr-PRS-110 of 5.9, 1.8 and 1.7 %ID/g in H441, U87 and A2780 xenografts respectively, which correlated with c-Met expression levels. Tumor : blood ratios of 89Zr-PRS-110 compared to 89Zr-Tlc-PEG confirmed these finding. Ex vivo fluorescence revealed intracellular presence of PRS-110 96 h after tracer injection. Conclusion: 89Zr-PRS-110 specifically accumulates in c-Met expressing tumors. PET imaging with this tracer provides real-time non-invasive information about PRS-110 distribution and tumor accumulation. This makes 89Zr-PRS-110, which is ready for clinical evaluation, of interest for the clinical development of PRS-110. Citation Format: Anton G.T. Terwisscha van Scheltinga, Elisabeth G.E. de Vries, Marlon Hinner, Remy B. Verheijen, Andrea Allesdorfer, Laurent Audoly, Wouter B. Nagengast, Carolien P. Schröder, Martin Hülsmeyer, Jos G.W. Kosterink, Marjolijn N. Lub-de Hooge, Shane A. Olwill. Next generation PET imaging agents: The development of radiolabeled c-Met specific Anticalin 89Zr-PRS-110 with diagnostic and therapeutic drug monitoring applications. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2664. doi:10.1158/1538-7445.AM2013-2664

Compton imaging or Compton camera imaging has been studied well, but its advantages in nuclear medicine and molecular imaging have not been demonstrated yet. Therefore, the aim of this work was to compare Compton imaging with positron emission tomography (PET) by using the same imaging platform of whole gamma imaging (WGI). WGI is a concept that combines PET with Compton imaging by inserting a scatterer ring into a PET ring. This concept utilizes diverse types of gamma rays for 3D tomographic imaging. In this paper, we remodeled our previous WGI prototype for small animal imaging, and we developed an image reconstruction method based on a list-mode ordered subset expectation maximization algorithm incorporating detector response function modeling, random correction and normalization (sensitivity correction) for either PET and Compton imaging. To the best of our knowledge, this is the world’s first realization of a full-ring Compton imaging system. We selected 89Zr as an imaging target because a 89Zr nuclide emits a 909 keV single-gamma ray as well as a positron, and we can directly compare Compton imaging of 909 keV photons with PET, a well-established modality. We measured a cylindrical phantom and a small rod phantom filled with 89Zr solutions of 10.3 MBq and 10.2 MBq activity, respectively, for 1 h each. The uniform radioactivity distribution of the cylindrical phantom was reconstructed with normalization in both PET and Compton imaging. Coefficients of variation for region-of-interest values were 4.2% for Compton imaging and 3.3% for PET; the difference might be explained by the difference in the detected count number. The small rod phantom experiment showed that the WGI Compton imaging had spatial resolution better than 3.0 mm at the peripheral region although the center region had lower resolution. PET resolved 2.2 mm rods clearly at any location. We measured a mouse for 1 h, 1 d after injection of 9.8 MBq 89Zr oxalate. The 89Zr assimilated in the mouse bony structures was clearly depicted, and Compton imaging results agreed well with PET images, especially for the region inside the scatterer ring. In conclusion, we demonstrated the performance of WGI using the developed Compton image reconstruction method. We realized Compton imaging with a quality approaching that of PET, which is supporting a future expectation that Compton imaging outperforms PET.

A wide array of positron emission tomography (PET) ligands have been developed that provide information relevant to multiple aspects of addiction (1-3).Locations of targets are approximated on this diagram, which is color-coded by functional roles.On the presynaptic side (pink), targets include neurotransmitter precursors (orange, example [ 18 F]-fluorodopa, FDOPA), modulatory receptors (yellow, examples [ 11 C] GR103545, [ 11 C] LY27950509 and [ 18 F] LY2459989 for kappa opioid receptors, KOR; [ 18 F]FMPEP for cannabinoid 1 receptors, CB1), and neurotransmitter reuptake transporters (light green, examples [ 11 C] PE2I and [ 18 F] FE-PE2I for the dopamine transporter, DAT).On the postsynaptic side (purple), targets include neurotransmitter receptors (blue, examples [ 11 C] raclopride and [ 11 C]-(1)-PHNO for dopamine D 2 and D 3 receptors, D 2 R; [ 11 C] carfentanil for mu opioid receptors, MOR; [ 18 F] LY2459989 for both mu and kappa opioid receptors; 2-[ 18 F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine for nicotinic acetylcholine receptors, nAChR).Some PET ligands target more generic functions.[ 18 F]-fluoro-deoxy-glucose (FDG) PET provides a measure of cerebral metabolic rate.